<?xml version="1.0" encoding="iso-8859-1"?><rss version="2.0" xmlns:drug="http://www.aidsinfo.nih.gov/" d1p1:noNamespaceSchemaLocation="http://www.aidsinfo.nih.gov/DrugsNew/drugRSSFeedschema.xsd" xmlns:d1p1="drug"><channel><title>AidsInfo Drugs RSS Feed</title><link><![CDATA[http://aidsinfo.nih.gov/DrugsNew/]]></link><description><![CDATA[This RSS Feed provides information about the drugs used in the treatment of HIV/AIDS.]]></description><item><title><![CDATA[Efavirenz / Emtricitabine / Tenofovir disoproxil fumarate]]></title><description><![CDATA[Atripla includes three antiretroviral drugs: efavirenz (Sustiva), emtricitabine (Emtriva), and tenofovir disoproxil fumarate (tenofovir DF or Viread). Efavirenz is a type of medicine called a non-nucleoside reverse transcriptase inhibitor (NNRTI). Both emtricitabine and tenofovir DF are medicines called nucleoside reverse transcriptase inhibitors (NRTIs). NNRTIs and NRTIs block reverse transcriptase, a protein that HIV needs to make more copies of itself.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=424]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Efavirenz / Emtricitabine / Tenofovir disoproxil fumarate]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[ef-FAH-ver-enz / em-tri-SIT-uh-bean / te-NOE-fo-veer]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Atripla]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Efavirenz / Emtricitabine / Tenofovir disoproxil fumarate]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Combination Drugs]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Atripla is a fixed-dose combination tablet containing three antiretroviral medications. One tablet of Atripla is equivalent to one tablet of efavirenz 600 mg, a non-nucleoside reverse transcriptase inhibitor (NNRTI), and one tablet of Truvada. Truvada is a fixed-dose combination tablet of two nucleoside reverse transcriptase inhibitors (NRTIs), emtricitabine 200 mg and tenofovir disoproxil fumarate (tenofovir DF) 300 mg. These three FDA-approved antiretroviral medications have been administered as separate pills in combination for the treatment of HIV infection before the development of Atripla.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Atripla (efavirenz, emtricitabine, and tenofovir DF) was approved by the FDA on July 12, 2006, for the treatment of HIV-1 infection in adults. Atripla is indicated as a complete regimen or in combination with other antiretroviral medications. Clinical studies support use of Atripla in antiretroviral-naive patients. Atripla is not recommended for use in the pediatric population.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Film-coated tablet containing efavirenz 600 mg, emtricitabine 200 mg, and tenofovir DF 300 mg.

The recommended adult dose of Atripla is one tablet once daily on an empty stomach, alone or in combination with other antiretroviral medications.]]></drug:dosageform><drug:storage><![CDATA[Store tablets in a tightly closed container at 25 C (77 F), with excursions permitted at 15 C to 30 C (59 F to 86 F).]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[One Atripla tablet is bioequivalent to one efavirenz tablet (600 mg), one emtricitabine capsule (200 mg), and one tenofovir DF tablet (300 mg) after single-dose administration to fasting healthy volunteers. In combination studies evaluating the antiviral activity of emtricitabine and efavirenz together, efavirenz and tenofovir together, and emtricitabine and tenofovir together, additive to synergistic antiviral effects were observed.

Efavirenz is an NNRTI. Efavirenz activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase (RT). Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate, which inhibits the activity of the HIV-1 RT by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA, resulting in chain termination. Tenofovir DF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir DF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5'-triphosphate and terminates the chain after incorporation into DNA. (For more information, see individual drug fact sheets for efavirenz, emtricitabine, and tenofovir DF.)

In HIV infected patients, time-to-peak plasma concentrations (Cmax) of efavirenz were approximately 3 to 5 hours, and steady-state plasma concentrations were reached in 6 to 10 days. In 35 patients receiving efavirenz 600 mg once daily, the mean Cmax was 12.9 g/ml, and the mean area under the concentration-time curve (AUC) was 184 g(hr)/ml. Efavirenz is nearly 100% bound to plasma proteins, predominantly albumin. In vitro studies suggest cytochrome P450 (CYP) 3A4 and CYP2B6 are the major isozymes responsible for efavirenz metabolism. Efavirenz has been shown to induce CYP enzymes, resulting in induction of its own metabolism. Efavirenz has a terminal half-life of 52 to 76 hours after single doses and of 40 to 55 hours after multiple doses. Between 14% and 34% of efavirenz, mostly as metabolites, is eliminated renally; 16% to 61%, mostly as parent drug, is recovered in the feces.

Following oral administration, emtricitabine is rapidly absorbed, with the Cmax occurring at 1 to 2 hours post-dose. Following multiple-dose, oral administration of emtricitabine to 20 HIV infected patients, the steady-state mean Cmax was 1.8 g/ml, and the mean AUC was 10.0 g hr/ml. The mean absolute bioavailability of emtricitabine was 93%. In vitro binding of emtricitabine to human plasma proteins is less than 4% and is independent of concentration over the range of 0.02 to 200 g/ml. Emtricitabine is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose, the half-life is approximately 10 hours. Approximately 86% of emtricitabine is recovered in the urine, and 13% is recovered as metabolites.

Following oral administration of a single, 300-mg dose of tenofovir DF to fasting patients, the mean Cmax (achieved in approximately 1 hour) was 296 ng/ml, and the mean AUC was 2,287 ng(h)/ml. The oral bioavailability of tenofovir from tenofovir DF in fasting patients is approximately 25%. In vitro binding of tenofovir to human plasma proteins is less than 0.7% and is independent of concentration over the range of 0.01 to 25 g/ml. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose, the terminal elimination half-life is approximately 17 hours. Approximately 79% to 80% of an IV dose is recovered unchanged in the urine.

Atripla is in FDA Pregnancy Category D. There are no adequate and well-controlled studies of Atripla in pregnant women. Pregnancy should be avoided in women receiving Atripla. Barrier contraception should always be used in combination with other methods of contraception. Atripla should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus, such as in pregnant women without other therapeutic options. To monitor fetal outcomes of pregnant women, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients who become pregnant online at http://www.APRegistry.com or by calling 1-800-258-4263.

As of July 2006, the Antiretroviral Pregnancy Registry has received prospective reports of 322 pregnancies exposed to efavirenz-containing regimens, nearly all of which (316) were first-trimester exposures. Birth defects occurred in 6 of 255 live births after first-trimester exposure and in 1 of 17 live births after second- or third-trimester exposure. None of these prospectively reported defects were neural tube defects. However, there have been four retrospective reports of findings consistent with neural tube defects, including meningomyelocele. All mothers were exposed to efavirenz-containing regimens in the first trimester. Although a causal relationship of these events to the use of efavirenz has not been established, similar defects have been observed in preclinical studies of efavirenz.

HIV-1 isolates with reduced susceptibility to the combination of emtricitabine and tenofovir have been selected in cell culture and in clinical studies. Genotypic analysis of these isolates identified the M184V/I and K65R amino acid substitutions in the viral reverse transcriptase. The most frequently observed amino acid substitution in clinical studies with efavirenz is K103N. Reduced susceptibility to emtricitabine is associated with the M184V/I mutation. Reduced susceptibility to tenofovir selected in cell culture was expressed as a K65R mutation.

In a clinical study of treatment-naive patients receiving efavirenz in combination with emtricitabine and tenofovir DF or with zidovudine/lamivudine, genotypic resistance to efavirenz, predominantly the K103N substitution, was the most common form of resistance that developed. Resistance to efavirenz occurred in 9/12 (75%) patients in the emtricitabine/tenofovir DF group and in 16/22 (73%) patients in the zidovudine/lamivudine group.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Adverse effects commonly associated with efavirenz use include impaired concentration, anorexia, abdominal pain, anxiety, and pruritus. Pancreatitis has been reported, although a causal relationship with efavirenz has not been established.

Adverse effects that occurred in at least 5% of patients receiving emtricitabine and tenofovir DF include anxiety, arthralgia, increased cough, dyspepsia, fever, myalgia, abdominal pain, peripheral neuropathy, rash, pruritus, urticaria, and paresthesia. Skin discoloration has been reported with higher frequency among emtricitabine-treated patients. The hyperpigmentation of the palms and soles was generally mild and asymptomatic. (For more information on adverse effects of each drug, please see individual drug fact sheets for efavirenz, emtricitabine, and tenofovir DF.)

Study 934 reported adverse events associated with the combination of efavirenz and Truvada (emtricitabine and tenofovir DF). The most common adverse reactions were diarrhea, nausea, fatigue, dizziness, headache, and rash. In HIV infected patients taking efavirenz and Truvada, elevated fasting cholesterol and serum amylase were noted in 15% and 7% of patients, respectively.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Atripla should be taken on an empty stomach. However, Atripla has not been evaluated in the presence of food. Administration of efavirenz with a high-fat meal increased the mean Cmax significantly compared with the fasted state.

Saquinavir should not be the only protease inhibitor administered with Atripla. Atazanavir and lopinavir/ritonavir may increase tenofovir concentrations and tenofovir-related adverse effects, and atazanavir concentrations may be reduced with concomitant Atripla administration. In addition, patients receiving concomitant Atripla and didanosine should be monitored for didanosine-related adverse effects.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Atripla is contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the product.

Tenofovir DF and efavirenz have not been studied in patients younger than 3 years of age or weighing less than 13 kg (28.7 lbs). Atripla is not recommended for pediatric administration.

Atripla should not be administered concurrently with midazolam, triazolam, or ergot derivatives, because competition for CYP3A4 liver enzymes by efavirenz could result in inhibition of metabolism of these drugs and could create the potential for serious adverse events, including cardiac arrhythmias and respiratory depression. Atripla should not be coadministered with voriconazole, because efavirenz significantly decreases voriconazole plasma concentrations.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with other antiretrovirals. The safety of Atripla has not been established in patients coinfected with HIV and hepatitis B virus (HBV). Severe acute exacerbations of HBV have been reported in patients who have discontinued emtricitabine or tenofovir DF. Hepatic function should be monitored closely for at least several months in patients who discontinue Atripla and are coinfected with HIV and HBV. If appropriate, initiation of HBV therapy may be warranted. Atripla is not indicated for use in patients coinfected with HIV and chronic HBV.

Because of the nature of the fixed-dose combination tablet, Atripla should not be used in combination with the individual component medications efavirenz, emtricitabine, and tenofovir DF. In addition, because of similarities between emtricitabine and lamivudine, Atripla should not be coadministered with drugs containing lamivudine, including the brand medications Combivir, Epivir, Epzicom, or Trizivir.]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[Efavirenz: 2H-3,1-Benzoxazin-2-one, 6-chloro-4-(cyclopropylethynyl)-1,4- dihydro-4-(trifluoromethyl)-, (4S)-Emtricitabine: (2R-cis)-4-Amino-5-fluoro- 1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] -2(1H)-pyrimidinoneTenofovir DF: Bis(hydroxymethyl) [[(R)-2(6-Amino- 9H-purin-9-yl)-1-methylethoxy] methyl]phosphonate,bis(isopropyl carbonate) (ester), fumarate (1:1)]]></drug:casname><drug:casnumber><![CDATA[Efavirenz: 154598-52-4Emtricitabine: 143491-57-0Tenofovir DF: 147127-20-6]]></drug:casnumber><drug:molecularformula><![CDATA[Efavirenz: C14-H9-Cl-F3-N-O2; Emtricitabine: C8-H10-F-N3-O3-S; Tenofovir DF: C19-H30-N5-O10-P.C4-H4-O4]]></drug:molecularformula><drug:elementalcomposition><![CDATA[Efavirenz: C53.27%, H2.87%, Cl11.23%, F18.05%, N4.44%, O10.14%; Emtricitabine: C38.86%, H4.08%, F7.68%, N17.00%, O19.41%, S12.97%; Tenofovir DF: C43.47%, H5.39%, N11.02%, O35.25%, P4.87%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[Efavirenz: 139 C to 141 C; Emtricitabine: 136 C to 140 C (276.8 F to 284 F) as solid white from ether and methanol.]]></drug:meltingpoint><drug:molecularweight><![CDATA[Efavirenz: 315.68; Emtricitabine: 247.25; Tenofovir DF: 635.51]]></drug:molecularweight><drug:physicaldescription><![CDATA[Efavirenz: White to slightly pink crystalline powder.

Emtricitabine: White to off-white crystalline powder.

Tenofovir DF: White to off-white crystalline powder.]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[Efavirenz: Practically insoluble in water (less than 10 mcg/ml); Emtricitabine: Soluble in 25 C at 112 mg/ml; Tenofovir DF: Soluble in 25 C water at 13.4 mg/ml.]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform" /><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[Atripla Prescribing Information from the FDA Web site <A HREF="http://www.fda.gov/cder/foi/label/2006/021937lbl.pdf">[PDF]</A>. A more current version may be available on the manufacturer's Web site.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16421366 Gallant JE, DeJesus E, Arribas JR, Pozniak AL, Gazzard B, Campo RE, Lu B, McColl D, Chuck S, Enejosa J, Toole JJ, Cheng AK; Study 934 Group. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med. 2006 Jan 19;354(3):251-60.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16421366&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16556093 Gazzard BG. Use of tenofovir disoproxil fumarate and emtricitabine combination in HIV-infected patients. Expert Opin Pharmacother. 2006 Apr;7(6):793-802. Review.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16556093&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17266471 Goicoechea M, Best B. Efavirenz/emtricitabine/tenofovir disoproxil fumarate fixed-dose combination: first-line therapy for all? Expert Opin Pharmacother. 2007 Feb;8(3):371-82.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17266471&dopt=Abstract]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Efavirenz / Emtricitabine / Tenofovir disoproxil fumarate]]></drug:drugname><drug:companyname><![CDATA[Bristol - Myers Squibb Co]]></drug:companyname><drug:address1><![CDATA[PO Box 4500]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Princeton]]></city><drug:state><![CDATA[NJ]]></drug:state><drug:zipcode><![CDATA[08543-4500]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 321-1335]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Efavirenz / Emtricitabine / Tenofovir disoproxil fumarate]]></drug:drugname><drug:companyname><![CDATA[Gilead Sciences Inc]]></drug:companyname><drug:address1><![CDATA[333 Lakeside Dr]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Foster City]]></city><drug:state><![CDATA[CA]]></drug:state><drug:zipcode><![CDATA[94404]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 445-3235]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Atripla]]></drug:drugname><drug:companyname><![CDATA[Bristol - Myers Squibb Co]]></drug:companyname><drug:address1><![CDATA[PO Box 4500]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Princeton]]></city><drug:state><![CDATA[NJ]]></drug:state><drug:zipcode><![CDATA[08543-4500]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 321-1335]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Atripla]]></drug:drugname><drug:companyname><![CDATA[Gilead Sciences Inc]]></drug:companyname><drug:address1><![CDATA[333 Lakeside Dr]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Foster City]]></city><drug:state><![CDATA[CA]]></drug:state><drug:zipcode><![CDATA[94404]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 445-3235]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[August 6, 2007]]></drug:lastupdated></item><item><title><![CDATA[Enfuvirtide]]></title><description><![CDATA[Enfuvirtide, also known as Fuzeon or T-20, is a type of medicine called a fusion inhibitor. Fusion inhibitors work by blocking HIV from entering human cells.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=306]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Enfuvirtide]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[en-FYOO-vir-tide]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Fuzeon]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Enfuvirtide]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Entry and Fusion Inhibitors]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Enfuvirtide is a linear 36-amino acid synthetic peptide with an acetylated N-terminus and a carboxamide C-terminus. It is composed of naturally occurring L-amino acid residues.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Enfuvirtide was approved by the FDA on March 13, 2003, for the treatment of HIV-1 infection in combination with other antiretroviral agents in previously treated adults and children 6 years of age or older with evidence of HIV-1 replication despite ongoing antiretroviral therapy.

Enfuvirtide has been and continues to be studied to determine if it will decrease the level of HIV in resting CD4 cells in patients already on antiretroviral therapy or starting an antiretroviral drug regimen for the first time.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Subcutaneous injection.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Single-use glass vials containing enfuvirtide 108 mg for the delivery of approximately 90 mg/ml when reconstituted with 1.1 ml of Sterile Water for Injection. Enfuvirtide is available in a convenience kit containing 60 single-use vials with appropriate ancillary supplies.

The recommended dose of enfuvirtide for adults is 90 mg (1 ml) twice daily. For children age 6 to 16 years, the recommended dose is 2 mg/kg twice daily (maximum dose 90 mg twice daily). The manufacturer's prescribing information provides pediatric dosing guidelines by weight. Insufficient data are available to establish a recommended dose for children younger than 6 years old.

Enfuvirtide should not be injected near any areas of the body where large nerves course close to the skin, such as near the elbow, knee, groin or the inferior or medial sections of the buttocks; skin abnormalities, including directly over a blood vessel; into moles, scar tissue, or bruises; or near the navel, surgical scars, tattoos, or burn sites.]]></drug:dosageform><drug:storage><![CDATA[Store vials at 25 C (77 F); excursions permitted from 15 C to 30 C (59 F to 86 F).]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Enfuvirtide interferes with the entry of HIV-1 into cells by inhibiting fusion of viral and cellular membranes. Enfuvirtide binds to the first heptad repeat (HR1) in the gp41 subunit of the viral envelope glycoprotein and prevents the conformational changes required for the fusion of viral and cellular membranes.

The initial step of HIV-1 entry into the human host cell is the binding of virions with the CD4 molecule and chemokine coreceptor molecules (CXCR4 or CCR5) on the surface of the target cell. Entry of HIV-1 into the target cell is mediated by two viral envelope glycoproteins, gp120 and gp41, which form complexes that facilitate entry of the virion into the host cell. The surface glycoprotein gp120 mediates CD4 and coreceptor binding. The function of the transmembrane glycoprotein gp41 is to anchor the gp120-gp41 glycoprotein complex within the viral envelope and mediate envelope-host cell membrane fusion.

Following gp120 interactions with CD4 and the coreceptors, conformational changes occur in gp41 that expose a fusion peptide located near the N-terminus, which is believed to insert into the target cell membrane. It is thought that the bridged target cell and viral membranes are brought together via two heptad repeats (HR1 and HR2) within gp41. Studies have shown that HR1 and HR2 are essential for virus-host cell fusion to occur. Enfuvirtide corresponds to a linear 36 amino acid sequence within HR2 and likely interacts with a target sequence in HR1, inhibiting association with native HR2 and preventing apposition of the viral and cellular membranes.

The mean maximum plasma concentration (Cmax) following a single 90 mg subcutaneous (SQ) injection of enfuvirtide into the abdomen in 12 HIV-1 infected adult and pediatric patients was approximately 4.59 mcg/ml; area under the plasma concentration-time curve (AUC) was approximately 55.8 mcg hr/ml; the median time to maximum plasma concentration (Tmax) was 8 hours (ranging from 3 to 12 h). The absolute bioavailability (using a 90 mg IV dose as a reference) was approximately 84.3%. Following 90 mg twice daily dosing of SQ enfuvirtide in combination with other antiretroviral agents in 11 HIV-1 infected patients, the mean steady-state Cmax was approximately 5.0 mcg/ml and AUC from zero to 12 hours was approximately 48.7 mcg hr/ml. The median Tmax was 4 hours (ranging from 4 to 8 h). Absorption of the 90 mg dose was comparable when injected into the subcutaneous tissue of the abdomen, thigh, or arm. The mean steady-state volume of distribution after IV administration of a 90 mg dose of enfuvirtide was approximately 5.5 liters.

As a peptide, enfuvirtide is expected to undergo catabolism to its constituent amino acids, with subsequent recycling of the amino acids in the body pool. Mass balance studies to determine elimination pathways of enfuvirtide have not been performed in humans. In vitro studies with human microsomes and hepatocytes indicate that enfuvirtide undergoes hydrolysis to form a deamidated metabolite at the C-terminal phenylalanine residue, M3. The M3 metabolite is detected in human plasma following administration of enfuvirtide, with an AUC ranging from 2.4% to 15% of the enfuvirtide AUC.

Following a 90 mg single SQ dose of enfuvirtide in 12 patients, the mean elimination half-life was approximately 3.8 hours and the mean apparent clearance was approximately 24.8 +/- 4.1 ml/hr/kg. Following 90 mg twice-daily dosing of enfuvirtide SQ in combination with other antiretroviral agents in 11 HIV-1 infected patients, the mean apparent clearance was approximately 30.6 +/- 10.6 ml/hr/kg.

Enfuvirtide is approximately 92% bound to plasma proteins in HIV infected plasma over a concentration range of 2 to 10 mcg/ml. It is bound predominantly to albumin and to a lower extent to alpha-1 acid glycoprotein.

Enfuvirtide is in FDA Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women. Enfuvirtide should be used during pregnancy only if clearly needed. To monitor maternal-fetal outcomes of pregnant women exposed to enfuvirtide and other antiretroviral drugs, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263 or online at http://www.APRegistry.com. It is not known whether enfuvirtide is distributed into human milk; however, it is distributed into milk in laboratory animals.  Because of the potential for HIV transmission and adverse effects in breastfed infants, mothers should be instructed not to breastfeed while they are taking enfuvirtide.

Formal pharmacokinetic studies of enfuvirtide have not been conducted in patients with hepatic insufficiency. Analysis of plasma concentration data from participants in clinical trials indicated the clearance of enfuvirtide is not affected in patients with creatinine clearance greater than 35 ml/min.

HIV-1 isolates with reduced susceptibility to enfuvirtide have been selected in vitro. Genotypic analysis of the in vitro-selected resistant isolates showed mutations in the gp41 HR1 domain (amino acids 36 to 38). Phenotypic analysis of site-directed mutants at positions 36 to 38 in an HIV-1 molecular clone showed a fivefold to 684-fold decrease in susceptibility to enfuvirtide.

In clinical trials, HIV-1 isolates with reduced susceptibility to enfuvirtide have been recovered from patients treated with enfuvirtide in combination with other antiretroviral agents. Post-treatment HIV-1 from 185 patients exhibited decreases in susceptibility to enfuvirtide. The decreased susceptibility ranged from 0.4- to 6318-fold (median 33.4-fold) relative to their respective baseline virus and coincided with genotypic changes in gp41 amino acids 36 to 45. Substitutions in this region were observed with decreasing frequency at amino acid positions 38, 43, 36, 40, 42, and 45.

HIV-1 clinical isolates resistant to nucleoside analogue reverse transcriptase inhibitors, non-nucleoside analogue reverse transcriptase inhibitors, and protease inhibitors were susceptible to enfuvirtide in vitro.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[The most common adverse effects associated with enfuvirtide use include local injection site reactions, peripheral neuropathy, sinusitis, conjunctivitis, pancreatitis, skin papilloma, anxiety, decreased appetite, asthenia, cough, depression, herpes simplex, pruritis, insomnia, myalgia, and weight loss.

The majority of local injection site reactions were associated with mild to moderate pain and discomfort, induration, erythema, nodules and cysts, pruritus, and ecchymosis. Infection at the injection site, including abscess and cellulitis, was reported in 1.7% of study patients receiving enfuvirtide. Ninety-eight percent of patients had at least one local injection site reaction, and 7% of patients discontinued enfuvirtide treatment due to these reactions.

Nerve pain (neuralgia and/or paresthesia) lasting up to 6 months associated with administration at anatomical sites where large nerves course through the skin, bruising, and hematomas have occurred with use of the needle-free device provided with the product. Individuals taking anticoagulants or who have hemophilia or other coagulation disorders may have a higher risk of postinjection bleeding after enfuvirtide use.

An increased rate of bacterial pneumonia was observed in trial patients treated with enfuvirtide compared to control patients. It is unclear if the increased incidence of pneumonia is related to enfuvirtide use. Risk factors for pneumonia included low initial CD4 count, high initial viral load, IV drug use, smoking, and a prior history of lung disease.

Hypersensitivity reactions have been associated with enfuvirtide therapy and may recur on rechallenge. Hypersensitivity reactions have included rash, fever, nausea and vomiting, chills, rigors, hypotension, and elevated serum liver transaminases. Other adverse events that may be immune-mediated and have been reported in patients receiving enfuvirtide include primary immune complex reaction, respiratory distress, glomerulonephritis, and Guillain-Barre syndrome. Patients developing signs and symptoms suggestive of a systemic hypersensitivity reaction should discontinue enfuvirtide and should seek medical evaluation immediately. Therapy with enfuvirtide should not be restarted following systemic signs and symptoms consistent with a hypersensitivity reaction. Risk factors that may predict the occurrence or severity of hypersensitivity to enfuvirtide have not been identified.

There is a theoretical risk that enfuvirtide use may lead to the production of anti-enfuvirtide antibodies that cross react with HIV gp41. This could result in a false-positive enzyme-linked immunosorbent assay (ELISA) diagnostic HIV test in HIV uninfected patients. A confirmatory western blot test would be expected to be negative in such cases.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including enfuvirtide. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis, which may necessitate further evaluation and treatment.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Based on the results from an in vitro study, enfuvirtide is not an inhibitor of CYP450 enzymes. A human metabolism study reported that enfuvirtide did not alter the metabolism of CYP3A4, CYP2D6, CYP1A2, CYP2C19, or CYP2E1 substrates.

Coadministration of ritonavir, saquinavir/ritonavir, and rifampin did not result in clinically significant pharmacokinetic interactions with enfuvirtide. No drug interactions with other antiretroviral medications have been identified that would warrant alteration of either the enfuvirtide dose or the dose of the other antiretroviral medication.

Enfuvirtide exhibited additive to synergistic effects in vitro when combined with individual members of various antiretroviral classes, including zidovudine, lamivudine, nelfinavir, indinavir, and efavirenz. In vitro studies of enfuvirtide in combination with an investigational HIV-1 entry inhibitor, PRO542, and with an investigational CXCR4 blocker, AMD-3100]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Enfuvirtide is contraindicated in patients with known hypersensitivity to the drug or any of its components.]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[L-Phenylalaninamide,N-acetyl-L-tyrosyl- L-threonyl-L-seryl-L-leucyl- L-isoleucyl-L-histadyl-L-seryl- L-leucyl-L-isoleucyl-L-alpha- glutamyl-L-a-glutamyl- L-seryl-L-glutaminyl- L-asparaginyl- L-glutaminyl- L-glutaminyl-L-alpha- glutamyl-L-lysyl- L-asparaginyl-L-alpha- glutamyl-L-glutaminyl- L-alpha-glutamyl-L-leucyl- L-leucyl-L-alpha-glutamyl- L-leucyl-L-alpha- aspartyl-L-lysyl- L-tryptophyl-L-alan]]></drug:casname><drug:casnumber><![CDATA[262434-79-7159519-65-0]]></drug:casnumber><drug:molecularformula><![CDATA[C204-H301-N51-O64]]></drug:molecularformula><drug:elementalcomposition><![CDATA[C54.55%, H6.75%, N15.90%, O22.80%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[4491.88]]></drug:molecularweight><drug:physicaldescription><![CDATA[White to off-white sterile amorphous solid.]]></drug:physicaldescription><drug:stability><![CDATA[Reconstituted solution should be stored under refrigeration at 2 C to 8 C (36 F to 46 F) and used within 24 hours.]]></drug:stability><drug:solubility><![CDATA[Negligible solubility in pure water; 85 to 142 g/100 ml in aqueous buffers (pH 7.5).]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:othername><![CDATA[T-20]]></drug:othername></drug:othernames><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[Fuzeon Prescribing Information from the FDA Web site <a href="http://www.fda.gov/cder/foi/label/2007/021481s011lbl.pdf">[PDF]</a>. A more current version may be available on the manufacturer's Web site.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/12167274 Kilby JM, Lalezari JP, Eron JJ, Carlson M, Cohen C, Arduino RC, Goodgame JC, Gallant JE, Volberding P, Murphy RL, Valentine F, Saag MS, Nelson EL, Sista PR, Dusek A. The safety, plasma pharmacokinetics, and antiviral activity of subcutaneous enfuvirtide (T-20), a peptide inhibitor of gp41-mediated virus fusion, in HIV-infected adults. AIDS Res Hum Retroviruses. 2002 Jul 1;18(10):685-93.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=12167274&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/15794736 Lazzarin A. Enfuvirtide: the first HIV fusion inhibitor. Expert Opin Pharmacother. 2005 Mar;6(3):453-64.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15794736&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16918361 Manfredi R, Sabbatani S. A novel antiretroviral class (fusion inhibitors) in the management of HIV infection. Present features and future perspectives of enfuvirtide (T-20). Curr Med Chem. 2006;13(20):2369-84. Review.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16918361&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/15907147 Oldfield V, Keating GM, Plosker G. Enfuvirtide: a review of its use in the management of HIV infection. Drugs. 2005;65(8):1139-60.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15907147&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/15044424 Rockstroh JK, Mauss S. Clinical perspective of fusion inhibitors for treatment of HIV. J Antimicrob Chemother. Epub 2004 Mar 24.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15044424&dopt=Abstract]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Enfuvirtide]]></drug:drugname><drug:companyname><![CDATA[Roche Laboratories]]></drug:companyname><drug:address1><![CDATA[340 Kingsland Street]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Nutley]]></city><drug:state><![CDATA[NJ]]></drug:state><drug:zipcode><![CDATA[07110]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(973) 235-5000]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Enfuvirtide]]></drug:drugname><drug:companyname><![CDATA[Trimeris Inc]]></drug:companyname><drug:address1><![CDATA[4727 Univ Dr]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Durham]]></city><drug:state><![CDATA[NC]]></drug:state><drug:zipcode><![CDATA[27707]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(919) 419-6050]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Fuzeon]]></drug:drugname><drug:companyname><![CDATA[Roche Laboratories]]></drug:companyname><drug:address1><![CDATA[340 Kingsland Street]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Nutley]]></city><drug:state><![CDATA[NJ]]></drug:state><drug:zipcode><![CDATA[07110]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(973) 235-5000]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[February 2, 2007]]></drug:lastupdated></item><item><title><![CDATA[Maraviroc]]></title><description><![CDATA[Maraviroc, also known as Selzentry, is a type of medicine called an entry inhibitor. Entry inhibitors work by blocking HIV from entering human cells.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=408]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Maraviroc]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[mah-RAV-er-rock]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Selzentry]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Maraviroc]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Entry and Fusion Inhibitors]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Maraviroc, also known as Selzentry, is a chemokine receptor antagonist that acts as an entry inhibitor. It is designed to prevent HIV infection of CD4 cells by blocking chemokine receptor 5 (CCR5), a coreceptor necessary for HIV entry, from binding to HIV.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Maraviroc, a first-in-its-class, selective, CCR5-coreceptor antagonist, was granted accelerated regulatory review in the United States and Europe in February 2007. In April 2007, the FDA's Antiviral Drugs Evaluation Committee unanimously recommended accelerated approval of maraviroc for treatment-experienced patients. Maraviroc received accelerated approval by the FDA on August 6, 2007. The accelerated approval was based on 24-week, interim data from two ongoing trials. FDA evaluation of longer term data will be required for traditional approval.

Maraviroc is approved for use in combination with other antiretroviral (ARV) medications for the treatment of CCR5-tropic HIV-1 (R5 virus) in adults whose viral loads remain detectable despite existing ARV treatment or who have multiple-drug--resistant virus. Among treatment-experienced patients, approximately 50% to 60% have R5 virus. Maraviroc is not approved for use in patients 16 years of age or younger. Safety and efficacy are not established in treatment-naive HIV infected people or in those with dual- or mixed-tropic or with CXCR4-tropic virus.

In 2006, Pfizer opened a worldwide expanded access program (EAP) to provide maraviroc to patients with HIV who have limited or no treatment options. The multinational EAP will continue to provide maraviroc in countries in which it is not yet available. Patients and health care professionals can visit http://www.maraviroceap.com for more information.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Maraviroc is available as 150- and 300-mg film-coated tablets. The recommended dosage is maraviroc 300 mg twice daily.

Maraviroc must be given in combination with other antiretroviral medications. Safety and efficacy have not been established in patients 16 years of age or younger. Dosage adjustments are required when maraviroc is administered in combination with CYP inhibitors or inducers; specific adjustments according to the coadministered medication can be found in the manufacturer prescribing information.]]></drug:dosageform><drug:storage><![CDATA[Film-coated tablets should be stored at 25 C (77 F), with excursions permitted between 15 C and 30 C (59 F and 86 F). Maraviroc tablet shelf-life is 24 months.]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Maraviroc binds to CCR5, preventing HIV from binding to this receptor. When CCR5 is unavailable, CCR5-tropic HIV cannot engage a CD4 cell to infect the cell. The CCR5-tropic variant of the virus is common in earlier HIV infection, whereas viruses adapted to use the CXCR4 receptor gradually become dominant as HIV infection progresses. Maraviroc did not display efficacy against CXCR4-tropic or mixed- or dual-tropic virus in Phase II efficacy studies.

Peak plasma concentrations (Cmax) of maraviroc are achieved between 0.5 and 4 hours after single oral doses of maraviroc 1,200 mg in healthy volunteers. Maraviroc pharmacokinetics are not dose proportional. The absolute bioavailability of a 100-mg dose is 23% and is predicted to be 33% after a 300-mg dose.

Maraviroc is metabolized by the cytochrome P450 (CYP) liver enzyme system, primarily by CPY3A; metabolites of maraviroc are inactive against HIV-1. The terminal half-life of maraviroc at steady-state is between 14 and 18 hours. Maraviroc, rather than metabolites, was the main component recovered.

Maraviroc is moderately protein bound (approximately 76%) and has a volume of distribution of approximately 194 liters. Renal clearance accounts for approximately 25% of total clearance of maraviroc. Drug concentrations may be increased in patients with renal impairment, although the safety and efficacy of maraviroc have not been studied in this patient population. Dialysis may be useful in reducing maraviroc levels.

Maraviroc is in Pregnancy Category B. No adequate and well-controlled studies have been conducted in pregnant women. However, the incidence of fetal malformations in animal studies, conducted at doses up to 20-fold higher than recommended human doses, was not increased. To monitor maternal-fetal outcomes of pregnant women exposed to maraviroc and other ARV medications, an Antiretroviral Pregnancy Registry has been established. Physicians may register patients online at http://www.APRegistry.com or by calling 800-258-4263.

In a small, Phase I study conducted in 2003, 24 HIV infected adults with CCR5-tropic HIV were randomized to receive maraviroc 25 mg once daily, 100 mg twice daily, or placebo. Steady-state drug levels were reached within 7 days, with more favorable drug levels achieved in the fasted state. By Day 14, those receiving 100 mg doses had experienced a viral load decline of more than 20-fold compared with a nearly threefold reduction in the 25-mg group. The drug was well tolerated, and viral load did not rebound immediately upon cessation of the drug, indicating that a proportion of the receptors remain blocked for some time.  

Interim Week 24 results of the two Phase IIb/III placebo-controlled studies MOTIVATE-1 and -2 indicate that treatment with maraviroc plus optimized background therapy (OBT) leads to superior viral control compared with OBT alone. These studies are following a total of 1,049 participants, residing in Europe, Australia, Canada, and the United States, who are triple class resistant, had baseline viral loads of more than 5,000 copies/ml, and had baseline CD4 counts of approximately 150 cells/mm3. With maraviroc treatment, these participants had viral load reductions of as much as 99% from baseline at a dosage of maraviroc 300 mg once or twice daily while on OBT. CD4 counts in these participants also increased by 56% to 74% from baseline during this time period. Long-term Week 48 data demonstrate that maraviroc plus OBT significantly increase CD4 count compared with OBT alone. In addition, 3 times as many participants receiving maraviroc plus OBT achieved undetectable viral load levels compared with those receiving OBT alone.

Because the impairment of CCR5 could have a negative impact on regular immune function, safety studies have been performed in both healthy and HIV-1 infected people at doses of up to 1,200 mg of maraviroc daily for 10 to 28 days. These studies showed that maraviroc did not have an effect on immune function, and no increased frequency or severity in infections was seen. However, an increase in CD4 count also was not seen over this time period.

In an evaluation of 973 treatment-experienced patients in two ongoing Phase III trials, important predictors of virologic success (viral load less than 400 copies/ml at 24 weeks) included the mean predicted trough concentration of maraviroc, the baseline viral load, and the baseline CD4 count.

HIV-1 variants with reduced susceptibility to maraviroc have been selected in cell cultures. In an in vitro study using six primary CCR5 HIV-1 isolates, those able to replicate in the presence of high maraviroc concentrations emerged gradually after multiple passages of all isolates. Two isolates resistant to maraviroc continued to use the CCR5 receptor and one isolate developed the ability to use the CXCR4 receptor. In the viruses that remained R5 tropic, two different sets of mutations developed in the gp120 V3 loop region; this and other data suggest that changes in viral tropism are independent of maraviroc. All CCR5 antagonists bind to CCR5 in a pocket formed by transmembrane helices and extracellular loop 2 (ECL2); it appears that subtle differences in occupation of the binding pocket may block replication of some HIV strains. As a result, scientists are optimistic that resistance to an HIV coreceptor antagonist will not necessarily lead to drug class resistance.

Clinical resistance to maraviroc has not yet been fully defined. Virologic failure has been associated with viral tropism switches that occur over time. In an examination of 5 participants who had CCR5-tropic virus at the time of treatment failure while on maraviroc, all 5 had mutations at position 13 or 26 of the V3 loop of CCR5. In an examination of 20 participants who had CXCR4-tropic virus at the time of treatment failure while on maraviroc, 14 participants experienced outgrowth of CXCR4-tropic virus that was undetectable at study entry, whereas 6 experienced a tropism switch. Of the 1,043 patients with R5 virus at screening for the 2 ongoing Phase III trials, 7.6% displayed dual- or mixed-tropism at baseline measurements taken approximately 5 weeks later. In subsequent interim analysis, CXCR4-tropic virus was identified in approximately 60% of patients who failed treatment on maraviroc compared with 6% of patients who experienced treatment failure while on placebo.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[In the two Phase II/III MOTIVATE-1 and -2 studies, adverse effects at Week 24 interim analysis were similar to those that occurred with optimized background therapy (OBT) alone. In these studies, 5% or fewer study participants in both placebo and treatment groups discontinued treatment because of adverse events.

These two studies showed no increase in mortality or malignancy and no clear evidence of hepatotoxicity. However, an increase in Candida, herpes, and influenza infections were observed in these studies.

In 24-week analysis of these two clinical studies, the most common maraviroc-related adverse effects (occurring in more than 8% of patients and more often than in the placebo group) were cough, fever, upper respiratory infections, rash, musculoskeletal symptoms, abdominal pain, and dizziness. Additional adverse effects noted with greater incidence in the once-daily treatment arm included diarrhea, edema, sleep disorders, rhinitis, and urinary abnormalities. Serious adverse events occurred in less than 2% of maraviroc-treated patients and included cardiovascular abnormalities (e.g., angina, heart failure, myocardial infarction), hepatic cirrhosis or failure, cholestatic jaundice, viral meningitis, pneumonia, myositis, osteonecrosis, and rhabdomyolysis. Grade 3 to 4 treatment-emergent laboratory abnormalities occurring in at least 2% of patients included increased bilirubin, amylase, lipase, AST, and ALT levels. At Week 48 analysis of the same studies, the most commonly observed adverse events in the maraviroc plus OBT arm were diarrhea, nausea, fatigue, and headache, all of which occurred with similar incidence in the OBT-only arm.

One case of possible drug-associated hepatotoxicity with allergy has been reported in a study of healthy volunteers. Systemic allergic reaction prior to the onset of hepatotoxicity may involve pruritic rash, eosinophilia, or increased IgE levels. Although no statistically significant increases in Grade 3 to 4 liver function tests have been reported, an increased rate of hepatic adverse events has been observed in treatment-experienced patients. Immediate evaluation and possible discontinuation of maraviroc are warranted in patients exhibiting signs or symptoms of hepatotoxicity, including systemic rash reactions or abnormal  liver function tests. To date, only 6% of patients in clinical studies have been coinfected with hepatitis B or C virus; large-scale clinical trials with coinfected individuals are needed to determine the risk of hepatic adverse events in these patients. Maraviroc should be prescribed to patients with HIV and hepatitis coinfections with caution.

Immune reconstitution syndrome has also been reported. In addition, patients taking maraviroc should be monitored for risk of infection because of CCR5-antagonism effects on some immune cells.

Cardiovascular events, including myocardial ischemia or infarction, have been observed at higher rates in maraviroc-treated patients than in placebo. QT prolongation has been observed in animal studies at up to 12 times the recommended human dosage, but no prolongation has been noted in treatment-experienced patients taking recommended dosages. When given to HIV infected patients in Phase III studies at recommended dosages, no greater rates of postural hypotension were observed. However, the dose-limiting adverse effect in clinical studies, observed at daily doses of maraviroc 600 mg, is postural hypotension.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Coadministration of a 300-mg tablet and a high-fat meal has resulted in reduced Cmax and AUC by 33% each in healthy volunteers. However, because no food restrictions were enacted during clinical trials, maraviroc may be taken with or without food.

Maraviroc is a cytochrome P450 (CYP) 3A and p-glycoprotein (Pgp) substrate and may require dosage adjustments when administered with CYP- or Pgp-modulating medications. CYP3A/Pgp inhibitors such as ketoconazole, lopinavir/ritonavir, saquinavir, and atazanavir increase maraviroc Cmax and AUC; CYP3A/Pgp inducers such as carbamazepine, phenytoin, phenobarbital, rifampin, and efavirenz decrease maraviroc Cmax and AUC. Tipranavir/ritonavir, a CPY3A inhibitor but a Pgp inducer, does not affect maraviroc pharmacokinetics.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[Cyclohexanecarboxamide, 4,4-difluoro-N-((1S)-3-((3-exo)-3- (3-methyl-5-(1-methylethyl)-4H -1,2,4-triazol-4-yl)-8-azabicyclo(3.2.1) oct-8-yl)-1-phenylpropyl)-]]></drug:casname><drug:casnumber><![CDATA[376348-65-1]]></drug:casnumber><drug:molecularformula><![CDATA[C29-H41-F2-N5-O]]></drug:molecularformula><drug:elementalcomposition><![CDATA[C67.81%, H8.04%, F7.40%, N13.63%, 03.11%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[513.67]]></drug:molecularweight><drug:physicaldescription><![CDATA[White to pale-colored powder.]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[Highly soluble across the pH range of 1 to 7.5.]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:othername><![CDATA[UK-427,857]]></drug:othername><drug:othername><![CDATA[MVC]]></drug:othername></drug:othernames><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[PMID/15265463 Marks K, Gulick RM. New Antiretroviral Agents for the Treatment of HIV Infection. Curr Infect Dis Rep. 2004 Aug;6(4):333-339.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15265463&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/15650075 Walker D, Abel S, Comby P, Muirhead G, Nedderman A, Smith DA. Species differences in the disposition of the CCR5 antagonist, UK-427,857, a new potential treatment for HIV. Drug Metab Dispos. 2005 Apr;33(4):587-95.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15650075&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[Nelson, M, Fatkenheuer, G, Konourina I, Lazzarin, A,  Clumeck, N, Horbam, A, Tawadrous M, Sullivan, J, Mayer, H, van der Ryst, E. Efficacy and Safety of Maraviroc plus Optimized Background Therapy in Viremic, ART-experienced Patients Infected with CCR5-tropic HIV-1 in Europe, Australia, and North America: 24-Week Results. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA, Abstract 104aLB, 2007.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[Lalezare, J, Goodrich, J, DeJesus, E, Lampiris, H, Gulick, R, Saag, M, Redgway, C, McHale, M, van der Ryst, E, Mayer, H. Efficacy and Safety of Maraviroc plus Optimized Background Therapy in Viremic ART-experienced Patients Infected with CCR5-tropic HIV-1: 24-Week Results of a Phase 2b/3 Study in the US and Canada. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA, Abstract 104bLB, 2007.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Maraviroc]]></drug:drugname><drug:companyname><![CDATA[Pfizer Inc]]></drug:companyname><drug:address1><![CDATA[235 East 42nd Street]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[New York]]></city><drug:state><![CDATA[NY]]></drug:state><drug:zipcode><![CDATA[10017-5755]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 438-1985]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Selzentry]]></drug:drugname><drug:companyname><![CDATA[Pfizer Inc]]></drug:companyname><drug:address1><![CDATA[235 East 42nd Street]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[New York]]></city><drug:state><![CDATA[NY]]></drug:state><drug:zipcode><![CDATA[10017-5755]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 438-1985]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[September 19, 2007]]></drug:lastupdated></item><item><title><![CDATA[Raltegravir]]></title><description><![CDATA[Raltegravir, also known as Isentress and MK-0518, is a type of medicine called an integrase inhibitor. Integrase inhibitors work by blocking integrase, a protein that HIV needs to insert its viral genetic material into the genetic material of an infected cell.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=420]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Raltegravir]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[ral-TEG-ra-vir]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Isentress]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Raltegravir]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Integrase Inhibitors]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Raltegravir, also known as MK-0518, is a first-in-its-class oral integrase inhibitor. Inhibition of integrase prevents insertion of HIV DNA into the human DNA genome, thus blocking the ability of HIV to replicate.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Raltegravir was approved by the FDA on October 12, 2007, for use with other anti-HIV agents in the treatment of HIV infection. It is the first integrase inhibitor approved by the FDA. This drug received accelerated approval for use in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral regimens. The FDA's decision was based on a 24-week clinical trial's analysis, in which raltegravir with optimized background therapy (OBT) in treatment-experienced HIV infected patients led to significant reductions in HIV viral load and increases in CD4 counts. Raltegravir was also investigated in Phase II trials for the treatment of HIV in patients who are treatment-naive.

Two Phase III trials are ongoing to further investigate raltegravir in patients who have multidrug-resistant HIV strains. On August 17, 2006, Merck opened a worldwide expanded access program (EAP) for HIV patients with limited or no treatment options. Patients and health care professionals can call 1-888-577-8839 or visit http://www.earmrk.com for more information. The EAP for raltegravir is a noncomparative, multicenter, open-label, voluntary treatment use study. The study will continue for a short time after FDA approval and the start of commercial marketing. Enrolled patients will receive twice-daily 400-mg raltegravir in addition to OBT; safety and tolerability will be monitored.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Tablets containing raltegravir 400 mg.

The recommended dose of raltegravir in treatment-experienced HIV infected adults is one 400-mg tablet twice daily. No dosage adjustment is necessary in patients with mild to moderate hepatic or severe renal impairment.

Raltegravir 100, 200, 400, or 600 mg taken every 12 hours and given for up to 48 weeks was previously studied in a Phase II trial. Raltegravir 400 mg twice daily is being studied in ongoing Phase III trials.]]></drug:dosageform><drug:storage><![CDATA[Store tablets at a controlled room temperature of 20 C to 25 C (68 F to 77 F); excursions are permitted to 15 C to 30 C (59 F to 86 F).]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Raltegravir inhibits the catalytic activity of HIV-1 integrase, an HIV-1-encoded enzyme required for viral replication. Inhibition of integrase prevents covalent insertion of unintegrated, linear HIV-1 DNA into the host cell genome, therefore preventing the formation of HIV-1 provirus. In preliminary studies, raltegravir did not significantly inhibit human phosphoryltransferases, including DNA polymerases alpha, beta, and gamma.

Administration of raltegravir following a high-fat meal increased the raltegravir area under the concentration-time curve (AUC) by approximately 19%. A high-fat meal slowed the rate of absorption, resulting in an approximately 34% decrease in the maximum plasma concentration (Cmax), an 8.5-fold increase in the plasma concentration at 12 hours, and a delay in the time to maximum concentration (Tmax) following a single 400-mg dose. The effect of consumption of a range of food types on steady-state pharmacokinetics (PK) is not known. Raltegravir was administered without regard to food in pivotal safety and efficacy studies in HIV-1 infected patients. Raltegravir is absorbed with a Tmax of approximately 3 hours postdose in the fasted state.

The raltegravir AUC and Cmax increase dose proportionally over the dose range of 100 mg to 1,600 mg. With twice-daily dosing, PK steady state is achieved within approximately the first 2 days of dosing. Considerable variability was observed in the PK of raltegravir in clinical trials. In clinical trial participants receiving twice-daily raltegravir 400 mg, drug exposures were characterized by a geometric mean AUC within the first 12 hours of 14.3 mcM(hr) and a plasma concentration at 12 hours of 142 nM. The absolute bioavailablilty of raltegravir has not been established.

Long-term (2-year) carcinogenicity studies of raltegravir in rodents are ongoing. No evidence of mutagenicity or genotoxicity was observed in vitro during microbial mutagenesis (Ames) tests, alkaline elution assays for DNA breakage, or in vitro and in vivo during chromosomal aberration studies. No effect on fertility was seen in male and female rats at doses up to 600 mg/kg/day, which resulted in an exposure threefold greater than the exposure seen with the recommended human dose.

Raltegravir is in FDA Pregnancy Category C. No adequate or well-controlled studies of raltegravir have been done in pregnant women; also, no PK studies have been conducted to date in pregnant women. In animal studies, no treatment-related effects on embryonic/fetal survival or fetal weights were observed in rabbits (up to 1,000 mg/kg/day) and rats (up to 600 mg/kg/day) receiving up to three- to fourfold the exposure at the recommended human dose of raltegravir. No treatment-related external, visceral, or skeletal changes were observed in rabbits. However, treatment-related increases compared with controls in the incidence of supernumerary ribs were seen in rats at dosages of 600 mg/kg/day (exposures threefold the exposure at the recommended human dose of raltegravir). Plasma transfer of raltegravir was demonstrated in both rabbits and rats. At a maternal dosage of 600 mg/kg/day in rats, mean raltegravir concentrations in fetal plasma were approximately 1.5- and 2.5-fold greater than in maternal plasma at 1 hour and 24 hours postdose, respectively. Mean raltegravir concentrations in fetal plasma were approximately 2% of the mean maternal concentration at both 1 and 24 hours postdose at a maternal dosage of 1,000 mg/kg/day in rabbits.

Raltegravir should be used during pregnancy only if clearly needed. To monitor maternal-fetal outcomes of pregnant women exposed to raltegravir and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians may register patients online at http://www.APRegistry.com or by calling 1-800-258-4263. It is not known whether raltegravir or its metabolites are distributed into human milk; however, raltegravir is secreted into the milk of lactating rats. Mean raltegravir concentrations in milk were approximately threefold greater than those in maternal plasma at a maternal dosage of 600 mg/kg/day in rats. Because of both the potential for HIV transmission and serious adverse reactions in nursing infants, HIV infected mothers should be instructed not to breastfeed their infants if they are receiving raltegravir.

Raltegravir is approximately 83% bound to human plasma protein over the concentration range of 2 to 10 mcM. The apparent terminal half-life of raltegravir is approximately 9 hours, with a shorter alpha-phase half-life (about 1 hour) accounting for much of the AUC. Following administration of an oral dose of radiolabeled raltegravir, approximately 51% and 32% of the dose was excreted in feces and urine, respectively. In feces, only raltegravir was present, most of which is likely derived from hydrolysis of raltegravir-glucuronide secreted in bile as observed in preclinical trials in animals. Two components, raltegravir and raltegravir-glucuronide, were detected in urine and accounted for approximately 9% and 23% of the dose, respectively. The major circulating compound was raltegravir, which represented 70% of the radioactivity; the remaining radioactivity in plasma was accounted for by raltegravir-glucuronide. Studies using isoform-selective chemical inhibitors and cDNA-expressed uridine diphosphate glucuronosyltransferases (UGTs) show that UGT1A1 is the main enzyme responsible for formation of raltegravir-glucuronide; thus, the data indicate the major mechanism of clearance of raltegravir in humans is UGT1A1-mediated glucuronidation.

A two-part, Phase II, dose-ranging trial in treatment-naive patients compared 10-day raltegravir monotherapy in 28 patients with placebo in 7 patients. At least 50% of patients in each raltegravir dose group achieved a viral load of at least 400 copies/ml by Day 10. After 16 weeks of therapy, dosages of raltegravir 100, 200, 400, or 600 mg twice daily achieved greater than 50-fold viral load level reductions. In 50% to 57% of patients taking raltegravir, viral load levels decreased to less than 400 copies/ml and to less than 50 copies/ml in 13% to 29% of patients. All dose groups had superior, statistically significant antiretroviral activity compared with placebo. In the second part of the study, 198 treatment-naive patients were randomly assigned to receive either the same dosages of raltegravir twice daily or efavirenz 600 mg once daily, both in combination with tenofovir disoproxil fumarate and lamivudine. At Week 24 of therapy, 85% to 95% of patients on raltegravir-based regimens achieved viral load levels less than 50 copies/ml across all dosages. In the efavirenz-based regimen, 92% of patients achieved viral load levels less than 50 copies/ml. By Week 48, these viral reductions had been maintained by 85% to 98% of raltegravir-receiving patients and by 83% to 88% of efavirenz-receiving patients. Viral loads became undetectable more rapidly in patients who received raltegravir at any dose than in those who received efavirenz. CD4 cell responses were similar among treatment arms. Virologic failure occurred in 3% of patients in each group; of the 5 raltegravir recipients who experienced virologic failure before Week 48, 2 had viruses with the N155H amino acid substitution, a mutation known from in vitro experiments to be selected by raltegravir. Viral load reduction was achieved more quickly with the raltegravir regimen compared with the efavirenz regimen; however, the overall potent and durable antiretroviral activity of raltegravir was otherwise similar to efavirenz at Weeks 24 and 48.

A second Phase II, randomized, double-blind, placebo-controlled trial compared 200, 400, and 600 mg twice-daily dosages of raltegravir with placebo; all patients received optimized background therapy (OBT). All 179 patients enrolled had viral loads of greater than 5,000 copies/ml, were failing highly active antiretroviral therapy (HAART), and had resistance to at least one drug in each anti-HIV drug class. At Week 24 analysis, mean viral load decreases from baseline observed in all the raltegravir-receiving groups and the placebo group were 99% and 50%, respectively. Four patients discontinued the study because of adverse events: 3 (2%) across all raltegravir-treated groups and 1 (2%) in the placebo group. Forty-one study participants (14 [11%] across all raltegravir-treated groups and 27% [60%] in the placebo group) discontinued because of lack of efficacy of their treatment assignments. Raltegravir at all doses studied provided better viral suppression than placebo when added to OBT.

Two ongoing Phase III, randomized, double-blind, placebo-controlled trials in participants failing HAART on OBT are evaluating the efficacy, safety, and tolerability of raltegravir. These trials, BNCHMRK-1 and -2, are triple-blind, randomized studies comparing oral raltegravir 400 mg twice daily with placebo in addition to OBT in HIV infected participants. All participants were failing existing HAART regimens and were resistant to three classes of oral anti-HIV drug therapy. Each trial included more than 200 participants in the treatment arms and more than 100 in the placebo arms. Primary endpoints for both studies are CD4 count increases from baseline, percentage of participants with viral load reduction to less than 400 copies/ml, and percentage of participants with viral load reduction to less than 50 copies/ml. Raltegravir demonstrated superior efficacy compared with placebo in all endpoints at Week 16 and Week 24 interim analyses. In BNCHMRK-1's Week 16 analysis, viral load decreased to less than 400 copies/ml in 77% of treatment arm participants and in 41% of placebo arm participants. Viral load decreased to less than 50 copies/ml in 61% and 33% of treatment arm and placebo arm participants, respectively. CD4 counts increased from baseline on average by 83 cells/mm3 and by 31 cells/mm3 in treatment and placebo arms, respectively. In BNCHMRK-2's Week 16 analysis, 77% of treatment arm participants and 43% of placebo arm participants displayed viral load levels less than 400 copies/ml. The analysis also showed that 62% of the treatment arm participants and 36% of the placebo arm participants displayed levels less than 50 copies/ml. CD4 counts increased from baseline by 86 cells/mm3 in treatment arm participants and by 40 cells/mm3 in placebo arm participants. Endpoint differences were statistically significant in favor of raltegravir efficacy in both trials.

Raltegravir at concentrations of 6 to 50 nM resulted in 95% inhibition (EC95) of viral spread in mitogen-activated human peripheral blood mononuclear cells (PBMCs) infected with diverse, primary clinical isolates of HIV-1, including isolates resistant to reverse transcriptase inhibitors and protease inhibitors (PIs). Raltegravir also inhibited replication of an HIV-2 isolate when tested in CEMx174 cells (EC95 value = 6 nM). Additive to synergistic antiretroviral activity was observed when human T cells infected with the H9IIIB variant of HIV-1 were incubated with raltegravir in combination with non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, and nevirapine), nucleoside analog reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine), PIs (amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), or the entry inhibitor enfuvirtide.(15)

Mutations observed in the HIV-1 coding sequence that contributed to raltegravir resistance (evolved from either in cell culture or in clinical trial participants who receive raltegravir) generally included an amino acid substitution at either Q148 (changed to H, K, or R) or N155 (changed to H) plus one or more substitutions (e.g., L74M/R, E92Q, T97A, E138A/K, G140/S, C151I, G163R, H183P, Y226D/F/H, S230R, D232N). Amino acid substitution at Y143C/H/R is another pathway to raltegravir resistance.

In a resistance study of another investigational integrase inhibitor, GS-9137, site-directed mutant viruses carrying the T66I mutation remained susceptible to raltegravir. However, mutant viruses with the E92Q mutation experienced resistance to GS-9137 and cross resistance to raltegravir. No cross resistance to approved antiretrovirals has been observed with raltegravir.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[In Phase II studies, the most commonly reported treatment-related adverse effects were diarrhea, nausea, fatigue, headache, and itching. Other reported adverse effects included constipation, flatulence, and sweating. Overall, raltegravir was well tolerated, and its adverse effects were comparable to those in the placebo group. In the second part of one Phase II study, the most common adverse effects occurring after 24 weeks of treatment were headache, dizziness, and nausea. Eight serious, nondrug-related adverse effects occurred overall (7/160 in the raltegravir arm and 1/38 in the efavirenz arm); one patient taking twice-daily raltegravir 600 mg discontinued treatment because of elevated liver function tests. Drug-related clinical adverse events were less common with raltegravir than with efavirenz.

Raltegravir has been generally well tolerated in ongoing Phase III studies (BENCHMRK-1 and -2) as well. The most common adverse effects of all intensities, regardless of causality, reported in treatment-experienced adult study participants so far include diarrhea, nausea, headache, and pyrexia. Additionally, Grade 2 to 4 creatine kinase laboratory abnormalities were observed in clinical trial participants treated with raltegravir. The manufacturer notes that because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be compared directly to rates in the clinical trials of another drug and may not reflect rates observed in practice.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy; this may include raltegravir-containing regimens. During the initial phase of combination antiretroviral treatment, a patient whose immune system improves may develop an inflammatory response to indolent or residual opportunistic infections, (e.g., Mycobacterium avium infection, cytomegalovirus infections, Pneumocystis jirovecii pneumonia, tuberculosis, or reactivation of varicella zoster virus), which may necessitate further evaluation and treatment.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Based on the results of drug interaction studies and clinical trials data, no dose adjustment of raltegravir is required when raltegravir is coadministered with antiretroviral agents. The addition of enfuvirtide to a raltegravir-containing regimen appears to increase virologic response. At Week 24 analysis of one dose-ranging study conducted in treatment-experienced, HIV infected participants, viral load decreased to less than 400 copies/ml in 60% of participants receiving raltegravir monotherapy and in 90% of patients receiving combined raltegravir and enfuvirtide.

Raltegravir should be used with caution when administered with strong inducers of UGT1A1, including rifampin. These inducers of UGT1A1 may reduce plasma concentrations of raltegravir. Similar to rifampin, ritonavir-boosted tipranavir reduces plasma concentrations of raltegravir. However, in clinical trials, comparable efficacy of raltegravir was observed in this treatment group when compared with study participants not receiving ritonavir-boosted tipranavir.

Drugs that inhibit UGT1A1 may increase plasma levels of raltegravir. Clinical trial data suggested that concomitant use of raltegravir and atazanavir (a strong inhibitor of UGT1A1) boosted with ritonavir caused increased plasma concentrations of raltegravir. However, this increase was not significant enough to warrant dose adjustment when coadministering raltegravir and atazanavir.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[4-Pyrimidinecarboxamide, N-((4-fluorophenyl)methyl)-1,6- dihydro-5-hydroxy-1-methyl-2-(1-methyl-1- (((5-methyl-1,3,4-oxadiazol-2-yl)carbonyl) amino)ethyl)-6-oxo- monopotassium salt]]></drug:casname><drug:casnumber><![CDATA[518048-05-0]]></drug:casnumber><drug:molecularformula><![CDATA[C20-H20-F-K-N6-O5 (monopotassium salt)]]></drug:molecularformula><drug:elementalcomposition><![CDATA[]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[482.51]]></drug:molecularweight><drug:physicaldescription><![CDATA[White to off-white powder.]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[Soluble in water, slightly soluble in methanol, very slightly soluble in ethanol and acetonitrile, and insoluble in isopropanol.]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:othername><![CDATA[MK-0518]]></drug:othername></drug:othernames><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[Isentress Prescribing Information from the FDA Web site <A HREF="http://www.fda.gov/cder/foi/label/2007/022145lbl.pdf">[PDF]</A>. A more current version may be available on the manufacturer's Web site.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17434401 Grinsztejn B, Nguyen BY, Katlama C, Gatell JM, Lazzarin A, Vittecoq D, Gonzalez CJ, Chen J, Harvey CM, Isaacs RD; Protocol 005 Team. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Lancet. 2007 Apr 14;369(9569):1261-9.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17434401&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17133211 Markowitz M, Morales-Ramirez JO, Nguyen BY, Kovacs CM, Steigbigel RT, Cooper DA, Liporace R, Schwartz R, Isaacs R, Gilde LR, Wenning L, Zhao J, Teppler H. Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1-infected individuals. J Acquir Immune Defic Syndr. 2006 Dec 15;43(5):509-15.
]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17133211&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17721395 Markowitz M, Nguyen BY, Gotuzzo E, Mendo F, Ratanasuwan W, Kovacs C, Prada G, Morales-Ramirez JO, Crumpacker CS, Isaacs RD, Gilde LR, Wan H, Miller MD, Wenning LA, Teppler H; the Protocol 004 Part II Study Team. Rapid and Durable Antiretroviral Effect of the HIV-1 Integrase Inhibitor Raltegravir as Part of Combination Therapy in Treatment-Naive Patients With HIV-1 Infection: Results of a 48-Week Controlled Study. J Acquir Immune Defic Syndr. 2007 Oct 1;46(2):125-33.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17721395&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[Cooper D, Gatell J, Rockstroh J, Katlama C, Yeni P, Lazzarin A, Chen J, Isaacs R, Teppler H, Nguyen B, and for the BENCHMRK-1 Study Group. Results of BENCHMRK-1, a Phase III Study Evaluating the Efficacy and Safety of MK-0518, a Novel HIV-1 Integrase Inhibitor, in Patients with Triple-class Resistant Virus. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA, Abstract 105aLB, 2007.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[Steigbigel R, Kumar P, Eron J, Schechter M, Markowitz M, Loufty M, Zhao J, Isaacs R, Nguyen B, Teppler H, and for the BENCHMRK-2 Study Group. Results of BENCHMRK-2, a Phase III Study Evaluating the Efficacy and Safety of MK-0518, a Novel HIV-1 Integrase Inhibitor, in Patients with Triple-class Resistant Virus. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA, Abstract 105bLB, 2007.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[A Study to Evaluate the Safety and Efficacy of MK-0518 in HIV-Infected Patients Failing Current Antiretroviral Therapies. Available at: http://clinicaltrials.gov/show/NCT00293267. Accessed 10/15/07.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[A Study to Evaluate the Safety and Efficacy of MK-0518 in HIV-Infected Patients Failing Current Antiretroviral Therapies. Available at: http://clinicaltrials.gov/show/NCT00293254. Accessed 10/15/07.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Isentress]]></drug:drugname><drug:companyname><![CDATA[Merck & Company, Inc]]></drug:companyname><drug:address1><![CDATA[One Merck Dr]]></drug:address1><drug:address2><![CDATA[P.O. Box 100]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Whitehouse Station]]></city><drug:state><![CDATA[NJ]]></drug:state><drug:zipcode><![CDATA[08889-0100]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 609-4618]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Raltegravir]]></drug:drugname><drug:companyname><![CDATA[Merck & Company, Inc]]></drug:companyname><drug:address1><![CDATA[One Merck Dr]]></drug:address1><drug:address2><![CDATA[P.O. Box 100]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Whitehouse Station]]></city><drug:state><![CDATA[NJ]]></drug:state><drug:zipcode><![CDATA[08889-0100]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 609-4618]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[October 18, 2007]]></drug:lastupdated></item><item><title><![CDATA[Delavirdine]]></title><description><![CDATA[Delavirdine, also known as Rescriptor, is a type of medicine called a non-nucleoside reverse transcriptase inhibitor (NNRTI). NNRTIs block reverse transcriptase, a protein that HIV needs to make more copies of itself.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=166]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Delavirdine]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[de-la-VIR-deen]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Rescriptor]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Delavirdine]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Non-nucleoside Reverse Transcriptase Inhibitors]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Delavirdine mesylate is a bis(heteroaryl)piperazine (BHAP) derivative nonnucleoside reverse transcriptase inhibitor (NNRTI).]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Delavirdine mesylate was approved by the FDA on April 4, 1997, for use in combination with at least two other antiretroviral agents for the treatment of adults with HIV-1 infection. The safety and effectiveness of delavirdine have not been established in neonates and children younger than 16 years of age.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Tablets containing delavirdine mesylate 100 or 200 mg. 

The recommended dose of delavirdine for adults is 400 mg (four 100 mg or two 200 mg tablets) three times daily.]]></drug:dosageform><drug:storage><![CDATA[Store tablets at controlled room temperature between 20 C to 25 C (68 F to 77 F). Keep container tightly closed. Protect from high humidity.]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Delavirdine binds directly to HIV-1 reverse transcriptase (RT) and blocks RNA- and DNA-dependent DNA polymerase activities. Delavirdine does not compete with template, primer, or deoxynucleoside triphosphates. HIV-2 RT and human cellular DNA polymerases are not inhibited by delavirdine. HIV-1 group O, a group of highly divergent strains that are uncommon in North America, may not be inhibited by delavirdine.

Delavirdine is rapidly absorbed following oral administration. The bioavailability of delavirdine 100 mg tablets is increased by approximately 20% when the medication is dissolved in water prior to administration; however, this is not necessarily a preferred method of administration in patients able to swallow oral tablets.  Delavirdine 200 mg tablets do not readily disperse in water and should be swallowed intact. When multiple doses of delavirdine were administered with food, peak plasma concentration (Cmax) was reduced by approximately 25%, but area under the plasma concentration-time curve (AUC) and minimum plasma concentration (Cmin) were not altered.

Delavirdine is distributed predominantly into blood plasma. Delavirdine is approximately 98% bound to plasma proteins, principally albumin. The percentage that is protein bound is constant over delavirdine concentrations of 0.23 to 89.5 mcg/ml.  In HIV-1 infected patients whose total daily dose of delavirdine ranged from 600 to 1,200 mg, cerebrospinal fluid concentrations of delavirdine averaged 0.4% of the corresponding plasma delavirdine concentrations; this represents about 20% of the fraction not bound to plasma proteins. Steady-state delavirdine concentrations in the saliva of HIV-1 infected patients and in the semen of healthy volunteers were about 6% and 2%, respectively, of the corresponding plasma delavirdine concentrations collected at the end of a dosing interval.

Delavirdine is in FDA Pregnancy Category C; no adequate and well-controlled studies of delavirdine have been conducted in pregnant women. It is not known whether delavirdine crosses the placenta in humans, but this does occur in laboratory animals. Delavirdine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. To monitor maternal-fetal outcomes of pregnant women exposed to delavirdine and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263 or online at http://www.APRegistry.com. It is not known whether delavirdine is distributed into human breast milk; however, it is distributed into milk in rats. Breastfeeding is not recommended for HIV infected mothers because of the potential for HIV transmission to the breastfed infant.

Delavirdine is extensively converted to several inactive metabolites. It is primarily metabolized by cytochrome P(CYP) 450 3A, but in vitro data suggest that delavirdine may also be metabolized by CYP2D6. Delavirdine reduces the activity of CYP3A, thereby inhibiting its own metabolism. Inhibition of CYP3A by delavirdine is reversible within 1 week after discontinuation of therapy. The major metabolic pathways for delavirdine are N-desalkylation and pyridine hydroxylation.

Delavirdine exhibits nonlinear steady-state elimination pharmacokinetics, with apparent oral clearance decreasing by about 22-fold as the total daily dose of delavirdine increases from 60 to 1,200 mg/day. Mean elimination time from plasma is approximately 5.8 hours following treatment with 400 mg three times a day. The apparent half-life increases with dose. The time to peak plasma concentration is approximately 1 hour. The mean steady-state concentration in plasma is approximately 16.1 mcg/ml following doses of 400 mg three times a day. Systemic exposure as measured by the AUC is approximately 82.8 mcg/ml per hour; trough concentration is approximately 6.9 mcg/ml. The median AUC in female patients is 31% higher than in male patients.

In a study of six healthy adults who received multiple doses of delavirdine, approximately 44% of the radiolabeled dose was recovered in feces and approximately 51% of the dose was excreted in urine as metabolites. Less than 5% of the dose was recovered unchanged in urine. The pharmacokinetics of delavirdine in patients with hepatic or renal impairment have not been investigated; however, delavirdine is metabolized primarily by the liver and should be used with caution in patients with impaired hepatic function.

Resistant virus emerges rapidly when delavirdine is used as monotherapy. Acquisition of a single mutation can confer resistance to delavirdine. Genotypic analysis of viral isolates from patients receiving delavirdine and zidovudine revealed that 84% had resistance-associated mutations after 24 weeks of therapy. Mutations occurred predominantly at HIV RT amino acid position 103 but also at positions 181 and 236.

Delavirdine may confer cross resistance to other NNRTIs. Cross resistance between nucleoside reverse transcriptase inhibitors or protease inhibitors (PIs) is unlikely.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Rash is the most frequently reported adverse effect of delavirdine. Most cases occur within the first 1 to 3 weeks of therapy; severe rash generally occurs within the first 28 days. The rash is usually diffuse, maculopapular, erythematous, and often pruritic, appearing mainly on the upper body and proximal arms and decreasing on the neck, face, and the rest of the trunk and limbs. In most cases, the rash lasts less than 2 weeks and does not require dose reduction or discontinuation. If delavirdine therapy is interrupted due to rash, most patients are able to resume therapy with the drug after rechallenge.

Severe rash, including rare cases of erythema multiforme and Stevens-Johnson syndrome, has been reported in patients receiving delavirdine. Any patient experiencing severe rash or rash accompanied by symptoms such as fever, blistering, oral lesions, conjunctivitis, swelling, and muscle or joint aches should discontinue delavirdine and consult a physician.

Adverse events of moderate to severe intensity reported by at least 5% of patients receiving delavirdine in clinical trials involved the following systems: body as a whole (generalized abdominal pain, asthenia, fatigue, fever, flu syndrome, headache, and localized pain); digestive (diarrhea, nausea, and vomiting); nervous (anxiety, depressive symptoms, and insomnia); and respiratory (bronchitis, cough, pharyngitis, sinusitis, and upper respiratory tract infections.

Postmarketing adverse events not reported in clinical trials have included hepatic failure, hemolytic anemia, rhabdomyolysis, and acute kidney failure. Because these events were observed during clinical practice, their frequency cannot be determined.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Dose adjustment of delavirdine and/or other drugs may be necessary in patients receiving concomitant therapy with drugs that are extensively metabolized by or induce or inhibit CYP3A, CYP2C9, CYP2D6, and CYP2C19. Delavirdine may inhibit the metabolism of and is predicted to result in clinically important plasma concentration increases in certain amphetamines; anticoagulants (warfarin); anti-infectives (clarithromycin, dapsone, rifabutin, and saquinavir); sedative hypnotics (alprazolam, midazolam, triazolam); cardiovascular agents (nifedipine, quinidine); ergot alkaloids and derivatives; GI drugs (cisapride); HMG-CoA reductase inhibitors (atorvastatin, cerivastatin, fluvastatin); immunosuppressive agents (cyclosporine, sirolimus, tacrolimus); methadone; or sildenafil.

Because delavirdine is an inhibitor of CYP3A, concomitant use with an HIV PI may result in increased plasma concentrations of the PI. Delavirdine may inhibit metabolism of indinavir, increasing the Cmax and AUC of indinavir. Although no pharmacokinetic studies have been performed, the possibility exists that delavirdine may increase plasma concentrations of amprenavir and lopinavir. Concomitant use of delavirdine with nelfinavir may result in increased concentration of nelfinavir and decreased concentration of delavirdine and the active nelfinavir metabolite (nelfinavir hydroxy-t-butylamide). Concomitant use of delavirdine with saquinavir may result in increased AUC of saquinavir. Recent studies indicate that concomitant administration of delavirdine and ritonavir may result in a 70% increase of ritonavir trough concentrations and ritonavir systemic exposure. 

Pharmacokinetic studies evaluating concomitant use of delavirdine and other NNRTIs have not been performed. 

Doses of delavirdine and buffered preparations of didanosine should be separated by at least 1 hour.

Concurrent administration of delavirdine with aluminum and magnesium oral suspension decreased the AUC for delavirdine by approximately 44%; patients should be advised not to take antacids within 1 hour of taking delavirdine.

Coadministration of St. John's wort or St. John's wort-containing products with NNRTIs, including delavirdine, is expected to substantially decrease NNRTI concentrations and may result in suboptimal levels of delavirdine and lead to loss of virologic response and possible resistance to delavirdine and other NNRTIs.

Concurrent use of delavirdine with carbamazepine, phenobarbital, or phenytoin substantially decreases the trough plasma concentration of delavirdine.

Cimetidine, famotidine, nizatidine, and ranitidine increase gastric pH and may reduce absorption of delavirdine; long-term use of these medications with delavirdine is not recommended.

Concurrent administration of delavirdine with clarithromycin increases the AUC for delavirdine by approximately 44%. The AUC for clarithromycin increases by approximately 100%.

Concurrent administration of delavirdine and fluoxetine increases the trough plasma concentration of delavirdine by approximately 50%.

Concurrent administration of delavirdine and ketoconazole increases the trough plasma concentration of delavirdine by approximately 50%.

Concurrent administration of delavirdine with rifabutin or rifampin decreases the AUC for delavirdine by approximately 80% and 96%, respectively, and increases the AUC for rifabutin by at least 100%.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Delavirdine is contraindicated in patients with known hypersensitivity to any of the tablet's ingredients. Coadministration of delavirdine mesylate is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life threatening events. These drugs include ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine), neuroleptics (pimozide), sedatives/hypnotics (alprazolam, midazolam, triazolam), and three drugs that are no longer available in the United States (astemizole, terfenadine, and cisapride).]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[Piperazine, 1-[3-[(1-methylethyl)amino)-2- pyridinyl]-2-pyridinyl]-4-[[5-[(methylsulfonyl) amino]-1H-indol-2-yl]carbonyl]-, monomethanesulfonate]]></drug:casname><drug:casnumber><![CDATA[147221-93-0]]></drug:casnumber><drug:molecularformula><![CDATA[C22-H28-N6-O3-S.C-H4-O3-S]]></drug:molecularformula><drug:elementalcomposition><![CDATA[C49.98%, H5.84%, N15.21%, O17.37%, S11.60%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[226 C to 228 C]]></drug:meltingpoint><drug:molecularweight><![CDATA[552.68]]></drug:molecularweight><drug:physicaldescription><![CDATA[Odorless white-to-tan crystalline powder.]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[2,942 mcg/ml at pH 1.0, 295 mcg/ml at pH 2.0, and 0.81 mcg/ml at pH 7.4 (aqueous solubility of delavirdine free base at 23 C).]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:othername><![CDATA[U-90152S]]></drug:othername><drug:othername><![CDATA[DLV]]></drug:othername></drug:othernames><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[Rescriptor Prescribing Information from the FDA Web site <a href="http://www.fda.gov/cder/foi/label/2002/20705slr009lbl.pdf">[PDF]</a>. A more current version may be available on the manufacturer's Web site.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/15199327 Engelhorn C, Hoffmann F, Kurowski M, Stocker H, Kruse G, Notheis G, Belohradsky BH, Wintergerst U. Long-term pharmacokinetics of amprenavir in combination with delavirdine in HIV-infected children. AIDS. 2004 Jul 2;18(10):1473-5.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15199327&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/14640386 Harrigan PR, Hertogs K, Verbiest W, Larder B, Yip B, Brumme ZL, Alexander C, Tilley J, O'Shaughnessy MV, Montaner JS. Modest decreases in NNRTI susceptibility do not influence virological outcome in patients receiving initial NNRTI-containing triple therapy. Antivir Ther. 2003 Oct; 8(5):395-402.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=14640386&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/15634033 Smith PF, Dicenzo R, Forrest A, Shelton M, Friedland G, Para M, Pollard R, Fischl M, DiFrancesco R, Morse GD. Population pharmacokinetics of delavirdine and N-delavirdine in HIV-infected individuals. Clin Pharmacokinet. 2005;44(1):99-109.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15634033&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/14742351 Yazdanpanah Y, Sissoko D, Egger M, Mouton Y, Zwahlen M, Chene G. Clinical efficacy of antiretroviral combination therapy based on protease inhibitors or non-nucleoside analogue reverse transcriptase inhibitors: indirect comparison of controlled trials. BMJ. 2004 Jan 31;328(7434):249. Epub 2004 Jan 23.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=14742351&dopt=Abstract]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Delavirdine]]></drug:drugname><drug:companyname><![CDATA[Pfizer Inc]]></drug:companyname><drug:address1><![CDATA[235 East 42nd Street]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[New York]]></city><drug:state><![CDATA[NY]]></drug:state><drug:zipcode><![CDATA[10017-5755]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 438-1985]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Rescriptor]]></drug:drugname><drug:companyname><![CDATA[Pfizer Inc]]></drug:companyname><drug:address1><![CDATA[235 East 42nd Street]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[New York]]></city><drug:state><![CDATA[NY]]></drug:state><drug:zipcode><![CDATA[10017-5755]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 438-1985]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[January 31, 2007]]></drug:lastupdated></item><item><title><![CDATA[Efavirenz]]></title><description><![CDATA[Efavirenz, also known as EFV or Sustiva, is a type of medicine called a non-nucleoside reverse transcriptase inhibitor (NNRTI). NNRTIs block reverse transcriptase, a protein that HIV needs to make more copies of itself.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=269]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Efavirenz]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[ef-FAH-ver-enz]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Sustiva]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Efavirenz]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Non-nucleoside Reverse Transcriptase Inhibitors]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Efavirenz, also known as EFV, is a benzoxazinone derivative non-nucleoside reverse transcriptase inhibitor (NNRTI).]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Efavirenz was approved by the FDA on September 17, 1998, for use in combination with other antiretroviral agents for the treatment of HIV-1 infection. Efavirenz was approved under the FDA's accelerated review process, which allows approval based on analysis of surrogate markers or response, such as T-cell counts and HIV RNA viral levels, rather than clinical endpoints such as disease progression or survival. The safety and efficacy of efavirenz in children less than 3 years of age have not been established.

Efavirenz, in combination with either zidovudine and lamivudine or emtricitabine and tenofovir disoproxil fumarate, is part of two of the preferred  regimens for treatment-naive patients.

Efavirenz may be used with other antiretroviral agents as part of an expanded postexposure prophylaxis regimen for health care workers and other individuals exposed occupationally to tissues, blood, or other body fluids associated with a high risk for HIV transmission.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral (capsule, tablet).]]></drug:modeofdelivery><drug:dosageform><![CDATA[Capsules containing efavirenz 50, 100, or 200 mg and film-coated tablets containing efavirenz 600 mg.

The recommended dose of efavirenz for adults and children weighing more than 40 kg (88 lbs) is 600 mg once daily.  Dosing recommendations for pediatric patients 3 years of age or older who weigh between 10 and 40 kg are provided in the manufacturer's prescribing information.]]></drug:dosageform><drug:storage><![CDATA[Store at 25 C (77 F); excursions permitted between 15 C and 30 C (59 F to 86 F).]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Efavirenz is a noncompetitive inhibitor of HIV-1 reverse transcriptase (RT). It has no inhibitory effect on HIV-2 RT or human cellular DNA polymerases alpha, beta, gamma, or delta. Efavirenz binds directly to RT and inhibits viral RNA- and DNA-dependent DNA polymerase activities by disrupting the catalytic site.  Although the drug-RT-template complex may continue to bind deoxynucleoside triphosphate and to catalyze its incorporation into the newly forming viral DNA, it does so at a slower rate.

Following oral administration of a single 100 mg to 1,600 mg dose of efavirenz in healthy adults, peak plasma drug concentrations (Cmax) of 0.51 to 2.9 mcg/ml were attained within 5 hours. Increases in Cmax and area under the plasma concentration-time curve (AUC) were dose proportional for 200, 400, and 600 mg efavirenz doses; the increases were less than proportional for a 1,600 mg efavirenz dose, suggesting reduced absorption at higher doses. Times to peak plasma concentrations were approximately 3 to 5 hours, and steady-state plasma concentrations were reached in 6 to 10 days. Following oral administration of a single 400 mg efavirenz dose in individuals with chronic liver disease or healthy individuals, Cmax averaged 1.2 or 1.8 mcg/ml, respectively, and AUC averaged 94.4 or 96.3 (hr)mcg/ml.

Normal meals had no significant effect on the bioavailability of 100 mg of efavirenz administered twice a day for 10 days. The relative bioavailability of a single 1,200 mg dose of efavirenz in uninfected volunteers was increased by 50% following a high fat meal.

Distribution of efavirenz into body tissues and fluids has not been fully characterized. In animal models, efavirenz's volume of distribution following IV administration suggests extensive tissue distribution. In HIV infected patients who received 200 mg to 600 mg of efavirenz once a day for at least 1 month, cerebrospinal fluid concentrations ranged from 0.26% to 1.19% of the corresponding plasma concentration. This proportion is approximately threefold higher than the nonprotein-bound (free) fraction of efavirenz in plasma. Efavirenz is highly bound (approximately 99.5% to 99.75%) to human plasma proteins, principally albumin.

Efavirenz is in FDA Pregnancy Category D. Efavirenz may cause fetal harm when administered during the first trimester of pregnancy. No adequate and well-controlled studies have been performed in pregnant women. In prospective reports, birth defects have occurred in 5 of 228 live births after first trimester maternal exposure; none were neural tube defects. Four retrospective reports identified findings consistent with neural tube defects, including meningomyelocele, in mothers exposed to efavirenz during the mother's first trimester. Although a causal relationship has not been established, similar defects have been observed in preclinical studies of efavirenz.

Two methods of birth control, with a barrier method in combination with a nonbarrier method such as an oral or other hormonal contraceptive, should be used to avoid pregnancy in women taking efavirenz. Before initiating therapy with efavirenz, women of childbearing potential should undergo pregnancy testing. It is recommended that efavirenz not be given to pregnant women except in situations in which there are no therapeutic alternatives. An Antiretroviral Pregnancy Registry has been established to monitor the outcomes of pregnant women exposed to efavirenz. Physicians may register patients online at http://www.APRegistry.com or by calling 1-800-258-4263. It is not known whether efavirenz is distributed into breast milk in humans; however, efavirenz is distributed into the milk of laboratory animals. Breastfeeding is not recommended during efavirenz therapy.

Efavirenz is metabolized primarily by the hepatic cytochrome P450 (CYP) isoenzymes 3A4 and 2B6 into hydroxylated, inactive metabolites. These metabolites undergo subsequent glucuronidation. Ten days of therapy with 200 mg to 400 mg of efavirenz daily resulted in a lower than expected accumulation of medication (22% to 42% lower) and a shorter terminal half-life (40 to 55 hours) compared to the single-dose half-life (52 to 76 hours).

Efavirenz appears to induce its own metabolism. Terminal elimination half-life is prolonged in patients with chronic liver disease. Following oral administration of a single 400 mg dose of efavirenz, a half-life of 152 or 118 hours was reported, with or without chronic liver disease, respectively. Efavirenz is excreted principally in the feces, both as metabolites and unchanged drug. Approximately 14% to 34% of a radiolabeled dose of efavirenz was recovered in the urine (less than 1% as unchanged drug) and 16% to 61% of a radiolabeled dose was recovered (primarily as unchanged drug).

Although the mechanism of viral resistance or reduced susceptibility to efavirenz has not been fully determined, the principal mechanism of resistance appears to be mutation of HIV RT. Like the other NNRTIs nevirapine and delavirdine, exposure to efavirenz selects for mutations that usually involve the regions of HIV RT that include amino acid positions 98 through 108 and 179 through 190, although mutations at position 225 have also been reported. Acquisition of a single mutation can result in resistance to efavirenz. HIV-1 strains with decreased susceptibility to efavirenz, nevirapine, and delavirdine have been isolated from patients receiving efavirenz in conjunction with other agents. Maintaining adequate trough concentrations of efavirenz may delay emergence of highly resistant viral variants.

The potential for cross resistance between efavirenz and nucleoside reverse transcriptase inhibitors (NRTIs) is considered low because the drugs bind at different sites and have different mechanisms of action. Cross resistance between efavirenz and HIV protease inhibitors (PIs) is unlikely because of the different enzyme targets involved.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Efavirenz's most common adverse effects are depression, pruritis, and skin rash.

Fifty-two percent of patients treated with efavirenz reported central nervous system (CNS) or psychiatric symptoms. In 2.6% of patients, these symptoms were severe and resulted in discontinuation of efavirenz. CNS symptoms included abnormal dreams, abnormal thinking, agitation, amnesia, confusion, depersonalization, dizziness, euphoria, hallucinations, impaired concentration, insomnia, somnolence, and stupor. Symptoms usually appeared within the first or second day of treatment and generally resolved after 2 to 4 weeks. After 4 weeks of therapy, the prevalence of CNS symptoms of at least moderate severity ranged from 5% to 9% in patients treated with efavirenz-containing regimens, compared to 3% to 5% in patients treated with a control regimen. Adverse CNS effects may be more tolerable with bedtime dosing.

Depression, anxiety, and nervousness have been reported in patients taking efavirenz. Severe depression, suicidal ideation, nonfatal suicide attempts, aggressive behavior, paranoid reactions, and mania reactions have been reported in 0.4% to 1.6% of patients receiving efavirenz in controlled clinical studies. Although a causal relationship with efavirenz has not been established, there have been occasional postmarketing reports of death by suicide, delusions, or psychosis-like behavior in patients taking efavirenz. There is no evidence that patients who develop adverse CNS effects during efavirenz therapy are at greater risk of developing psychiatric symptoms.

Skin rashes usually appear as mild or moderate maculopapular skin eruptions that occur within the first 2 weeks of efavirenz therapy. In controlled clinical trials, 26% of patients treated with 600 mg of efavirenz experienced new onset skin rash, compared with 18% of patients treated in control groups. In most patients, rash resolves within 1 month with continuing efavirenz therapy. Efavirenz can be reinitiated in patients interrupting therapy because of rash. Rash associated with blistering, moist desquamation, or ulceration occurred in less than 1% of patients taking efavirenz. The incidence of Grade 4 rash such as erythema multiforme or Stevens-Johnson syndrome in patients treated with efavirenz in all studies and expanded access programs was 0.1%. The discontinuation rate for rash in clinical trials was 1.7%. Efavirenz should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement, or fever.

Substantial increases in liver enzymes and hepatic failure have been reported in patients receiving efavirenz, with or without coinfection with hepatitis B or C virus. It is unclear if these increases reflect drug-induced enzyme induction rather than liver toxicity. Moderate to severe gastrointestinal effects have been reported in up to 14% of adults receiving efavirenz in clinical studies. Nausea, diarrhea, vomiting, dyspepsia, abdominal pain, anorexia, constipation, and malabsorption have been reported. Although the clinical importance remains to be determined, total serum cholesterol and high-density lipoprotein (HDL) concentrations were increased in healthy individuals receiving efavirenz. Monitoring of cholesterol and triglycerides should be considered in patients treated with efavirenz. Flushing and palpitations have been reported during postmarketing surveillance.

Pancreatitis has been reported in a few patients receiving efavirenz. Asymptomatic serum amylase concentration increases to greater than 1.5 times the upper limit of normal have been reported in 10% of patients receiving efavirenz compared with 6% of patients in control groups. Lipodystrophy, moderate or severe pain, abnormal vision, arthralgia, asthenia, dyspnea, gynecomastia, myalgia, myopathy, and tinnitus have also been reported.

Although the types and severity of adverse reactions related to efavirenz experienced by pediatric patients were generally similar to those of adults, children experienced a higher incidence of rash (46% of children compared to 26% of adults). The incidence of Grade 3 or 4 moderate to severe rash was also higher in children, with 5% of children developing a severe rash compared to 0.9% of adults.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Efavirenz should not be taken with high fat meals, which may increase absorption of efavirenz.

Metabolism of efavirenz is mediated in part by CYP3A4; drugs that induce this isoenzyme may reduce efavirenz plasma concentrations. In vitro studies have shown that efavirenz inhibits CYP2C9, CYP2C19, and CYP3A4. Coadministration of efavirenz with drugs primarily metabolized by CYP2C9, CYP2C19, and CYP3A4 may result in altered plasma concentrations of the coadministered drug. Astemizole, cisapride, ergot alkaloids and derivatives, midazolam, or triazolam should not be used concomitantly with efavirenz.

Clinically important pharmacokinetic interactions occur when efavirenz is used in conjunction with PIs. Plasma concentrations of amprenavir, indinavir, lopinavir (in fixed dose combination with ritonavir), nelfinavir, and saquinavir were decreased. However, concomitant use of ritonavir and efavirenz resulted in increased AUC for both drugs and a higher incidence of adverse effects. Pharmacokinetic studies evaluating concomitant use of efavirenz and the other NNRTIs have not been performed and concomitant use of these drugs is not recommended. Clinically important pharmacokinetic interactions are not expected between efavirenz and NRTIs, as these drugs have different metabolic pathways and are unlikely to compete for the same metabolic enzymes.

Concurrent use of rifampin decreases efavirenz plasma concentrations; concurrent use of rifabutin does not effect efavirenz plasma concentrations but decreases rifabutin plasma concentrations. Efavirenz may decrease the plasma concentration of clarithromycin; however, coadministration of azithromycin with efavirenz did not result in any clinically significant pharmacokinetic interactions. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with efavirenz.

Coadministration of methadone and efavirenz decreased the Cmax and AUC of methadone by 45% and 52%, respectively, and resulted in manifestations of opiate withdrawal. The maintenance dosage of methadone was increased by 22% to alleviate withdrawal symptoms. Anticonvulsant levels should be monitored in patients taking efavirenz and carbamazepine, phenobarbitol, or phenytoin. Administration of efavirenz in patients receiving psychoactive drugs may result in increased CNS effects.

Plasma concentrations of ethinyl estradiol found in oral and other hormonal contraceptives may be increased by efavirenz; the clinical significance is unknown. The addition of a reliable method of barrier contraception is recommended for patients taking efavirenz. Concurrent use of St. John's wort (Hypericum perforatum) or St. John's wort-containing products with efavirenz is expected to substantially decrease efavirenz plasma concentrations, which may result in suboptimal efavirenz levels and lead to loss of virologic response or resistance to efavirenz.

Plasma concentrations and clinical effects of warfarin, a drug with a narrow therapeutic margin, may be either increased or decreased when used concurrently with efavirenz.

Although efavirenz does not bind to cannabinoid receptors, false-positive urine cannabinoid test results have been reported in uninfected volunteers who received efavirenz. The false-positive results have been observed only with the CEDIA DAU Multi-Level THC assay used for screening and were not observed with other cannabinoid assays, including those used for confirmation of positive results.

Based on data from an open-label randomized study and retrospective database analyses, clinicians are advised to use caution when administering tenofovir disoproxil fumarate, enteric-coated didanosine, and either efavirenz or nevirapine in the treatment of treatment-naive HIV infected patients with high baseline viral loads.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Efavirenz is contraindicated in patients with clinically significant hypersensitivity to any of its components. Efavirenz should not be administered concurrently with astemizole, cisapride, midazolam, triazolam, or ergot derivatives because competition for CYP3A4 could result in inhibition of metabolism of these drugs and create the potential for serious or life-threatening adverse events, such as cardiac arrhythmias, prolonged sedation, or respiratory depression. Efavirenz should not be administered concurrently with voriconazole because efavirenz significantly decreases voriconazole plasma concentrations.

Risk-benefit should be considered when using efavirenz therapy for patients with impaired hepatic function and/or hepatitis B or C virus infection.]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[2H-3,1-Benzoxazin-2-one, 6-chloro-4-(cyclopropylethynyl)-1,4- dihydro-4-(trifluoromethyl)-, (4S)-]]></drug:casname><drug:casnumber><![CDATA[154598-52-4]]></drug:casnumber><drug:molecularformula><![CDATA[C14-H9-Cl-F3-N-O2]]></drug:molecularformula><drug:elementalcomposition><![CDATA[C53.27%, H2.87%, Cl11.23%, F18.05%, N4.44%, O10.14%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[315.67]]></drug:molecularweight><drug:physicaldescription><![CDATA[White to slightly pink crystalline powder.]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[Practically insoluble in water (less than 10 mcg/ml).]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:othername><![CDATA[EFV]]></drug:othername></drug:othernames><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[Sustiva Prescribing Information from the FDA Web site <a href="http://www.fda.gov/cder/foi/label/2007/020972s029,021360s016lbl.pdf">[PDF]</a>. A more current version may be available on the manufacturer's Web site.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17367260 Arendt G, de Nocker D, von Giesen HJ, Nolting T. Neuropsychiatric side effects of efavirenz therapy. Expert Opin Drug Saf. 2007 Mar;6(2):147-54.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17367260&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/14727217 Gallego L, Barreiro P, del Rio R, Gonzalez De Requena D, Rodriguez-Albarino A, Gonzalez-Lahoz J, Soriano V.  Analyzing Sleep Abnormalities in HIV-Infected Patients Treated with Efavirenz. Clin Infect Dis. 2004 Feb 1; 38(3): 430-2.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=14727217&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17357053 Kuritzkes DR, Ribaudo HJ, Squires KE, Koletar SL, Santana J, Riddler SA, Reichman R, Shikuma C, Meyer WA 3rd, Klingman KL, Gulick RM; ACTG A5166s Protocol Team. Plasma HIV-1 RNA Dynamics in Antiretroviral-Naive Subjects Receiving either Triple-Nucleoside or Efavirenz-Containing Regimens: ACTG A5166s. J Infect Dis. 2007 Apr 15;195(8):1169-76. Epub 2007 Mar 6.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17357053&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16192249 Sheran M. The nonnucleoside reverse transcriptase inhibitors efavirenz and nevirapine in the treatment of HIV. HIV Clin Trials. 2005 May-Jun;6(3):158-68. Review.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16192249&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/15764851 van Leth F, Andrews S, Grinsztejn B, Wilkins E, Lazanas MK, Lange JM, Montaner J; 2NN study group. The effect of baseline CD4 cell count and HIV-1 viral load on the efficacy and safety of nevirapine or efavirenz-based first-line HAART.  AIDS. 2005 Mar 25;19(5):463-71.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15764851&dopt=Abstract]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Efavirenz]]></drug:drugname><drug:companyname><![CDATA[Bristol - Myers Squibb Co]]></drug:companyname><drug:address1><![CDATA[PO Box 4500]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Princeton]]></city><drug:state><![CDATA[NJ]]></drug:state><drug:zipcode><![CDATA[08543-4500]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 321-1335]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Sustiva]]></drug:drugname><drug:companyname><![CDATA[Bristol - Myers Squibb Co]]></drug:companyname><drug:address1><![CDATA[PO Box 4500]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Princeton]]></city><drug:state><![CDATA[NJ]]></drug:state><drug:zipcode><![CDATA[08543-4500]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 321-1335]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[October 5, 2007]]></drug:lastupdated></item><item><title><![CDATA[Etravirine (TMC125)]]></title><description><![CDATA[Etravirine, also known as Intelence or TMC125, is a type of medicine called a non-nucleoside reverse transcriptase inhibitor (NNRTI). NNRTIs work by blocking reverse transcriptase, a protein that HIV needs to make more copies of itself.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=398]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Etravirine (TMC125)]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Intelence]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Etravirine (TMC125)]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Non-nucleoside Reverse Transcriptase Inhibitors]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Etravirine, also known as Intelence or TMC125, is a diarylpyrimidine (DAPY) derivative with potent in vitro activity against HIV.

In vitro, etravirine has equipotent activity against wild-type HIV and NNRTI-resistant variants that encode L100I, K103N, Y181C, Y188L, and G190A/S mutations.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Etravirine, also known as Intelence or TMC125, was approved by the FDA on January 18, 2008 for use for use in combination with at least two other antiretroviral agents for the treatment of adults with HIV-1 infection. This medication does not cure HIV infection or AIDS and does not reduce the risk of passing the virus to other people.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Tablets containing etravirine 100 mg.]]></drug:dosageform><drug:storage><![CDATA[]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[TMC125 was designed by Belgian scientists to reduce drug resistance, partly by making a flexible molecule that can fit in the active pocket of HIV's reverse transcriptase in different ways, even when the shape of that pocket changes because of viral mutations that would defeat other drugs. TMC125 is a highly flexible compound with low in vitro toxicity. TMC125 has garnered attention because of its activity against NNRTI-resistant HIV strains.

A substantial improvement in the relative oral bioavailabililty of TMC125 was achieved with new tablet formulation, compared with tablet formulations used in initial studies. In the TMC125-C170 trial, all 45 HIV uninfected participants received 1 reference dose of 400 mg TMC125. After a 2-week washout period, participants received 1 of 4 test formulations of TMC125. Pharmacokinetics of TMC125 were assessed for 96 hours postdose. Results indicated marked increases in the area under the concentration-time curve (AUC) and the maximum serum concentration (Cmax) for all test formulations compared with the reference dose. The time to maximum concentration (Tmax) and the elimination half-life were similar for all treatments. Less intersubject variability was observed for the test formulations compared with the reference dose. Treatment with TMC125 was generally safe and well tolerated. The new tablet formulation also reduces pill burden. 

Several studies of TMC125 in HIV infected people have been promising. In the TMC125-C207 study conducted in London, England, TMC125's effectiveness in HIV infected men with documented efavirenz resistance taking an NNRTI-containing regimen was evaluated. In this open-label, Phase IIa study of 16 HIV infected men with 10- to 500-fold resistance to efavirenz, treatment with TMC125 for 7 days resulted in a median decrease in viral load of slightly less than 10-fold. Seven patients (44%) had a viral load decrease greater than 10-fold. There was no relationship between response to the drug and patient genotype or phenotype.

In the TMC125-C208 trial conducted in the Russian Federation in 2001, a 7-day monotherapy course of TMC125 at a dosage of 900 mg twice daily was given to 12 HIV infected, antiretroviral therapy (ART)-naive patients. The treatment duration was limited to 7 days to prevent the selection of NNRTI-resistant mutants, because a rapid emergence of resistance has been observed for first-generation NNRTIs when given as monotherapy. TMC125-C208's results were compared to the Dutch ERA study that took place between 1997 and 2000, which evaluated the effect of a 5-drug, triple-class ART regimen in ART-naive individuals with either primary or chronic HIV-1 infection. Analysis indicated that 1 week of TMC125 monotherapy resulted in a similar decline in viral load compared with 1 week of therapy with a 5-drug regimen. The apparent ability of TMC125 to substantially reduce HIV viral load in only 7 days of monotherapy suggests that starting treatment with a TMC125-containing regimen could provide better long-term suppression of HIV replication.

In the TMC125-C223 trial, 199 HIV infected patients with NNRTI- and PI-resistant HIV were randomly assigned to receive an investigator-selected background therapy of TMC125 at either 400 mg or 800 mg twice daily or a standard-of-care regimen. At Week 24, viral load was reduced by more than 90% in the 2 TMC125 treatment arms compared with less than 50% in the control arm. These reductions in each treatment arm were statistically significant when compared individually with the control arm. Week 48 analysis indicated mean HIV viral load log10 reductions of -0.88, 1.01, and -0.14 for the 400-mg, 800-mg, and standard-of-care groups, respectively. At Week 48, TMC125 showed high rates of sustained efficacy in these heavily pretreated patients. Analysis of response compared with baseline resistance suggests that TMC125 retains activity in the presence of multiple NNRTI mutations, a situation in which current NNRTIs are not expected to be effective.

Highly treatment-experienced HIV infected patients with drug-resistant HIV may benefit from using TMC125 together with darunavir, a protease inhibitor (PI) approved by the FDA in 2006. Five men started taking twice-daily darunavir 600 mg with ritonavir 100 mg, and twice-daily 20-mg TMC125, with a combination of nucleoside reverse transcriptase inhibitors and/or enfuvirtide. Viral load, CD4 count, and safety parameters were followed from baseline to Week 24; genotypic resistance was assessed at baseline and on the most recent blood sample with detectable viral load. About a month after initiating study treatment, TMC125 coadministered with ritonavir-boosted darunavir were well tolerated. Interim results at Week 4 for the first four study participants indicate that viral load decreased and CD4 count increased, with no PI-associated mutations observed by Week 4.

DUET-1 and DUET-2 are two randomized, double-blind, Phase III trials that evaluated the safety and efficacy of etravirine compared with placebo. Both treatment and control arms were administered in combination with background antiretroviral therapy that contains ritonavir-boosted darunavir, nucleoside reverse transcriptase inhibitors, and optional enfuvirtide. All enrolled patients have documented, treatment-resistant HIV. At Week 24 analysis of 591 patients enrolled in DUET-2, TMC125 was statistically superior to the control arm; 75% of patients receiving TMC125 had a viral load less than 400 copies/ml compared with 54% of patients in the control arm. Of the 612 patients enrolled in DUET-1, Week 24 analysis was similar, with a more than 100-fold reduction in viral load seen in the TMC125 arm compared with a 50-fold reduction in the control arm.

In the ongoing Phase III trials of TMC125 combined with ritonavir-boosted darunavir, 13 NNRTI-associated mutations that decreased viral response to TMC125 were observed during interim analyses. V179F, Y181V, Y106I, and V179O appeared in the patients who were considered the worst responders to treatment. The V179F and Y181C mutations always appeared together; this combination has been observed in approved NNRTIs, such as efavirenz and nevirapine, as well. Virologic response, measured by the 50% effective concentration (EC50), decreased proportionally with the increasing number of mutations. Complete resistance appears rare, but intermediate resistance to TMC125 may be likely. Only 15% of trial participants displayed 3 or more resistance-associated mutations; these participants displayed the largest decrease in virologic response.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[In the TMC125-C206 and TMC125-C216 trials, HCV/HIV and HBV/HIV coinfected patients experienced worsening of hepatitis-related symptoms when treated with etravirine as compared with non-coinfected patients treated with etravirine.

Nausea and rash are the most frequently reported adverse events of etravirine.

In the TMC125-C223 trial, approximately 15% of patients receiving etravirine developed rash, and several of these individuals had to discontinue therapy.

Other less common adverse events of etravirine include abdominal pain, fatigue, peripheral neuropathy, headache and hypertension.

Severe rash, including rare cases of Stevens-Johnson syndrome, have been reported in patients receiving etravirine. Any patient experiencing severe rash or rash accompanied by symptoms such as fever, blistering, oral lesions, conjunctivitis, swelling, and muscle or joint aches should discontinue etravirine and consult a physician.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Dose adjustment of etravirine and/or other drugs may be necessary in patients receiving concomitant therapy with drugs that are extensively metabolized by or induce or inhibit CYP3A, CYP2C9 and CYP2C19. Etravirine may inhibit the metabolism of and is predicted to result in clinically important plasma concentration increases of certain anticoagulants (warfarin); antifungals (fluconazole); and benzodiazepines (diazepam).

Because etravirine is an inducer of CYP3A4, coadministration of CYP3A4 substrates with etravirine may result in altered plasma concentrations of the coadministered substrate drug. Etravirine interacts with numerous boosted and unboosted PIs, which results in altered concentrations of etravirine and of the PI. Increased concentrations of amprenavir and nelfinavir, but decreased concentrations of atazanavir and indinavir, have been observed when these PIs were coadministered with etravirine. Concentrations of etravirine may decrease with concomitant administration of ritonavir alone, boosted tipranavir, and boosted darunavir; etravirine concentrations may increase with concomitant boosted atazanavir or lopinavir/ritonavir. Therefore, etravirine should not be administered with any unboosted PI or with the following boosted PIs: tipranavir, fosamprenavir, or atazanavir. Etravirine may be administered at normal dosages with boosted darunavir and saquinavir and may be administered with caution with lopinavir/ritonavir.

Combining etravirine with another NNRTI has not been shown to be beneficial and use of etravirine with efavirenz or nevirapine may cause a significant decrease in the plasma concentration of etravirine. Combining etravirine with delavirdine may cause a significant increase in the plasma concentration of etravirine. Therefore, etravirine and other NNRTIs should not be coadministered.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[Benzonitrile, 4-((6-amino-5-bromo-2- ((4-cyanophenyl)amino)-4-pyrimidinyl)oxy) -3,5-dimethyl-]]></drug:casname><drug:casnumber><![CDATA[269055-15-4]]></drug:casnumber><drug:molecularformula><![CDATA[C20-H15-Br-N6-O]]></drug:molecularformula><drug:elementalcomposition><![CDATA[C55.18%, H3.48%, Br18.35%, N19.31%, O3.68%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[435.31]]></drug:molecularweight><drug:physicaldescription><![CDATA[Odorless white to off-white powder.]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:othername><![CDATA[TMC125]]></drug:othername></drug:othernames><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[Intelence Prescribing Information from the FDA Web site: http://www.fda.gov/cder/foi/label/2008/022187lbl.pdf. A more current version may be available on the manufacturer's Web site.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17617271 Lazzarin A, Campbell T, Clotet B, Johnson M, Katlama C, Moll A, Towner W, Trottier B, Peeters M, Vingerhoets J, de Smedt G, Baeten B, Beets G, Sinha R, Woodfall B; DUET-2 study group. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. 2007 Jul 7;370(9581):39-48.
]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17617271&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17617270 Madruga JV, Cahn P, Grinsztejn B, Haubrich R, Lalezari J, Mills A, Pialoux G, Wilkin T, Peeters M, Vingerhoets J, de Smedt G, Leopold L, Trefiglio R, Woodfall B; DUET-1 study group. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised,double-blind, placebo-controlled trial.Lancet. 2007 Jul 7;370(9581):29-38.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17617270&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17413684 Nadler JP. Efficacy and Safety of Etravirine (TMC125) in Patients With Highly Resistant HIV-1: Primary 24-Week Analysis. AIDS. 2007;21(6):F1-F10.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17413684&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17713162 Scholler-Gyure M, Kakuda TN, Sekar V, Woodfall B, De Smedt G, Lefebvre E, Peeters M, Hoetelmans RM. Pharmacokinetics of darunavir/ritonavir and TMC125 alone and coadministered in HIV-negative volunteers. Antivir Ther. 2007;12(5):789-96.
]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17713162&dopt=Abstract]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Etravirine (TMC125)]]></drug:drugname><drug:companyname><![CDATA[Tibotec]]></drug:companyname><drug:address1><![CDATA[1029 Stony Hill Road]]></drug:address1><drug:address2><![CDATA[Suite 300]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Yardley]]></city><drug:state><![CDATA[PA]]></drug:state><drug:zipcode><![CDATA[19067]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(609) 730-7500]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[January 25, 2008]]></drug:lastupdated></item><item><title><![CDATA[Nevirapine]]></title><description><![CDATA[Nevirapine, also known as Viramune, is a type of medicine called a non-nucleoside reverse transcriptase inhibitor (NNRTI). NNRTIs block reverse transcriptase, a protein that HIV needs to make more copies of itself.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=116]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Nevirapine]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[ne-VYE-ra-peen]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Viramune]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Nevirapine]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Non-nucleoside Reverse Transcriptase Inhibitors]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Nevirapine is a dipyridodiazepine derivative non-nucleoside reverse transcriptase inhibitor (NNRTI).]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Nevirapine was approved by the FDA on June 21, 1996, for use in combination with other antiretroviral agents for the treatment of HIV-1 infection. Nevirapine is approved for use in adults and in children 2 months and older.

Administration of single-dose nevirapine to the mother intrapartum and to the infant postpartum effectively reduces vertical transmission of HIV-1. This regimen, recommended only for use in HIV infected women in labor who have had no prior therapy for HIV, includes a single nevirapine dose given to the mother at the onset of labor and a single nevirapine dose given to the neonate 48 to 72 hours after birth.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral (capsule, suspension).]]></drug:modeofdelivery><drug:dosageform><![CDATA[Tablets containing nevirapine 200 mg.

Oral suspension containing nevirapine 50 mg (as nevirapine hemihydrate) per 5 ml.

The recommended adult dose of nevirapine is one 200 mg tablet a day for the first 14 days, followed by one 200 mg tablet twice a day. As of June 2008, the recommended dose of nevirapine 50 mg/5 ml oral suspension for pediatric patients is based on body surface area (BSA) rather than on weight. Pediatric patients who are 15 days or older should receive 150 mg/m2 once daily for 14 days (lead-in period) and twice daily thereafter, with a maximum of 400 mg/day. The decision to calculate pediatric dosing by BSA instead of weight was based on pharmacokinetic data from more than 600 participants in a 48-week pediatric trial and in an analysis of five Pediatric AIDS Clinical Trial Group protocols. BSA-calculated doses for these studies provided nevirapine trough concentrations that were effective and comparable to those achieved with weight-based doses.]]></drug:dosageform><drug:storage><![CDATA[Store tablets and oral suspension at 25 C (77F), with excursions permitted between 15 C and 30 C (59 F to 86 F).]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Nevirapine exerts a virustatic effect by acting as a specific, noncompetitive HIV-1 reverse transcriptase (RT) inhibitor. The drug binds directly to heterodimeric HIV-1 RT and appears to inhibit RT activity by disrupting the catalytic site of the enzyme. Nevirapine has a very limited spectrum of antiviral activity. The drug has in vitro virustatic activity against HIV-1, but is inactive against HIV-2 and animal retroviruses.

Nevirapine is more than 90% absorbed after oral administration in healthy adults and adults with HIV-1 infection. Absolute bioavailability in a trial of 12 healthy adults following single-dose administration was 93% for a 50 mg oral tablet and 91% for 5 ml (nevirapine hemihydrate 50 mg) of oral suspension. When nevirapine was administered to 24 healthy adults with either a high-fat breakfast or an antacid, the extent of absorption was comparable to that seen under fasting conditions.

Although distribution of nevirapine into body tissues and fluids has not been fully characterized, animal studies indicate that nevirapine is widely distributed into most tissues after administration. Nevirapine is highly lipophilic and is essentially nonionized at physiologic pH. Time to peak concentration is 4 hours after a single 200 mg dose. Following IV administration of nevirapine in healthy adults, the apparent volume of distribution is 1.21 l/kg, suggesting that the drug is widely distributed in humans. Nevirapine concentrations in cerebrospinal fluid were 45% of the concentrations in plasma at a ratio approximately equal to the fraction not bound to plasma protein.

Nevirapine is in FDA Pregnancy Category C. There are no adequate and well-controlled studies of nevirapine in pregnant women. Nevirapine readily crosses the placenta and achieves neonatal blood concentrations comparable to those in the mother (cord-to-maternal blood ratio approximately 0.9). Evidence of impaired fertility was seen in female rats at doses providing systemic exposure approximately equivalent to that attained with the recommended clinical dose of nevirapine. Teratogenic effects of nevirapine have not been observed in reproductive studies with rats and rabbits. However, in rats, a significant decrease in fetal weight occurred at doses producing systemic concentrations approximately 50% higher than human therapeutic exposure. Nevirapine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. To monitor maternal-fetal outcomes of pregnant women exposed to nevirapine and other antiretrovirals, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 800-258-4263 or online at http://www.APRegistry.com.

Nevirapine is readily distributed into breast milk. Following administration of a single 100- to 200-mg dose of nevirapine to pregnant women several hours prior to delivery, postpartum concentrations of nevirapine in milk have been reported to be 25% to 122% of maternal serum concentrations. HIV infected mothers should not breastfeed their infants in order to avoid risk of HIV transmission and the potential for serious nevirapine-related adverse reactions in the nursing infant.

Nevirapine is about 60% bound to plasma proteins in the plasma concentration range of 1 to 10 mcg/ml.

Nevirapine is extensively biotransformed via cytochrome P450 (CYP) metabolism to several hydroxylated metabolites. Biotransformation is primarily by isozymes from the CYP3A family, but other isozymes may be involved with nevirapine metabolism. In a pharmacokinetic study, approximately 81% of a radiolabeled dose was recovered in the urine, with greater than 80% of that made up of glucuronide conjugates of hydroxylated metabolites. Approximately 10% of a radiolabeled dose was recovered in the feces. Less than 5% of the recovered radiolabeled dose was made up of the parent compound; therefore, renal excretion plays a minor role in elimination of the parent compound. In children, nevirapine elimination accelerates during the first years of life, reaching a maximum at around 2 years of age, followed by a gradual decline during the rest of childhood.

The mechanism of resistance or reduced susceptibility to nevirapine has not been fully determined, but mutation of HIV RT appears to be involved. A single mutation may be sufficient to result in high-level resistance to nevirapine. Drug-resistant HIV emerges rapidly and uniformly when nevirapine is administered as monotherapy. Mutations conferring resistance to nevirapine could be observed after a single dose, even with a low level of viral replication. Therefore, nevirapine should always be administered in combination with at least one other antiretroviral agent. Resistance to nevirapine usually confers class resistance to other NNRTIs (efavirenz and delavirdine). However, nevirapine-resistant isolates were susceptible to the nucleoside analogues zidovudine and didanosine. Similarly, zidovudine-resistant isolates were susceptible to nevirapine in vitro.

Nevirapine demonstrated additive to synergistic in vitro activity against HIV-1 in combination regimens with zidovudine, didanosine, stavudine, lamivudine, saquinavir, and indinavir. Because nevirapine and HIV protease inhibitors (PIs), such as amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, have different enzyme targets, cross resistance between nevirapine and these drugs is unlikely.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Granulocytopenia (occurring more frequently in children), skin rash, fever, hepatitis prodromal symptoms, hepatotoxicity, Stevens-Johnson syndrome, toxic epidermal necrolysis, gastrointestinal effects, fatigue, and headache are the most common adverse effects seen with nevirapine use.

Clinically symptomatic hepatotoxicity has been observed with initiation of and during continued use of nevirapine. Among the NNRTIs, nevirapine has the greatest potential for causing clinical hepatitis. Severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis, and hepatic failure, has been reported in patients treated with nevirapine. In some cases, patients presented with nonspecific prodromal signs or symptoms of hepatitis and progressed to hepatic failure. The greatest risk of severe and potentially fatal hepatic events, often associated with rash, occurs in the first 6 weeks of nevirapine treatment. Approximately two-thirds of the cases of nevirapine-associated clinical hepatitis occur within the first 12 weeks of use. However, the risk continues after this time and patients should be monitored closely for the first 18 weeks of treatment. Clinical hepatitis and hepatic failure may be isolated or associated with signs of hypersensitivity, which may include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction. Patients who have signs or symptoms of hepatitis or those who have moderate (Child Pugh class 3 or 4) hepatic impairment must seek medical evaluation immediately and should be advised to discontinue nevirapine, because hepatic impairment can increase nevirapine levels. In some cases, hepatic injury progresses despite discontinuation of treatment. 

Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled studies, nevirapine should not be initiated in adult females with CD4 counts greater than 250 cells/mm3 or in adult males with CD4 counts greater than 400 cells/mm3 unless the benefit outweighs the risk.

Severe, life-threatening skin reactions, including fatal cases, have occurred in patients treated with nevirapine. These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction. Severe or life-threatening rash occurred in approximately 2% of clinically treated patients. Fever, in the absence of any apparent cause, is a significant predictor for the development of rash in patients receiving nevirapine. Patients who develop signs or symptoms of severe skin reactions or hypersensitivity reactions must discontinue nevirapine as soon as possible and must limit the nevirapine-only treatment time to 28 days.

It is essential that patients be monitored intensively during the first 18 weeks of nevirapine therapy to detect potentially life-threatening hepatotoxicity or skin reactions. Because of the potential severity of clinical hepatitis, some clinicians advise close monitoring of liver enzymes and clinical symptoms after nevirapine initiation such as every 2 weeks for the first month, then monthly for the first 12 weeks, and every 1 to 3 months thereafter. Nevirapine should not be restarted following severe hepatic, skin, or hypersensitivity reactions. In some cases, hepatic injury has progressed despite discontinuation of treatment. In addition, the 14-day lead-in period with nevirapine 200 mg daily dosing must be strictly followed. Lead-in has been found to lessen the frequency of rash.

Because most occupational HIV exposures do not result in transmission of HIV, health care providers considering prescribing postexposure prophylaxis for exposed persons must balance the risk for HIV transmission represented by the exposure and the exposure source against the potential toxicity of the specific agents used for postexposure prophylaxis. In many circumstances, the risks associated with nevirapine as part of a postexposure prophylaxis regimen outweigh the anticipated benefits. However, no serious toxicity has been reported in women or infants receiving two-dose nevirapine (the HIVNET 012 clinical trial regimen) for prevention of perinatal transmission of HIV.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Nevirapine is metabolized by and induces the activity of CYP3A isoenzymes, with maximal induction occurring within 2 to 4 weeks of initiating multidose therapy. The induction of CYP3A by nevirapine may result in lower plasma concentrations of concurrently administered drugs that are extensively metabolized by CYP3A.

Caution is required when nevirapine is administered concurrently with a PI, as the plasma concentrations of PIs may be reduced to subtherapeutic concentrations due to nevirapine-induced hepatic metabolism. Nevirapine decreases the area under the plasma concentration-time curve (AUC) and peak plasma concentrations (Cmax) of indinavir, saquinavir, and ritonavir; nevirapine and nelfinavir do not appear to interact significantly. In contrast, PIs do not appear to affect the pharmacokinetics of nevirapine. No dosage adjustments are required when nevirapine is concurrently administered with ritonavir or nelfinavir.

Concomitant use of nevirapine and hormonal contraceptives containing ethinyl estradiol may result in decreased plasma concentrations of the contraceptive. Therefore, hormonal contraceptives should not be used as the primary means of contraception when nevirapine is prescribed to women of childbearing potential.

Concurrent use of ketoconazole with nevirapine is not recommended, as it results in significantly reduced plasma concentrations of ketoconazole and a modest increase in plasma concentrations of nevirapine; concurrent use is not recommended. Nevirapine may decrease plasma concentrations of methadone by increasing its hepatic metabolism. Narcotic withdrawal syndrome has been reported in patients treated with nevirapine and methadone concurrently. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. Concurrent use of prednisone with nevirapine has resulted in increased incidence and severity of rash in the first 6 weeks of nevirapine therapy; concurrent use is not recommended.

Rifampin and rifabutin accelerate the metabolism of NNRTIs through induction of CYP isoenzymes, resulting in subtherapeutic levels of nevirapine. Nevirapine retards the metabolism of rifampin and rifabutin, resulting in increased serum levels of these drugs. Dosage adjustment may be necessary when these drugs are administered with nevirapine.

Concurrent use of St. John's wort (Hypericum perforatum) or St. John's wort-containing products with nevirapine is expected to substantially decrease nevirapine concentrations and may result in suboptimal levels of nevirapine, loss of virologic response, and development of nevirapine resistance; concurrent use is not recommended.

Based on data from an open-label randomized study and retrospective database analyses, clinicians are advised to use caution when administering tenofovir disoproxil fumarate, enteric-coated didanosine, and either efavirenz or nevirapine in the treatment of treatment-naive HIV infected patients with high baseline viral loads.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Nevirapine is contraindicated in patients with clinically significant hypersensitivity to any of the components contained in the tablet or the oral suspension.

Except under special circumstances, nevirapine should not be used in patients with severe hepatic function impairment. Nevirapine is hepatotoxic and extensively metabolized by the liver. It is associated with a significant incidence of hepatotoxicity, usually occurring in the initial month of therapy. Risk-benefit should be considered in patients with hepatitis B or C infection, because of extensive liver metabolism, or with renal function impairment, as nevirapine metabolites are extensively eliminated by the kidneys.]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[6H-Dipyrido(3,2-b:2',3'-e)(1,4)diazepin-6-one, 11-cyclopropyl-5,11-dihydro-4-methyl-]]></drug:casname><drug:casnumber><![CDATA[129618-40-2]]></drug:casnumber><drug:molecularformula><![CDATA[C15-H14-N4-O]]></drug:molecularformula><drug:elementalcomposition><![CDATA[C67.65%, H5.30%, N21.04%, O6.01%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[247 to 249 C]]></drug:meltingpoint><drug:molecularweight><![CDATA[266.30]]></drug:molecularweight><drug:physicaldescription><![CDATA[White to off-white crystalline powder.]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[Solubility in water 0.1 mg/ml at neutral pH; highly soluble at pH less than 3.]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:othername><![CDATA[NVP]]></drug:othername></drug:othernames><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[Viramune Prescribing Information from the FDA Web site <a href="http://www.fda.gov/cder/foi/label/2005/20636s025,20933s014lbl.pdf">[PDF]</a>. A more current version may be available on the manufacturer's Web site.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16425125 Eshleman SH, Hoover DR, Hudelson SE, Chen S, Fiscus SA, Piwowar-Manning E, Jackson JB, Kumwenda NI, Taha TE. Development of nevirapine resistance in infants is reduced by use of infant-only single-dose nevirapine plus zidovudine postexposure prophylaxis for the prevention of mother-to-child transmission of HIV-1.
J Infect Dis. 2006 Feb 15;193(4):479-81. Epub 2006 Jan 11.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16425125&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17163296 Giaquinto C, Rampon O, De Rossi A. Antiretroviral therapy for prevention of mother-to-child HIV transmission: focus on single-dose nevirapine. Clin Drug Investig. 2006;26(11):611-27.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17163296&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16052084 Gray GE, Urban M, Chersich MF, Bolton C, van Niekerk R, Violari A, Stevens W, McIntyre JA; for the PEP Study Group. A randomized trial of two postexposure prophylaxis regimens to reduce mother-to-child HIV-1 transmission in infants of untreated mothers. AIDS. 2005 Aug 12;19(12):1289-97.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16052084&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/14562858 Harris M. Efficacy and durability of nevirapine in antiretroviral-experienced patients. J Acquir Immune Defic Syndr. 2003 Sep; 34 Suppl 1: S53-8. Review.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=14562858&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/12853746 Verweel G, Sharland M, Lyall H, Novelli V, Gibb DM, Dumont G, Ball C, Wilkins E, Walters S, Tudor-Williams G. Nevirapine use in HIV-1-infected children. AIDS. 2003 Jul 25; 17(11): 1639-47.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=12853746&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/14562852 Wainberg MA. HIV resistance to nevirapine and other non-nucleoside reverse transcriptase inhibitors. J Acquir Immune Defic Syndr. 2003 Sep; 34 Suppl 1: S2-7. Review.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=14562852&dopt=Abstract]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Nevirapine]]></drug:drugname><drug:companyname><![CDATA[Boehringer Ingelheim Pharmaceuticals Inc]]></drug:companyname><drug:address1><![CDATA[900 Ridgebury Rd / PO Box 368]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Ridgefield]]></city><drug:state><![CDATA[CT]]></drug:state><drug:zipcode><![CDATA[06877-0368]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 542-6257]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Viramune]]></drug:drugname><drug:companyname><![CDATA[Boehringer Ingelheim Pharmaceuticals Inc]]></drug:companyname><drug:address1><![CDATA[900 Ridgebury Rd / PO Box 368]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Ridgefield]]></city><drug:state><![CDATA[CT]]></drug:state><drug:zipcode><![CDATA[06877-0368]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 542-6257]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[June 30, 2008]]></drug:lastupdated></item><item><title><![CDATA[Abacavir]]></title><description><![CDATA[Abacavir sulfate, also known as Ziagen or ABC, is a type of medicine called a nucleoside reverse transcriptase inhibitor (NRTI). NRTIs block reverse transcriptase, a protein that HIV needs to make more copies of itself.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=257]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Abacavir]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[a-BAK-a-veer]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Ziagen]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Abacavir]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Nucleoside Reverse Transcriptase Inhibitors]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Abacavir is a synthetic analogue of guanine, a naturally occurring purine nucleoside. It differs structurally from other reverse transcriptase inhibitors (didanosine, lamivudine, stavudine, zalcitabine, and zidovudine) in that it is a carbocyclic nucleoside analogue rather than a dideoxynucleoside analogue.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Abacavir sulfate was approved by the FDA on December 17, 1998, for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and children. A patient's medical history should be reviewed for prior exposure to any abacavir-containing product before abacavir sulfate is administered in order to avoid reintroduction in a patient with a history of hypersensitivity to abacavir.

Abacavir is used in conjunction with other antiretroviral agents for postexposure prophylaxis of HIV infection in health care workers and other individuals exposed occupationally via percutaneous injury or mucous membrane or nonintact skin contact with blood, tissues, or other body fluids associated with a risk for HIV transmission.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Film-coated tablets containing abacavir 300 mg.

Oral solution containing abacavir 20 mg/ml.

The recommended dose of abacavir for adults is 600 mg (300 mg twice daily or 600 mg once daily) in combination with other antiretroviral agents. The recommended dosage of abacavir for adolescents and pediatric patients age 3 months to 16 years is 8 mg/kg twice daily (up to a maximum of 300 mg twice daily) in combination with other antiretroviral agents. The recommended dosage of abacavir in patients with mild hepatic impairment (Child-Pugh score 5-6) is 200 mg twice daily. To enable dose reduction, abacavir oral solution (10 ml twice daily) should be used for the treatment of these patients.]]></drug:dosageform><drug:storage><![CDATA[Store tablets and oral solution at controlled room temperature of 20 C to 25 C (68 F to 77 F).

Oral solution may be refrigerated but should not be frozen.]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Abacavir is a carbocyclic nucleoside analogue. It is converted by cellular enzymes to the active metabolite, carbovir triphosphate. An analogue of deoxyguanosine-5'-triphosphate (dGTP), carbovir triphosphate inhibits HIV-1 reverse transcriptase (RT) by competing with the natural substrate dGTP for incorporation into viral DNA. Once incorporated, carbovir triphosphate causes premature termination of viral DNA synthesis, because the incorporated nucleoside analogue lacks a 3'-OH group, thus preventing formation of the 5' to 3' phosphodiester linkage essential for DNA chain elongation. Abacavir is a weak inhibitor of cellular DNA polymerases alpha, beta, and gamma. Abacavir is active in vitro against HIV-1 and -2.

Abacavir sulfate is well absorbed following oral administration. Absorption is rapid and extensive. Abacavir sulfate has an absolute bioavailability of approximately 83%, which is not affected by food. After oral administration of 300 mg twice daily, the mean steady-state peak serum abacavir concentration (Cmax) was 3.0 +/- 0.89 mcg/ml, and the area under the concentration-time curve (AUC) was 6.02 +/- 1.73 mcg(hour)/ml. After oral administration of a single 600 mg dose, the Cmax was 4.26 +/- 1.19 mcg/ml, and the AUC was 11.95 +/- 2.5 mcg(hour)/ml. Systemic absorption is comparable following administration of tablets and oral solution.

Following IV administration of abacavir sulfate, the apparent volume of distribution is 0.86 +/- 0.15 L/kg, suggesting distribution into extravascular spaces. Abacavir is distributed into cerebrospinal fluid (CSF). The steady-state CSF-to-plasma AUC ranges from 27% to 33%. Abacavir also readily distributes into erythrocytes. Plasma protein binding is approximately 50% and is independent of drug concentration.

Abacavir is metabolized in the liver by alcohol dehydrogenase and glucuronyl transferase to form the metabolites 5'-carboxylic acid and 5'-glucuronide, neither of which has antiviral activity. Involvement of cytochrome P450 isoenzymes in metabolizing abacavir is limited. Following oral administration of a 600 mg dose of radiolabeled abacavir, 82.2% of the dose is excreted in urine and 16% is excreted as feces, with unchanged abacavir accounting for 1.2% of recovered radioactivity in urine. The elimination half-life following a single dose is approximately 1.5 hours. It is unknown whether abacavir is removable by hemodialysis or peritoneal dialysis.

Abacavir sulfate is in FDA Pregnancy Category C. No adequate or well-controlled studies of abacavir have been done in pregnant women. Studies in laboratory animals have shown that abacavir crosses the placenta, with evidence of fetal toxicity at dosage levels many times higher than the corresponding dosage for humans. Abacavir should be used in pregnancy only if the potential benefits outweigh the risks. An Antiretroviral Pregnancy Registry has been established to monitor the outcomes of pregnant women exposed to abacavir and other antiretroviral agents. Physicians may register patients by calling 1-800-258-4263 or online at http://www.APRegistry.com. It is not known whether abacavir is excreted in human milk; it is excreted in the milk of laboratory animals. Because of the potential for HIV transmission and for serious adverse effects from abacavir to the breastfed infant, women should be instructed not to breastfeed while taking abacavir.

HIV-1 isolates with reduced sensitivity to abacavir have been selected in vitro and also have been obtained from patients treated with abacavir. Genetic analysis of isolates from abacavir-treated patients showed point mutations in the RT gene resulting in amino acid substitutions of K65R, L74V, Y115F, and M184V. The mutation M184V/I was the commonly observed mutation in virologic failure isolates from patients receiving abacavir. In vitro, abacavir has synergistic activity in combination with amprenavir, nevirapine, and zidovudine and additive activity in combination with didanosine, lamivudine, stavudine, and zalcitabine.

Recombinant laboratory strains of HIV-1 containing multiple RT abacavir resistance mutations exhibited cross resistance to didanosine, emtricitabine, lamivudine, tenofovir disoproxil fumarate, and zalcitabine in vitro. An increasing number of thymidine analogue mutations (TAMs) is associated with a progressive reduction in abacavir susceptibility. There is evidence that HIV isolates that are highly resistant to multiple dideoxynucleoside reverse transcriptase inhibitors have reduced susceptibility to abacavir.

Cross resistance between abacavir and protease inhibitors (PIs) is unlikely because the drugs target different enzymes; cross resistance between abacavir and non-nucleoside reverse transcriptase inhibitors (NNRTIs) is also unlikely because of different binding sites and mechanisms of action.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Fatal hypersensitivity reactions have been associated with abacavir therapy. Patients developing signs or symptoms of hypersensitivity (including fever; skin rash; fatigue; gastrointestinal symptoms, such as nausea, vomiting, diarrhea, or abdominal pain; and respiratory symptoms such as pharyngitis, dyspnea, or cough) should discontinue abacavir as soon as a hypersensitivity reaction is suspected. To avoid a delay in diagnosis and minimize the risk of a life-threatening hypersensitivity reaction, abacavir should be permanently discontinued if hypersensitivity cannot be ruled out, even when other diagnoses are possible (e.g., acute onset respiratory diseases, gastroenteritis, or reactions to other medications). Abacavir should not be restarted following a hypersensitivity reaction, because more severe symptoms will recur within hours and may include life-threatening hypotension and death. Severe or fatal hypersensitivity reactions can occur within hours after reintroduction of abacavir in patients who have no identified history of unrecognized symptoms of hypersensitivity to abacavir therapy. To facilitate reporting of hypersensitivity reactions and collection of information on each case, an Abacavir Hypersensitivity Registry has been established. Physicians should register patients by calling 1-800-270-0425.

In clinical studies, hypersensitivity reactions have been reported in approximately 8% of adult and pediatric patients receiving abacavir in conjunction with lamivudine and zidovudine. Hypersensitivity-related fatalities have also been reported with abacavir use. Hypersensitivity reactions are characterized by symptoms indicating involvement of multiple organ and body systems and usually appear within the first 6 weeks of abacavir therapy, although they may appear at any time. Signs and symptoms of hypersensitivity include skin rash or a combination of two or more of the following: fever; fatigue; gastrointestinal symptoms such as nausea, vomiting, diarrhea, or abdominal pain; and respiratory symptoms such as pharyngitis, dyspnea, and cough. Other signs and symptoms include malaise, lethargy, myalgia, myolysis, headache, arthralgia, edema, paresthesia, lymphadenopathy, and mucous membrane lesions such as conjunctivitis and mouth ulcerations. Laboratory abnormalities indicating hypersensitivity reaction include lymphopenia and increases in serum concentrations of liver enzymes, creatine kinase, or creatinine. Anaphylaxis, liver failure, renal failure, hypotension, and death have occurred in association with hypersensitivity reactions.

Lactic acidosis and severe hepatomegaly with steatosis have been reported with the use of nucleoside analogues alone or in combination, including abacavir and other antiretroviral agents. These conditions are sometimes fatal. The majority of cases have occurred in women. Obesity and prolonged nucleoside exposure may be risk factors. Caution should be exercised in any patient with known risk factors for liver disease; however, cases have been reported in patients with no known risk factors. Treatment with abacavir sulfate should be suspended in any patient who develops clinical or laboratory findings that suggest lactic acidosis or pronounced hepatotoxicity.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including abacavir. During the initial phase of combination antiretroviral treatment, a patient whose immune system improves may develop an inflammatory response to indolent or residual opportunistic infections, such as Mycobacterium avium infection, cytomegalovirus infections, Pneumocystis jirovecii pneumonia, or tuberculosis. Symptoms of immune reconstitution syndrome necessitate further evaluation and treatment.

Redistribution of body fat, peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance have been observed in patients receiving antiretroviral therapy.

In a clinical trial performed in treatment-naive adults given abacavir, lamivudine, and zidovudine twice daily, the most common adverse effects observed were nausea, headache, malaise and fatigue, and vomiting. In this clinical study, laboratory abnormalities (e.g., creatine phosphokinase elevations, liver function test [specifically, ALT] abnormalities, neutropenia) were observed with similar frequencies as in treatment-naive adults who received indinavir three times daily  and lamivudine and zidovudine twice daily.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Abacavir may be taken with or without food.

Concurrent use of abacavir and ethanol or other alcohol-containing products may result in increased concentrations and an increased half-life of abacavir as a result of competition for common metabolic pathways via alcohol dehydrogenase.

Concomitant use of abacavir and methadone resulted in a methadone clearance increase by 22% in patients stabilized on oral methadone maintenance therapy who started abacavir therapy with abacavir 600 mg twice daily. Increases in clearance may not be clinically significant in a majority of patients, but methadone dosage increases may be required in some patients.

In human liver microsomes, abacavir did not significantly inhibit cytochrome P450 isoforms 2C9, 2D6, or 3A4; therefore, clinically important interactions between abacavir and drugs metabolized through these pathways are not expected.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Abacavir is contraindicated in patients with previously demonstrated hypersensitivity to abacavir sulfate or to any of the components of the products. A Medication Guide and Warning Card summarizing the symptoms of abacavir hypersensitivity reactions should be dispensed by the pharmacist with each new prescription and refill of abacavir (or abacavir-containing products, such as Epzicom and Trizivir). Patients being treated with abacavir sulfate should carry the warning card with them.

Serious and sometimes fatal hypersensitivity reactions have been associated with abacavir sulfate. Hypersensitivity to abacavir is a multiorgan clinical syndrome usually characterized by a sign or symptom in two or more of the following groups: fever, rash, gastrointestinal problems (including nausea, vomiting, diarrhea, or abdominal pain), constitutional problems (including generalized malaise, fatigue, or achiness), and respiratory problems (including dyspnea, cough, or pharyngitis). Abacavir should not be restarted following a hypersensitivity reaction to abacavir, because more severe symptoms can occur within hours and may include life-threatening hypotension and death. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including abacavir sulfate and other antiretroviral agents.]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[(1S,4R)-4-[2-Amino-6- (cyclopropylamino)-9H-purin-9-yl]-2- cyclopentene-1-methanol sulfate (salt) (1:1)]]></drug:casname><drug:casnumber><![CDATA[188062-50-2 (abacavir sulfate)]]></drug:casnumber><drug:molecularformula><![CDATA[(C14-H18-N6-O)2-H2SO4]]></drug:molecularformula><drug:elementalcomposition><![CDATA[C50.1%, H5.7%, N25.1%, O14.3%, S4.8%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[165 C]]></drug:meltingpoint><drug:molecularweight><![CDATA[670.76 (abacavir sulfate)]]></drug:molecularweight><drug:physicaldescription><![CDATA[Tablets: white to off-white solid.

Oral solution: clear to opalescent, yellowish, strawberry-banana flavored liquid.]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[77 mg/ml in distilled water at 25 C.]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:othername><![CDATA[ABC]]></drug:othername><drug:othername><![CDATA[Abacavir sulfate]]></drug:othername></drug:othernames><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[Ziagen Tablets and Oral Solution Prescribing Information from the FDA Web site <A href="http://www.fda.gov/cder/foi/label/2007/020977s016,020978s019lbl.pdf">[PDF]</a>. A more current version may be available on the manufacturer's Web site.
]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16944966 Castillo SA, Hernandez JE, Brothers CH. Long-term safety and tolerability of the lamivudine/abacavir combination as components of highly active antiretroviral therapy. Drug Saf. 2006;29(9):811-26]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16944966&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16741878 Cozzi-Lepri A, De Luca A, Phillips AN, Bongiovanni M, Di Giambenedetto S, Mena M, Moioli MC, Arlotti M, Sighinolfi L, Narciso P, Lichtner M, Cauda R, Monforte A; ICoNA Study Group; UCSC-Roma HIV Cohort Study Group; IMIT Study Group. A comparison between abacavir and efavirenz as the third drug used in combination with a background therapy regimen of 2 nucleoside reverse-transcriptase inhibitors in patients with initially suppressed viral loads. J Infect Dis. 2006 Jul 1;194(1):20-8. Epub 2006 May 16.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16741878&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/15956231 Goedken AM, Herman RA. Once-daily abacavir in place of twice-daily administration. Ann Pharmacother. 2005 Jul-Aug;39(7-8):1302-8. Epub 2005 Jun 14. Review.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15956231&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16354121 Martin A, Nolan D, Almeida CA, Rauch A, Mallal S. Predicting and diagnosing abacavir and nevirapine drug hypersensitivity: from bedside to bench and back again. Pharmacogenomics. 2006 Jan;7(1):15-23. Review.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16354121&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/15712395 Moyle GJ. The impact of abacavir on lipids and lipodystrophy. AIDS Read. 2005 Feb;15(2):62-6. Review.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15712395&dopt=Abstract]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Abacavir]]></drug:drugname><drug:companyname><![CDATA[GlaxoSmithKline]]></drug:companyname><drug:address1><![CDATA[5 Moore Drive]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Research Triangle Park]]></city><drug:state><![CDATA[NC]]></drug:state><drug:zipcode><![CDATA[27709]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(888) 825-5249]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Ziagen]]></drug:drugname><drug:companyname><![CDATA[GlaxoSmithKline]]></drug:companyname><drug:address1><![CDATA[5 Moore Drive]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Research Triangle Park]]></city><drug:state><![CDATA[NC]]></drug:state><drug:zipcode><![CDATA[27709]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(888) 825-5249]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[June 21, 2007]]></drug:lastupdated></item><item><title><![CDATA[Abacavir/Lamivudine]]></title><description><![CDATA[Epzicom is a combination of two antiretroviral drugs: abacavir sulfate (Ziagen) and lamivudine (Epivir). Both of these medicines are nucleoside reverse transcriptase inhibitors (NRTIs). NRTIs block reverse transcriptase, a protein that HIV needs to make more copies of itself.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=407]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Abacavir/Lamivudine]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[a-BAK-a-veer, la-MI-vyoo-deen]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Epzicom]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Abacavir/Lamivudine]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Nucleoside Reverse Transcriptase Inhibitors]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Abacavir sulfate/lamivudine (Epzicom) is a fixed-dose tablet containing two nucleoside reverse transcriptase inhibitors (NRTIs): abacavir sulfate and lamivudine. Each tablet contains abacavir sulfate 600 mg and lamivudine 300 mg.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Epzicom was approved by the FDA on August 2, 2004, for combined use with other antiretroviral agents in the treatment of HIV-1 infection. When used as part of a three-drug HIV treatment regimen, Epzicom should be used with antiretroviral agents from different pharmacologic classes rather than with other NRTIs.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Film-coated tablet containing abacavir sulfate 600 mg and lamivudine 300 mg. 

Because it is a fixed-dose tablet, Epzicom should not be prescribed for patients requiring dosage adjustment.]]></drug:dosageform><drug:storage><![CDATA[Store at 25 C (77 F); excursions permitted at 15 C to 30 C (59 F to 86 F).]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Both of the nucleoside analogues contained in Epzicom inhibit HIV reverse transcriptase (RT), an enzyme essential for HIV replication. Abacavir, a carbocyclic synthetic nucleoside analogue, is phosphorylated intracellularly to the active metabolite carbovir triphosphate, an analogue of deoxyguanosine-5'-triphophate (dGTP). Carbovir triphosphate inhibits the activity of HIV-1 RT by competing with dGTP for incorporation into viral DNA, resulting in termination of the DNA chain. Lamivudine, also a synthetic nucleoside analogue, is phosphorylated intracellularly to the active metabolite lamivudine triphosphate (L-TP), which inhibits HIV DNA synthesis in a manner analogous to abacavir.

Following oral administration, abacavir is rapidly absorbed and extensively distributed. After administration of a single oral dose of abacavir 600 mg, the peak plasma concentration (Cmax) is 4.26 mcg/ml, and the area under the plasma concentration-time curve (AUC) is 11.95 mcg (hr)/ml. Binding to plasma proteins is approximately 50% and is independent of concentration. Abacavir distributes readily into erythrocytes. The primary routes of abacavir elimination are metabolism by alcohol dehydrogenase to form the 5'-carboxylic acid and by glucuronyl transferase to form 5'-glucuronide.

Following oral administration, lamivudine is also rapidly absorbed and extensively distributed. After multiple-dose oral administration of lamivudine 300 mg once daily for 7 days in healthy subjects, steady-state Cmax was 2.04 mcg/ml and the 24-hour, steady-state AUC was 8.87 mcg (hr)/ml. Binding to plasma protein is low. Approximately 70% of an IV dose of lamivudine is recovered unchanged in urine; metabolism is a minor route of elimination.

Results of a bioavailability study comparing administration of one Epzicom tablet to simultaneous administration of two 300 mg abacavir tablets and two 150 mg lamivudine tablets in healthy subjects showed no difference in absorption, as measured by AUC and Cmax.

Epzicom is in FDA Pregnancy Category C. No adequate or well-controlled studies have been done in pregnant women. Studies in rats have shown that abacavir crosses the placenta. Fetal malformations and developmental toxicity occur in rats given a dose of abacavir equivalent to 35 times the recommended human exposure. In rabbits, no developmental toxicity or increased fetal malformations occurred at doses equivalent to 8.5 times the recommended human exposure. Studies of lamivudine in rats have shown that the drug crosses the placenta. No lamivudine-associated teratogenicity was observed in rats or in rabbits given doses equivalent to 35 times the recommended human exposure. Evidence of early embryolethality was seen in rabbits at exposure levels similar to the recommended human exposure; however, no embryolethality was observed in rats at exposure levels up to 35 times the recommended human dose. An Antiretroviral Pregnancy Registry has been established to monitor the outcomes of pregnant women exposed to antiretroviral agents, including Epzicom. Physicians may register patients by calling 1-800-258-4263 or online at http://www.APRegistry.com.

Abacavir is secreted into the milk of lactating rats, and lamivudine is excreted into milk in rats and humans. Because of the potential for HIV transmission and for serious adverse drug effects in breastfed infants, women who are receiving Epzicom should be instructed not to breastfeed.

HIV-1 isolates with reduced susceptibility to the combination of abacavir and lamivudine have been selected in vitro and have also been obtained from patients failing abacavir/lamivudine-containing regimens. Genotypic characterization of abacavir/lamivudine-resistant viruses selected in vitro identified the following amino acid substitutions in HIV-1 RT: M184V/I, K65R, L74V, and Y115F. In a study of treatment-naive adults receiving abacavir 600 mg once daily or 300 mg twice daily with a background regimen of both lamivudine 300 mg and efavirenz 600 mg once daily, the abacavir- and lamivudine-associated resistance mutation M184V/I was the most commonly observed.

Cross resistance has been observed among NRTIs. Viruses containing abacavir and lamivudine resistance-associated mutations, namely K65R, L74V, M184V, and Y115F, exhibit cross resistance to didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zalcitabine both in vitro and in patients. The K65R mutation can confer resistance to abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zalcitabine; the L74V mutation can confer resistance to abacavir, didanosine, and zalcitabine; and the M184V mutation can confer resistance to abacavir, didanosine, emtricitabine, lamivudine, and zalcitabine. Viruses with the K65R mutation (with or without the M184V/I mutation), the L74V plus M184V/I mutation, and the M184V/I mutation plus thymidine analogue mutations (TAMs) M41L, D67N, K70R, L210W, T215Y/F, and K219E/R/H/Q/N have demonstrated decreased susceptibility to Epzicom. An increasing number of TAMs are associated with a progressive reduction in abacavir susceptibility.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Epzicom contains abacavir sulfate, which has been associated with serious and sometimes fatal hypersensitivity reactions. In clinical studies, hypersensitivity to abacavir was reported in approximated 8% of patients. Symptoms usually appear within the first 6 weeks of treatment but may occur at any time during therapy. Hypersensitivity to abacavir is a multiorgan syndrome usually characterized by at least two of the following manifestations: fever; rash; malaise, fatigue, or achiness; gastrointestinal symptoms of nausea, vomiting, diarrhea, or abdominal pain; and respiratory symptoms of dyspnea, cough, or pharyngitis. Less common signs and symptoms of hypersensitivity include lethargy, myolysis, edema, abnormal chest x-ray, and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, and death have occurred in association with hypersensitivity reactions. In one study, once-daily dosing of abacavir was associated with more severe hypersensitivity reactions. Physical findings associated with abacavir hypersensitivity include lymphadenopathy, mucous membrane lesions, and a rash that is usually maculopapular or urticarial. There have also been reports of erythema multiforme with abacavir use. Suspected Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving abacavir in combination with other medications associated with SJS and TEN. Because the clinical signs and symptoms of abacavir hypersensitivity overlap with those of SJS and TEN, and because some patients may have multiple drug sensitivities, patients with suspected SJS or TEN should discontinue Epzicom treatment. Laboratory abnormalities associated with abacavir hypersensitivity include elevated liver function tests, elevated creatine phosphokinase, elevated creatinine, and lymphopenia. An Abacavir Hypersensitivity Registry has been established to facilitate reporting of hypersensitivity reactions. Physicians should register patients by calling 1-800-270-0425.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues (alone or in combination), including abacavir and lamivudine. Female gender, obesity, and prolonged nucleoside analogue exposure may be risk factors. Caution should be exercised in any patient with known risk factors for liver disease; however, liver problems have been reported in patients with no known risk factors. Treatment with Epzicom should be suspended in any patient who develops clinical or laboratory findings that suggest lactic acidosis or pronounced hepatotoxicity. Exacerbation of hepatitis has occurred in patients treated for chronic hepatitis B infection after discontinuation of lamivudine therapy.

Immune reconstitution syndrome has been reported with the use of combination anti-HIV therapy, including abacavir/lamivudine. Patients who develop immune system responses to anti-HIV therapy may develop an inflammatory response to residual opportunistic infections (e.g., Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia, tuberculosis).

Other reported adverse effects of abacavir and lamivudine include redistribution of body fat, stomatitis, hyperglycemia, generalized weakness, aplastic anemia, other anemias, lymphadenopathy, splenomegaly, pancreatitis, muscle weakness, rhabdomyolysis, paresthesia, peripheral neuropathy, seizures, abnormal breath sounds and wheezing, and alopecia.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Epzicom may be administered with or without food. Administration of Epzicom with a high-fat meal does not change the bioavailability of lamivudine. Food does not alter the extent of systemic exposure to abacavir, but the rate of absorption decreases by approximately 24% compared with fasted conditions.

Abacavir and lamivudine are not significantly metabolized by the cytochrome P 450 enzymes, nor do they inhibit or induce this enzyme system; therefore, it is unlikely that clinically significant drug interactions will occur with drugs metabolized through these pathways. Abacavir administered at twice the recommended dose increased methadone clearance by 22%. A small number of patients receiving both Epzicom and methadone may need a methadone dosage adjustment. Consumption of alcohol may cause an increase in abacavir exposure. The AUC of lamivudine was increased by 43% when coadministered with sulfamethoxazole/trimethoprim. Concurrent administration of lamivudine and nelfinavir resulted in a 10% increase in the AUC of lamivudine.

Results of in vitro studies indicate that ribavirin reduces the phosphorylation of pyrimidine nucleoside analogues, including lamivudine.  Liver decompensation has occurred in patients coinfected with HIV and hepatitis C virus receiving combination antiretroviral therapy for HIV and interferon alfa with or without ribavirin.

Epzicom contains fixed doses of abacavir and lamivudine and should not be administered concomitantly with other abacavir- or lamivudine-containing products.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Epzicom is contraindicated in patients with previously demonstrated hypersensitivity to abacavir or to any other component of the product. Following a hypersensitivity reaction to abacavir, patients should never restart Epzicom or any other abacavir-containing product. Fatal reactions have been associated with readministration of abacavir to patients with a history of abacavir hypersensitivity. Epzicom is also contraindicated in patients with hepatic impairment and in patients with creatinine clearance less than 50 ml/min.]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[Abacavir sulfate: (1S,4R)-4-[2-Amino- 6-(cyclopropylamino)-9H-purin-9-yl]-2- cyclopentene-1-methanol sulfateLamivudine: 2(1H)-Pyrimidinone, 4-amino-1-[2-(hydroxymethyl)-1,3- oxathiolan-5-yl]-,(2R-cis)]]></drug:casname><drug:casnumber><![CDATA[Abacavir sulfate: 188062-50-2Lamivudine: 134678-17-4]]></drug:casnumber><drug:molecularformula><![CDATA[Abacavir sulfate: C14-H18-N6-O.1/2H2-O4-S / Lamivudine: C8-H11-N3-O3-S]]></drug:molecularformula><drug:elementalcomposition><![CDATA[Abacavir sulfate: C50.1%, H5.7%, N25.1%, O14.3%, S4.8% / Lamivudine: C41.91%, H4.84%, N18.33%, O20.94%, S13.99%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[Abacavir: 165 C / Lamivudine: 160 to 162 C]]></drug:meltingpoint><drug:molecularweight><![CDATA[Abacavir sulfate: 670.76 / Lamivudine: 229.26]]></drug:molecularweight><drug:physicaldescription><![CDATA[Abacavir sulfate: white to off-white solid.

Lamivudine: white to off-white crystalline solid.]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[Abacavir sulfate: 77 mg/ml in distilled water at 25 C.

Lamivudine: 70 mg/ml in water at 20 C.]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:othername><![CDATA[Abacavir sulfate/Lamivudine]]></drug:othername></drug:othernames><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[Epzicom Prescribing Information from the FDA Web site <a href="http://www.fda.gov/cder/foi/label/2007/021652s005lbl.pdf">[PDF]</a>. A more current version may be available on the manufacturer's Web site.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16944966 Castillo SA, Hernandez JE, Brothers CH. Long-term safety and tolerability of the lamivudine/abacavir combination as components of highly active antiretroviral therapy. Drug Saf. 2006;29(9):811-26.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16944966&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/15631548 Dando TM, Scott LJ.  Abacavir plus lamivudine: a review of their combined use in the management of HIV infection.  Drugs. 2005;65(2):285-302. Review.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15631548&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/15307010 DeJesus E, McCarty D, Farthing CF, Shortino DD, Grinsztejn B, Thomas DA, Schrader SR, Castillo SA, Sension MG, Gough K, Madison SJ; EPV20001 International Study Team. Once-daily versus twice-daily lamivudine, in combination with zidovudine and efavirenz, for the treatment of antiretroviral-naive adults with HIV infection: a randomized equivalence trial. Clin Infect Dis. 2004 Aug 1;39(3):411-8. Epub 2004 Jul 15.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15307010&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17150010 Waters L, Moyle G. Abacavir/lamividune combination in the treatment of HIV-1 infection: a review. Expert Opin Pharmacother. 2006 Dec;7(18):2571-80.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17150010&dopt=Abstract]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Abacavir/Lamivudine]]></drug:drugname><drug:companyname><![CDATA[GlaxoSmithKline]]></drug:companyname><drug:address1><![CDATA[5 Moore Drive]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Research Triangle Park]]></city><drug:state><![CDATA[NC]]></drug:state><drug:zipcode><![CDATA[27709]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(888) 825-5249]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Epzicom]]></drug:drugname><drug:companyname><![CDATA[GlaxoSmithKline]]></drug:companyname><drug:address1><![CDATA[5 Moore Drive]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Research Triangle Park]]></city><drug:state><![CDATA[NC]]></drug:state><drug:zipcode><![CDATA[27709]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(888) 825-5249]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[May 29, 2007]]></drug:lastupdated></item><item><title><![CDATA[Abacavir/Lamivudine/ Zidovudine]]></title><description><![CDATA[Trizivir includes three antiretroviral drugs: abacavir sulfate (Ziagen), lamivudine (Epivir), and zidovudine (Retrovir). Each of these drugs is a nucleoside reverse transcriptase inhibitor (NRTI). NRTIs block reverse transcriptase, a protein that HIV needs to make more copies of itself.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=325]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Abacavir/Lamivudine/ Zidovudine]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[a-BAK-a-veer, la-MI-vyoo-deen, zye-DOE-vyoo-deen]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Trizivir]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Abacavir/Lamivudine/ Zidovudine]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Nucleoside Reverse Transcriptase Inhibitors]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Abacavir/lamivudine/zidovudine (Trizivir) is a fixed-dose tablet containing three synthetic nucleoside analogues: abacavir sulfate, lamivudine, and zidovudine. Each tablet contains abacavir sulfate 300 mg, lamivudine 150 mg, and zidovudine 300 mg, each of which inhibits HIV-1 viral reverse transcriptase.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Trizivir was approved by the FDA on November 14, 2000, for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults or adolescents weighing more than 40 kg (88 lbs). When used as part of a three-drug HIV treatment regimen, Trizivir should be used with antiretroviral agents from different pharmacological classes and not with other NRTIs.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Film-coated tablet containing abacavir sulfate 300 mg, lamivudine 150 mg, and zidovudine 300 mg.

The recommended dosage for adults and adolescents is one tablet twice daily. Because it is in a fixed-dose tablet, Trizivir is not recommended for use in adults or adolescents who weigh less than 40 kg (88 lbs) or in patients requiring dosage adjustment, such as those with creatinine clearance less than 50 ml/min or those experiencing dose-limiting adverse events.]]></drug:dosageform><drug:storage><![CDATA[Store at 25 C (77 F); excursions permitted to 15 C to 30 C (59 F to 86 F).]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Each of the three synthetic nucleoside analogues contained in Trizivir inhibits viral reverse transcriptase (RT), an enzyme HIV requires in order to replicate. Abacavir, lamivudine, and zidovudine work by incorporating themselves into viral DNA and terminating the viral DNA chain. For more information, see individual drug fact sheets for abacavir sulfate, lamivudine, and zidovudine.

Abacavir is a carbocyclic nucleoside analogue that is converted by cellular enzymes to the active metabolite, carbovir triphosphate. Carbovir triphosphate is an analogue of deoxyguanosine-5'-triphosphate (dGTP). Carbovir triphosphate inhibits RT by competing with the natural substrate dGTP and by incorporation into viral DNA. The lack of a 3'-OH group in the incorporated nucleoside analogue prevents the formation of the 5' to 3' phosphodiester linkage essential for DNA chain elongation. In vitro, abacavir had synergistic activity in combination with amprenavir, nevirapine, and zidovudine and additive activity with didanosine, lamivudine, stavudine, and zalcitabine. Following oral dosing, abacavir is rapidly absorbed and extensively distributed. Binding of abacavir to human plasma proteins is about 50%, independent of concentration. Abacavir is primarily eliminated by metabolism by alcohol dehydrogenase to form the 5'-carboxylic acid and glucuronyl transferase to form the 5'-glucuronide.

Lamivudine is a synthetic nucleoside analogue that is phosphorylated intracellularly to its active 5'-triphosphate metabolite, lamivudine triphosphate (L-TP). L-TP inhibits viral RT by DNA chain termination. In vitro, lamivudine had synergistic antiretroviral activity with zidovudine. Following oral dosing, lamivudine is rapidly absorbed and extensively distributed. Plasma protein binding is low and about 70% of an intravenous dose is excreted unchanged in the urine. Metabolism is a minor route of elimination.

Zidovudine is phosphorylated intracellularly to its active 5'-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). ZDV-TP also inhibits RT by DNA chain termination. In vitro, zidovudine demonstrates synergistic activity with delavirdine, didanosine, indinavir, nelfinavir, nevirapine, ritonavir, saquinavir, and zalcitabine and additive activity with interferon alfa. Following oral dosing, zidovudine is rapidly absorbed and extensively distributed. Plasma protein binding is low and elimination is primarily by hepatic metabolism. The major metabolite is 3'-azido-3'-deoxy-5'-O-beta-D- glucopyranuronosylthymidine. A second metabolite, 3'-amino-3'-deoxythymidine, has been identified.

In a bioavailability study of Trizivir compared to separate tablets of the three components given simultaneously to healthy adults, there was no difference in absorption. One Trizivir tablet was bioequivalent to dosing with one tablet each of abacavir sulfate 300 mg, lamivudine 150 mg, and zidovudine 300 mg in healthy, fasting adults.

Trizivir is in FDA Pregnancy Category C. No adequate or well-controlled studies of the combination drug have been done in pregnant women. A study of zidovudine therapy in women in the last trimester of pregnancy showed that although this drug does cross the placenta, there was no evidence of drug accumulation, and zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery. Studies in laboratory animals have shown that abacavir and lamivudine cross the placenta, with evidence of fetal toxicity at dosage levels many times higher than the corresponding dose for humans. Trizivir should be used in pregnancy only if the potential benefits outweigh the risks. An Antiretroviral Pregnancy Registry has been established to monitor the outcomes of pregnant women exposed to Trizivir and other antiretrovirals. Physicians may register patients online at http://www.APRegistry.com or by calling 1-800-258-4263. Zidovudine is excreted in human milk, and abacavir and lamivudine are excreted in the milk of laboratory animals.

HIV-1 isolates with reduced sensitivity to abacavir, lamivudine, or zidovudine have been selected in vitro and have also been obtained from patients treated with that combination or lamivudine plus zidovudine. Treatment for 12 weeks with lamivudine and zidovudine restored sensitivity to zidovudine in some patients with zidovudine-resistant virus. Combination therapy delayed the emergence of mutations conferring resistance to zidovudine. Higher levels of resistance were associated with greater numbers of mutations. Laboratory strains of HIV-1 containing multiple RT mutations conferring abacavir resistance exhibited cross resistance to lamivudine, didanosine, and zalcitabine in vitro. Cross resistance to didanosine and zalcitabine has been observed in some patients who harbor lamivudine-resistant HIV-1 isolates. Multiple drug resistance, including resistance to lamivudine and stavudine, has been observed in HIV isolates from patients treated for more than 1 year with zidovudine plus didanosine or zalcitabine.

Cross resistance to didanosine, emtricitabine, lamivudine, tenofovir, and zalcitabine has been seen in patients treated with abacavir.  Cross resistance to abacavir, didanosine, tenofovir, and zalcitabine has been seen in patients treated with lamivudine. Multiple drug resistance, including resistance to lamivudine, didanosine, stavudine, zalcitabine, and zidovudine, has been observed in HIV isolates from some patients treated for more than 1 year with zidovudine plus didanosine or zalcitabine.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Trizivir contains abacavir sulfate, which has been associated with fatal hypersensitivity reactions. In clinical studies, approximately 5% of adult and pediatric patients receiving abacavir developed a hypersensitivity reaction. Hypersensitivity reactions are characterized by symptoms indicating multi-organ/body system involvement, usually appearing within the first 6 weeks of abacavir therapy, although they may appear at any time. Frequently observed signs and symptoms of hypersensitivity include fever, skin rash, fatigue, and gastrointestinal symptoms such as nausea, vomiting, diarrhea, or abdominal pain. Other signs and symptoms include malaise, lethargy, myalgia, myolysis, arthralgia, edema, cough, dyspnea, headache, and paresthesia. The diagnosis of hypersensitivity reaction should be considered for patients presenting with symptoms of acute onset respiratory diseases such as pneumonia, bronchitis, or flu-like illnesses. Physical findings associated with hypersensitivity reactions include lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and sometimes a maculopapular or urticarial rash. Laboratory abnormalities include elevated liver function tests, increased creatine phosphokinase or creatinine, and lymphopenia. Anaphylaxis, liver failure, renal failure, hypotension, and death have occurred in association with hypersensitivity reactions. Severe or fatal hypersensitivity reactions can occur within hours after reintroduction of abacavir in patients who have no identified history or who have unrecognized symptoms of hypersensitivity to abacavir. Trizivir should be discontinued permanently if hypersensitivity cannot be ruled out. An Abacavir Hypersensitivity Registry has been established to facilitate reporting of hypersensitivity reactions. Physicians should register patients by calling 1-800-270-0425.

Lactic acidosis and severe hepatomegaly with steatosis have been reported with the use of nucleoside analogues alone or in combination. These conditions are sometimes fatal. Female gender, obesity, and prolonged nucleoside exposure may be risk factors. Caution should be exercised in any patient with known risk factors for liver disease; however, liver problems have been reported in patients with no known risk factors. Treatment with Trizivir should be suspended in any patient who develops clinical or laboratory findings that suggest the presence of lactic acidosis or pronounced hepatotoxicity. Neutropenia and anemia are the most frequent adverse effects associated with zidovudine therapy. Myopathy and myositis have occurred with prolonged use of zidovudine and may occur during therapy with Trizivir. Peripheral neuropathy has been reported in adults receiving lamivudine but has rarely resulted in interruption or discontinuance of treatment. Post-treatment exacerbations of hepatitis B virus (HBV) infections have been reported in both HIV infected and uninfected participants treated with lamivudine for chronic HBV when lamivudine therapy was discontinued.

Immune reconstitution syndrome has been reported with the use of combination anti-HIV therapy, including abacavir/lamivudine/zidovudine.  Patients who develop immune system responses to anti-HIV therapy may develop an inflammatory response to residual opportunisitic infections (e.g., Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia, tuberculosis).

Other adverse effects occurring in clinical trials of Trizivir or its component drugs include nausea, vomiting, diarrhea, abdominal pain or cramping, dyspepsia, anorexia, insomnia and other sleep disorders, fever and/or chills, headache, dizziness, malaise and/or fatigue, depressive disorders, neuropathy, musculoskeletal pain, myalgia, arthralgia, and skin rashes. Adverse events reported during post-approval use of abacavir, lamivudine, and/or zidovudine that may potentially be related to these drugs include cardiomyopathy, stomatitis, oral mucosal pigmentation, gynecomastia, hyperglycemia, vasculitis, weakness, anemia, aplastic anemia, lymphadenopathy, pure red cell aplasia, splenomegaly, lactic acidosis and hepatic steatosis, pancreatitis, post-treatment exacerbation of hepatitis B, sensitization reactions and urticaria, muscle weakness, creatine phosphokinase (CPK) elevation, rhabdomyolysis, paresthesia, peripheral neuropathy, seizures, abnormal breath sounds/wheezing, alopecia, erythema multiforme, and Stevens-Johnson syndrome.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Trizivir may be administered with or without food. Administration of Trizivir with food did not alter the extent of abacavir, lamivudine, and zidovudine area under the concentration-time curve (AUC), compared with administration under fasting conditions.

Abacavir, lamivudine, and zidovudine (studied as individual drugs) are not significantly metabolized by the cytochrome P 450 enzymes; therefore, it is unlikely that clinically significant drug interactions will occur with drugs metabolized through these pathways.

Abacavir administered at twice the recommended dose increased methadone clearance by 22%. A small number of patients receiving both abacavir and methadone may need a methadone dosage adjustment. Because abacavir elimination is decreased by alcohol, consumption of alcohol may cause an increase in abacavir exposure.

Because lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another, Trizivir should not be coadministered with zalcitabine. The AUC of lamivudine was increased by 43% and renal clearance was decreased by 30% when coadministered with sulfamethoxazole/trimethoprim. Concurrent administration of lamivudine and zidovudine in one small study resulted in a 39% increase in the Cmax of zidovudine with no change observed in the AUC. Concurrent administration of lamivudine with indinavir and zidovudine resulted in a 6% decrease in the AUC of lamivudine, no change in the AUC of indinavir, and a 36% increase in the AUC of zidovudine. No adjustment in dose is necessary. Concurrent administration of lamivudine with drugs associated with pancreatitis (alcohol, didanosine, IV pentamidine, sulfonamides, and zalcitabine) or with drugs associated with peripheral neuropathy (dapsone, didanosine, isoniazid, stavudine, and zalcitabine) should be avoided or used cautiously.

Zidovudine may interact with atovaquone, fluconazole, methadone, probenecid, ribavirin, valproic acid, nelfinavir, and ritonavir. The hematologic toxicity of zidovudine may be increased when zidovudine is coadministered with bone marrow depressant agents such as ganciclovir or interferon alfa, blood dyscrasia-causing medications, cytotoxic agents, or radiation therapy. Medications that are metabolized by hepatic glucuronidation such as acetaminophen, aspirin, benzodiazepines, cimetidine, indomethacin, lorazepam, and oxazepam may in theory increase the risk of toxicity of zidovudine or the coadministered medication. Antagonistic relationships between zidovudine and stavudine, doxorubicin, and ribavirin have been reported in vitro. Concomitant use of zidovudine with any of these three drugs should be avoided.

Results of in vitro studies indicate that ribavirin reduces the phosphorylation of pyrimidine nucleoside analogues, including lamivudine. Liver decompensation has occurred in patients coinfected with HIV and hepatitis C virus receiving combination antiretroviral therapy for HIV and interferon alfa with or without ribavirin.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Trizivir tablets are contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the product. Trizivir contains abacavir sulfate, which has been associated with fatal hypersensitivity reactions. An actual or suspected hypersensitivity reaction to abacavir sulfate is an absolute contraindication to Trizivir use.

Due to the fixed-dose formulation of Trizivir, there is no way to accommodate the dosage reduction of zidovudine that may be necessary in individuals with impaired liver function or the dosage adjustment of both lamivudine and zidovudine that may be necessary in those with renal insufficiency (creatinine clearance less than 50 ml/min). Additionally, dosage adjustments cannot be made for pediatric or geriatric patients, for patients who weigh less than 40 kg, or for any patient with special dosing requirements. Trizivir is not recommended for these patients.]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[Zidovudine: Thymidine, 3'-azido-3'-deoxy-Abacavir sulfate: (1S,4R)-4-[2-Amino- 6-(cyclopropylamino)-9H-purin-9-yl]-2- cyclopentene-1-methanol sulfateLamivudine: 2(1H)-Pyrimidinone, 4-amino-1-[2-(hydroxymethyl)-1,3- oxathiolan-5-yl]-,(2R-cis)-]]></drug:casname><drug:casnumber><![CDATA[Zidovudine: 30516-87-1Abacavir sulfate: 188062-50-2Lamivudine: 134678-17-4]]></drug:casnumber><drug:molecularformula><![CDATA[Abacavir sulfate: C14-H18-N6-O.1/2H2-O4-S; Lamivudine: C8-H11-N3-O3-S; Zidovudine: C10-H13-N5-O4]]></drug:molecularformula><drug:elementalcomposition><![CDATA[Abacavir sulfate: C50.1%, H5.7%, N25.1%, O14.3%, S4.8%; Lamivudine: C41.91%, H4.84%, N18.33%, O20.94%, S13.99%; Zidovudine: C44.94%, H4.90%, N26.21%, O23.95%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[Abacavir: 165 C; Lamivudine: 160 to 162 C; Zidovudine: 106 to 112 C]]></drug:meltingpoint><drug:molecularweight><![CDATA[Abacavir sulfate: 670.76; Lamivudine: 229.26; Zidovudine: 267.24]]></drug:molecularweight><drug:physicaldescription><![CDATA[Abacavir sulfate: white to off-white solid.

Lamivudine: white to off-white crystalline solid.

Zidovudine: white to beige crystalline solid.]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[Abacavir sulfate: 77 mg/ml in distilled water at 25 C.

Lamivudine: 70 mg/ml in water at 20 C.

Zidovudine: 20.1 mg/ml in water at 25 C.]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:othername><![CDATA[Abacavir sulfate / Lamivudine / Zidovudine]]></drug:othername></drug:othernames><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[Trizivir Prescribing Information from the FDA Web site <a href="http://www.fda.gov/cder/foi/label/2007/021205s018lbl.pdf">[PDF]</a>. A more current version may be available on the manufacturer's Web site.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17309342 Keiser P, Nassar N. Abacavir sulfate/lamivudine/zidovudine fixed combination in the treatment of HIV infection. Expert Opin Pharmacother. 2007 Mar;8(4):477-83.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17309342&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16369448 Kessler HA.  Triple-nucleoside analog antiretroviral therapy: is there still a role in clinical practice? A review.  MedGenMed. 2005 Jun 2;7(2):70.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16369448&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17059380 Mastroianni CM, d'Ettorre G, Vullo V. Evolving simplified treatment strategies for HIV infection: the role of a single-class quadruple-nucleoside/nucleotide regimen of trizivir and tenofovir. Expert Opin Pharmacother. 2006 Nov;7(16):2233-41.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17059380&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/15608053 Orkin C, Stebbing J, Nelson M, Bower M, Johnson M, Mandalia S, Jones R, Moyle G, Fisher M, Gazzard B.  A randomized study comparing a three- and four-drug HAART regimen in first-line therapy (QUAD study).  J Antimicrob Chemother. 2005 Feb;55(2):246-51.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15608053&dopt=Abstract]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Abacavir/Lamivudine/ Zidovudine]]></drug:drugname><drug:companyname><![CDATA[GlaxoSmithKline]]></drug:companyname><drug:address1><![CDATA[5 Moore Drive]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Research Triangle Park]]></city><drug:state><![CDATA[NC]]></drug:state><drug:zipcode><![CDATA[27709]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(888) 825-5249]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[May 31, 2007]]></drug:lastupdated></item><item><title><![CDATA[Didanosine]]></title><description><![CDATA[Didanosine, also known as ddI or Videx, is a type of antiretroviral drug called a nucleoside reverse transcriptase inhibitor (NRTI). NRTIs block reverse transcriptase, a protein that HIV needs to make more copies of itself.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=16]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Didanosine]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[dye-DAN-oh-seen]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Videx, Videx EC]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Didanosine]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Nucleoside Reverse Transcriptase Inhibitors]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Didanosine, a synthetic antiretroviral agent, is a nucleoside reverse transcriptase inhibitor. Didanosine, a synthetic antiretroviral agent, is a synthetic analogue of deoxyadenosine, a naturally occurring purine nucleoside. Didanosine differs from deoxyadenosine in that the 3'-hydroxyl group on the ribose moiety is replaced with hydrogen.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Didanosine was approved by the FDA on October 9, 1991, and enteric-coated didanosine was approved by the FDA on October 31, 2000. A generic delayed-release capsule formulation was approved by the FDA on December 3, 2004. Didanosine is used in conjunction with other antiretroviral agents for the treatment of HIV-1 infection in adults, adolescents, and pediatric patients.

Didanosine is used with other antiretrovirals for postexposure prophylaxis of HIV infection in health care workers and other individuals exposed occupationally via percutaneous injury or mucous membrane or nonintact skin contact with tissues or body fluids associated with a risk of HIV transmission.

Because of a decline in clinical demand for the buffered tablet formulation of didanosine, this formulation was discontinued in the U.S. by the manufacturer in February 2006. The discontinuation of the less popular buffered tablets is voluntary and does not reflect any problems with safety or efficacy.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Chewable buffered tablets containing didanosine 25, 50, 100, 150, or 200 mg.

Buffered powder for oral solution in single-dose packets containing didanosine 100, 167, or 250 mg.

Pediatric powder for oral solution in 4- or 8-ounce bottles containing didanosine 2 or 4 g, respectively.

Delayed-release capsules of enteric-coated beadlets containing didanosine 125, 200, 250, or 400 mg.

Bioequivalent generic delayed-release capsules containing didanosine 200, 250, or 400 mg.

The recommended doses of didanosine are dependent on drug form and patient weight. For adults weighing 60 kg (132 lbs) or more, the recommended doses are 200 mg twice daily (tablets), 250 mg twice daily (buffered powder), or 400 mg once daily (enteric-coated capsules). For adults weighing less than 60 kg (132 lbs), the recommended doses are 125 mg twice daily (tablets), 167 mg twice daily (buffered powder), or 250 mg once daily (enteric-coated capsules). The recommended dose of didanosine in pediatric patients age 2 weeks to 8 months is 100 mg/m2 twice daily, and the recommended dose for pediatric patients older than 8 months is 120 mg/m2 twice daily.

In patients with impaired renal function, the doses and dosing intervals of didanosine should be adjusted to compensate for the slower rate of elimination. Recommendations for didanosine dosing in renal impairment are provided in the Videx and Videx EC prescribing information from the manufacturer.]]></drug:dosageform><drug:storage><![CDATA[Store didanosine chewable/dispersible tablets and powder for oral solution between 15 C and 30 C (59 F and 86 F). Delayed-release capsules should be stored at 25 C (77 F), with excursions between 15 C and 30 C (59 F and 86 F) permitted.]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Didanosine is converted by cellular enzymes to the active metabolite 2,3-dideoxyadenosine-5-triphosphate (ddA-TP), which inhibits HIV-1 reverse transcriptase by competing with the natural substrate, deoxyadenosine 5'-triphosphate, for incorporation into viral DNA. Once incorporated, ddA-TP causes termination of viral DNA synthesis.

Didanosine is acid labile. All oral formulations of didanosine contain or are compounded with buffering agents to increase gastric pH. Didanosine is rapidly absorbed, with peak plasma concentrations (Cmax) observed from 0.25 to 1.50 hours following oral dosing with a buffered formulation (in tablet or powder form) and 2 hours following oral dosing with the enteric-coated formulation. Extent of absorption depends on several factors, including dosage form, gastric pH, and presence of food in the gastrointestinal (GI) tract. There is considerable interindividual variation in Cmax and areas under the plasma concentration curve (AUC) of didanosine attained following oral administration.

Didanosine's Cmax and AUC were decreased by approximately 55% when didanosine buffered tablets were administered up to 2 hours after a meal. Administration of didanosine tablets up to 30 minutes before a meal did not result in any significant changes in bioavailability. The Cmax and AUC for the enteric-coated formulation were reduced by approximately 46% and 19%, respectively, in the presence of food.

Because gastric secretions may inactivate didanosine following oral administration, didanosine chewable/dispersible tablets and powder for oral solution either contain buffering agents or must be admixed with antacids prior to administration. Each adult dose of the buffered tablet formulation of didanosine must consist of 2 tablets to ensure adequate acid-neutralizing capacity. The delayed-release capsules contain enteric-coated beadlets, which protect didanosine from degradation by stomach acid.

Didanosine is distributed into cerebrospinal fluid (CSF) following IV administration. CSF concentrations average 19% to 21% of concurrent plasma concentrations in samples obtained 1 hour after a single IV dose. In a study of HIV infected pediatric patients who received oral or intravenous didanosine, CSF concentrations averaged 46% (over a range of 12% to 85%) of concurrent plasma concentrations. Binding of didanosine to plasma proteins in vitro is less than 5%.

Didanosine is in FDA Pregnancy Category B. No adequate or well-controlled studies of didanosine have been done in pregnant women. In animal studies, didanosine and/or its metabolites were transferred to the fetus through the placenta. Animal studies with didanosine have not shown evidence of impaired fertility or harm to the fetus. Nevertheless, the drug should be used during pregnancy only if clearly needed. To monitor maternal-fetal outcomes of pregnant women exposed to didanosine and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians may register patients online at http://www.APRegistry.com or by calling 1-800-258-4263. It is not known whether didanosine or its metabolites are distributed into human milk; however, the drug and/or its metabolites are distributed into milk in laboratory animals. Because of both the potential for HIV transmission and serious adverse reactions in nursing infants, HIV infected mothers should be instructed not to breastfeed their infants if they are receiving didanosine.

The metabolic fate of didanosine has not been fully evaluated in humans. Because didanosine is an analogue of a naturally occurring purine nucleoside, metabolism of the drug is presumed to occur via the same pathways as endogenous purines. The in vivo intracellular half-life of the active metabolite, ddA-TP, has not been determined; the in vitro intracellular half-life of ddA-TP is 8 to 24 hours. In HIV infected adults, the plasma half-life of didanosine averages 0.97 to 1.6 hours. In HIV infected pediatric patients, the plasma half-life averages 0.8 hours.

Didanosine is eliminated in urine by glomerular filtration and active tubular secretion. Following oral dosing in adults, the renal clearance of didanosine is approximately 50% of the total body clearance and averages 400 ml/min. Renal clearance has been reported to average 5.5 ml/min/kg in adult patients and 240 ml/min/m2 in pediatric patients. In HIV infected adults, approximately 20% of the dose is eliminated in the urine; in pediatric patients approximately 18% of the dose is eliminated in the urine.

The half-life of didanosine increases as creatinine clearance decreases. It is recommended that the didanosine dose be modified in patients with renal impairment and reduced creatinine clearance and in patients receiving maintenance hemodialysis. A 4-hour hemodialysis session reduces the serum didanosine concentration by approximately 20%. The effects of impaired hepatic function on the pharmacokinetics of didanosine have not been adequately studied.

HIV-1 isolates with reduced sensitivity to didanosine havebeen selected in vitro and were also obtained from patients treated with didanosine. Phenotypic analysis of HIV-1 isolates from 60 patients receiving from 6 to 24 months of didanosine monotherapy, some with prior exposure to zidovudine, showed that isolates from 10 of 60 patients exhibited an average of a 10-fold decrease in susceptibility to didanosine in vitro compared to baseline isolates.

HIV-1 isolates from 2 of 39 patients receiving combination therapy with zidovudine and didanosine for up to 2 years exhibited cross-resistance to zidovudine, didanosine, zalcitabine, stavudine, and lamivudine in vitro. The clinical relevance of these observations has not been established.

Further study is needed to evaluate more fully the extent of cross resistance among the dideoxynucleoside reverse transcriptase inhibitors. Although zidovudine-resistant HIV strains are susceptible to didanosine in vitro, some zidovudine-resistant strains may be cross resistant to didanosine or zalcitabine. In addition, some strains of HIV modified in vitro by site-directed mutagenesis have had decreased susceptibility to both didanosine and zalcitabine but were susceptible to zidovudine.

Cross resistance between didanosine and protein inhibitors (PIs), including amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, is highly unlikely since the drugs have different target enzymes. The potential for cross resistance between didanosine and non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, and nevirapine) is considered to be low since the drugs bind on different sites of reverse transcriptase and have different mechanisms of action.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Fatal and nonfatal pancreatitis has occurred during therapy with didanosine used alone or in combination regimens in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression. Didanosine should be suspended in patients with signs or symptoms of pancreatitis and discontinued in patients with confirmed pancreatitis. Patients treated with didanosine in combination with stavudine, with or without hydroxyurea, may be at increased risk for pancreatitis. When treatment with life-sustaining drugs known to cause pancreatic toxicity is required, suspension of didanosine therapy is recommended. In patients with risk factors for pancreatitis, didanosine should be used with extreme caution and only if clearly indicated. Patients with advanced HIV infection, especially the elderly, are at increased risk of pancreatitis and should be followed closely. Patients with renal impairment may be at greater risk for pancreatitis if treated without dose adjustment. The frequency of pancreatitis is dose related, as indicated in Phase III trials using buffered formulations of didanosine, with an incidence in adult patients of 1% to 10% in doses higher than currently recommended and 1% to 7% with recommended doses.

The use of didanosine and other nucleoside analogues, either alone or in combination with other antiretrovirals, has been associated with lactic acidosis and severe hepatomegaly with steatosis, including some fatal cases. Risk factors include female gender, obesity, and prolonged exposure to antiretroviral nucleoside analogues. Fatal lactic acidosis has been reported in pregnant women who received an antiretroviral regimen that included didanosine and stavudine. Cases have occurred in patients with and without known risk factors for liver disease. Didanosine use should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations.

Retinal changes and optical neuritis have been reported in patients taking didanosine. Periodic retinal examinations should be considered for patients taking didanosine.

Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients taking didanosine. Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance," have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Common, less serious adverse effects include central nervous system effects (anxiety, headache, insomnia, irritability, and restlessness), dry mouth, GI disturbances (diarrhea, dyspepsia, flatulence, nausea, vomiting), and skin rash.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Presence of food in the GI tract decreases the rate and extent of absorption of oral didanosine. Antacids increase the oral bioavailability of didanosine.

The manufacturer suggests that didanosine be discontinued in patients who require life-sustaining treatment with other drugs known to cause pancreatitis. Patients receiving didanosine in combination with stavudine, with or without hydroxyurea, may be at an increased risk for potentially fatal pancreatitis.

Didanosine and some (PIs), including amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir, have additive or synergistic activity against HIV-1, probably due to the different stages of virus replication at which these drugs are active. However, due to the buffering agents in some didanosine dosage forms and the requirement that most PIs be administered with food, dosing of these drugs should be separated.

Concomitant use of allopurinol and didanosine is not recommended. Allopurinol may increase plasma AUC of didanosine by two- to fourfold. In clinical studies, AUC and Cmax of didanosine increased 113% and 69%, respectively, when administered concomitantly with allopurinol in healthy adults.

Concomitant use of didanosine and drugs associated with pancreatic toxicity, such as alcohol, asparaginase, azathioprine, estrogens, furosemide, methyldopa, nitrofurantoin, pentamidine (IV), sulfonamides, sulindac, tetracyclines, thiazide diuretics, and valproic acid, may increase the risk of pancreatitis. Didanosine should be used with extreme caution and only when other alternatives are not available in patients receiving these drugs.

Didanosine should be avoided or used with caution in patients receiving other drugs that have been associated with peripheral neuropathy, such as chloramphenicol, cisplatin, dapsone, ethambutol, ethionamide, hydralazine, isoniazid, lithium, metronidazole, nitrofurantoin, nitrous oxide, phenytoin, stavudine, vincristine, and zalcitabine.

When buffered preparations of didanosine are administered with medications that require an acidic environment, didanosine may cause decreased absorption of the coadministered drug. Drugs that depend on gastric acidity for optimal absorption, including dapsone, itraconazole, and ketoconazole, should be administered at least 2 hours before or 2 hours after didanosine is given.

Concurrent administration of delavirdine or indinavir and didanosine may decrease absorption of these drugs. If either of these drugs are taken together, delavirdine or indinavir should be given 1 hour prior to didanosine administration.

Coadministration of tenofovir disoproxil fumarate (tenofovir DF) with didanosine causes increased absorption of didanosine. Increased exposure may cause or worsen didanosine-related toxicities, including pancreatitis, hyperlactatemia/lactic acidosis, and peripheral neuropathy. Coadministration of tenofovir DF with didanosine should be undertaken with caution, and patients should be monitored closely for didanosine-related toxicities.

In vitro studies demonstrate that concurrent administration of didanosine and oral ganciclovir resulted in a 111% increase in the steady-state AUC of didanosine and may result in increased didanosine-related toxicities. Because valganciclovir is rapidly and completely converted to ganciclovir, drug interactions associated with ganciclovir are expected to occur with valganciclovir as well. Patients receiving concomitant therapy with didanosine and ganciclovir or valganciclovir should be monitored for didanosine toxicity.

The oral absorption and plasma concentrations of fluoroquinolone antibiotics or tetracyclines may be decreased in the presence of antacids such as those present in the buffering agents of certain oral didanosine dosage forms. Dosages of didanosine and quinolones should be separated by at least 2 hours.

Exposure to didanosine or its active metabolite (dideoxyadenosine 5'-triphosphate) is increased when didanosine is coadministered with ribavirin. Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and hyperlactatemia/lactic acidosis have been reported in patients taking both didanosine and ribavirin. Coadministration of ribavirin with didanosine is not recommended.

Based on data from an open-label randomized study and retrospective database analyses, clinicians are advised to use caution when administering enteric-coated didanosine, tenofovir DF, and either efavirenz or nevirapine in the treatment of treatment-naive HIV infected patients with high baseline viral loads.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Didanosine is contraindicated in patients with previously demonstrated, clinically significant hypersensitivity to any component of the formulation.

Risk-benefit should be considered in patients with peripheral neuropathy; active alcoholism; history of or current hypertriglyceridemia; history of pancreatitis; or conditions requiring a low-sodium diet, including cardiac failure, cirrhosis of the liver, severe hepatic disease, peripheral or pulmonary edema, hypernatremia, hypertension, renal function impairment, toxemia of pregnancy, gouty arthritis, hepatic function impairment, or phenylketonuria.

Patients with phenylketonuria should be made aware that didanosine chewable buffered tablets contain up to 73 mg of phenylalanine per two-tablet dose.]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[Inosine, 2',3'-dideoxy-]]></drug:casname><drug:casnumber><![CDATA[69655-05-6]]></drug:casnumber><drug:molecularformula><![CDATA[C10-H12-N4-O3]]></drug:molecularformula><drug:elementalcomposition><![CDATA[C50.84%, H5.12%, N23.72%, O20.32%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[160 to 163 C]]></drug:meltingpoint><drug:molecularweight><![CDATA[236.23]]></drug:molecularweight><drug:physicaldescription><![CDATA[White crystalline powder.]]></drug:physicaldescription><drug:stability><![CDATA[Didanosine is stable at neutral or slightly alkaline pH, but is unstable at acid pH. To provide adequate buffering, at least two of the appropriate strength tablets of the buffered formulation (but no more than 4 tablets) should be thoroughly chewed or dispersed in at least 1 ounce of water prior to consumption. Solutions made from didanosine chewable/dispersible buffered tablets that have been dispersed in water or dispersed in clear apple juice are stable for 1 hour at room temperature. The dispersion should be stirred just prior to consumption.

After reconstitution with the appropriate admixture of water and liquid antacid by a pharmacist, the resulting suspension of didanosine pediatric powder for oral solution may be stored for up to 30 days in a refrigerator at 2 C to 8 C (36 F to 46 F). Discard any unused portion after 30 days.]]></drug:stability><drug:solubility><![CDATA[27.3 mg/ml in aqueous solution of pH 6 at 25 C.]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:othername><![CDATA[ddI]]></drug:othername></drug:othernames><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[Videx EC and Videx Prescribing Information from the FDA Web site <a href="http://www.fda.gov/cder/foi/label/2006/020154s50,20155s39,20156s40,21183s16lbl.pdf">[PDF]</a>. A more current version may be available on the manufacturer's Web site.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17205478 Cooper DA. Update on didanosine. J Int Assoc Physicians AIDS Care (Chic Ill). 2002 Winter; 1(1): 15-25.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17205478&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16152703 Lewis W. Nucleoside reverse transcriptase inhibitors, mitochondrial DNA and AIDS therapy. Antivir Ther. 2005;10 Suppl 2:M13-27. Review.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16152703&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17310813 Marcelin AG, Flandre P, Furco A, Wirden M, Molina JM, Calvez V; AI454-176 Jaguar Study Team. Impact of HIV-1 reverse transcriptase polymorphism at codons 211 and 228 on virological response to didanosine. Antivir Ther. 2006;11(6):693-9.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17310813&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16176639 Masia M, Gutierrez F, Padilla S, Ramos JM, Pascual J. Severe toxicity associated with the combination of tenofovir and didanosine: case report and review. Int J STD AIDS. 2005 Sep;16(9):646-8. Review.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16176639&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/14731163 Reiss P, Casula M, De Ronde A, Weverling GJ, Goudsmit J, Lange JM. Greater and more rapid depletion of mitochondrial DNA in blood of patients treated with dual (zidovudine+didanosine or zidovudine+zalcitabine) vs. single (zidovudine) nucleoside reverse transcriptase inhibitors. HIV Med. 2004 Jan; 5(1): 11-14.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=14731163&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17434879 Torti C, Lapadula G, Barreiro P, Soriano V, Mandalia S, De Silvestri A, Suter F, Maggiolo F, Antinori A, Antonucci F, Maserati R, El Hamad I, Pierotti P, Sighinolfi L, Migliorino G, Ladisa N, Carosi G. CD4+ T cell evolution and predictors of its trend before and after tenofovir/didanosine backbone in the presence of sustained undetectable HIV plasma viral load. J Antimicrob Chemother. 2007 Apr 13.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17434879&dopt=Abstract]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Didanosine]]></drug:drugname><drug:companyname><![CDATA[Barr Laboratories Inc]]></drug:companyname><drug:address1><![CDATA[2 Quaker Rd / PO Box D-2900]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Pomona]]></city><drug:state><![CDATA[NY]]></drug:state><drug:zipcode><![CDATA[10970]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 227-7522]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Videx]]></drug:drugname><drug:companyname><![CDATA[Bristol - Myers Squibb Co]]></drug:companyname><drug:address1><![CDATA[PO Box 4500]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Princeton]]></city><drug:state><![CDATA[NJ]]></drug:state><drug:zipcode><![CDATA[08543-4500]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 321-1335]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Videx EC]]></drug:drugname><drug:companyname><![CDATA[Bristol - Myers Squibb Co]]></drug:companyname><drug:address1><![CDATA[PO Box 4500]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Princeton]]></city><drug:state><![CDATA[NJ]]></drug:state><drug:zipcode><![CDATA[08543-4500]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 321-1335]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[May 20, 2008]]></drug:lastupdated></item><item><title><![CDATA[Emtricitabine]]></title><description><![CDATA[Emtricitabine, also known as Emtriva or FTC, is a type of medicine called a nucleoside reverse transcriptase inhibitor (NRTI). NRTIs block reverse transcriptase, a protein that HIV needs to make more copies of itself.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=208]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Emtricitabine]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[em-tri-SIT-uh-bean]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Emtriva]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Emtricitabine]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Nucleoside Reverse Transcriptase Inhibitors]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Emtricitabine, also referred to as FTC, is a nucleoside reverse transcriptase inhibitor (NRTI). Emtricitabine is the (-) enantiomer of a thio analogue of cytidine; it differs from other cytidine analogues by a fluorine in the 5 position.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Emtricitabine was approved by the FDA on July 2, 2003, for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults. Emtricitabine oral solution was approved by the FDA on September 28, 2005, and is approved for use with other anti-HIV drugs for the treatment of HIV-1 infection in patients older than 3 months of age. Emtricitabine may be considered for treatment-experienced patients with HIV strains that are susceptible to emtricitabine as assessed by genotypic or phenotypic testing.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral (capsules, oral solution).]]></drug:modeofdelivery><drug:dosageform><![CDATA[Capsules containing emtricitabine 200 mg.

Oral solution containing emtricitabine 10 mg/ml.

The recommended dose of emtricitabine for adults is 200 mg in capsule form or 240 mg (24 ml) oral solution once a day in combination with other antiretroviral agents. The recommended dose of emtricitabine for children is based on age and weight. Children who weigh more than 33 kg (72.8 lbs) and who can swallow an intact capsule should take 200 mg in capsule form once a day in combination with other antiretroviral agents.

The dosing interval of emtricitabine in capsule form should be adjusted in patients with baseline creatinine clearance (CrCl) less than 50 ml/min as follows: 200 mg every 48 hours for CrCl 30 to 49 ml/min; 200 mg every 72 hours for CrCl 15 to 29 ml/min; and 200 mg every 96 hours for CrCl less than 15 ml/min. The dosing interval of emtricitabine oral solution should be adjusted with baseline CrCl less than 50 ml/min as follows: 120 mg (12 ml) every 24 hours for CrCl 30 to 49 ml/min; 80 mg (8 ml) every 24 hours for CrCl 15 to 29 ml/min; and 60 mg (6 ml) every 24 hours for CrCl less than 15 ml/min. There are insufficient data to recommend a specific dose adjustment of emtricitabine in pediatric patients with renal impairment, but a reduction in dose or an increase in the dosing interval similar to adjustments for adults should be considered for these patients. Patients taking emtricitabine concurrently with hemodialysis should receive emtricitabine 200 mg every 96 hours after the completion of dialysis.]]></drug:dosageform><drug:storage><![CDATA[Store capsules at 25 C (77 F); excursions permitted at 15 C to 30 C (59 F to 86 F). Store oral solution refrigerated between 2 C and 8 C (36 F to 46 F); oral solution should be used within 3 months if stored by the patient at 25 C (77 F), with excursions permitted at 15 C to 30 C (59 F to 86 F).]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Emtricitabine, a synthetic nucleoside analogue of cytosine, undergoes phosphorylation by cellular enzymes to emtricitabine 5'-triphosphate. The active phosphate drug inhibits viral DNA synthesis by competing with the natural substrate deoxycytidine 5'-triphosphate for incorporation into viral DNA and by terminating the DNA chain at the point of incorporation.

Emtricitabine is rapidly and extensively absorbed following oral administration, reaching peak plasma concentrations (Cmax) at 1 to 2 hours post dose. In one clinical trial, the mean absolute bioavailability of emtricitabine was 93% following multiple doses of the drug. The mean steady state Cmax was 1.8 mcg/ml, and the area under the plasma concentration-time curve (AUC) over a 24-hour dosing interval was 10 hr(mcg)/ml. The mean steady state plasma trough concentration 24 hours after an oral dose was 0.09 mcg/ml.

Emtricitabine is in FDA Pregnancy Category B. Animal studies reveal no increased incidences of fetal variations or malformations in mice and rabbits at 60- and 120-fold higher drug exposures, respectively, than the human exposure at the recommended daily dose. However, there are no adequate and well-controlled studies in pregnant women. Results of animal studies are not always predictive of human response, and emtricitabine should be used during pregnancy only if clearly needed. An Antiretroviral Pregnancy Registry has been established to monitor fetal outcomes when the mother was exposed to antiretroviral drugs during pregnancy. Physicians can register patients online at http://www.APRegistry.com or by calling 1-800-258-4263. It is not known whether emtricitabine is distributed into human milk. Mothers should avoid nursing while taking emtricitabine.

Emtricitabine is less than 4% bound to plasma proteins, and protein binding is independent of drug concentration over a range of 0.02 to 200 mcg/ml. In vitro studies indicate that emtricitabine does not inhibit CYP450 enzymes. Biotransformation occurs through glucuronidation and oxidation. Following administration of carbon-14-emtricitabine, 86% of the dose was recovered in urine and 14% in feces. Of the urine-recovered dose, 13% was recovered as metabolites, including 3'-sulfoxide diastereomers and 2'O-glucuronide. The plasma half-life of emtricitabine is approximately 10 hours. Renal clearance of the drug exceeds estimated creatinine clearance, indicating elimination by both glomerular filtration and active tubular secretion. In patients with renal impairment, both Cmax and AUC were increased. Hemodialysis treatment removes about 30% of an emtricitabine dose over a 3-hour period, but it is unknown whether emtricitabine can be removed by peritoneal dialysis.

HIV isolates with reduced susceptibility to emtricitabine have been recovered from some patients treated with emtricitabine alone or in combination with other antiretroviral agents. Viral isolates from 37.5% of patients with virologic failure had reduced susceptibility to emtricitabine, attributed to M184V/I mutations in the HIV reverse transcriptase gene. Cross resistance has been noted among some nucleoside analogues. Emtricitabine-resistant isolates were cross resistant to lamivudine and zalcitabine but retained susceptibility to abacavir, didanosine, stavudine, tenofovir, and zidovudine as well as to the non-nucleoside reverse transcriptase inhibitors delavirdine, efavirenz, and nevirapine. Viruses with mutations leading to decreased susceptibility to stavudine, zidovudine, or didanosine remained sensitive to emtricitabine. Isolates containing the K65R mutation demonstrated decreased susceptibility to emtricitabine.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[The most frequently reported adverse effects of emtricitabine are mild to moderate headache, nausea, diarrhea, and skin rash. Skin discoloration on palms and soles was reported with higher frequency in emtricitabine-treated patients than in control groups, but the mechanism of skin discoloration is unknown.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including emtricitabine. In some patients coinfected with HIV and hepatitis B virus (HBV), exacerbation of hepatitis has been reported after discontinuing treatment with emtricitabine.

Redistribution of body fat, peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance have been observed in patients receiving antiretroviral therapy, including emtricitabine.

Treatment-emergent Grade 3 or 4 laboratory abnormalities have been reported in at least 1% of patients receiving emtricitabine. These abnormalities include triglycerides greater than 750 mg/dl and creatine kinase more than four times the upper limit of normal.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including emtricitabine. During the initial phase of combination antiretroviral treatment, a patient whose immune system improves may develop an inflammatory response to indolent or residual opportunistic infections, (e.g., Mycobacterium avium infection, cytomegalovirus infections, Pneumocystis jirovecii pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Emtricitabine capsules and oral solution may be administered with or without food. AUC was unchanged and Cmax decreased by 29% when the capsule form of the drug was administered with a 1,000-calorie, high-fat meal. AUC and Cmax were unaffected when oral solution was administered with either a high- or low-fat meal.

Emtricitabine has been evaluated in healthy volunteers in combination with tenofovir disoproxil fumarate (tenofovir DF), zidovudine, indinavir, famciclovir, and stavudine. A 20% increase in plasma trough concentrations of emtricitabine occurred when it was administered concurrently with tenofovir DF. When emtricitabine was given concurrently with zidovudine, zidovudine's AUC and Cmax increased by 13% and 17%, respectively.   Because renal elimination of emtricitabine is through glomerular filtration and active tubular secretion, there may be competition for elimination with other compounds that are also renally eliminated.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Emtricitabine is contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the drug product. Emtricitabine should be discontinued in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or severe hepatotoxicity. There have been reports of severe acute exacerbations of hepatitis B after discontinuation of emtricitabine treatment in patients coinfected with HIV and HBV; hepatic function should be monitored closely for at least several months after discontinuing emtricitabine in such patients.]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[(2R-cis)-4-Amino-5-fluoro- 1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] -2(1H)-pyrimidinone]]></drug:casname><drug:casnumber><![CDATA[143491-57-0]]></drug:casnumber><drug:molecularformula><![CDATA[C8-H10-F-N3-O3-S]]></drug:molecularformula><drug:elementalcomposition><![CDATA[C38.86%, H4.08%, F7.68%, N17.00%, O19.41%, S12.97%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[136 C to 140 C as solid white from ether and methanol]]></drug:meltingpoint><drug:molecularweight><![CDATA[247.25]]></drug:molecularweight><drug:physicaldescription><![CDATA[White to off-white powder.]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[Approximately 112 mg/ml in water at 25 C (77 F).]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:othername><![CDATA[FTC]]></drug:othername></drug:othernames><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[Emtriva Prescribing Information from the FDA Web site <A HREF="http://www.fda.gov/cder/foi/label/2006/021896s001,021500s007lbl.pdf">[PDF]</A>. A more current version may be available on the manufacturer's Web site.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17725415 Borroto-Esoda K, Waters JM, Bae AS, Harris JL, Hinkle JE, Quinn JB, Rousseau FS. Baseline genotype as a predictor of virological failure to emtricitabine or stavudine in combination with didanosine and efavirenz. AIDS Res Hum Retroviruses. 2007 Aug;23(8):988-95]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17725415&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16764056 Jenny-Avital ER.  Tenofovir DF and emtricitabine vs. zidovudine and lamivudine. N Engl J Med. 2006 Jun 8;354(23):2506-8; author reply 2506-8. No abstract available.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16764056&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17058783 Marconi P, Lorenzini P, Borrelli I, Liuzzi G, Sette P, Zaccarelli M, Antinori A.  Safety and efficacy of regimens containing emtricitabine in HIV-infected patients taking highly active antiretroviral therapy.New Microbiol. 2006 Jul;29(3):169-75.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17058783&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17646352 McKinney RE Jr, Rodman J, Hu C, Britto P, Hughes M, Smith ME, Serchuck LK, Kraimer J, Ortiz AA, Flynn P, Yogev R, Spector S, Draper L, Tran P, Scites M, Dickover R, Weinberg A, Cunningham C, Abrams E, Blum MR, Chittick GE, Reynolds L, Rathore M; Pediatric AIDS Clinical Trials Group Protocol P1021 Study Team. Long-term safety and efficacy of a once-daily regimen of emtricitabine, didanosine, and efavirenz in HIV-infected, therapy-naive children and adolescents: Pediatric AIDS Clinical Trials Group Protocol P1021. Pediatrics. 2007 Aug;120(2):e416-23. Epub 2007 Jul 23.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17646352&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17591032 Molina JM, Journot V, Furco A, Palmer P, De Castro N, Raffi F, Morlat P, May T, Rancinan C, Chene G; Montana (ANRS 091) Study Group. Five-year follow up of once-daily therapy with emtricitabine, didanosine and efavirenz (Montana ANRS 091 trial). Antivir Ther. 2007;12(3):417-22.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17591032&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16323102 Saag MS.  Emtricitabine, a new antiretroviral agent with activity against HIV and hepatitis B virus.  Clin Infect Dis. 2006 Jan 1;42(1):126-31. Epub 2005 Nov 23. Review.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16323102&dopt=Abstract]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Emtricitabine]]></drug:drugname><drug:companyname><![CDATA[Gilead Sciences Inc]]></drug:companyname><drug:address1><![CDATA[333 Lakeside Dr]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Foster City]]></city><drug:state><![CDATA[CA]]></drug:state><drug:zipcode><![CDATA[94404]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 445-3235]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Emtriva]]></drug:drugname><drug:companyname><![CDATA[Gilead Sciences Inc]]></drug:companyname><drug:address1><![CDATA[333 Lakeside Dr]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Foster City]]></city><drug:state><![CDATA[CA]]></drug:state><drug:zipcode><![CDATA[94404]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 445-3235]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[December 20, 2007]]></drug:lastupdated></item><item><title><![CDATA[Emtricitabine/Tenofovir disoproxil fumarate]]></title><description><![CDATA[Truvada is a combination of two antiretroviral drugs: emtricitabine (Emtriva) and tenofovir disoproxil fumarate (tenofovir DF or Viread). Both of these medicines are called nucleoside reverse transcriptase inhibitors (NRTIs). NRTIs block reverse transcriptase, a protein that HIV needs to make more copies of itself.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=406]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Emtricitabine/Tenofovir disoproxil fumarate]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[em-tri-SIT-uh-bean, te-NOE-fo-veer dye soe PROX il]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Truvada]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Emtricitabine/Tenofovir disoproxil fumarate]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Nucleoside Reverse Transcriptase Inhibitors]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Truvada is a fixed-dose tablet containing two synthetic nucleoside analogues: emtricitabine and tenofovir disoproxil fumarate (DF). Each tablet contains emtricitabine 200 mg and tenofovir DF 300 mg.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Truvada (emtricitabine/tenofovir DF) was approved by the FDA on August 2, 2004, for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults.

The approval of Truvada is based on safety and efficacy data that exist for both components individually and on bioequivalence studies demonstrating similar pharmacokinetic parameters of the combination product and the individual products. Efficacy results from studies using the combination of tenofovir and lamivudine are being extrapolated to support the use of Truvada. Truvada should be considered as an alternative to tenofovir and lamivudine for treatment-naive patients who might benefit from a once-a-day regimen.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Film-coated tablets containing emtricitabine 200 mg and tenofovir DF 300 mg (equivalent to 245 mg of tenofovir disoproxil).

The recommended dosage of Truvada for adults 18 years or older is one tablet once a day.

Patients with lowered creatinine clearance (30 to 49 ml/min) should receive one tablet every 48 hours.

Truvada should not be prescribed for patients requiring dosage adjustment, such as those with reduced renal function (creatinine clearance less than 30 ml/min or requiring hemodialysis).]]></drug:dosageform><drug:storage><![CDATA[Store tablets at 25 C (77 F); excursions permitted between 15 C and 30 C (59 F and 86 F). Keep container tightly closed and dispense only in original container. Do not use if seal over bottle opening is broken or missing.]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Emtricitabine and tenofovir DF each inhibit viral reverse transcriptase (RT), an enzyme HIV requires in order to replicate, by incorporating into viral DNA and terminating the viral DNA chain. (For more information, see the individual drug records for emtricitabine and tenofovir DF.)

Emtricitabine, a synthetic nucleoside analogue of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxycytidine 5'-triphosphate and by incorporating into nascent viral DNA, which results in chain termination. Emtricitabine 5'-triphosphate is a weak inhibitor of mammalian DNA polymerases alpha, beta, and epsilon and of mitochondrial DNA polymerase gamma.

Tenofovir DF is an acyclic nucleoside phosphonate diester analogue of adenosine monophosphate and requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir disphosphate. Tenofovir disphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5'-triphosphate and by incorporating into DNA, which results in chain termination. Tenofovir disphosphate is a weak inhibitor of mammalian DNA polymerases alpha and beta and of mitochondrial DNA polymerase gamma.

Truvada may be administered with or without food. Administration of Truvada following a high-fat meal or a light meal delayed the time of tenofovir peak plasma concentrations (Cmax) by approximately 0.75 hour. The mean increases in tenofovir area under the concentration-time curve (AUC) and Cmax were approximately 35% and 15%, respectively, when administered with a high-fat or light meal, compared with administration in the fasted state. In previous safety and efficacy studies, tenofovir DF was administered under fed conditions. Emtricitabine AUC and Cmax were unaffected when Truvada was administered with either a high-fat or a light meal.

Emtricitabine is rapidly and extensively absorbed following oral administration, reaching Cmax at 1 to 2 hours post-dose. In one clinical trial, the mean absolute bioavailability of emtricitabine was 93% following multiple doses of the drug. The mean steady state Cmax was 1.8 mcg/ml and the AUC over a 24-hour dosing interval was 10.0 hr mcg/ml. The mean steady state plasma trough concentration 24 hours after an oral dose was 0.09 mcg/ml.

In vitro binding of emtricitabine to plamsa proteins is less than 4%, and protein binding is independent of drug concentration over a range of 0.02 to 200 mcg/ml. In vitro studies indicate that emtricitabine does not inhibit cytochrome P450 (CYP) enzymes. Following administration of 14C-emtricitabine, the drug was 86% recovered in urine and 14% in feces. Thirteen percent of urine-recovered drug were metabolites, including 3'-sulfoxide diastereomers and 2'O-glucuronide; no other metabolites were identified. The plasma half-life of emtricitabine is approximately 10 hours. Renal clearance of the drug exceeds estimated creatinine clearance, indicating elimination by glomerular filtration and active tubular secretion. In patients with renal impairment, Cmax and AUC were increased.

Oral bioavailability of tenofovir in fasted patients is approximately 25%. Administration of tenofovir with a high-fat meal increases the oral bioavailability, with an increase in tenofovir AUC of approximately 40% and an increase in Cmax of approximately 14%. Food delays the time to tenofovir Cmax by approximately 1 hour. Following oral administration of a single 300-mg dose of tenofovir to HIV infected patients in the fasted state, Cmax is achieved in approximately 1 hour. Cmax and AUC values are approximately 296 ng/ml and approximately 2,287 hr(ng)/ml, respectively. The pharmacokinetics of tenofovir are dose proportional over a wide dose range and are not affected by repeated dosing. In vitro binding of tenofovir to human plasma or serum proteins is less than 0.7% and 7.2%, respectively, over the tenofovir concentration range of 0.01 to 25 mcg/ml. Following intravenous (IV) administration of tenofovir in doses of 1.0 mg/kg and 3.0 mg/kg, the volume of distribution at steady-state approximates 1.3 l/kg and 1.2 l/kg, respectively.

In vitro studies indicate that neither tenofovir DF nor tenofovir are substrates of CYP enzymes. Following IV administration of tenofovir, approximately 70% to 80% of the dose is recovered in the urine as unchanged drug within 72 hours of dosing. Following single dose, oral administration, the terminal half-life is approximately 17 hours.  After multiple oral doses of tenofovir DF under fed conditions, approximately 32% of the administered dose is recovered in urine over 24 hours. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also renally eliminated. Tenofovir is principally eliminated by the kidney. Dosing adjustment is recommended in all patients with creatinine clearance less than 50 ml/min. Dosage adjustments for renal impairment are available in the prescribing information. However, no safety data are available in patients with renal dysfunction who received tenofovir using these guidelines.

One Truvada tablet is bioequivalent to one emtricitabine tablet (200 mg) plus one tenofovir DF tablet (300 mg) following single-dose administration to healthy adults.

HIV-1 isolates with reduced susceptibility to the combination of emtricitabine and tenofovir have been selected in vitro. Genotypic analysis of these isolates identified the M184I/V and K65R amino acid substitutions in viral RT. Cross resistance among certain nucleoside reverse transcriptase inhibitors has been recognized. These in vitro substitutions are also observed in some HIV-1 isolates from patients failing treatment with tenofovir in combination with either lamivudine or emtricitabine and with either abacavir or didanosine. Therefore, cross resistance among these drugs may occur in patients whose virus harbors either or both of these amino acid substitutions.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Severe, acute exacerbations of hepatitis B virus (HBV) have been reported in patients who have discontinued emtricitabine or tenofovir DF. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue Truvada and are coinfected with HBV and HIV. If appropriate, initiation of anti-HBV therapy may be warranted.

Immune reconstitution syndrome has been reported in some patients treated with combination antiretroviral therapy, including Truvada. During the initial phase of combination antiretroviral therapy, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.

Emtricitabine and tenofovir DF are principally eliminated in the kidney; therefore, dosing interval adjustments of Truvada are recommended for patients with decreased creatinine clearance. Truvada should not be administered to patients with low creatinine clearance or to those who require hemodialysis.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[The manufacturer recommends that Truvada not be used as a component of a triple-nucleoside regimen. Use of Truvada should be avoided in patients who are concurrently using or have recently used a nephrotoxic agent. Patients at risk for, or with a history of, renal dysfunction and patients receiving concomitant nephrotoxic agents should be monitored for changes in serum creatinine and phosphorus.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Truvada is contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the product, including emtricitabine and tenofovir DF.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with other antiretroviral medications. Truvada is not indicated for the treatment of chronic HBV infection, and the safety and efficacy of Truvada have not been established in patients coinfected with HBV and HIV.]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[Emtricitabine: 143491-57-0 / Tenofovir disproxil fumarate: 202138-50-9]]></drug:casname><drug:casnumber><![CDATA[Emtricitabine: (2R-cis)-4-Amino-5-fluoro-1- [2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)- pyrimidinone / Tenofovir disoproxil fumarate: Bis(hydroxymethyl) [[(R)-2(6-Amino- 9H-purin-9-yl)-1-methylethoxy] methyl]phosphonate,bis(isopropyl carbonate) (ester), fumarate (1:1)]]></drug:casnumber><drug:molecularformula><![CDATA[Emtricitabine: C8-H10-F-N3-O3-S / Tenofovir disoproxil fumarate: C19-H30-N5-O10-P.C4-H4-O4]]></drug:molecularformula><drug:elementalcomposition><![CDATA[Emtricitabine: C38.86%, H4.08%, F7.68%, N17.00%, O19.41%, S12.97% / Tenofovir disoproxil fumarate: C43.47%, H5.39%, N11.02%, O35.25%, P4.87%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[Emtricitabine: 136 C to 140 C]]></drug:meltingpoint><drug:molecularweight><![CDATA[Emtricitabine: 247.24 / Tenofovir disoproxil fumarate: 635.52]]></drug:molecularweight><drug:physicaldescription><![CDATA[Emtricitabine: White to off-white crystalline powder.

Tenofovir DF: White to off-white crystalline powder.]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[Emtricitabine: 112 mg/ml in water at 25 C.

Tenofovir DF: 13.4 mg/ml in water at 25 C.]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform" /><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[Truvada Prescribing Information from the FDA Web site <A HREF=" http://www.fda.gov/cder/foi/label/2007/021356s021,021752s011lbl.pdf">[PDF]</A>. A more current version may be available on the manufacturer's Web site.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16718888 [No authors listed] Truvada trials hold promise for new HIV prevention strategy. Once-a-day might keep HIV away.   AIDS Alert. 2006 May;21(5):49-52.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16718888&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16556093 Gazzard BG.  Use of tenofovir disoproxil fumarate and emtricitabine combination in HIV-infected patients.  Expert Opin Pharmacother. 2006 Apr;7(6):793-802.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16556093&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17009933 Muñoz de Benito RM, Arribas López JR. Tenofovir disoproxil fumarate-emtricitabine coformulation for once-daily dual NRTI backbone.  Expert Rev Anti Infect Ther. 2006 Aug;4(4):523-35.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17009933&dopt=Abstract]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Emtricitabine/Tenofovir disoproxil fumarate]]></drug:drugname><drug:companyname><![CDATA[Gilead Sciences Inc]]></drug:companyname><drug:address1><![CDATA[333 Lakeside Dr]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Foster City]]></city><drug:state><![CDATA[CA]]></drug:state><drug:zipcode><![CDATA[94404]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 445-3235]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Truvada]]></drug:drugname><drug:companyname><![CDATA[Gilead Sciences Inc]]></drug:companyname><drug:address1><![CDATA[333 Lakeside Dr]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Foster City]]></city><drug:state><![CDATA[CA]]></drug:state><drug:zipcode><![CDATA[94404]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 445-3235]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[August 6, 2007]]></drug:lastupdated></item><item><title><![CDATA[Lamivudine]]></title><description><![CDATA[Lamivudine, also known as Epivir or 3TC, is a type of medicine called a nucleoside reverse transcriptase inhibitor (NRTI). NRTIs block reverse transcriptase, a protein that HIV needs to make more copies of itself.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=126]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Lamivudine]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[la-MI-vyoo-deen]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Epivir]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Lamivudine]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Nucleoside Reverse Transcriptase Inhibitors]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Lamivudine, a synthetic antiretroviral agent, is a dideoxynucleoside reverse transcriptase inhibitor. Lamivudine is the negative enantiomer of a dideoxy analogue of cytidine and is structurally similar to zalcitabine (2',3'-dideoxycytidine, ddC). Lamivudine differs structurally from zalcitabine in that the 3'-carbon of the ribose ring is replaced with sulfur, forming an oxathiolane ring. The absence of a free 3'-hydroxy group on the oxathiolane ring results in the inability of lamivudine to form phosphodiester linkages at this position. Both the positive and negative enantiomers of 2',3'-dideoxy,3'-thiacytidine exhibit antiviral activity in vitro, but lamivudine appears to exhibit greater antiviral activity and to be considerably less cytotoxic than the positive enantiomer.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Lamivudine was approved by the FDA on November 17, 1995, for use in combination with other antiretroviral agents for the treatment of HIV infection in adults and in pediatric patients 3 months of age and older. Lamivudine should always be used in conjunction with other antiretroviral agents and should not be used alone in the management of HIV infection. Lamivudine usually is used in three- or four-drug regimens that include another nucleoside reverse transcriptase inhibitor (NRTI) and either one or two protease inhibitors (PIs) or a non-nucleoside reverse transcriptase inhibitor (NNRTI).

Lamivudine has been used in combination with zidovudine for prevention of mother-to-child transmission of HIV. Although the safety and efficacy of this two-drug regimen has not been established, it is considered one of several options used in HIV infected women in labor who have received no prior antiretroviral therapy. Lamivudine is also used in conjunction with zidovudine or, alternatively, with stavudine for postexposure prophylaxis of HIV infection in health care workers and other individuals exposed occupationally to blood, body fluids, or tissues associated with a risk for transmission of HIV.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Lamivudine is used to treat chronic hepatitis B virus (HBV) infection associated with evidence of hepatitis B viral replication and active liver inflammation. For HBV therapy, it is administered in doses lower than those used to treat HIV infection. The formulation and dosage of lamivudine used in HBV therapy are not appropriate for patients coinfected with HIV and HBV. Patients with HIV infection should receive only dosing forms appropriate for treatment of HIV. The safety and efficacy of lamivudine have not been established for treatment of chronic HBV in patients coinfected with HIV and HBV.]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Film-coated tablets that contain lamivudine 300 mg. Scored, film-coated tablets, appropriate for pediatric dosing, that contain lamivudine 150 mg.

Oral solution containing lamivudine 10 mg/ml in 240 ml bottles.

The recommended dose of lamivudine for HIV infected adults is 300 mg once daily or 150 mg twice daily, in combination with other antiretroviral agents. The recommended dose of lamivudine for HIV infected children age 3 months to 16 years is 4 mg/kg twice daily, up to a maximum of 150 mg twice daily, in combination with other antiretroviral agents.

Lamivudine dosage should be adjusted in accordance with renal function in patients with creatinine clearance below 50 ml/min. No additional dosing of lamivudine is required after routine (4-hour) hemodialysis or peritoneal dialysis.]]></drug:dosageform><drug:storage><![CDATA[Store tablets at 25 C (77 F); excursions permitted between 15 C and 30 C (59 F and 86 F). Store oral solution at 25 C (77 F) in tightly closed bottles; oral solution need not be reconstituted.]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Lamivudine exerts a virustatic effect against retroviruses by acting as a reverse transcriptase inhibitor. Lamivudine is phosphorylated intracellularly to its active 5'-triphosphate metabolite, lamivudine triphosphate (L-TP, also known as 3TC-TP), which inhibits HIV reverse transcription and HBV polymerase activity via viral DNA chain termination. The principal mode of action of L-TP is inhibition of HIV reverse transcription via viral DNA chain termination after incorporation of the nucleoside analogue. L-TP is a weak inhibitor of mitochondrial DNA polymerase and mammalian DNA polymerases alpha and beta. 3TC-LP is a structural analogue of deoxycytidine triphosphate (dC-TP), the natural substrate for reverse transcriptase. 3TC-TP appears to compete with naturally occurring dC-TP for incorporation into viral DNA by reverse transcriptase. Following incorporation of 3TC-TP into the viral DNA chain instead of dC-TP, viral DNA synthesis is terminated prematurely because the absence of a 3'-hydroxyl group on the oxathiolane ring prevents further 5' to 3' phosphodiester linkages. Lamivudine has in vitro virustatic activity against HIV-1, HIV-2, and HBV, but it appears to be inactive against other common human viruses (e.g., cytomegalovirus, Epstein-Barr virus, influenza virus, herpes simplex virus types 1 and 2, respiratory syncytial virus, varicella-zoster virus).

Lamivudine is rapidly absorbed, with bioavailability from 80% to 88% in adults and adolescents and from 66% to 68% in children. Food delays the peak serum concentration; however, there is no significant difference in bioavailability when lamivudine is taken with food. Time to peak concentration (Tmax) is approximately 0.5 to 2 hours after a single 100 mg dose; with food, it increases to approximately 3.2 hours; with fasting, Tmax is about 1 hour.

Lamivudine is widely distributed after administration. Lamivudine crosses the blood-brain barrier and is distributed into the cerebrospinal fluid (CSF) to a limited extent. In children, CSF concentrations have ranged from 10% to 17% of the corresponding non-steady-state serum concentration. Apparent volume of distribution after intravenous (IV) administration in 20 patients was 1.3 +/- 0.4 l/kg, suggesting that lamivudine distributes into extravascular spaces. The volume of distribution was independent of dose and did not correlate with body weight.

Plasma protein binding is low (36%). Metabolism is a minor route of elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite. Within 12 hours after a single oral dose in six HIV infected adults, 5.2% +/- 1.4% was excreted as the trans-sulfoxide metabolite in the urine. Serum concentrations of this metabolite have not been determined. The majority of lamivudine is eliminated unchanged in urine by active organic cationic secretion. In 20 HIV-infected patients given a single IV dose, renal clearance was 280.4 +/- 75.2 ml/min, representing 71% +/- 16% of total clearance of the drug. In most single-dose studies in infected patients, the mean elimination half-life ranged from 5 to 7 hours. Oral clearance and elimination half-life were independent of dose and body weight over an oral dosing range of 0.25 mg/kg to 10 mg/kg. The half-life of intracellular lamivudine triphosphate is 11 to 15 hours; serum half-life of lamivudine is about 2.6 hours in adults and 1.7 to 2 hours in children. The renal clearance of lamivudine is greater than the glomerular filtration rate, implying active secretion into the renal tubules. Hemodialysis increases lamivudine clearance by a range of 64 to 88 ml/min, but the length of dialysis treatment (i.e., 4 hours) may not be long enough to alter mean lamivudine exposure. It is not known if lamivudine is removed by continuous (24 hour) hemodialysis.

Resistance to lamivudine can be produced in vitro by serial passage of HIV-1 in the presence of increasing concentrations of the drug, and strains of HIV-1 with in vitro resistance to lamivudine have emerged during therapy with the drug. Primary infection with lamivudine-resistant HIV-1 has been reported rarely in adults who were treatment naive. While some strains of zidovudine-resistant HIV-1 may be susceptible to lamivudine, strains resistant to both zidovudine and lamivudine have been isolated. HIV isolates resistant to zalcitabine, zidovudine, didanosine, lamivudine, and stavudine have been isolated from a limited number of patients who received zidovudine in conjunction with zalcitabine or didanosine for 1 year or longer. Mutations identified in these multidrug-resistant isolates were Ala62 to Val, Val75 to Ile, Phe77 to Leu, Phe116 to Tyr, and Gln151 to Met; the mutation at position 151 appears to play an important role in the development of multidrug resistance. The possibility of cross resistance among lamivudine, didanosine, and zalcitabine based on reverse transcriptase codon 184 mutations also is of concern.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including lamivudine and other antiretrovirals. Female gender, obesity, and prolonged exposure to antiretroviral nucleoside analogues may be risk factors. Such cases have occurred in patients with and without known risk factors for liver disease. Treatment with lamivudine should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis, even in the absence of marked transaminase elevations).

Post-treatment exacerbations of HBV infection have been reported in HIV uninfected patients treated with lamivudine for chronic HBV infection when lamivudine therapy was discontinued. Similar exacerbations of HBV infection have been reported in patients infected with both HIV and HBV when lamivudine therapy was switched to a regimen not containing lamivudine. The causal relationship between discontinuation of lamivudine therapy and exacerbation of HBV infection is unknown. Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. There is insufficient evidence to determine whether reinitiation of lamivudine alters the course of post-treatment exacerbations of hepatitis.

Adverse effects seen with the use of lamivudine include pancreatitis, paresthesia and peripheral neuropathy, skin rash, or splenomegaly, and are more commonly observed in pediatric patients than in adults.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another. Consequently, lamivudine should not be coadministered with zalcitabine.

Lamivudine exposure was increased by 44% and lamivudine renal clearance was decreased by 30% when coadministered with sulfamethoxazole/trimethoprim. Concurrent administration of lamivudine and zidovudine in one small study resulted in a 39% increase in peak plasma concentration of zidovudine with no significant changes in the area under the concentration-time curve (AUC) or total clearance of lamivudine or zidovudine.

Concurrent administration of lamivudine with indinavir and zidovudine resulted in a 6% decrease in AUC of lamivudine, no change in AUC of indinavir, and a 36% increase in AUC of zidovudine. No adjustment in dose is necessary. Concurrent administration of lamivudine with drugs associated with pancreatitis (e.g., alcohol, didanosine, IV pentamidine, sulfonamides) or with drugs associated with peripheral neuropathy (e.g., dapsone, didanosine, isoniazid, stavudine,  zalcitabine) should be avoided or done with caution.

The higher and lower dose formulations of lamivudine should not be used concurrently. Concurrent administration of products that also contain lamivudine should be avoided, including the coformulations of abacavir sulfate and lamivudine; lamivudine and zidovudine; and abacavir sulfate, lamivudine, and zidovudine.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Lamivudine is contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any of the components of the products.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including lamivudine and other antiretrovirals. Lamivudine for HIV (brand name Epivir) in oral solution or tablet form contains higher doses of the active ingredient (lamivudine) than the lamividune formulation used to treat chronic HBV infection (brand name Epivir-HBV). Patients with HIV infection should receive only dosing forms appropriate for treatment of HIV.

In pediatric patients with a history of prior antiretroviral nucleoside exposure, a history of pancreatitis, or other significant risk factors for the development of pancreatitis, lamivudine should be used in caution. Treatment with lamivudine should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur.

Risk-benefit should be considered in HIV infected patients with renal function impairment.]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[2(1H)-Pyrimidinone, 4-amino-1-  ((2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan- 5-yl)-]]></drug:casname><drug:casnumber><![CDATA[134678-17-4]]></drug:casnumber><drug:molecularformula><![CDATA[C8-H11-N3-O3-S]]></drug:molecularformula><drug:elementalcomposition><![CDATA[C41.91%, H4.84%, N18.33%, O20.94%, S13.99%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[160 to 162 C]]></drug:meltingpoint><drug:molecularweight><![CDATA[229.26]]></drug:molecularweight><drug:physicaldescription><![CDATA[White to off-white crystalline solid.]]></drug:physicaldescription><drug:stability><![CDATA[Lamivudine oral solution need not be reconstituted.]]></drug:stability><drug:solubility><![CDATA[Approximately 70 mg/ml in water at 20 C.]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:othername><![CDATA[3TC]]></drug:othername></drug:othernames><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[Epivir Prescribing Information from the FDA Web site <a href=" http://www.fda.gov/cder/foi/label/2006/020596s025,020564s024lbl.pdf">[PDF]</a>. A more current version may be available on the manufacturer's Web site.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16896585 Lehmann C, Wyen C, Fatkenheuer G. Rapid Improvement of Liver Function in a Patient with HIV and Hepatitis B Coinfection Treated with Lamivudine and Tenofovir. Infection. 2006 Aug;34(4):234-5.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16896585&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16732152 LePrevost M, Green H, Flynn J, Head S, Clapson M, Lyall H, Novelli V, Farrelly L, Walker AS, Burger DM, Gibb DM. Pediatric European Network for the Treatment of AIDS 13 Study Group. Adherence and acceptability of once daily Lamivudine and abacavir in human immunodeficiency virus type-1 infected children. Pediatr Infect Dis J. 2006 Jun;25(6):533-7.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16732152&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16941375 Levy V, Grant RM. Antiretroviral Therapy for Hepatitis B Virus-HIV-Coinfected Patients: Promises and Pitfalls.
Clin Infect Dis. 2006 Oct 1;43(7):904-10. Epub 2006 Aug 23.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16941375&dopt=Abstract]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Lamivudine]]></drug:drugname><drug:companyname><![CDATA[GlaxoSmithKline]]></drug:companyname><drug:address1><![CDATA[5 Moore Drive]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Research Triangle Park]]></city><drug:state><![CDATA[NC]]></drug:state><drug:zipcode><![CDATA[27709]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(888) 825-5249]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Epivir]]></drug:drugname><drug:companyname><![CDATA[GlaxoSmithKline]]></drug:companyname><drug:address1><![CDATA[5 Moore Drive]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Research Triangle Park]]></city><drug:state><![CDATA[NC]]></drug:state><drug:zipcode><![CDATA[27709]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(888) 825-5249]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[July 24, 2007]]></drug:lastupdated></item><item><title><![CDATA[Lamivudine/Zidovudine]]></title><description><![CDATA[Combivir, is a combination of the two antiretroviral drugs: lamivudine (Epivir) and zidovudine (Retrovir). Both of these medicines are nucleoside reverse transcriptase inhibitors (NRTIs). NRTIs block reverse transcriptase, a protein that HIV needs to make more copies of itself.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=285]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Lamivudine/Zidovudine]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[la-MI-vyoo-deen, zye-DOE-vyoo-deen]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Combivir]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Lamivudine/Zidovudine]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Nucleoside Reverse Transcriptase Inhibitors]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Lamivudine/zidovudine is a fixed-dose tablet containing two synthetic nucleoside analogues: lamivudine and zidovudine. Each tablet contains 150 mg of lamivudine and 300 mg of zidovudine, each of which inhibits HIV-1 viral reverse transcriptase.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Lamivudine/zidovudine was approved by the FDA on September 27, 1997, for use in combination with other antiretroviral agents for the treatment of HIV infection. Lamivudine/zidovudine tablets are an alternate regimen to lamivudine and zidovudine given as separate formulations.

Lamivudine is used with zidovudine for postexposure prophylaxis of HIV infection in health care workers and other individuals exposed occupationally via percutaneous injury or mucous membrane or nonintact skin contact with blood, tissues, or other body fluids associated with a risk for HIV transmission.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Film-coated tablets containing lamivudine 150 mg and zidovudine 300 mg.

The recommended dose of lamivudine/zidovudine for adults and adolescents at least 12 years of age is one tablet twice daily. Lamivudine/zidovudine should not be prescribed for patients requiring dosage adjustment such as those with reduced renal function (creatinine clearance less than 50 ml/min), those experiencing dose-limiting adverse events, or those with impaired hepatic function or liver cirrhosis.]]></drug:dosageform><drug:storage><![CDATA[Store between 2 C and 30 C (36 F to 86 F).]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Lamivudine and zidovudine each inhibit viral reverse transcriptase (RT), an enzyme HIV requires in order to replicate, by incorporating into viral DNA and terminating the viral DNA chain. (For more information, see the individual drug records for lamivudine and zidovudine.) 

Lamivudine is a synthetic nucleoside analogue that is phosphorylated intracellularly to its active 5'-triphosphate metabolite, lamivudine triphosphate (L-TP). In vitro, lamivudine with zidovudine had synergistic antiretroviral activity. L-TP, also referred to as 3TC-TP, is a structural analogue of deoxycytidine triphosphate (dC-TP), the natural substrate for viral RT. L-TP competes with naturally occurring dC-TP for incorporation into viral DNA by reverse transcriptase and once incorporated, causes premature termination of viral DNA synthesis.

Following oral dosing, lamivudine is rapidly absorbed. Absolute bioavailability in adults was 86% for the tablet dosage form. Lamivudine is extensively distributed. It crosses the blood-brain barrier and is distributed in the cerebrospinal fluid (CSF). The ratio of CSF/plasma concentration of lamivudine as reported by the manufacturer is 0.12 (range 0.04 to 0.47). Plasma protein binding is less than 36%. Lamivudine serum half-life is 2.5 +/- 0.5 hours. About 70% of an intravenous dose is excreted unchanged in the urine. Metabolism is a minor route of elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite. Within 12 hours after a single oral dose in six adults, 5.2% of the metabolite was excreted in the urine. In most single-dose studies in infected patients, the mean elimination half-life ranged from 5 to 7 hours.

Zidovudine is also a synthetic nucleoside analogue that is phosphorylated intracellularly to its active 5'-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). ZDV-TP appears to compete with thymidine triphosphate for the RT enzyme and incorporation into viral DNA. After incorporation of ZDV-TP, DNA synthesis is prematurely terminated because the 3'-azido group in the zidovudine molecule prevents further 5' to 3' phosphodiester linkages. In cell culture drug combination studies, zidovudine demonstrates synergistic activity with abacavir, delavirdine, didanosine, indinavir, nelfinavir, nevirapine, ritonavir, saquinavir, and zalcitabine, and additive activity with interferon alfa.

Zidovudine is rapidly absorbed from the gastrointestinal tract and extensively distributed, with peak serum concentrations occurring within 0.4 to 1.5 hours; however, absorption following oral administration shows considerable individual variability. In fasting adults, about 64% of an oral dose reaches systemic circulation as unchanged drug. There is limited information on the distribution of zidovudine in the body, but the drug appears to be widely distributed. Zidovudine is distributed into the CSF. The ratio of CSF/plasma concentration of zidovudine as reported by the manufacturer is 0.6 (range 0.04 to 2.62). However, animal studies indicate that, although zidovudine distributes easily into the CSF, distribution into the brain interstitial fluid may be minimal.(10) Plasma protein binding is low and elimination is primarily by hepatic metabolism. The major metabolite is 3'-azido-3'-deoxy-5'-O- beta-D-glucopyranuronosylthymidine (GZDV). Some 14% to 18% of unchanged zidovudine and 72% to 74% of the drug as its major metabolite, GZDV, are eliminated through the urine.

One lamivudine/zidovudine tablet is bioequivalent to one lamivudine tablet (150 mg) plus one zidovudine tablet (300 mg) following single-dose administration to healthy adults.

Lamivudine/zidovudine is in FDA Pregnancy Category C. No adequate or well-controlled studies of the combination drug have been done in pregnant women. A study of zidovudine therapy in women in the last trimester of pregnancy showed that although this drug does cross the placenta, there was no evidence of drug accumulation, and zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery. Studies in laboratory rabbits and rats have shown that lamivudine crosses the placenta, with evidence of embryo lethality in rabbits but not in rats at dosage levels many times higher than the corresponding dose for humans. Lamivudine/zidovudine should be used in pregnancy only if the potential benefits outweigh the risks. An Antiretroviral Pregnancy Registry has been established to monitor the outcomes of pregnant women exposed to lamivudine/zidovudine and other antiretrovirals. Physicians are encouraged to register patients by calling 1-800-258-4263 or online at http://www.APRegistry.com. Zidovudine is excreted in human milk, and lamivudine is excreted in the milk of laboratory animals.

Lamivudine-resistant isolates of HIV-1 have been selected in vitro and have also been isolated from patients treated with lamivudine or lamivudine plus zidovudine. The resistant isolates showed reduced susceptibility to lamivudine. In patients receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV-1 isolates from most patients became phenotypically and genotypically resistant to lamivudine within 12 weeks. In some patients harboring zidovudine-resistant virus, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with zidovudine and lamivudine. Lamivudine/zidovudine combination therapy delayed the emergence of mutations conferring zidovudine resistance. HIV strains resistant to both lamivudine and zidovudine have been isolated from patients after prolonged lamivudine/zidovudine therapy.

Cross resistance to didanosine and zalcitabine has been seen in patients treated with lamivudine alone or in combination with zidovudine. In some patients treated with zidovudine plus didanosine or zalcitabine, isolates resistant to multiple RT inhibitors, including lamivudine, have emerged. Multiple drug resistance, including resistance to lamivudine, didanosine, stavudine, zalcitabine, and zidovudine, has been observed in HIV isolates from some patients treated for more than 1 year with zidovudine plus didanosine or zalcitabine. The pattern of mutations with combination therapy was different from that seen with zidovudine monotherapy.

Cross-resistance between zidovudine and HIV protease inhibitors is unlikely because the drugs have different target enzymes. The potential of cross resistance between zidovudine and non-nucleoside reverse transcriptase inhibitors (NNRTIs) is also considered to be low since the drugs bind at different sites on the reverse transcriptase and have different mechanisms of action.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Lactic acidosis and severe hepatomegaly with steatosis have been reported with the use of nucleoside analogues alone or in combination. These conditions are sometimes fatal. Female gender, obesity, and prolonged nucleoside exposure may be risk factors. Caution should be exercised in any patient with known risk factors for liver disease; however, cases have been reported in patients with no known risk factors. Treatment with lamivudine/zidovudine should be suspended in any patient who develops clinical or laboratory findings that suggest the presence of lactic acidosis or pronounced hepatotoxicity. Zidovudine has been associated with hematologic toxicity, including neutropenia and severe anemia, particularly in patients with advanced HIV disease. Myopathy and myositis have occurred with prolonged use of zidovudine and may occur during therapy with lamivudine/zidovudine. 

Post-treatment exacerbations of hepatitis B virus (HBV) infections have been reported in both HIV infected and uninfected patients treated with lamivudine for chronic HBV when lamivudine therapy was discontinued.  Deterioration of liver disease has been reported in some patients coinfected with HIV and HIV when lamivudine therapy was discontinued.

Immune reconstitution syndrome has been reported in patients receiving anti-HIV therapy, including lamivudine/zidovudine. Patients who exhibit an inflammatory response to indolent or residual opportunistic infections may require further evaluation before initiating certain anti-HIV regimens.

Other reported adverse events occurring in clinical trials of lamivudine/zidovudine affected the following body systems: body as a whole (headache, malaise, fatigue, fever, chills); digestive (nausea, diarrhea, vomiting, anorexia and/or decreased appetite, abdominal pain and cramps, dyspepsia); nervous system (neuropathy, insomnia and other sleep disorders, dizziness, depressive disorders); respiratory (nasal signs and symptoms, cough); skin (rash); and musculoskeletal (musculoskeletal pain, myalgia, arthralgia). Adverse events reported during post-approval use of lamivudine/zidovudine or either of the component drugs occurred in the following body systems: body as a whole (redistribution or accumulation of body fat); cardiovascular (cardiomyopathy); endocrine and metabolic (gynecomastia, hyperglycemia); gastrointestinal (oral mucosal pigmentation, stomatitis); general (vasculitis, weakness); hemic and lymphatic (aplastic anemia, anemia, lymphadenopathy, pure red cell aplasia, splenomegaly); hepatic and pancreatic (lactic acidosis and hepatic steatosis, pancreatitis); hypersensitivity (sensitization reactions, including anaphylaxis, urticaria); musculoskeletal (muscle weakness, creatine phosphokinase elevation, rhabdomyolysis); nervous (paresthesia, peripheral neuropathy, seizures); respiratory (abnormal breath sounds, wheezing ); and skin (alopecia, erythema multiform, Stevens-Johnson syndrome).]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Lamivudine/zidovudine tablets may be administered with or without food. Administering the drug with food did not alter the area under the concentration-time curve (AUC) for lamivudine or zidovudine, as compared to administration under fasting conditions.

Because lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another, lamivudine/zidovudine should not be coadministered with zalcitabine. Lamivudine exposure (AUC) was increased by 44% and lamivudine renal clearance was decreased by 30% when co-administered with sulfamethoxazole/trimethoprim. Concurrent administration of lamivudine and zidovudine in one small study resulted in a 39% increase in peak plasma concentration of zidovudine with no change observed in AUC. Concurrent administration of lamivudine with indinavir and zidovudine resulted in a 6% decrease in AUC of lamivudine, no change in AUC of indinavir, and a 36% increase in AUC of zidovudine. No adjustment in dose is necessary. Concurrent administration of lamivudine with drugs associated with pancreatitis (e.g., alcohol, didanosine, IV pentamidine, sulfonamides, zalcitabine) or with drugs associated with peripheral neuropathy (e.g., dapsone, didanosine, isoniazid, stavudine, zalcitabine) should be avoided or used cautiously.

Zidovudine may interact with atovaquone, clarithromycin, fluconazole, methadone, phenytoin, probenecid, rifampin, and valproic acid. The hematologic toxicity of zidovudine may be increased when zidovudine is coadministered with bone marrow depressant agents such as ganciclovir or interferon-alpha and others, or with blood dyscrasia-causing medications, cytotoxic agents, or radiation therapy. Medications that are metabolized by hepatic glucuronidation such as (e.g., acetaminophen, aspirin, benzodiazepines, cimetidine, indomethacin, morphine, sulfonamides) may in theory increase the risk of toxicity of zidovudine or the other medication.  An antagonistic relationship between zidovudine and stavudine, doxorubicin, and ribavirin has been reported in vitro. Concomitant use of zidovudine with any of these three drugs should be avoided. Coadministration of zidovudine and stavudine is not recommended due to limited evidence of in vivo antagonism.

In vitro studies show that ribavirin reduces the phosphorylation of pyrimidine nucleoside analogues, including lamivudine and zidovudine.  No evidence of an interaction was seen when ribavin was coadministered with lamivudine/zidovudine in patients coinfected with HIV and hepatitis C virus (HCV).  However, hepatic decompensation (some fatal) has occurred in patients coinfected with HIV and HCV receiving combination anti-HIV therapy with interferon alfa and ribavirin.

Combivir is a fixed dose formulation of lamivudine and zidovudine and ordinarily should not be administered concomitantly with lamivudine, zidovudine, or Trizivir, a fixed-dose combination of abacavir sulfate, lamivudine, and zidovudine.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Lamivudine/zidovudine tablets are contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any of the components of the products.

Due to the fixed-dose formulation of lamivudine/zidovudine, there is no way to accommodate the dosage reduction of zidovudine that may be necessary in individuals with impaired liver function or the dosage adjustment of both lamivudine and zidovudine that may be necessary in those with renal insufficiency (creatinine clearance less than 50 ml/min). Additionally, dosage adjustments cannot be made for patients younger than 12 years old or for any patient with special dosing requirements. Lamivudine/zidovudine is not recommended for these patients.]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[Lamivudine: 2(1H)-Pyrimidinone, 4-amino-1-[2-(hydroxymethyl)-1,3-oxathiolan- 5-yl]-,(2R-cis)-Zidovudine: Thymidine, 3'-azido-3'-deoxy-]]></drug:casname><drug:casnumber><![CDATA[Lamivudine: 134678-17-4Zidovudine: 30516-87-1]]></drug:casnumber><drug:molecularformula><![CDATA[Lamivudine: C8-H11-N3-O3-S; Zidovudine: C10-H13-N5-O4]]></drug:molecularformula><drug:elementalcomposition><![CDATA[Lamivudine: C41.91%, H4.84%, N18.33%, O20.94%, S13.99%; Zidovudine: C44.94%, H4.90%, N26.21%, O23.95%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[Lamivudine: 160 to 162 C; Zidovudine: 106 to 112 C]]></drug:meltingpoint><drug:molecularweight><![CDATA[Lamivudine: 229.26; Zidovudine: 267.24]]></drug:molecularweight><drug:physicaldescription><![CDATA[Lamivudine: White to off-white crystalline solid.

Zidovudine: White to beige, odorless, crystalline solid ]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[Lamivudine: 70 mg/ml in water at 20 C.

Zidovudine: 20.1 mg/ml in water at 25 C.]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform" /><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[Combivir Prescribing Information from the FDA web site <A HREF="http://www.fda.gov/cder/foi/label/2004/20857slr014_combivir_lbl.pdf">[PDF]</A>. A more current version may be available on the manufacturer's Web site.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16944966 Castillo SA, Hernandez JE, Brothers CH. Long-term safety and tolerability of the lamivudine/abacavir combination as components of highly active antiretroviral therapy. Drug Saf. 2006;29(9):811-26.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16944966&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/14620390 Fischl MA, Burnside AE Jr, Farthing CE, Thompson MA, Bellos NC, Williams VC, Kauf TL, Wannamaker PG, Shaefer MS; ESS40005 Study Team. Twice-daily Trizivir versus Combivir-abacavir in antiretroviral-experienced adults with human immunodeficiency virus-1 infection: a formulation-switch trial. Pharmacotherapy. 2003 Nov;23(11):1432-40.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=14620390&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16420253 Kumar P, Rodriguez-French A, Thompson M, Tashima K, Averitt D, Wannamaker P, Williams V, Shaefer M, Pakes G, Pappa K; ESS40002 Study Team. A prospective, 96-week study of the impact of Trizivir, Combivir/nelfinavir, and lamivudine/staviudine/nelfinavir on lipids, metabolic parameters and efficacy in antiviral-naïve patients: effect of sex and ethnicity. HIV Med. 2006 Mar;7(2):85-98.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16420253&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/12741629 Matheron S, Descamps D, Boue F, Livrozet JM, Lafeuillade A, Aquilina C, Troisvallets D, Goetschel A, Brun-Vezinet F, Mamet JP, Thiaux C; CNA3007 Study Group. Triple nucleoside combination zidovudine/lamivudine/abacavir versus zidovudine/lamivudine/nelfinavir as first-line therapy in HIV-1-infected adults: a randomized trial. Antivir Ther. 2003 Apr;8(2):163-71.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=12741629&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/12916008 Ruane PJ, Parenti DM, Margolis DM, Shepp DH, Babinchak TJ, Van Kempen AS, Kauf TL, Danehower SA, Yau L, Hessenthaler SM, Goodwin D, Hernandez JE; COL30336 Study Team. Compact quadruple therapy with the lamivudine/zidovudine combination tablet plus abacavir and efavirenz, followed by the lamivudine/zidovudine/abacavir triple nucleoside tablet plus efavirenz in treatment-naive HIV-infected adults. HIV Clin Trials. 2003 Jul-Aug;4(4):231-43.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=12916008&dopt=Abstract]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Lamivudine/Zidovudine]]></drug:drugname><drug:companyname><![CDATA[GlaxoSmithKline]]></drug:companyname><drug:address1><![CDATA[5 Moore Drive]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Research Triangle Park]]></city><drug:state><![CDATA[NC]]></drug:state><drug:zipcode><![CDATA[27709]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(888) 825-5249]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Combivir]]></drug:drugname><drug:companyname><![CDATA[GlaxoSmithKline]]></drug:companyname><drug:address1><![CDATA[5 Moore Drive]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Research Triangle Park]]></city><drug:state><![CDATA[NC]]></drug:state><drug:zipcode><![CDATA[27709]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(888) 825-5249]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[May 10, 2007]]></drug:lastupdated></item><item><title><![CDATA[Stavudine]]></title><description><![CDATA[Stavudine, also known as Zerit or d4T, is a type of medicine called a nucleoside reverse transcriptase inhibitor (NRTI). This class of medicines blocks reverse transcriptase, a protein that HIV needs to make more copies of itself.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=43]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Stavudine]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[STAV-yoo-deen]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Zerit]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Stavudine]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Nucleoside Reverse Transcriptase Inhibitors]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Stavudine, a synthetic antiretroviral agent, is a dideoxynucleoside reverse transcriptase inhibitor. It is an analogue of thymidine, a naturally occurring pyrimidine nucleoside. It differs from thymidine in the 2'-3' double bond on the deoxyribose moiety and in the replacement of the 3'-hydroxyl group with hydrogen. The absence of a free 3'-hydroxyl group results in the inability of stavudine to form phosphodiester linkages at this position.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Stavudine was approved by the FDA on June 24, 1994, for use in combination with other antiretroviral agents and is indicated for the treatment of HIV-1 infection in adults and pediatric patients. Additionally, stavudine is indicated for the treatment of patients with HIV infection who have received prolonged previous treatment with zidovudine. The duration of clinical benefit from antiretroviral therapy involving stavudine may be limited.  If disease progression occurs during stavudine treatment, an alternative antiretroviral therapy is recommended.

Although stavudine was used as monotherapy in initial studies evaluating the safety and efficacy of the drug, it should not be used alone in the management of HIV infection. Stavudine is also used in conjunction with other antiretroviral agents for postexposure prophylaxis in health care workers and in other individuals exposed occupationally to blood, tissues, or other body fluids associated with a risk for transmission of the HIV virus.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Immediate-release (IR) capsules containing stavudine 15, 20, 30, or 40 mg.

Oral solution containing stavudine 1 mg/ml.

Extended-release (XR) capsules containing stavudine 37.5, 50, 75, or 100 mg.

The recommended dosages based on body weight are as follows: 40 mg twice daily for patients weighing 60 kg (132 lbs) or more and 30 mg twice daily for patients weighing less than 60 kg (132 lbs). The interval between doses of stavudine should be 12 hours. The recommended dose for pediatric patients at least 14 days old and weighing less than 30 kg (66 lbs) is 1 mg/kg/dose, given every 12 hours. Pediatric patients weighing 30 kg (66 lbs) or greater should receive the recommended adult dosage.

Dosing should be adjusted in patients with impaired renal function, according to the recommendations in the manufacturer's prescribing information. For patients on hemodialysis, the recommended dosage is 20 mg every 24 hours for patients weighing more than 60 kg or 15 mg every 24 hours  for patients weighing less than 60 kg.]]></drug:dosageform><drug:storage><![CDATA[Store stavudine immediate-release capsules and powder for reconstitution in tightly closed containers at 25 C (77 F). Excursions between 15 C and 30 C (59 F and 86 F) are permitted. Protect powder from excessive moisture. Refrigerate reconstituted solution at 2 C to 8 C (36 F to 46 F) and discard unused solution after 30 days. Store stavudine extended-release capsules in tightly closed containers at 25 C (77 F). Excursions between 15 C and 30 C (59 F and 86 F) are permitted.]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Stavudine is phosphorylated by cellular kinases to the active metabolite stavudine triphosphate. Stavudine triphosphate inhibits HIV replication by two known mechanisms. It inhibits HIV reverse transcriptase (RT) by competing with the natural substrate deoxythymidine triphosphate. Its incorporation into viral DNA causes termination of DNA chain elongation, because stavudine lacks the essential 3'-OH group. Stavudine triphosphate inhibits cellular DNA polymerase beta and gamma, and markedly reduces the synthesis of mitochondrial DNA. A stavudine concentration ranging from 0.009 to 4 micromolar is required to inhibit HIV replication by 50% in vitro. The in vitro potency of stavudine against HIV is similar to that of zidovudine.

Following oral administration to HIV-infected patients, stavudine is rapidly absorbed, with the peak plasma concentration (Cmax) occurring within 1 hour after dosing. The systemic exposure to stavudine is the same following administration of capsules or solution. Stavudine has an oral bioavailability of 86% in adults and 77% in children. Stavudine may be taken with or without food; administration with food results in a decrease in Cmax and time to Cmax but does not have an appreciable effect on the area under the concentration time curve (AUC) of the drug. Data from single- and multiple-dosing studies indicate that the Cmax and AUC of stavudine increase in proportion to dose over the dose range of 0.03 to 4 mg/kg; there is no evidence that accumulation occurs following multiple doses.

Stavudine distributes equally between red blood cells and plasma. In a study of 8 children, stavudine crossed the blood brain barrier and distributed into the cerebrospinal fluid (CSF) with a mean CSF-to-plasma concentration of 59%. Stavudine is distributed into CSF following oral administration.  In a limited number of HIV infected adults receiving oral stavudine at a dosage of 40 mg twice daily in conjunction with other antiretroviral agents, CSF concentrations of the drug averaged 71 ng/ml in samples taken 1 hour after a dose at 8 weeks of therapy; steady-state Cmax at this time averaged 930 ng/ml.  Similar CSF and plasma concentrations of stavudine were measured in these patients after almost 2 years of continuous therapy. Following a single intravenous dose in HIV infected individuals, the volume of distribution is 46 l in adults and 0.73 l/kg in pediatric patients 5 weeks to 15 years of age. Results of a study in HIV infected men indicate that stavudine is distributed into semen in concentrations approximating those of concurrent plasma concentrations.

Stavudine is in FDA Pregnancy Category C. Adequate and well-controlled studies have not been done in pregnant women.  It is not known whether stavudine crosses the placenta in humans; however, it does cross the placenta in rats. It is not known whether stavudine reduces perinatal transmission of HIV infection as does zidovudine. Stavudine should be used with caution during pregnancy and only if clearly needed. No evidence of impaired fertility was seen in rats given stavudine at doses that resulted in a Cmax that was 216 times that observed in humans who received a clinical dosage of 1 mg/kg per day. Rats and rabbits exposed to levels of stavudine up to 399 and 183 times, respectively, the clinical dosage for humans revealed no evidence of teratogenicity. The incidence of common skeletal variation, incomplete ossification, and neonatal mortality increased in rats exposed to 399 times the human exposure. A slight postimplantation loss was seen at 216 times the human exposure. To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral medications, including stavudine, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263 or online at http://www.APRegistry.com.

It is not known whether stavudine is distributed into human milk; however, it is distributed into milk in rats. Because of the potential for HIV transmission and for potential adverse effects in breastfed infants, mothers receiving antiretroviral medications should be instructed not to breastfeed.

Binding of stavudine to serum proteins is negligible over the concentration range of 0.01 to 11.4 mcg/ml. The mean elimination half-life of stavudine following a single oral dose is 1.6 hours in HIV infected adults and 0.96 hours in HIV infected pediatric patients (5 weeks to 15 years of age). In patients with renal function impairment (creatinine clearances of less than 25 ml/min), the half-life is approximately 3.7 to 5.5 hours. The time to Cmax is 0.5 to 1.5 hours. The intracellular half-life of stavudine triphosphate is approximately 3.5 hours, with peak serum concentration of approximately 1.4 mcg/ml after a single oral dose of 70 mg stavudine.

Renal elimination accounts for about 40% of overall clearance into urine over a 6 to 24 hour period, regardless of the route of administration. Approximately 50% of an administered dose undergoes nonrenal elimination. The exact metabolic fate of stavudine is unknown. Intracellularly, in both virus-infected and uninfected cells, stavudine is converted to stavudine monophosphate by cellular thymidine kinase. The monophosphate is subsequently converted to stavudine diphosphate and then to stavudine triphosphate. It is not known whether stavudine is removed by peritoneal dialysis. The mean renal clearance is about twice the average endogenous creatinine clearance, indicating active tubular secretion in addition to glomerular filtration. Oral clearance of stavudine decreases and the terminal elimination half-life increases as creatinine clearance decreases; therefore, dosage of stavudine should be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis.

HIV-1 isolates with reduced susceptibility to stavudine have been selected in vitro and were also obtained from patients treated with stavudine. Phenotypic analysis of HIV-1 isolates from 61 stavudine-treated patients receiving prolonged, 6- to 29-months treatment of stavudine monotherapy showed that post-therapy isolates from four patients exhibited IC50 values more than fourfold (ranging from 7- to 16-fold) higher than the average pretreatment susceptibility of baseline isolates. Of these, HIV-1 isolates from one patient contained the zidovudine-resistance-associated mutations T215Y and K219E, and isolates from another patient contained the multiple-nucleoside-resistance-associated mutation Q151M.  Mutations in the RT gene of HIV-1 isolates from the other two patients were not detected. The genetic basis for stavudine susceptibility changes has not been identified.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Common adverse effects seen with the use of stavudine include peripheral neuropathy, arthralgia, hypersensitivity, myalgia, anorexia, chills and fever, rash, asthenia, gastrointestinal disturbances, headache, insomnia, and fat redistribution.

Studies suggest that lactic acidosis and severe hepatomegaly with steatosis may be more often associated with antiretroviral regimens containing stavudine. Female gender, obesity, and prolonged nucleoside exposure may be risk factors; however, fatal lactic acidosis has been reported in patients with and without known risk factors for liver disease. Generalized fatigue, digestive symptoms (nausea, vomiting, abdominal pain, and sudden unexplained weight loss), respiratory symptoms (tachypnea, dyspnea), or neurologic symptoms such as motor weakness might be indicative of lactic acidosis. Therapy with stavudine should be suspended in patients with suspected lactic acidosis. Permanent discontinuation of stavudine should be considered in patients with confirmed lactic acidosis.

An increased risk of hepatotoxicity, which may be fatal, may occur in patients treated with stavudine in combination with didanosine and hydroxyurea. Fatal and nonfatal pancreatitis has occurred when stavudine was part of a combination regimen that included didanosine with or without hydroxyurea. Treatment should be suspended in patients with suspected pancreatitis. Reinstitution of stavudine after a confirmed diagnosis of pancreatitis should be undertaken with caution. The new regimen should not include either didanosine or hydroxyurea. Fatal lactic acidosis has occurred in pregnant women who received the combination of stavudine and didanosine with other antiretroviral agents. It is unclear if pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues.

Motor weakness has been reported rarely in patients receiving combination antiretroviral therapy including stavudine. Most of these cases have occurred in the setting of lactic acidosis. If motor weakness develops, stavudine therapy should be discontinued. Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving stavudine. Peripheral neuropathy has occurred more frequently in patients with advanced HIV disease, a history of neuropathy, or concurrent neurotoxic drug therapy, including didanosine. Treatment with stavudine should be interrupted if symptoms of peripheral neuropathy occur. Stavudine-induced neuropathy may resolve completely if stavudine is withdrawn promptly; however, in some cases symptoms may worsen temporarily upon withdrawal. If symptoms resolve completely, patients may tolerate resumption of stavudine treatment at a lowered dose. If peripheral neuropathy recurs after resumption, permanent discontinuation of stavudine should be considered.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Caution should be used in coadministration of stavudine with other drugs that may cause peripheral neuropathy, such as chloramphenicol, cisplatin, dapsone, didanosine, ethambutol, ethionamide, hydralazine, isoniazid, lithium, metronidazole, nitrofurantoin, phenytoin, vincristine, and zalcitabine. Didanosine with or without hydroxyurea may increase the risk of peripheral neuropathy, liver function abnormalities, pancreatitis, or potentially fatal hepatotoxicity if taken concurrently with stavudine.

Concomitant use of stavudine and zidovudine is not recommended due to possible competitive inhibition of the intracellular phosphorylation of stavudine. In vitro studies detected an antagonistic antiviral effect between stavudine and zidovudine at a molar ratio of 20 to 1, respectively; concurrent use is not recommended until in vivo studies demonstrate that these medications are not antagonistic in their anti-HIV activity.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including stavudine and other antiretrovirals. Fatal lactic acidosis has been reported in pregnant women who received the combination of stavudine and didanosine with other antiretroviral agents. The combination of stavudine and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risks. Fatal and nonfatal pancreatitis has occurred during therapy when stavudine was part of a combination regimen that included didanosine, with or without hydroxyurea, in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression.

Stavudine is contraindicated in patients with clinically significant hypersensitivity to stavudine or to any of the components contained in the formulation.

Risk-benefit should be considered in patients with alcoholism, hepatic function impairment, peripheral neuropathy, or renal function impairment.]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[Thymidine, 2',3'-didehydro-3'-deoxy-]]></drug:casname><drug:casnumber><![CDATA[3056-17-5]]></drug:casnumber><drug:molecularformula><![CDATA[C10-H12-N2-O4]]></drug:molecularformula><drug:elementalcomposition><![CDATA[C53.57%, H5.39%, N12.49%, O28.54%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[165 C to 166 C (Horwitz); 174 C (Beach)]]></drug:meltingpoint><drug:molecularweight><![CDATA[224.22]]></drug:molecularweight><drug:physicaldescription><![CDATA[White to off-white crystalline solid.]]></drug:physicaldescription><drug:stability><![CDATA[Oral solution should be discarded 30 days after reconstitution.]]></drug:stability><drug:solubility><![CDATA[About 83 mg/ml in water and 30 mg/ml in propylene glycol at 23 C. The n-octanol/water partition coefficient of stavudine at 23 C is 0.144.]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:othername><![CDATA[d4T]]></drug:othername></drug:othernames><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[Zerit Prescribing Information from the FDA Web site<a href="http://www.fda.gov/cder/foi/label/2005/020412s024lbl.pdf">[PDF]</a>. A more current version may be available on the manufacturer's Web site.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[Zerit XR Prescribing Information from the FDA Web site<a href="http://www.fda.gov/cder/foi/label/2005/21453s004lbl.pdf">[PDF]</a>. A more current version may be available on the manufacturer's Web site.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/15809919 Blanche S.  Safety of stavudine during pregnancy.  J Infect Dis. 2005 May 1;191(9):1567-8; author reply 1568-9.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15809919&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17591031 Milinkovic A, Martinez E, Lopez S, de Lazzari E, Miro O, Vidal S, Blanco JL, Garrabou G, Laguno M, Arnaiz JA, Leon A, Larrousse M, Lonca M, Mallolas J, Gatell JM. The impact of reducing stavudine dose versus switching to tenofovir on plasma lipids, body composition and mitochondrial function in HIV-infected patients. Antivir Ther. 2007;12(3):407-15.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17591031&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17640745 Paolucci S, Baldanti F, Campanini G, Cancio R, Belfiore A, Maga G, Gerna G. NNRTI-selected mutations at codon 190 of human immunodeficiency virus type 1 reverse transcriptase decrease susceptibility to stavudine and zidovudine. Antiviral Res. 2007 Jul 2; [Epub ahead of print]]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17640745&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16625606 Siegfried NL, Van Deventer PJ, Mahomed FA, Rutherford GW. Stavudine, lamivudine and nevirapine combination therapy for treatment of HIV infection and AIDS in adults. Cochrane Database Syst Rev. 2006 Apr 19;(2):CD004535.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16625606&dopt=Abstract]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Stavudine]]></drug:drugname><drug:companyname><![CDATA[Bristol - Myers Squibb Co]]></drug:companyname><drug:address1><![CDATA[PO Box 4500]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Princeton]]></city><drug:state><![CDATA[NJ]]></drug:state><drug:zipcode><![CDATA[08543-4500]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 321-1335]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Zerit]]></drug:drugname><drug:companyname><![CDATA[Bristol - Myers Squibb Co]]></drug:companyname><drug:address1><![CDATA[PO Box 4500]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Princeton]]></city><drug:state><![CDATA[NJ]]></drug:state><drug:zipcode><![CDATA[08543-4500]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 321-1335]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[September 17, 2007]]></drug:lastupdated></item><item><title><![CDATA[Tenofovir disoproxil fumarate]]></title><description><![CDATA[Tenofovir disoproxil fumarate (tenofovir DF), also known as Viread, is a type of medicine called a nucleoside reverse transcriptase inhibitor (NRTI). NRTIs block reverse transcriptase, a protein that HIV needs to make more copies of itself.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=290]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Tenofovir disoproxil fumarate]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[te-NOE-fo-veer dye soe PROX il]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Viread]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Tenofovir disoproxil fumarate]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Nucleoside Reverse Transcriptase Inhibitors]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Tenofovir is an acyclic nucleotide analogue of deoxyadenosine 5'-monophosphate. Tenofovir disoproxil fumarate (tenofovir DF) is the water-soluble diester prodrug of the active ingredient tenofovir. Specifically, tenofovir DF is a fumaric acid salt of a bis-isopropxycarbonyloxymethyl ester derivative of tenofovir.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Tenofovir DF was approved by the FDA on October 26, 2001. Tenofovir DF is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. Tenofovir DF has also been studied for the treatment of lamivudine-resistant hepatitis B virus (HBV) infection in patients who are coinfected with HIV and HBV. A current clinical trial is testing tenofovir DF's efficacy on improving dyslipidemia in treatment-experienced HIV infected adults. Tenofovir as an antimicrobial vaginal gel is also being investigated for use by women to prevent the sexual transmission of HIV.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Tenofovir DF demonstrates anti-HBV activity in vitro. The efficacy of tenofovir DF in the treatment of HBV has been compared with adefovir dipivoxil in clinical trials. Patients treated with tenofovir DF showed a strong and early suppression of HBV DNA within a few weeks whether they were coinfected with HIV or were without comorbidity. In contrast, patients treated with adefovir dipivoxil showed considerable individual variations in HBV DNA decline. These data suggest tenofovir DF may become an effective alternative for the treatment of patients with lamivudine-resistant HBV infection.

Tenofovir DF has been evaluated in clinical trials in patients coinfected with HBV and HIV.]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Tablets containing tenofovir DF 300 mg, which is equivalent to tenofovir disoproxil 245 mg.

The recommended dosage of tenofovir is 300 mg once daily. The dosing interval of tenofovir should be adjusted in patients with baseline creatinine clearance (CrCl) less than 50 ml/min. Dosing interval recommendations are as follows: CrCl 30 to 49 ml/min, 300 mg every 48 hours; CrCl 10 to 29 ml/min, 300 mg twice weekly; and hemodialysis patients, 300 mg every 7 days.]]></drug:dosageform><drug:storage><![CDATA[Store tablets at a controlled room temperature, 25 C (77 F); excursions are permitted between 15 C and 30 C (59 F to 86 F).]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Tenofovir DF is the orally bioavailable form of tenofovir and requires metabolism to the active metabolite. Tenofovir DF is absorbed and then metabolized by diester hydrolysis to tenofovir, which is then metabolized by phosphorylation to the pharmacologically-active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits reverse transcriptase by competing with the natural substrate, deoxyadenosine 5'-triphosphate. Tenofovir diphosphate is incorporated into HIV viral DNA, causing DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases alpha, beta, and gamma and of mitochondrial DNA polymerase.

Oral bioavailability of tenofovir DF in fasted patients is approximately 25%. Administration of tenofovir DF with a high fat meal increases the oral bioavailability, with an increase in tenofovir area under the plasma concentration-time curve (AUC) of approximately 40% and an increase in maximum plasma concentration (Cmax) of approximately 14%. Food delays the time to tenofovir Cmax by approximately 1 hour. Following oral administration of a single 300-mg dose of tenofovir DF to HIV infected patients in the fasted state, Cmax is achieved in approximately 1 hour. Cmax and AUC values are approximately 296 ng/ml and 2,287 ng(h)/ml, respectively. The pharmacokinetics of tenofovir are dose proportional over a wide dose range and are not affected by repeat dosing. Following IV administration of tenofovir in doses of 1 mg/kg and 3 mg/kg, the volume of distribution at steady-state is approximately 1.3 l/kg and 1.2 l/kg, respectively.

Tenofovir DF is in FDA Pregnancy Category B. No adequate and well-controlled studies have been conducted in pregnant women. Reproduction studies have been performed in laboratory animals at doses up to 19 times the human dose and revealed no evidence of impaired fertility or harm to the fetus. To monitor fetal outcomes of pregnant women exposed to tenofovir DF and other antiretrovirals, an Antiretroviral Pregnancy Registry has been established. Health care providers are encouraged to register patients online at http://www.APRegistry.com or by calling 1-800-258-4263. It is not known whether tenofovir is excreted in human milk; however, tenofovir has been found in the milk of laboratory animals.(4)

In vitro binding of tenofovir to human plasma or serum proteins is less than 0.7% and 7.2%, respectively, over the tenofovir concentration range of 0.01 to 25 mcg/ml. In vitro studies indicate that neither tenofovir DF nor tenofovir are substrates of cytochrome P450 (CYP450) enzymes. Following IV administration of tenofovir, approximately 70% to 80% of the dose is recovered in the urine as unchanged drug within 72 hours of dosing. After multiple oral doses of tenofovir DF under fed conditions, approximately 32% of the administered dose is recovered in urine over 24 hours. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also renally eliminated.

Tenofovir is principally eliminated by the kidneys by a combination of glomerular filtration and active tubular secretion. Dosing adjustment is recommended in all patients with CrCl less than 50 ml/min. Dosage adjustments for renal impairment are available in the prescribing information. Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single dose of tenofovir DF, a 4-hour hemodialysis session removed approximately 10% of the administered tenofovir dose. Tenofovir is not metabolized by liver enzymes; consequently, the impact of liver impairment should be limited. There were no substantial alterations in tenofovir pharmacokinetics in patients with hepatic impairment following a single 300-mg single dose of tenofovir DF. The manufacturer states that no change in tenofovir dosing is required in patients with hepatic impairment.

The virologic response to tenofovir DF therapy has been evaluated in treatment-experienced patients participating in clinical trials. In these studies, 94% of the participants had baseline HIV isolates expressing at least one nucleoside reverse transcriptase inhibitor (NRTI) mutation. These included resistance mutations associated with zidovudine (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N), lamivudine/abacavir (M184V), and others. Varying degrees of cross resistance of tenofovir DF to pre-existing zidovudine-associated mutations were observed and appeared to depend on the number of specific mutations. HIV-1 isolated from 20 patients whose HIV-1 expressed a mean of 3 zidovudine-associated reverse transcriptase mutations that included either the M41L or L210W mutation showed a 3.1-fold decrease in the susceptibility to tenofovir. Also, multinucleoside resistant HIV-1 with a T69S double insertion mutation in the reverse transcriptase showed reduced susceptibility to tenofovir. The K65R mutation selected by tenofovir is also selected in some HIV-1 infected individuals treated with abacavir, didanosine, or zalcitabine. HIV isolates with this mutation also show reduced susceptibility to emtricitabine and lamivudine. Therefore, cross resistance among these drugs may occur in patients whose virus harbors the K65R mutation.

Virologic response to tenofovir DF was not reduced in patients with HIV that expressed the lamivudine/abacavir-associated M184V mutation. Cross resistance between tenofovir DF and HIV PIs is unlikely because of the different enzyme targets involved.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[The most common adverse effects associated with tenofovir DF include asthenia, diarrhea, nausea, and vomiting. Less common side effects of tenofovir DF include hepatotoxicity, including lactic acidosis; abdominal pain; anorexia; and flatulence. Some side effects of tenofovir DF occurring with undetermined incidence include allergic reaction, dyspnea, Fanconi's syndrome, hypophosphatemia, pancreatitis, proximal tubulopathy, renal failure or insufficiency, and acute tubular necrosis. Higher tenofovir concentrations could potentiate tenofovir DF-associated adverse events, including renal disorders.

Fatal lactic acidosis and severe hepatomegaly with steatosis have been reported with the use of nucleoside analogues alone or in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside analogue exposure may be risk factors. However, cases have been reported in patients with no known risk factors. Particular caution should be exercised when administering nucleoside analogues to any patient with known risk factors for liver disease. Treatment with tenofovir DF should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity.

Redistribution/accumulation of body fat, including central obesity and dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance," have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events is unknown. Bone toxicities were seen in laboratory animals receiving tenofovir or tenofovir DF at exposures greater than or equal to sixfold those seen in humans. The mechanisms underlying bone toxicity are unknown. In a 48-week study in HIV infected patients, decreases from baseline in bone mineral density were seen at the lumbar spine and hip. In addition, there were significant increases in levels of serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide, and urinary N-telopeptide. It is not known if long-term administration of tenofovir DF (greater than 1 year) will cause bone abnormalities.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including tenofovir DF. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium infection, cytomegalovirus, Pneumocystis pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Tenofovir DF may be taken with or without food.

When administered with tenofovir DF, the Cmax and AUC of buffered and enteric-coated didanosine increased significantly; the mechanism of this interaction is unknown. Increases in didanosine concentrations of this magnitude could potentiate didanosine-associated adverse events, including pancreatitis and neuropathy. Coadministration of tenofovir DF and didanosine should be undertaken with caution, and patients receiving this combination should be monitored closely for didanosine-associated adverse events. Didanosine should be discontinued in patients who develop didanosine-associated adverse events.

Atazanavir and lopinavir/ritonavir have been shown to increase tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving atazanavir or lopinavir/ritonavir and tenofovir DF should be monitored for tenofovir-associated adverse events. Tenofovir DF should be discontinued in patients who develop tenofovir-associated adverse events. Tenofovir DF decreases the AUC and the minimum plasma concentration (Cmin) of atazanavir. When coadministered with tenofovir DF, it is recommended that atazanavir 300 mg be given with ritonavir 100 mg; atazanavir should not be coadministered with tenofovir DF unless given with ritonavir.

When tenofovir DF 300 mg once daily was coadministered with indinavir 800 mg three times daily for 7 days, an increase in tenofovir Cmax and a decrease in indinavir Cmax was observed. Concurrent administration of tenofovir DF and lamivudine resulted in an average 24% decrease in the Cmax of lamivudine.

When tenofovir DF is taken concurrently with saquinavir/ritonavir, an increase in these three drugs' Cmin has been observed. Increases in Cmax and AUC of saquinavir/ritonavir have also been noted. However, these increases are not expected to be clinically relevant, so no dose adjustments for any of the drugs have been recommended by the manufacturer.

Coadministration with other drugs that are eliminated by active tubular secretion, such as adefovir dipivoxil, cidofovir, acyclovir, valacyclovir, ganciclovir, and valganciclovir, may increase serum concentrations of either tenofovir or the coadministered drug due to competition for this elimination pathway.

Tenofovir did not inhibit drug metabolism mediated by the human CYP450 isoforms CYP3A4, CYP2D6, CYP2C9, and CYP2E1 in vitro. However, a small (6%) but statistically significant reduction in metabolism of CYP1A substrate was observed. Based on these results and the known elimination pathway of tenofovir, the potential for CYP450-mediated interaction with other drug products is low.

Based on data from an open-label randomized study and retrospective database analyses, clinicians are advised to use caution when administering tenofovir DF, enteric-coated didanosine, and either efavirenz or nevirapine in the treatment of treatment-naive HIV infected patients with high baseline viral loads.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Tenofovir DF is contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the product.

Tenofovir DF is not indicated for the treatment of chronic HBV infection, and the safety and efficacy of tenofovir DF have not been established in patients coinfected with HBV and HIV. Severe acute exacerbations of HBV have been reported in patients who are coinfected with HBV and HIV and have discontinued tenofovir DF. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue tenofovir DF and are coinfected with HIV and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted.]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[Bis(hydroxymethyl) [[(R)-2(6-Amino- 9H-purin-9-yl)-1-methylethoxy] methyl]phosphonate,bis(isopropyl carbonate) (ester), fumarate (1:1).]]></drug:casname><drug:casnumber><![CDATA[202138-50-9]]></drug:casnumber><drug:molecularformula><![CDATA[C19-H30-N5-O10-P.C4-H4-O4]]></drug:molecularformula><drug:elementalcomposition><![CDATA[C43.47%, H5.39%, N11.02%, O35.25%, P4.87%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[635.52]]></drug:molecularweight><drug:physicaldescription><![CDATA[White to off-white crystalline powder.]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[13.4 mg/ml in distilled water at 25 C. It has an octanol/phosphate buffer (pH 6.5) partition coefficient (log p) of 1.25 at 25 C.]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:othername><![CDATA[PMPA Prodrug]]></drug:othername><drug:othername><![CDATA[TDF]]></drug:othername></drug:othernames><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[Viread Prescribing Information from the FDA Web site <a href="http://www.fda.gov/cder/foi/label/2006/021356s016lbl.pdf">[PDF]</a>. A more current version may be available on the manufacturer's Web site.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16496322 Benhamou Y, Fleury H, Trimoulet P, Pellegrin I, Urbinelli R, Katlama C, Rozenbaum W, Le Teuff G, Trylesinski A, Piketty C; TECOVIR Study Group. Anti-hepatitis B virus efficacy of tenofovir disoproxil fumarate in HIV-infected patients.
Hepatology. 2006 Mar;43(3):548-55.
]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16496322&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17503745 Gerard L, Chazallon C, Taburet AM, Girard PM, Aboulker JP, Piketty C. Renal function in antiretroviral-experienced patients treated with tenofovir disoproxil fumarate associated with atazanavir/ritonavir. Antivir Ther. 2007;12(1):31-9.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17503745&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17545703 Nelson MR, Katlama C, Montaner JS, Cooper DA, Gazzard B, Clotet B, Lazzarin A, Schewe K, Lange J, Wyatt C, Curtis S, Chen SS, Smith S, Bischofberger N, Rooney JF. The safety of tenofovir disoproxil fumarate for the treatment of HIV infection in adults: the first 4 years. AIDS. 2007 Jun 19;21(10):1273-81.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17545703&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17525796 Peterson L, Taylor D, Roddy R, Belai G, Phillips P, Nanda K, Grant R, Clarke EE, Doh AS, Ridzon R, Jaffe HS, Cates W. Tenofovir disoproxil fumarate for prevention of HIV infection in women: a phase 2, double-blind, randomized, placebo-controlled trial. PLoS Clin Trials. 2007 May 25;2(5):e27.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17525796&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16863446 Pham PA, Gallant JE. Tenofovir disoproxil fumarate for the treatment of HIV infection. Expert Opin Drug Metab Toxicol. 2006 Jun;2(3):459-69.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16863446&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/12965939 Squires K, Pozniak AL, Pierone G Jr, Steinhart CR, Berger D, Bellos NC, Becker SL, Wulfsohn M, Miller MD, Toole JJ, Coakley DF, Cheng A; Study 907 Team. Tenofovir disoproxil fumarate in nucleoside-resistant HIV-1 infection: a randomized trial. Ann Intern Med. 2003 Sep 2; 139(5 Pt 1):313-20. Summary for patients in: Ann Intern Med. 2003 Sep 2; 139(5 Pt 1):I22.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=12965939&dopt=Abstract]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Viread]]></drug:drugname><drug:companyname><![CDATA[Gilead Sciences Inc]]></drug:companyname><drug:address1><![CDATA[333 Lakeside Dr]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Foster City]]></city><drug:state><![CDATA[CA]]></drug:state><drug:zipcode><![CDATA[94404]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 445-3235]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Tenofovir disoproxil fumarate]]></drug:drugname><drug:companyname><![CDATA[Gilead Sciences Inc]]></drug:companyname><drug:address1><![CDATA[333 Lakeside Dr]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Foster City]]></city><drug:state><![CDATA[CA]]></drug:state><drug:zipcode><![CDATA[94404]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 445-3235]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[December 27, 2007]]></drug:lastupdated></item><item><title><![CDATA[Zidovudine]]></title><description><![CDATA[Zidovudine, also known as AZT, ZDV, or Retrovir, is a type of medicine called a nucleoside reverse transcriptase inhibitor (NRTI). NRTIs block reverse transcriptase, a protein that HIV needs to make more copies of itself. ]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=4]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Zidovudine]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[zye-DOE-vyoo-deen]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Retrovir]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Zidovudine]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Nucleoside Reverse Transcriptase Inhibitors]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Zidovudine, a synthetic antiretroviral agent, is a nucleoside reverse transcriptase inhibitor (NRTI), and an analogue of the naturally occurring nucleoside thymidine.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Zidovudine was approved by the FDA on March 19, 1987, for the treatment of HIV infection in combination with other antiretroviral agents. Studies indicate that zidovudine in combination with other antiretroviral agents is superior to monotherapy for one or more of the following endpoints: delaying death, delaying development of AIDS, increasing CD4 counts, and decreasing plasma HIV RNA.

Because monotherapy with any single antiretroviral agent is no longer considered an acceptable option in the treatment of HIV infection, except in the prevention of perinatal transmission of HIV from an HIV infected mother to her child, zidovudine is used in conjunction with other antiretroviral agents for initial antiretroviral therapy in the management of HIV infection in treatment-naive patients. When zidovudine is included in an antiretroviral regimen that includes other nucleoside reverse transcriptase inhibitors (NRTIs), didanosine or lamivudine is usually preferred, and zalcitabine is considered an alternative. Although two-drug regimens that include only NRTIs are no longer preferred regimens for previously treated adults, several studies have evaluated the efficacy of other two-drug and three-drug regimens containing zidovudine in treatment-experienced patients. Results indicate that regimens that include zidovudine and lamivudine or an HIV protease inhibitor (PI) (e.g., indinavir, ritonavir, saquinavir) are generally more effective than zidovudine monotherapy at increasing CD4 counts and decreasing plasma HIV-1 RNA levels in treatment-experienced patients. Zidovudine has also been used in conjunction with nevirapine, a non-nucleoside reverse transcriptase inhibitor (NNRTI), as part of treatment for previously-treated, HIV infected adults.

Zidovudine is also approved for the prevention of vertical transmission of the HIV virus from an HIV infected mother to her fetus, as part of a regimen that includes oral zidovudine administered to the mother beginning at 14 to 34 weeks of gestation, intravenous zidovudine syrup administered to the mother during labor, and zidovudine administered to the neonate for the first 6 weeks of life. However, transmission to infants may still occur in some cases, despite the use of this regimen.

Zidovudine is used in conjunction with lamivudine for postexposure prophylaxis of HIV infection in health care workers and other individuals exposed occupationally via percutaneous injury or mucous membrane or nonintact skin contact with blood, tissues, or other body fluids associated with a risk for HIV transmission.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral (capsules, solution, and tablets).

 Intravenous injection.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Capsules containing zidovudine 100 mg.

Oral solution containing zidovudine 50 mg per 5 ml in 240 ml bottle.

Film-coated tablets containing zidovudine 300 mg.

Intravenous (IV) infusion containing zidovudine 10 mg/ml in 20 ml single-use vials.

The recommended oral dose of zidovudine is 600 mg daily (either 300 mg twice daily or 200 mg three times daily). The recommended dose in pediatric patients ages 6 weeks to 12 years is 160 mg/m2 every 8 hours (480 mg/m2/day up to a maximum of 200 mg every 8 hours). The recommended dosing regimen for administration to pregnant women (more than 14 weeks of pregnancy) is 100 mg, five times daily, until the start of labor. During labor and delivery, IV zidovudine should be administered at 2 mg/kg (total body weight) over 1 hour followed by a continuous IV infusion of 1 mg/kg/hr (total body weight) until clamping of the umbilical cord. The neonate should receive 2 mg/kg orally every 6 hours starting within 12 hours after birth and continuing through 6 weeks of age. In patients maintained on hemodialysis or peritoneal dialysis, the recommended dose of zidovudine is 100 mg every 6 to 8 hours.]]></drug:dosageform><drug:storage><![CDATA[Store zidovudine capsules and film-coated tablets between 15 C and 25 C (59 F and 77 F). Capsules may become discolored or brittle as a result of heat and sunlight exposure, so protect capsules from light, heat, and moisture.

Store zidovudine oral solution at 15 C to 25 C (59 F to 77 F).

Store zidovudine for injection concentrate for IV infusion at 15 C to 25 C (59 F to 77 F) and protect from light.]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Zidovudine is virustatic, acting as a reverse transcriptase inhibitor. Zidovudine is phosphorylated intracellularly to its active 5'-triphosphate metabolite, zidovudine triphosphate (ZDV-TP), by cellular kinases. Neither zidovudine itself nor its intermediate monophosphate metabolite has in vitro activity against HIV. Further study is needed to determine if the intermediate diphosphate metabolite has antiretroviral activity. Because phosphorylation of zidovudine depends on cellular enzymes rather than viral enzymes, conversion to the active triphosphate derivative occurs in HIV infected and uninfected cells. Following conversion, the pharmacologically-active metabolite inhibits in vitro replication of HIV by interfering with the viral RNA-directed DNA polymerase, reverse transcriptase (RT). ZDV-TP appears to compete with thymidine triphosphate for incorporation into viral DNA by the RT enzyme. After incorporation of ZDV-TP, DNA synthesis is prematurely terminated because the 3'-azido group in the zidovudine molecule prevents further 5' to 3' phosphodiester linkages. Intracellular (host cell) conversion of zidovudine to the triphosphate derivative is necessary for the antiviral activity of the drug; however, activation for antibacterial action does not depend on phosphorylation within host cells but rather depends on conversion within bacterial cells.

Zidovudine is absorbed rapidly and almost completely from the gastrointestinal tract, with peak serum concentrations (Cmax) occurring in adults within 0.4 to 1.5 hours after an oral dose. Zidovudine appears to undergo first-pass metabolism. In fasting adults, about 64% of an oral dose reaches systemic circulation as unchanged drug. Cmax achieved following administration of zidovudine tablets is equivalent to that following administration of capsules or oral solution; however, absorption following oral administration shows considerable individual variability.

There is limited information on the distribution of zidovudine in the body, but the drug appears to be widely distributed. The apparent volume of distribution for the drug in adults and children with HIV infection is 1.4 to 1.6 l/kg. Zidovudine is distributed into the cerebrospinal fluid (CSF) following both oral and IV administration; distribution to CSF averages 68% of the plasma concentration in children and 60% of the plasma concentration in adults. Time to peak concentration (Tmax) in serum is 0.5 to 1.5 hours.

Zidovudine is in FDA Pregnancy Category C. There are no adequate and well-controlled studies conducted in pregnant women. In rats, 3,000 mg/kg/day (resulting in Cmax 350 times the human Cmax) caused marked maternal toxicity and an increase in the incidence of fetal malformations. Teratogenic effects were not seen in this experiment at doses of 600 mg/kg per day or less. Zidovudine crosses the placenta and is distributed into cord blood, fetal blood, and amniotic fluid as well as fetal liver, muscle, and central nervous system tissue. 

Zidovudine is distributed into human milk. Potential toxicities of antiretroviral agents in infants exposed to the drugs via breast milk are unknown. In addition, efficacy of antiretroviral therapy for prevention of postpartum transmission of HIV through breast milk is unknown. Because of the risk of transmission of HIV to an uninfected infant through breast milk, the U.S. Centers for Disease Control and Prevention (CDC) currently recommends that HIV infected women not breastfeed infants. To monitor maternal-fetal outcomes of pregnant women exposed to zidovudine (or other antiretrovirals), an Antiretroviral Pregnancy Registry has been established. Physicians may register patients online at http://www.APRegistry.com or by calling 1-800-258-4263.

Plasma protein binding of zidovudine is low (30% to 38%). Zidovudine is rapidly metabolized via glucuronidation in the liver principally to 3'-azido -3'-deoxy- 5'-O-beta-d- glucopyranuronosylthymidine (GZDV).

Following hepatic metabolism, elimination of zidovudine is primarily renal. In adults, 63% to 95% of the dose is excreted in urine, approximately 14% to 18% by glomerular filtration and active tubular secretion. Approximately 72% to 74% of the GZDV metabolite is recovered in urine within 6 hours of administration. The plasma half-life of zidovudine in adults averages approximately 0.5 to 3 hours following oral or IV administration. Following IV administration, plasma concentrations decline in a biphasic manner; half-life in adults is less than 10 minutes in the initial phase and 1 hour in the terminal phase. Current data on the efficacy of removing zidovudine by dialysis vary, but hemodialysis and peritoneal dialysis appear to have a negligible effect. Hemodialysis does enhance the elimination of GZDV; however, dialysis clearance of GZDV is minimal compared to the clearance of GZDV in patients with normal renal function.

Emergence of zidovudine resistance appears to be a function of the duration of zidovudine therapy, the severity of HIV disease, and the overall potency of the regimen in which the drug is used. Resistance is most likely to develop in patients with advanced HIV infection, those with low initial absolute helper/inducer T-cell counts, and those receiving prolonged zidovudine therapy. Although it has been suggested that zidovudine resistance may develop at a slower rate in patients with asymptomatic HIV infection than in those with more advanced disease, high-level zidovudine resistance has emerged in patients with asymptomatic infection, especially in those who have received up to 3 years of zidovudine monotherapy.

Although the mechanisms of resistance or reduced susceptibility to NRTIs have not been fully determined to date, specific mutations of HIV RT at critical codons on the pol gene fragment have been associated with zidovudine resistance. Zidovudine resistance develops in a progressive, stepwise manner, and each reduction in susceptibility appears to be associated with the acquisition of an additional mutation in the HIV RT gene. The degree of resistance appears to depend on the number and combinations of these mutations.

Further study is needed to more fully evaluate the extent of cross resistance among the NRTIs. Some in vitro studies indicate that zidovudine-resistant HIV generally is susceptible to didanosine, zalcitabine, and stavudine; however, some zidovudine-resistant strains may also be cross resistant or have decreased susceptibility to other NRTIs, including didanosine, lamivudine, stavudine, and zalcitabine. The mutation at position 151 appears to play an important role in the development of multidrug resistance. The pattern of mutations with combination therapy is different from that seen with zidovudine monotherapy. Cross resistance between zidovudine and PIs is unlikely, because these drugs have different target enzymes. The potential for cross resistance between zidovudine and NNRTIs is also considered low, because the drugs bind at different sites on the RT enzyme and have different mechanisms of action.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Zidovudine has been associated with hematologic toxicity, including neutropenia, leukopenia, and severe anemia, particularly in patients with advanced HIV disease. Prolonged use of zidovudine has been associated with symptomatic myopathy. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including zidovudine and other antiretrovirals.

The most frequent adverse effects of zidovudine are granulocytopenia and anemia. These are inversely related to the CD4 count at the start of therapy and directly related to dosage and duration of therapy. Significant anemia most commonly occurs after 4 to 6 weeks of therapy. Other adverse effects include changes in platelet count, hepatotoxicity, lactic acidosis, myopathy, neurotoxicity, severe headache, insomnia, myalgia, nausea, changes in pigmentation, hyperpigmentation of nails, and bone marrow depression.

Immune reconstitution syndrome has been reported in some patients treated with combination antiretroviral therapy, including zidovudine. During the initial phase of combination antiretroviral therapy, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis carinii pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance," have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

In monotherapy clinical studies using zidovudine, the most common adverse events reported were headache, malaise, anorexia, and nausea.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Concurrent use of blood dyscrasia-causing medications, other bone marrow depressants, and radiation therapy with zidovudine may cause an additive or synergistic myelosuppression requiring dosage reduction of either or both drugs. Concurrent use of clarithromycin and zidovudine results in lower Cmax and delayed time to peak serum concentration of zidovudine.

Concurrent administration of ganciclovir or interferon alfa with zidovudine is not recommended because severe hematologic toxicity may occur. Patients receiving these medications concurrently should be monitored frequently for abnormalities in hemoglobin, hematocrit, and white blood cell count; dose reduction or discontinuation of one or both of the medications may be necessary.

Concurrent use of probenecid with zidovudine increases serum concentrations and prolongs elimination half-life for zidovudine, resulting in an increased risk of toxicity. In one small trial, a very high incidence of rash was observed in patients receiving probenecid concurrently with zidovudine. Influenza-like symptoms such as myalgia, malaise, and fever have also occurred.

Concurrent use of doxorubicin or ribavirin and zidovudine is not recommended; in vitro studies indicate an antagonistic relationship between doxorubicin or ribavirin with zidovudine. Ribavirin inhibits the phosphorylation of zidovudine to its active triphosphate form, thus antagonizing the in vitro antiviral activity of zidovudine against HIV. These drugs should not be used concurrently.

Low phenytoin plasma levels have been reported in some patients receiving zidovudine. A pharmacokinetic interaction study showed no effect on phenytoin kinetics, but a 30% decrease of zidovudine clearance was observed with concurrent use of phenytoin and zidovudine.

Total serum concentrations of zidovudine increase when atovaquone, fluconazole, methadone, probenecid, or valproic acid are coadministered with zidovudine. Nelfinavir, rifampin, or ritonavir coadministered with zidovudine decreases the total serum concentration of zidovudine.

Concurrent administration of products that also contain zidovudine, including the coformulations of lamivudine and zidovudine and abacavir sulfate, lamivudine, and zidovudine, should be avoided.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Zidovudine is contraindicated in patients who have potentially life-threatening allergic reactions to any of the components of the formulations. Zidovudine should not be administered concomitantly with any combination product tablets that contain zidovudine as one of the components.]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[Thymidine, 3'-azido-3'-deoxy-]]></drug:casname><drug:casnumber><![CDATA[30516-87-1]]></drug:casnumber><drug:molecularformula><![CDATA[C10-H13-N5-O4]]></drug:molecularformula><drug:elementalcomposition><![CDATA[C44.94%, H4.90%, N26.21%, O23.95%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[106 C to 112 C]]></drug:meltingpoint><drug:molecularweight><![CDATA[267.24]]></drug:molecularweight><drug:physicaldescription><![CDATA[White to beige, odorless, crystalline solid.]]></drug:physicaldescription><drug:stability><![CDATA[After dilution, zidovudine IV solutions are physically and chemically stable for 24 hours at room temperature, 15 C to 25 C (59 F to 77 F), and for 48 hours if refrigerated at 2 C to 8 C (36 F to 46 F). However, due to the risk of microbial contamination, diluted solutions should be administered within 8 hours if stored at 25 C (77 F) or within 24 hours if refrigerated at 2 C to 8 C (36 F to 46 F).]]></drug:stability><drug:solubility><![CDATA[20.1 mg/ml in water at 25 C.]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:othername><![CDATA[AZT]]></drug:othername><drug:othername><![CDATA[ZDV]]></drug:othername></drug:othernames><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[Retrovir Prescribing Information from the FDA Web site <A HREF="http://www.fda.gov/cder/foi/label/2006/019655s043lbl.pdf">[PDF]</A>.  A more current version may be available on the manufacturer's Web site.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[Retrovir IV Prescribing Information from the FDA Web site <a href="http://www.fda.gov/cder/foi/label/2006/019951s023lbl.pdf">[PDF]</a>. A more current version may be available on the manufacturer's Web site.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17919090 Arvold ND, Ngo-Giang-Huong N, McIntosh K, Suraseranivong V, Warachit B, Piyaworawong S, Changchit T, Lallemant M, Jourdain G; Perinatal HIV Prevention Trial (PHPT-1), Thailand. Maternal HIV-1 DNA load and mother-to-child transmission. AIDS Patient Care STDS. 2007 Sep;21(9):638-43.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17919090&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16810125 Cressey TR, Leenasirimakul P, Jourdain G, Tawon Y, Sukrakanchana PO, Lallemant M. Intensive pharmacokinetics of zidovudine 200 mg twice daily in HIV-1-infected patients weighing less than 60 kg on highly active antiretroviral therapy.
J Acquir Immune Defic Syndr. 2006 Jul;42(3):387-9. 
]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16810125&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17825650 Dao H, Mofenson LM, Ekpini R, Gilks CF, Barnhart M, Bolu O, Shaffer N. International recommendations on antiretroviral drugs for treatment of HIV-infected women and prevention of mother-to-child HIV transmission in resource-limited settings: 2006 update. Am J Obstet Gynecol. 2007 Sep;197(3 Suppl):S42-55. Review.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17825650&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17825647 Jamieson DJ, Clark J, Kourtis AP, Taylor AW, Lampe MA, Fowler MG, Mofenson LM. Recommendations for human immunodeficiency virus screening, prophylaxis, and treatment for pregnant women in the United States. Am J Obstet Gynecol. 2007 Sep;197(3 Suppl):S26-32.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17825647&dopt=Abstract]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Zidovudine]]></drug:drugname><drug:companyname><![CDATA[GlaxoSmithKline]]></drug:companyname><drug:address1><![CDATA[5 Moore Drive]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Research Triangle Park]]></city><drug:state><![CDATA[NC]]></drug:state><drug:zipcode><![CDATA[27709]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(888) 825-5249]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Zidovudine]]></drug:drugname><drug:companyname><![CDATA[Cipla Ltd]]></drug:companyname><drug:address1><![CDATA[Mumbai Central]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Mumbai]]></city><drug:state><![CDATA[]]></drug:state><drug:zipcode><![CDATA[]]></drug:zipcode><drug:country><![CDATA[India]]></drug:country><drug:phone><![CDATA[912223082891]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Retrovir]]></drug:drugname><drug:companyname><![CDATA[GlaxoSmithKline]]></drug:companyname><drug:address1><![CDATA[5 Moore Drive]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Research Triangle Park]]></city><drug:state><![CDATA[NC]]></drug:state><drug:zipcode><![CDATA[27709]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(888) 825-5249]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[December 26, 2007]]></drug:lastupdated></item><item><title><![CDATA[Acyclovir]]></title><description><![CDATA[Acyclovir, also known as Zovirax, is a type of medicine called an antiviral. Antivirals kill viruses or stop viruses from multiplying. Acyclovir is used to treat herpesvirus infections spread by direct skin-to-skin contact. Acyclovir will not cure herpes infections, but it may help keep the infections under control. ]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=8]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Acyclovir]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[ay-SYE-kloe-veer]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Zovirax]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Acyclovir]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Opportunistic Infection and Other Drugs]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Acyclovir is a synthetic purine nucleoside analogue with activity against herpesviruses.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Oral acyclovir is approved by the FDA for the treatment of initial and recurring episodes of herpes simplex virus (HSV-1) and genital herpes virus (HSV-2) infections in immunocompromised patients. Parenteral acyclovir is approved for the treatment of initial or recurrent HSV infections and herpes zoster infection (shingles) caused by varicella-zoster virus (VZV) in immunocompromised patients. Topical acyclovir is approved for the treatment of initial episodes of genital herpes and HSV infections in immunocompromised patients; however, systemic acyclovir is more effective and may be preferred.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Oral acyclovir was approved by the FDA on December 10, 1997, for treatment of initial and recurrent genital herpes infection, herpes zoster infection, and adult varicella infection (chickenpox) caused by VZV. It is not recommended for use in the treatment of uncomplicated chickenpox in healthy children. Parenteral acyclovir is approved for severe initial episodes of genital herpes infection, neonatal HSV infection, and herpes simplex encephalitis in immunocompetent patients.]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral; intravenous infusion: topical.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Capsules containing acyclovir 200 mg.

Tablets containing acyclovir 400 mg and 800 mg.

Oral banana-flavored suspension containing acyclovir 200 mg per 5 ml sorbitol with preservative.

Acyclovir sodium for injection (preservative-free) in 10 ml sterile vials containing the equivalent of acyclovir 500 mg and in 20 ml sterile vials containing the equivalent of acyclovir 1,000 mg.

5% topical ointment in 3 g and 15 g tubes containing acyclovir 50 mg in a polyethylene glycol base. Acyclovir 5% topical cream is available in Canada.]]></drug:dosageform><drug:storage><![CDATA[Store capsules, tablets, and suspension at temperatures between 15 C and 25 C (59 F and 77 F). Protect tablets and suspension from light; protect capsules from light and moisture.

Store acyclovir sodium for injection at temperatures between 15 C and 25 C (59 F and 77 F).

Store 5% topical ointment at temperatures between 15 C and 25 C (59 F and 77 F) in a dry place.]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Acyclovir inhibits HSV and VZV both in vitro and in vivo by interfering with DNA synthesis and inhibiting viral replication. Acyclovir is converted to acyclovir triphosphate by cellular kinases and is highly specific for thymidine kinase (TK) encoded by HSV and VZV. The activated phosphorylated form of acyclovir stops replication of viral DNA by competitive inhibition of viral DNA polymerase, incorporation into and termination of the viral DNA chain, and inactivation of viral DNA polymerase.

Acyclovir's absorption from the gastrointestinal (GI) tract is variable and incomplete; an estimated 10% to 30% of an oral dose is absorbed. Some data suggest that GI absorption of acyclovir may be saturable; in healthy adults, the extent of absorption decreases with increasing dose. Less than dose-proportional plasma concentration increases do not appear to be a function of the dosage form. Food does not appear to affect acyclovir's absorption. Peak plasma concentration of acyclovir usually occurs within 1.7 hours after oral administration and at the end of a 1-hour infusion with IV administration.

Acyclovir is widely distributed into body tissues and fluids, including the brain, kidney, saliva, lung, liver, muscle, spleen, uterus, vaginal mucosa and secretions, cerebrospinal fluid (CSF), herpetic vesicular fluid, and semen. The reported apparent volume of distribution of acyclovir is 32.4 to 61.8 l/1.73 m2 in adults. Following IV infusion, acyclovir generally diffuses well into CSF; in patients with uninflamed meninges, reported CSF concentrations of acyclovir are approximately 50% of concurrent serum acyclovir concentrations. 

Acyclovir is in FDA Pregnancy Category B. There are no adequate and well-controlled studies of acyclovir in pregnant women. When administered to mice, rabbits, and rats during organogenesis at doses up to 22 times normal human plasma levels, acyclovir was not teratogenic. Acyclovir did not impair fertility or reproduction in mice or rats, though at higher doses implantation efficacy decreased in rats and rabbits. Acyclovir crosses the placenta. Limited data indicate that the drug is distributed into milk at concentrations up to 4.1 times greater than concurrent maternal plasma concentrations. As a result, acyclovir should be administered to nursing mothers with caution and only when indicated.

In vitro, acyclovir is approximately 9% to 33% bound to plasma proteins at drug concentrations of 0.41 to 52 mcg/ml. In adults with normal renal function, the half-life of oral acyclovir ranges from 2.5 to 3.3 hours, and the half-life of parenteral acyclovir is approximately 2.5 hours. Acyclovir is excreted principally in urine via glomerular filtration and tubular secretion; most of a single IV dose of the drug is excreted unchanged in urine within 24 hours of administration. Limited data suggest that peritoneal dialysis and blood exchange transfusions do not appreciably remove the drug. Hemodialysis reduces plasma concentrations of acyclovir by about 60%. Doses and frequency of administration of the drug should be modified according to creatinine clearance and age.

Resistance to acyclovir can result from qualitative and quantitative changes in viral TK or DNA polymerase. Clinical isolates of HSV and VZV with reduced susceptibility to acyclovir have been recovered from immunocompromised patients, especially those with advanced HIV infection. Most acyclovir-resistant mutants are TK-deficient; these TK-negative mutants may cause severe disease in infants and immunocompromised adults. Although acyclovir is apparently unable to eliminate an established latent infection, acyclovir-resistant mutants appear less able of establishing a latent infection. The possibility of viral resistance to acyclovir should only be considered in patients who show poor clinical response during therapy.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Adverse reactions after oral or IV administration of acyclovir have generally been minimal. However, potentially serious reactions (e.g., renal failure, thrombotic thrombocytopenic purpura/hemolytic uremic syndrome in immunocompromised patients) can occur and may be fatal.

The most frequent adverse effects observed with acyclovir use are phlebitis (inflammation at the parenteral injection site), symptoms of acute renal failure, headache, malaise, and GI disturbances (e.g., nausea, vomiting, diarrhea). Rare but serious adverse effects include encephalopathy, urticaria, and hematologic abnormalities such as thrombocytopenia or thrombocytosis, hematuria, or anemia.

Adverse effects observed with topical acyclovir use include mild pain, burning, and stinging; itching, rash, and vulvitis may occur less frequently.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Dosage adjustment is recommended when administering acyclovir to patients with renal impairment or to patients receiving potentially nephrotoxic agents; acyclovir may increase the risk of renal dysfunction and of reversible central nervous system symptoms, such as those reported in patients treated with IV acyclovir.

Amphotericin B has strengthened the antiviral effect of acyclovir against pseudorabies virus in vitro. Interferon has also shown additive or synergistic antiviral effects with acyclovir in vitro against HSV-1 cultures. The clinical importance of these interactions is not known. Drugs with the potential for clinically significant interactions with acyclovir include antifungal agents (e.g., ketoconazole), probenecid, interferon, intrathecal methotrexate, and zidovudine. Neurotoxicity has been reported in one case of concurrent acyclovir and zidovudine administration.

Food does not appear to affect acyclovir's absorption; oral dosage forms may be given with or without food.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Acyclovir is contraindicated in patients with hypersensitivity to acyclovir or valacyclovir.

Acyclovir use should be carefully considered in patients with pre-existing renal function impairment or dehydration.]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[6H-Purin-6-one,2-amino-1,9-dihydro- 9-((2-hydroxyethoxy)methyl)-]]></drug:casname><drug:casnumber><![CDATA[59277-89-3]]></drug:casnumber><drug:molecularformula><![CDATA[C8-H11-N5-O3]]></drug:molecularformula><drug:elementalcomposition><![CDATA[C42.67%, H4.92%, N31.10%, O21.31%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[256.5 C to 257 C, crystals from methanol.]]></drug:meltingpoint><drug:molecularweight><![CDATA[225.20]]></drug:molecularweight><drug:physicaldescription><![CDATA[White crystalline powder; lyophilized monosodium salt.]]></drug:physicaldescription><drug:stability><![CDATA[After reconstitution with sterile water, each injectable vial of acyclovir 50 mg/ml is stable for 12 hours; after further dilution for administration, each dose of acyclovir sodium for injection should be used within 24 hours.

Prior to reconstitution, acyclovir suspension is stable without refrigeration for 24 months. Refrigeration causes formation of a precipitate, which redissolves when the suspension is returned to room temperature. The oral suspension requires shaking before administering a dose.]]></drug:stability><drug:solubility><![CDATA[Maximum solubility of 2.5 mg/ml in water at 37 C in a neutral pH.

Acyclovir sodium has a maximum solubility of greater than 100 mg/ml in water at 25 C, but at physiologic pH and 37 C, the drug is almost completely unionized and has a maximum solubility of 2.5 mg/ml.]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:othername><![CDATA[ACV]]></drug:othername></drug:othernames><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[Zovirax Capsules, Tablets, and Suspension Prescribing Information from the FDA Web site <a href="http://www.fda.gov/cder/foi/label/2005/018828s030,020089s019,019909s020lbl.pdf">[PDF]</a>. A more current version may be available on the manufacturer's Web site.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[Zovirax IV Prescribing Information from the FDA Web site <a href="http://www.fda.gov/cder/foi/label/2004/18603slr027_zovirax_lbl.pdf">[PDF]</a>. A more current version may be available on the manufacturer's Web site.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[Zovirax Cream Prescribing Information from the FDA Web site <a href="http://www.fda.gov/cder/foi/label/2002/21478_zovirax_lbl.pdf">[PDF]</a>. A more current version may be available on the manufacturer's Web site.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/15627220 Celum CL, Robinson NJ, Cohen MS. Potential effect of HIV type 1 antiretroviral and herpes simplex virus type 2 antiviral therapy on transmission and acquisition of HIV type 1 infection. J Infect Dis. 2005 Feb 1;191 Suppl 1:S107-14. Review.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15627220&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/12353184 Corey L. Challenges in genital herpes simplex virus management. J Infect Dis. 2002 Oct 15;186 Suppl 1:S29-33. Review.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=12353184&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16804851 Strick LB, Wald A, Celum C.  Management of herpes simplex virus type 2 infection in HIV type 1-infected persons.  ClinInfect Dis. 2006 Aug 1;43(3):347-56. Epub 2006 Jun 15.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16804851&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/12790345 Villarreal EC. Current and potential therapies for the treatment of herpes-virus infections. Prog Drug Res. 2003;60:263-307.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=12790345&dopt=Abstract]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Acyclovir]]></drug:drugname><drug:companyname><![CDATA[Alpharma, Inc.]]></drug:companyname><drug:address1><![CDATA[One Executive Drive]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Fort Lee]]></city><drug:state><![CDATA[NJ]]></drug:state><drug:zipcode><![CDATA[07024]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(201) 947-7774]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Acyclovir]]></drug:drugname><drug:companyname><![CDATA[Mylan Laboratories Inc]]></drug:companyname><drug:address1><![CDATA[1030 Century Building / 130 Seventh St]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Pittsburgh]]></city><drug:state><![CDATA[PA]]></drug:state><drug:zipcode><![CDATA[15222]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 796-9526]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Zovirax]]></drug:drugname><drug:companyname><![CDATA[GlaxoSmithKline]]></drug:companyname><drug:address1><![CDATA[5 Moore Drive]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Research Triangle Park]]></city><drug:state><![CDATA[NC]]></drug:state><drug:zipcode><![CDATA[27709]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(888) 825-5249]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[June 8, 2007]]></drug:lastupdated></item><item><title><![CDATA[Adefovir dipivoxil]]></title><description><![CDATA[Adefovir dipivoxil, also known as Hepsera, belongs to the class of medicines called antivirals. Antivirals kill viruses or stop viruses from multiplying. Adefovir is a nucleotide analogue that blocks hepatitis B virus (HBV) DNA polymerase, a protein that HBV needs to make more copies of itself.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=209]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Adefovir dipivoxil]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[a DEF oh veer]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Hepsera]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Adefovir dipivoxil]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Opportunistic Infection and Other Drugs]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Adefovir is an acyclic nucleotide analogue of adenosine monophosphate with activity against hepatitis B virus (HBV). Adefovir dipivoxil is the diester prodrug of adefovir.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Adefovir dipivoxil was at one time being developed for the treatment of HIV disease, achieving anti-HIV activity at a substantially higher dose than that used to treat HBV. However, nephrotoxicity was a treatment-limiting toxicity of adefovir dipivoxil therapy at the higher dose required for therapy for HIV infection. In December 1999, Gilead Sciences announced the termination of its adefovir dipivoxil development program for the treatment of HIV.There are limited data to support the use of adefovir dipivoxil in HIV/HBV coinfected individuals.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[The FDA approved adefovir dipivoxil on September 20, 2002, for the treatment of chronic HBV infection in adults with evidence of active viral replication and evidence of either persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.  Adefovir dipivoxil has been approved for use in patients 12 years of age or older.

Efficacy and safety have also been evaluated in patients with lamivudine-resistant virus and in pre-- and post--liver transplant patients.]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Tablets containing adefovir dipivoxil 10 mg.

Once-daily dosing is recommended by the manufacturer for patients with normal renal function. The manufacturer suggests the following altered dosage regimens for patients with renal impairment: 10 mg every other day for creatinine clearance (CrCl) of 20 to 49 ml/min, 10 mg every 3 days for CrCl of 10 to 19 ml/min, and 10 mg every 7 days after dialysis for patients receiving hemodialysis.]]></drug:dosageform><drug:storage><![CDATA[Store in original container at 25 C (77 F), with excursions permitted between 15 C and 30 C (59 F and 86 F).]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Adefovir dipivoxil is the diester prodrug of adefovir and is rapidly converted by diester hydrolysis after oral administration. Adefovir is phosphorylated to the active metabolite, adefovir diphosphate, by cellular kinases. Adefovir diphosphate, a nucleotide analogue, inhibits HBV polymerase by competing with the natural substrate deoxyadenosine triphosphate and by causing DNA chain termination after its incorporation into viral DNA.
 
The approximate oral bioavailability of adefovir from a single 10-mg dose of adefovir dipivoxil is 59%. Following oral administration of a single dose of adefovir dipivoxil 10 mg, the median peak adefovir plasma concentration (Cmax) was 18.4 ng/ml and occurred at a median 1.75 hours postdose. Terminal elimination half-life of plasma adefovir is approximately 7.48 hours.

In vitro binding of adefovir to human plasma or human serum proteins is less than or equal to 4% or less over the adefovir concentration range of 0.1 to 25 mcg/ml. The volume of distribution at steady state is approximately 392 and 352 ml/kg following IV administration of 1.0 or 3.0 mg/kg/day, respectively.

Adefovir is renally excreted by a combination of glomerular filtration and active tubular secretion; 45% of a dose is recovered in the urine over 24 hours. Thirty-five percent of a dose is removed during 4-hour hemodialysis.

Cmax, area under the plasma concentration-time curve (AUC), and half-life are increased in patients with moderately or severely impaired renal function or with end-stage renal disease requiring hemodialysis compared to people with normal renal function. It is recommended that the dosing interval be modified in patients with renal impairment.

Adefovir dipivoxil is in FDA Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. Studies in rats and rabbits at doses 23 to 40 times greater than human exposure, respectively, identified no embryotoxicity or teratogenicity. To monitor fetal outcomes of pregnant women exposed to adefovir dipivoxil, an Antiretroviral Pregnancy Registry has been established. Health care providers are encouraged to register patients online at http://www.APRegistry.com or by calling 1-800-258-4263. It is not known whether adefovir is excreted in human milk; breastfeeding is discouraged in women taking adefovir dipivoxil.

There are no data on the effect of adefovir on HBV transmission from mothers to infants. Infant immunization should be used to prevent neonatal HBV infection. The safety and efficacy of adefovir dipivoxil have not been established in the pediatric population.

N236T and A181V mutations have been identified in genotypic analyses as contributors to adefovir resistance. Both mutations have caused a decrease in lamivudine susceptibility in vitro. Recombinant HBV variants containing mutations associated with lamivudine resistance (L180M, M204V, V173L) in the HBV polymerase gene were susceptible to adefovir in vitro. HBV variants with polymerase mutations R or W501Q, both associated with resistance to HBV immunoglobulin, and T128N were susceptible to adefovir in vitro.

Adefovir has activity against HIV but only at much higher doses than those used to treat HBV infection. A chronic HBV patient with unrecognized or untreated HIV infection may develop HIV resistance to adefovir when taken at HBV-approved, non-HIV-suppressive doses. Although adefovir has not been shown to suppress HIV RNA in patients, limited data are available on the use of adefovir to treat patients coinfected with HBV and HIV.

A randomized, double-blind, placebo-controlled trial compared daily tenofovir disoproxil fumarate 300 mg to adefovir dipivoxil 10 mg therapy in 52 HIV/HBV coinfected patients on stable HAART. At baseline, 75% of patients had HIV RNA levels less than 50 copies/ml and 98% had compensated liver disease. During monthly evaluations over 48 weeks, both drugs successfully lowered HBV DNA levels and were considered safe and effective in HIV/HBV coinfected patients.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Severe acute exacerbation of hepatitis, rarely but potentially fatal, has been reported in patients who discontinue anti-HBV therapy with adefovir dipivoxil. Patients should be monitored for hepatic dysfunction at repeated intervals over a period of time; resumption of adefovir dipivoxil treatment may be warranted.

HIV resistance may emerge in HBV-infected individuals with untreated HIV infection who are treated with HBV medications, including adefovir dipivoxil.

Nephrotoxicity, characterized by a delayed onset of gradual increases in serum creatinine and decreases in serum phosphorus, is the primary dose-limiting toxicity of adefovir dipivoxil therapy at the substantially higher doses required for HIV antiviral activity. This toxicity is also possible at the lower dose required for HBV antiviral activity when given to chronic HBV patients in the long term.

Lactic acidosis and severe hepatomegaly with steatosis, potentially fatal, have been reported with the use of nucleoside analogues alone or in combination with other antiretrovirals. Female gender, obesity, and prolonged nucleoside analogue exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogues to any patient with known risk factors for liver disease; however, cases of hepatotoxicity have also been reported in patients with no known risk factors. Treatment with adefovir dipivoxil should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations.

Severe adverse effects possible with adefovir treatment include hematuria and glycosuria. Moderate adverse effects that have been reported in patients taking adefovir dipivoxil include asthenia; abdominal pain; headache; and, more rarely, diarrhea, dyspepsia, flatulence, heartburn, and nausea.

Pre-- and post--liver transplantation patients with chronic HBV and clinical evidence of lamivudine resistance and patients with underlying renal insufficiency or other risk factors for renal dysfunction represent special risk groups. Common treatment-related adverse events reported in these patients include hepatic failure, increases in ALT and AST, abnormal liver function, increased coughing, pharyngitis, sinusitis, pruritus, rash, increases in serum creatinine, renal failure, and renal insufficiency.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Adefovir dipivoxil may be taken without regard to food.

Because adefovir is eliminated by the kidney, coadministration of adefovir dipivoxil with renally excreted drugs or nephrotoxic drugs may cause further nephrotoxicity or may increase serum concentrations of either adefovir or the coadministered drugs. Patients should be monitored closely for adverse events when adefovir dipivoxil is coadministered with drugs that are excreted renally or are known to affect renal function, such as aminoglycosides, cyclosporin, and nonsteroidal anti-inflammatory drugs. Adefovir does not appear to interact with concurrently administered lamivudine, acetaminophen, or sulfamethoxazole/trimethoprim.

When adefovir dipivoxil was coadministered with ibuprofen 800 mg three times daily, adefovir Cmax and AUC increased by 33% and 23%, respectively. The clinical significance of this increase in adefovir exposure is unknown.

Adefovir does not inhibit or act as a substrate for cytochrome P-450 (CYP) enzymes. The potential for adefovir to induce CYP enzymes is not known. Based on the results of in vitro experiments and the renal elimination pathway of adefovir, the potential for CYP-mediated interactions between adefovir and other medicines is low.

Administration of adefovir dipivoxil with nucleoside analogues increases the risk of lactic acidosis and severe hepatomegaly with steatosis. Coadministration of these drugs should be suspended in patients who develop symptoms or laboratory findings indicative of hepatic toxicity.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Adefovir is contraindicated in patients with hypersensitivity to adefovir or any components of the formulation.]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[Propanoic acid, 2,2-dimethyl-, ([(2-[6-amino-9H-purin-9-yl]ethoxy) methyl]phosphinylidene) bis(oxymethylene) ester]]></drug:casname><drug:casnumber><![CDATA[142340-99-6]]></drug:casnumber><drug:molecularformula><![CDATA[C20-H32-N5-O8-P]]></drug:molecularformula><drug:elementalcomposition><![CDATA[C47.90%, H6.43%, N13.97%, O25.52%, P6.18%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[Greater than 250 C]]></drug:meltingpoint><drug:molecularweight><![CDATA[501.47]]></drug:molecularweight><drug:physicaldescription><![CDATA[Off-white crystalline powder.]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[19 mg/ml at pH 2 and 0.4 mg/ml at pH 7.2 (aqueous).]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform" /><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[Hepsera Prescribing Information from the FDA Web site <A HREF="http://www.fda.gov/cder/foi/label/2007/021449s011lbl.pdf">[PDF]</A>. A more current version may be available on the manufacturer's Web site.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16274835 Benhamou Y, Bonyhay L. Treatment of hepatitis B virus infection in patients coinfected with HIV. Gastroenterol Clin North Am. 2004 Sep;33(3):617-27. Review.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16274835&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/18279995 Gaia S, Barbon V, Smedile A, Olivero A, Carenzi S, Lagget M, Alessandria C, Rizzetto M, Marzano A. Lamivudine-resistant chronic hepatitis B: An observational study on adefovir in monotherapy or in combination with lamivudine. J Hepatol. 2008 Jan 31; [Epub ahead of print].
]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=18279995&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/15254439 Murphy MJ, Wilcox RD. Management of the coinfected patient: human immunodeficiency virus/hepatitis B and human immunodeficiency virus/hepatitis C. Am J Med Sci. 2004 Jul;328(1):26-36.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15254439&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17058225 Peters MG, Andersen J, Lynch P, Liu T, Alston-Smith B, Brosgart CL, Jacobson JM, Johnson VA, Pollard RB, Rooney JF, Sherman KE, Swindells S, Polsky B; ACTG Protocol A5127 Team. Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127. Hepatology. 2006 Nov;44(5):1110-6.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17058225&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16904047 Shepherd J, Jones J, Takeda A, Davidson P, Price A. Adefovir dipivoxil and pegylated interferon alfa-2a for the treatment of chronic hepatitis B: a systematic review and economic evaluation. Health Technol Assess. 2006 Aug;10(28):iii-iv, xi-xiv, 1-183. Review.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16904047&dopt=Abstract]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Hepsera]]></drug:drugname><drug:companyname><![CDATA[Gilead Sciences Inc]]></drug:companyname><drug:address1><![CDATA[333 Lakeside Dr]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Foster City]]></city><drug:state><![CDATA[CA]]></drug:state><drug:zipcode><![CDATA[94404]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 445-3235]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Adefovir dipivoxil]]></drug:drugname><drug:companyname><![CDATA[Gilead Sciences Inc]]></drug:companyname><drug:address1><![CDATA[333 Lakeside Dr]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Foster City]]></city><drug:state><![CDATA[CA]]></drug:state><drug:zipcode><![CDATA[94404]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 445-3235]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[January 9, 2008]]></drug:lastupdated></item><item><title><![CDATA[Aldesleukin]]></title><description><![CDATA[Aldesleukin is a synthetic form of interleukin-2 (IL-2), which is a substance the body produces to stimulate the growth of certain disease-fighting blood cells in the immune system. Aldesleukin, also known as Proleukin, belongs to the class of medicines called biological response modifiers. Biological response modifiers stimulate the body's response to infection and disease. Aldesleukin also belongs to the class of medicines called antineoplastics. Antineoplastics slow or stop the growth of cancer cells.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=21]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Aldesleukin]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[al-des-LOO-kin]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Proleukin]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Aldesleukin]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Opportunistic Infection and Other Drugs]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Aldesleukin, a human interleukin-2 (IL-2) derivative, is a biosynthetic lymphokine with antineoplastic and immunomodulating activities.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Aldesleukin has been shown to increase CD4 count in HIV infected individuals. Studies show that aldesleukin, in combination with antiretroviral medications, significantly increases CD4 counts in patients with HIV infection. Results from one longitudinal study indicate that intermittent, low-frequency doses of subcutaneous aldesleukin can maintain CD4 count increases for extended periods. The mean baseline CD4 count of 521 cells/mcl increased to 1,005 cells/mcl, and the mean baseline CD4 percent value increased from 27% to 38% at 90 months. Studies are now underway to determine whether aldesleukin, in combination with approved and investigational anti-HIV therapies and vaccines, can improve the immune system and delay the progression of HIV disease.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Aldesleukin is approved for the treatment of metastatic renal cell carcinoma and metastatic melanoma in adults.]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Intravenous infusion.

Subcutaneous injection.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Single-use vials, each containing aldesleukin 22 million international units (IU) (1.3 mg). It is reconstituted by adding 1.2 ml of sterile water for injection, resulting in a final concentration of aldesleukin 18 million IU (1.1 mg) per ml. For rapid IV infusion, the reconstituted solution is further diluted in 50 ml of 5% dextrose injection.]]></drug:dosageform><drug:storage><![CDATA[Store vials of lyophilized aldesleukin in a refrigerator between 2 C to 8 C (36 F to 46 F) and store in carton until time of use. Protect from light. Do not shake or freeze.]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Aldesleukin is a human recombinant interleukin-2 (IL-2) with the biologic activities of endogenous IL-2. In vitro studies performed on human cell lines have revealed multiple immunological effects, including enhanced lymphocyte mitogenesis and stimulation of long-term growth of human IL-2 dependent cell lines; enhancement of lymphocyte cytotoxicity; induction of lymphokine-activated and natural killer cells; and production of cytokines, such as tumor necrosis factor, IL-1, and gamma interferon. Mechanism of action studies indicate that IL-2 can induce polyclonal proliferation of CD4 and CD8 cells, even when the high-affinity IL-2 receptor is absent. Although IL-2 leads to a sixfold increase in T-cell proliferation and a twofold increase in T-cell death, the primary mechanism of action leading to expansion of the CD4 pool appears to be CD4 survival.

After IV infusion, approximately 30% of a dose of aldesleukin is detectable in plasma. Following IV infusion over short periods, aldesleukin distributes rapidly into the extravascular space. Radiolabeled aldesleukin in rats has an uptake of less than 1 minute into the lung, liver, kidney, and spleen.

In a study of HIV infected adults, aldesleukin injected subcutaneously in doses of 12, 15, or 18 MIU per day was found to be well absorbed; however, absorption was slow, with a mean time to maximum of 4.4 hours and a lag time of 26.9 hours. Elimination half-life was 3.3 hours. A study of ultra-low dose subcutaneous aldesleukin in HIV infected adults showed marked differences in plasma concentrations. Peak plasma concentrations of aldesleukin for a subcutaneous dose of 125,000 IU/m2 were 3.4 pM, whereas doubling the dose to 250,000 IU/m2 resulted in a fivefold increase in peak plasma concentrations.

Aldesleukin is in FDA Pregnancy Category C. Although there are no adequate and controlled studies in humans, aldesleukin has been shown to have embryolethal effects in rats when given in doses 27 to 36 times the usual human dose. Aldesleukin should be used during pregnancy only when the potential benefits justify the possible risks to the fetus. It is not known whether aldesleukin is distributed into human milk; however, because of the potential for serious adverse effects to the breastfed infant if the drug is distributed into milk, discontinuation either of breastfeeding or of aldesleukin therapy should be considered.

Aldesleukin is metabolized principally by the kidney; the active drug is undetectable in the urine or is present only in trace amounts. More than 80% of aldesleukin distributed to plasma, cleared from the circulation, and presented to the kidney is metabolized to amino acids in the proximal convoluted tubules. Following rapid IV infusion, elimination half-life of aldesleukin is 85 minutes.

Three mechanisms of clearance relate to the systemic removal of aldesleukin. In the first two, aldesleukin is cleared from the circulation by glomerular filtration and peritubular extraction in the kidney. This dual mechanism may account for the preservation of clearance in patients with elevated serum creatinine values. The third clearance pathway, an inducible receptor-mediated mechanism, was most evident in continuous IV studies in which 5 days of treatment in HIV infected patients resulted in a time-dependent decrease in aldesleukin serum concentrations that correlated with an increase in soluble aldesleukin receptor. The decreased aldesleukin concentrations were most likely due to induction of receptor-mediated clearance, which is related to the immunostimulatory effects of the drug. The associated decrease in aldesleukin serum levels is, therefore, an indicator of its activity.

Because children have a faster glomerular filtration than adults, the rate of renal aldesleukin elimination in pediatric patients may be faster than in adults. Children may not have fully developed immune systems, which may affect receptor-mediated clearance.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Aldesleukin is a highly toxic drug. Adverse effects associated with aldesleukin therapy are common, often serious, and sometimes fatal. The frequency and severity of these reactions depend on dose, method of administration, and dosing schedule. Effects are generally more frequent and severe with high-dose, relatively rapid IV infusion compared with low-dose, subcutaneous administration or continuous IV infusion. Subcutaneous route of administration for aldesleukin may be potentially more advantageous in HIV infected patients and may help reduce toxicity and adverse effects observed with IV aldesleukin.

Aldesleukin dosages currently used in HIV clinical trials are generally lower than those used for approved indications.(3) The most commonly reported adverse effects of low to intermediate doses of aldesleukin given subcutaneously or via continuous IV infusion include asthenia, chills, diarrhea, discoloration at injection site, dry skin, fatigue, fever, headache, lethargy, loss of appetite, myalgia, nausea and vomiting, rash or inflammation at the injection site, and weight loss. Serious but rare effects include hypertension; hypotension; lung congestion; shortness of breath; and worsening of Crohn's disease, diabetes, heart failure, heart rhythm irregularities, and psoriasis.

High-dose, rapid IV infusion of aldesleukin is FDA approved for the treatment of metastatic renal cell carcinoma and metastatic melanoma. The approved treatment is associated with severe, life-threatening effects and is therefore administered in a hospital setting. These effects include capillary leak syndrome, which may be associated with cardiac arrhythmias, angina, myocardial infarction, respiratory insufficiency requiring intubation, gastrointestinal bleeding or infarction, renal insufficiency, edema, and mental status changes. High-dose aldesleukin therapy is also associated with impaired neutrophil function and with an increased risk of disseminated infection, including sepsis and bacterial endocarditis. Most adverse reactions are self-limiting and usually reverse or improve within 2 or 3 days of discontinuation of therapy. Adverse reactions that may be permanent following aldesleukin therapy may include myocardial infarction, bowel perforation or infarction, and gangrene.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Because aldesleukin may affect central nervous system function, interactions are possible with concomitant administration of psychotropic drugs, such as narcotics, analgesics, antiemetics, sedatives, or tranquilizers. Concurrent use of drugs causing nephrotoxic, hepatotoxic, cardiotoxic, or myelotoxic effects may increase toxicity in these organ systems. In addition, reduced kidney and liver function secondary to aldesleukin therapy may delay elimination of concomitant medications and increase the risk of adverse effects from those drugs.

Hypersensitivity reactions have been reported in patients receiving combination regimens containing sequential high dose aldesleukin and antineoplastics, specifically, cisplatinum, dacarbazine, and tamoxifen. Concurrent use of aldesleukin and interferon alfa appears to increase the risk of myocardial infarction, myocarditis, severe rhabdomyolysis, and ventricular hypokinesia. This combination of agents can also cause or exacerbate autoimmune and inflammatory disorders such as bullous pemphigoid, crescentic IgA glomerulonephritis, inflammatory arthritis, oculobulbar myasthenia gravis, Stevens-Johnson syndrome, and thyroiditis.

Beta-blockers and other antihypertensive drugs may potentiate the hypotension associated with aldesleukin.

Although glucocorticoids have been shown to reduce some of the adverse effects of aldesleukin, including confusion, dyspnea, fever, hyperbilirubinemia, and renal insufficiency, concomitant use of these drugs with aldesleukin may reduce aldesleukin's effectiveness and thus should be avoided.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Aldesleukin is contraindicated in patients with a history of hypersensitivity to IL-2 or any component of the aldesleukin formulation. It also is contraindicated in patients with abnormal pulmonary function or thallium stress test results and in patients with organ allografts. Retreatment is contraindicated in patients who experienced the following adverse effects on prior use of the drug: sustained ventricular tachycardia (five or more beats), cardiac arrhythmias not controlled or unresponsive to management, chest pain with electrocardiogram (ECG) changes consistent with angina or myocardial infarction, cardiac tamponade, intubation for longer than 72 hours, renal failure requiring dialysis longer than 72 hours, coma or toxic psychosis lasting longer than 48 hours, repetitive or difficult-to-control seizures, bowel ischemia/perforation, or gastrointestinal bleeding requiring surgery.]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[125-L-Serine-2-133-interleukin 2 (human reduced)]]></drug:casname><drug:casnumber><![CDATA[110942-02-4]]></drug:casnumber><drug:molecularformula><![CDATA[C690-H1115-N177-O203-S6]]></drug:molecularformula><drug:elementalcomposition><![CDATA[]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[15,600 daltons]]></drug:molecularweight><drug:physicaldescription><![CDATA[White to off-white lyophilized cake.]]></drug:physicaldescription><drug:stability><![CDATA[Bacteriostatic water for injection or 0.9% sodium chloride injection should not be used for reconstitution because of increased aldesleukin aggregation.

Reconstituted or diluted aldesleukin is stable for up to 48 hours at refrigerated and room temperatures, between 2 to 25 C (36 to 77 F). However, the product should be refrigerated after reconstitution or dilution because it contains no preservative.]]></drug:stability><drug:solubility><![CDATA[]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:othername><![CDATA[IL-2]]></drug:othername><drug:othername><![CDATA[Interleukin-2, recombinant human]]></drug:othername><drug:othername><![CDATA[rIL-2]]></drug:othername></drug:othernames><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[Prescribing information from the <A HREF=http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails">FDA Web site.</A> A more current version may be available on the manufacturer's Web site.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/14682072 Conrad A. Interleukin-2--where are we going? J Assoc Nurses AIDS Care. 2003 Nov-Dec;14(6):83-8. Review.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=14682072&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/14726376 Farel CE, Chaitt DG, Hahn BK, Tavel JA, Kovacs JA, Polis MA, Masur H, Follmann DA, Lane HC, Davey RT Jr. Induction and maintenance therapy with intermittent interleukin-2 in HIV-1 infection. Blood. 2004 May 1;103(9):3282-6. Epub 2004 Jan 15.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=14726376&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/12556688 Levy Y, Durier C, Krzysiek R, Rabian C, Capitant C, Lascaux AS, Michon C, Oksenhendler E, Weiss L, Gastaut JA, Goujard C, Rouzioux C, Maral J, Delfraissy JF, Emilie D, Aboulker JP; and the ANRS 079 Study Group. Effects of interleukin-2 therapy combined with highly active antiretroviral therapy on immune restoration in HIV-1 infection: a randomized controlled trial. AIDS 2003 Feb 14; 17(3): 343-351.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=12556688&dopt=Abstract]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Aldesleukin]]></drug:drugname><drug:companyname><![CDATA[Chiron Corp]]></drug:companyname><drug:address1><![CDATA[4560 Horton Street]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Emeryville]]></city><drug:state><![CDATA[CA]]></drug:state><drug:zipcode><![CDATA[94608-2916]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 244-7668]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Proleukin]]></drug:drugname><drug:companyname><![CDATA[Chiron Corp]]></drug:companyname><drug:address1><![CDATA[4560 Horton Street]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Emeryville]]></city><drug:state><![CDATA[CA]]></drug:state><drug:zipcode><![CDATA[94608-2916]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 244-7668]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[February 12, 2007]]></drug:lastupdated></item><item><title><![CDATA[Amphotericin B]]></title><description><![CDATA[Amphotericin B, also known as Fungizone or Amphocin, belongs to the class of medicines called antifungals. Fungi are organisms that can cause infection in humans. Antifungals kill fungi or stop fungi from multiplying or spreading. Fungal infections occur more often in patients with weakened immune systems, including people with HIV, than in people with healthy immune systems. Fungal infections may also be more severe in patients with weakened immune systems, including people with HIV.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=6]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Amphotericin B]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[am-foe-TER-i-sin bee]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Amphocin, Fungizone, AmBisome, Abelecet, Amphotec]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Amphotericin B]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Opportunistic Infection and Other Drugs]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Amphotericin B is an amphoteric polyene macrolide antibiotic produced by Streptomyces nodosus. Amphotericin B, formulated with sodium deoxycholate, was the first parenteral amphotericin B preparation available commercially. Because amphotericin B deoxycholate is associated with certain dose-limiting toxicities (principally nephrotoxicity), other parenteral amphotericin B preparations have been developed with lipid-based drug delivery systems.  Amphotericin B is now commercially available as amphotericin B cholestryl sulfate complex (Amphotec), amphotericin B lipid complex (Abelcet), and amphotericin B liposomal (AmBisome).]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Amphotericin B deoxycholate is indicated in the treatment of invasive fungal infections, including aspergillosis, disseminated candidiasis, coccidioidomycosis, cryptococcosis, and histoplasmosis, which are common opportunistic infections in HIV infected patients. Because of concern about nephrotoxicity and the availability of alternative treatments (voriconazole, caspofungin, and lipid amphotericin formulations), the indication for amphotericin B deoxycholate therapy is limited to patients who have normal renal function, will receive less than 2 weeks of therapy, and have conditions that cannot be treated with azole antifungals.

Amphotericin B deoxycholate is used as an alternative agent for long-term suppressive therapy (i.e., secondary prophylaxis) or maintenance therapy to prevent recurrence or relapse of coccidioidomycosis, cryptococcosis, or histoplasmosis in HIV infected individuals who have received adequate treatment of these infections. Long-term suppressive or maintenance therapy is generally continued for life. The U.S. Public Health Service and Infectious Diseases Society of America make no recommendations for discontinuing therapy in patients receiving antiretroviral therapy who have CD4 cell counts greater than 100 cells/mm3. However, limited data suggest that discontinuing suppressive therapy in HIV infected adults and adolescents may be associated with low risk for recurrence of cryptococcosis. Individuals who consider discontinuing suppressive therapy should have successfully completed initial therapy for cryptococcosis, remained asymptomatic with respect to cryptococcosis, and have sustained (longer than 6 months) CD4 cell counts greater than 100 to 200 cells/mm3 in response to potent antiretroviral therapy.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Amphotericin B is indicated in the treatment of a variety of invasive fungal infections, including aspergillosis, blastomycosis, disseminated candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, mucormycosis, and sporotrichosis. It is indicated for treatment of fungal endocarditis, intra-abdominal infections, meningitis, septicemia, and urinary tract infections. Because of its toxicity, amphotericin B deoxycholate is indicated primarily in patients with progressive, potentially fatal infections in whom the diagnosis is firmly established.

Although some azole antifungal agents (e.g., itraconazole, fluconazole) are now also recognized as drugs of choice for the treatment of many systemic mycoses, amphotericin B deoxycholate remains the drug of first choice for the initial treatment of severe, life-threatening fungal infections, especially in immunocompromised patients. Because clinical experience with newer amphotericin B formulations is limited, these formulations have generally been reserved for second-line therapy in patients with invasive fungal infections that have not responded to amphotericin B deoxycholate or in patients who cannot tolerate amphotericin B deoxycholate. Specific indications are listed below by formulation.

Amphotericin B cholestryl sulfate complex is indicated for the treatment of invasive aspergillosis in cases where renal impairment or unacceptable toxicity precludes the use of amphotericin B deoxycholate in effective doses and in cases where prior amphotericin B deoxycholate therapy has failed.

Amphotericin B lipid complex is indicated for the treatment of invasive fungal infections in patients who are refractory to or intolerant of amphotericin B deoxycholate therapy.

Amphotericin B liposomal is indicated as empiric therapy for presumed fungal infections in febrile, neutropenic patients; treatment of cryptococcal meningitis in HIV infected patients; treatment of aspergillosis, candidiasis, or cryptococcosis in patients refractory to amphotericin B deoxycholate or with renal impairment that precludes the use of amphotericin B deoxycholate; and the treatment of leishmaniasis.

Amphotericin B deoxycholate may be the preferred agent for pregnant women with invasive fungal infections due to concerns regarding the use of azole antifungal agents during pregnancy. Intravenous amphotericin B has also been used for empiric therapy in febrile neutropenic patients and for prophylaxis in certain immunosuppressed individuals (e.g., cancer patients and bone marrow or solid organ transplant patients.

Amphotericin B is also used for the treatment of certain protozoal infections, including leishmaniasis and amebic meningoencephalitis. Amphotericin B is not effective against bacteria, rickettsiae, or viruses.]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Intravenous (IV) infusion.

May also be given intrathecally, intra-articularly, intrapleurally, and by local instillation or irrigation.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Vials containing amphotericin B powder 50 mg each.

The maximum recommended IV total daily dose for adults should not exceed 1.5mg/kg. Prior to initiation of conventional IV amphotericin B therapy, a single test dose of the drug (1 mg in 20 ml of 5% dextrose injection) should be administered  IV over 20 to 30 minutes and the patient carefully monitored every 30 minutes for 2 hours. Depending on the patient's cardio-renal status, dosage may gradually be increased by 5 to 10 mg daily to a final daily dosage of 0.5 to 0.7 mg/kg.

The recommended IV dose of amphotericin B for infants and small children is 0.2 to 0.5 mg/ml (base) per kg of body weight per day and is administered in 5% dextrose injection over a period of 6 hours.]]></drug:dosageform><drug:storage><![CDATA[Prior to reconstitution, store powder between 2 C and 8 C (36 F and 46 F). Protect from light.]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Amphotericin B is fungistatic or fungicidal, depending upon the susceptibility of the fungus and the concentration obtained in body fluids. Amphotericin binds to sterols in the fungal cell membrane, changing the membrane permeability and causing leakage of intracellular components. Cell death occurs in part because of these permeability changes, but other mechanisms may also contribute to amphotericin's antifungal activity. Amphotericin B is not active in vitro against organisms that do not contain sterols in their cell membranes (e.g., bacteria). Binding to sterols in mammalian cells (e.g., certain kidney cells, erythrocytes) may be responsible for the toxicities associated with amphotericin B therapy.

Amphotericin B is poorly absorbed from the gastrointestinal (GI) tract and must be given parenterally to treat systemic fungal infections. After completion of IV infusion of amphotericin B 50 mg, the average peak serum concentration was approximately 2 mcg/ml.(

Amphotericin B distributes into lungs, liver, spleen, kidneys, adrenal glands, muscle, and other tissues in potentially therapeutic concentrations. The volume of distribution is approximately 4 l/kg in adults. Concentrations attained in inflamed pleural, peritoneal, and synovial fluids and in aqueous humor are reportedly about 60% of concurrent plasma concentrations. Concentrations in cerebrospinal fluid (CSF) are approximately 3% of concurrent serum concentrations. To achieve fungistatic CSF concentrations, amphotericin B must be administered intrathecally.

Amphotericin B is in FDA Pregnancy Category B. Amphotericin B reportedly crosses the placenta, and low concentrations are attained in amniotic fluid. Safe use of amphotericin B during pregnancy has not been established. Animal studies have not revealed evidence of harm to the fetus. It is not known if amphotericin B is distributed into breast milk.

Amphotericin B is highly protein bound (greater than 90%). Metabolism of amphotericin B has not been fully elucidated. The initial plasma elimination half-life is 24 hours and the terminal elimination half-life is approximately 15 days. Amphotericin B is eliminated very slowly (weeks to months) by the kidneys; only about 40% of an administered dose is excreted over 7 days. Only 3% of a dose is excreted in the urine unchanged. Amphotericin B is not removed by hemodialysis.

Resistance to amphotericin B has been produced in vitro, and resistant strains have been isolated from patients who have received long-term therapy with amphotericin B deoxycholate. Fluconazole-resistant strains of Candida albicans that were cross resistant to amphotericin B have been isolated from a few immunocompromised patients. Cryptococcus neoformans isolates resistant to fluconazole and amphotericin B have also been documented. Fungi resistant to amphotericin B deoxycholate may also be resistant to amphotericin B cholestryl sulfate complex, amphotericin B lipid complex, and amphotericin B liposomal.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Most patients on amphotericin B deoxycholate therapy experience adverse effects.  Acute infusion reactions and nephrotoxicity are the two most common adverse effects.

The majority of patients receiving amphotericin B deoxycholate (50% to 90%) experience some degree of intolerance to initial doses. Acute infusion reactions of fever, shaking chills, hypotension, anorexia, nausea, vomiting, headache, dyspnea, and tachypnea may occur 1 to 3 hours after initiation of IV infusions. Lipid-based amphotericin B preparations are also associated with acute infusion reactions, although to a lesser degree. Administration of an antipyretic, an antihistamine, meperidine, or a corticosteroid just before the start of the infusion may reduce the incidence or severity of the reaction.

Rapid infusion of amphotericin B deoxycholate has been associated with a more severe reaction consisting of hypotension, bronchospasm, hypokalemia, arrhythmias, and shock. It may be difficult to determine whether these severe reactions indicate intolerance or hypersensitivity to amphotericin B. Anaphylaxis and anaphylactoid reactions have been reported in people taking all formulations of amphotericin B.

Nephrotoxicity is the major dose-limiting toxicity reported with amphotericin B deoxycholate, and nephrotoxicity occurs to some degree in the majority of patients receiving the drug. Adverse renal effects include decreased renal function, azotemia, hypokalemia, hyposthenuria, renal tubular acidosis, and nephrocalcinosis.  Increased blood urea nitrogen (BUN) and serum creatinine concentrations and decreased creatinine clearance, glomerular filtration rate, and renal plasma flow occur in most patients.  Nephrotoxicity associated with amphotericin B deoxycholate appears to involve several mechanisms, including direct vasoconstrictive effects on renal arterioles and lytic action on renal tubular cell membranes. Renal function usually improves within a few months of discontinuing therapy, but some impairment may remain. Lipid-based amphotericin B formulations are generally associated with a lower risk of nephrotoxicity than amphotericin B deoxycholate. However, abnormal renal lab values have been reported in patients using alternate formulations.

Amphotericin B intravenous infusion has also been associated with anemia, headache, thrombophlebitis, and GI effects (indigestion, loss of appetite, nausea, vomiting, diarrhea, stomach pain). Less frequently, blurred or double vision, cardiac arrhythmias, leukopenia, peripheral neuropathy, seizures, and thrombocytopenia have been reported.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Because nephrotoxic effects may be additive, the concurrent or sequential use of amphotericin B and other drugs with similar nephrotoxic effects (e.g., aminoglycosides, capreomycin, colistin, cisplatin, methoxyflurane, polymyxin B, vancomycin, cyclosporine, pentamidine) should be avoided. Intensive monitoring is recommended in patients requiring concomitant administration of any nephrotoxic medications.

Concomitant administration of zidovudine and amphotericin B may be associated with increased myelotoxicity and nephrotoxicity.

Concomitant administration of flucytosine and amphotericin B may have additive or slightly synergistic effects.  Amphotericin B-induced renal dysfunction may decrease the clearance of flucytosine and result in flucytosine adverse effects, such as bone marrow toxicity.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Amphotericin B deoxycholate and alternative formulations of amphotericin B are contraindicated in patients allergic to amphotericin B or any of the formulation components. Extreme caution should be exercised when using amphotericin B deoxycholate in patients with renal impairment.]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[(1R-(1R*,3S*,5R*,6R*,9R*,11R*, 15S*,16R*,17R*,18S*,19E,21E,23E,25E,27E,29E, 31E,33R*,35S*,36R*,37S*))-33-((3-Amino-3,6- dideoxy-beta-D-mannopyranosyl)oxy)-1,3,5,6,9, 11,17,37-octahydroxy-15,16,18-trimethyl-13-oxo- 14,39-dioxabicyclo(33.3.1)nonatriaconta-19,21, 23,25,27,29,31-heptaene-36-carboxylic acid]]></drug:casname><drug:casnumber><![CDATA[1397-89-3]]></drug:casnumber><drug:molecularformula><![CDATA[C47-H73-N-O17]]></drug:molecularformula><drug:elementalcomposition><![CDATA[C61.09%, H7.96%, N1.52%, O29.43%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[924.08]]></drug:molecularweight><drug:physicaldescription><![CDATA[Yellow to orange, odorless or practically odorless powder.]]></drug:physicaldescription><drug:stability><![CDATA[Concentrated solutions (5 mg/ml) in sterile water retain their potency for 24 hours at room temperature if protected from light, or for 1 week if refrigerated. Diluted solutions (0.1 mg/ml) in 5% dextrose should be used promptly after dilution.]]></drug:stability><drug:solubility><![CDATA[Crystalline amphotericin B is insoluble in water.  It is solubilized by the addition of sodium deoxycholate to form a mixture, which creates a colloidal dispersion.]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform" /><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[Prescribing Information from the <a href="http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm">FDA Web site</a>. More current versions may be available on the manufacturer's Web site.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17554704 Bicanic T, Meintjes G, Wood R, Hayes M, Rebe K, Bekker LG, Harrison T. Fungal burden, early fungicidal activity, and outcome in cryptococcal meningitis in antiretroviral-naive or antiretroviral-experienced patients treated with amphotericin B or fluconazole. Clin Infect Dis. 2007 Jul 1;45(1):76-80. Epub 2007 May 25. Erratum in: Clin Infect Dis. 2007 Aug 15;45(4):526.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17554704&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/18035917 Chamilos G, Luna M, Lewis RE, Chemaly R, Raad II, Kontoyiannis DP. Effects of liposomal amphotericin B versus an amphotericin B lipid complex on liver histopathology in patients with hematologic malignancies and invasive fungal infections: a retrospective, nonrandomized autopsy study. Clin Ther. 2007 Sep;29(9):1980-6.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=18035917&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/12877636 Herbrecht R, Natarajan-Ame S, Nivoix Y, Letscher-Bru V. The lipid formulations of amphotericin B. Expert Opin Pharmacother. 2003 Aug;4(8):1277-87.
]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=12877636&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17852947 Techapornroong M, Suankratay C. Alternate-day versus once-daily administration of amphotericin B in the treatment of cryptococcal meningitis: a randomized controlled trial.Scand J Infect Dis. 2007;39(10):896-901.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17852947&dopt=Abstract]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Fungizone]]></drug:drugname><drug:companyname><![CDATA[Bristol - Myers Squibb Co]]></drug:companyname><drug:address1><![CDATA[PO Box 4500]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Princeton]]></city><drug:state><![CDATA[NJ]]></drug:state><drug:zipcode><![CDATA[08543-4500]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 321-1335]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Amphotericin B]]></drug:drugname><drug:companyname><![CDATA[Bristol - Myers Squibb Co]]></drug:companyname><drug:address1><![CDATA[PO Box 4500]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Princeton]]></city><drug:state><![CDATA[NJ]]></drug:state><drug:zipcode><![CDATA[08543-4500]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 321-1335]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Amphocin]]></drug:drugname><drug:companyname><![CDATA[Pfizer Inc]]></drug:companyname><drug:address1><![CDATA[235 East 42nd Street]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[New York]]></city><drug:state><![CDATA[NY]]></drug:state><drug:zipcode><![CDATA[10017-5755]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 438-1985]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Abelecet]]></drug:drugname><drug:companyname><![CDATA[Enzon, Inc.]]></drug:companyname><drug:address1><![CDATA[20 Kingsbridge Road]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Piscataway]]></city><drug:state><![CDATA[NJ]]></drug:state><drug:zipcode><![CDATA[08854-3969]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(908) 541-8600]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Amphotec]]></drug:drugname><drug:companyname><![CDATA[Oryx Pharmaceuticals Inc.]]></drug:companyname><drug:address1><![CDATA[6500 Kitimat Road]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Mississauga, Ontario]]></city><drug:state><![CDATA[]]></drug:state><drug:zipcode><![CDATA[]]></drug:zipcode><drug:country><![CDATA[Canada]]></drug:country><drug:phone><![CDATA[]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[AmBisome]]></drug:drugname><drug:companyname><![CDATA[Fujisawa Healthcare Inc]]></drug:companyname><drug:address1><![CDATA[Parkway Center North / 3 Parkway North]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Deerfield]]></city><drug:state><![CDATA[IL]]></drug:state><drug:zipcode><![CDATA[60015-2548]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 727-7003]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[March 20, 2008]]></drug:lastupdated></item><item><title><![CDATA[Azithromycin]]></title><description><![CDATA[Azithromycin, also known as Zithromax, belongs to the class of medicines known as antibacterials or antibiotics. These medicines kill bacteria (small organisms that can cause infection in humans) or stop bacteria from growing.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=104]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Azithromycin]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[az-ith-roe-MYE-sin]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Zithromax]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Azithromycin]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Opportunistic Infection and Other Drugs]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Azithromycin is a semisynthetic azalide antibiotic, a subclass of macrolide antibiotics. Azalides are distinguished from other macrolides by the addition of nitrogen at position 9a of the lactone ring. Azithromycin differs structurally from erythromycin by a methyl-substituted nitrogen atom incorporated into the macrolide ring. Azithromycin has a broader spectrum of activity than that of erythromycins or clarithromycin.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Azithromycin was approved by the FDA on June 14, 1996, for the prevention of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection. Azithromycin may be an effective treatment for symptomatic Cryptosporidiosis in HIV infected patients; however, it is not effective in eradicting cryptosporidial infection.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Azithromycin is used to treat chronic bronchitis or acute otitis media; gonococcal or nongonococcal cervicitis; gonococcal or nongonococcal urethritis; chancroid; pelvic inflammatory disease; pharyngitis or tonsillitis; community-acquired pneumonia; and uncomplicated skin and soft tissue infections.  Azithromycin is active against many gram-positive and gram-negative aerobic and anaerobic bacteria, including streptococci, staphylococci, and Haemophilus influenzae.]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral.

Intravenous.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Film-coated tablets containing anhydrous azithromycin 250, 500, or 600 mg.

Oral suspension containing 100 or 200 mg of anhydrous azithromycin per 5 ml, or 1 g anhydrous azithromycin per single dose packet.

Lyophilized azithromycin in vacuum 10 ml vials containing the equivalent of 500 mg azithromycin.]]></drug:dosageform><drug:storage><![CDATA[Tablets should be stored below 30 C (86 F). Dry powder for reconstitution into azithromycin oral suspension should be stored below 30 C (86 F).]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Like other macrolides, azithromycin binds the 50S ribosomal subunit of the 70S ribosome of susceptible organisms, inhibiting RNA-dependent protein synthesis. Azithromycin is bactericidal for Streptococcus pyogenes, Streptococcus pneumoniae, and Haemophilus influenzae; it is bacteriostatic for staphylococci and most aerobic gram-negative species. Azithromycin concentrates in phagocytes; penetration of the drug into phagocytic cells is necessary for activity against intracellular pathogens (e.g., Staphylococcus aureus). The site of action appears to be the same as that of the macrolides, clindamycin, lincomycin, and chloramphenicol.

Azithromycin has an expanded spectrum of activity compared with erythromycin and clarithromycin. Azithromycin generally is more active in vitro against gram-negative organisms than erythromycin or clarithromycin and has activity comparable to erythromycin against most gram-positive organisms. Azithromycin is not inactivated by the beta-lactamases produced by Haemophilus influenzae or Moraxella catarrhalis.

Azithromycin is rapidly absorbed from the gastrointestinal (GI) tract after oral administration; absorption of the drug is incomplete but exceeds that of erythromycin. The absolute oral bioavailability of azithromycin is reported to be approximately 34% to 52% with single doses of 500 mg to 1.2 g administered as various oral dosage forms. Limited evidence indicates that the low bioavailability of azithromycin results from incomplete GI absorption rather than acid degradation of the drug or extensive first-pass metabolism. Time to peak concentration in adults is 2.1 to 3.2 hours for oral dosage forms and 1 to 2 hours for intravenous (IV) forms. For oral dosage forms, after a 500 mg loading dose on Day 1, then 250 mg once a day for Days 2 to 5, peak plasma concentrations in healthy adults were approximately 0.41 to 0.38 mcg/ml on Day 1 and 0.24 to 0.26 mcg/ml on Day 5.  For IV forms, peak plasma concentrations were approximately 1.1 mcg/ml after a 3-hour IV infusion of 500 mg at a concentration of 1 mg/ml and approximately 3.6 mcg/ml after a 1-hour IV infusion of 500 mg at a concentration of 2 mg/ml. Presence of food in the GI tract may affect the extent of absorption of oral azithromycin; however, the effect of food on absorption depends on the dosage form administered.

Azithromycin is rapidly and widely distributed throughout the body. Azithromycin concentrates intracellularly, resulting in tissue concentrations 10 to 100 times higher than those found in plasma or serum. Azithromycin is highly concentrated in fibroblasts and phagocytic cells. In addition to direct tissue uptake, it has been suggested that uptake and release of azithromycin by phagocytic cells contribute to the distribution of the drug into inflamed and infected tissues. Only very low concentrations of azithromycin have been detected in cerebrospinal fluid in patients with noninflamed meninges.

Azithromycin is in FDA Pregnancy Category B. Adequate and well-controlled studies have not been done in pregnant women. Reproduction studies done in rats and mice given azithromycin at doses of up to moderately maternally toxic levels (i.e., 200 mg/kg per day) have found no evidence of harm to the fetus. On a mg/m2 basis, these doses are estimated to be four and two times the human daily dose of 500 mg in rats and mice, respectively. Azithromycin has been detected in human milk. Physicians should exercise caution when administering azithromycin to nursing women.

Protein binding to azithromycin varies with concentration but is generally very low to moderate, with approximately 7% binding at 1 mcg/ml, to 50% at 0.02 to 0.05 mcg/ml. Plasma azithromycin concentrations following a single 500 mg oral or IV dose decline in a polyphasic manner, with a terminal elimination half-life average of 68 hours. More than 50% of azithromycin is eliminated through biliary secretion as unchanged drug. Azithromycin is excreted in feces primarily as unchanged drug. The primary route of biotransformation involves N-demethylation of the desoamine sugar or at the 9a position on the macrolide ring. While short-term administration of azithromycin produces hepatic accumulation of the drug and increases azithromycin demethylase activity, current evidence indicates that hepatic cytochrome P-450 induction or inactivation via cytochrome-metabolite complex formation does not occur. Approximately 4.5% of a dose is eliminated in urine as unchanged drug within 72 hours. Approximately 11% to 14% of an IV dose is eliminated in urine as unchanged drug within 24 hours.

Resistance to macrolide antibiotics may be natural or acquired. In studies evaluating prevention of disseminated MAC disease, drug-resistant isolates were detected in 29% to 58% of individuals in whom disease developed while receiving clarithromycin and in 11% of those receiving azithromycin. MAC isolates resistant to azithromycin are resistant to clarithromycin.  Erythromycin-resistant staphylococci and streptococci are also resistant to clarithromycin and azithromycin.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[The most frequently reported adverse effect seen with azithromycin use is thrombophlebitis; this effect occurs with the injection form only. Other adverse effects of all dosage forms include acute interstitial nephritis, allergic reactions, pseudomembranous colitis, GI disturbances, dizziness, and headache.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[When azithromycin is administered in capsule form, food decreases maximum concentration (Cmax) values by approximately 52% and area under the plasma concentration-time curve (AUC) values by approximately 43%.  In tablet form, food increases Cmax values by 23% and 34% for the 250 mg and 600 mg tablets, respectively, and has no effect on AUC values.  In oral suspension form, food increases the Cmax values by approximately 56% but has no effect on AUC values.

Concurrent use of aluminum- and magnesium-containing antacids decreases the Cmax of azithromycin by approximately 24%, but has no effect on AUC. Oral azithromycin should be administered at least 1 hour before or 2 hours after aluminum- and magnesium-containing antacids.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Azithromycin is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin, or any macrolide antibiotics.

Azithromycin should be administered to patients with hepatic function impairment with caution because biliary excretion is the major route of elimination for azithromycin.]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[1-Oxa-6-azacyclopentadecan-15-one, 13-((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha- L-ribo-hexopyranosyl)oxy)-2-ethyl-3,4,10- trihydroxy-3,5,6,8,10,12,14-heptamethyl-11- ((3,4,6-trideoxy-3-(dimethylamino)-beta-D- xylo-hexopyranosyl)oxy)-,]]></drug:casname><drug:casnumber><![CDATA[83905-01-5]]></drug:casnumber><drug:molecularformula><![CDATA[C38-H72-N2-O12]]></drug:molecularformula><drug:elementalcomposition><![CDATA[C60.94%, H9.69%, N3.74%, O25.63%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[113 to 115 C]]></drug:meltingpoint><drug:molecularweight><![CDATA[748.98]]></drug:molecularweight><drug:physicaldescription><![CDATA[White, crystalline powder (dihydrate form).]]></drug:physicaldescription><drug:stability><![CDATA[After reconstitution with sterile water, azithromycin solution for injection is stable for 24 hours when stored below 30 C (86 F) or for 7 days if stored under refrigeration at 5 C (41 F).]]></drug:stability><drug:solubility><![CDATA[]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform" /><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[Zithromax Prescribing Information from the FDA Web site <a href="http://www.fda.gov/cder/foi/label/2004/50784se1-004,slr006_zithromax_lbl.pdf">[PDF]</a>. A more current version may be available on the manufacturer's Web site.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[Zithromax for IV Infusion Prescribing Information from the FDA Web site <a href=http://www.fda.gov/cder/foi/label/2001/50733s5lbl.pdf>[PDF]</a>. A more current version may be available on the manufacturer's Web site.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/12432190 Kadappu KK, Nagaraja MV, Rao PV, Shastry BA. Azithromycin as treatment for cryptosporidiosis in human immunodeficiency virus disease. J Postgrad Med 2002 Jul-Sep;48(3):179-81.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=12432190&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/11774085 Phillips P, Chan K, Hogg R, Bessuille E, Black W, Talbot J, O'Shaughnessy M, Montaner J. Azithromycin prophylaxis for Mycobacterium avium complex during the era of highly active antiretroviral therapy: evaluation of a provincial program. Clin Infect Dis 2002 Feb 1;34(3):371-8.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=11774085&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/11956499 Pozniak A. Mycobacterial diseases and HIV. J HIV Ther 2002 Feb;7(1):13-6.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=11956499&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/TBD Shafran SD, Mashinter LD, Phillips P, Lalonde RG, Gill MJ, Walmsley SL, Toma E, Conway B, Fong IW, Rachlis AR, Williams KE, Garber GE, Schlech WF, Smaill F, Pradier C. Successful discontinuation of therapy for disseminated Mycobacterium avium complex infection after effective antiretroviral therapy. Ann Intern Med 2002 Nov 5;137(9):734-7.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=TBD&dopt=Abstract]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Azithromycin]]></drug:drugname><drug:companyname><![CDATA[Pfizer Inc]]></drug:companyname><drug:address1><![CDATA[235 East 42nd Street]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[New York]]></city><drug:state><![CDATA[NY]]></drug:state><drug:zipcode><![CDATA[10017-5755]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 438-1985]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Zithromax]]></drug:drugname><drug:companyname><![CDATA[Pfizer Inc]]></drug:companyname><drug:address1><![CDATA[235 East 42nd Street]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[New York]]></city><drug:state><![CDATA[NY]]></drug:state><drug:zipcode><![CDATA[10017-5755]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 438-1985]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[March 21, 2007]]></drug:lastupdated></item><item><title><![CDATA[Calcium hydroxylapatite]]></title><description><![CDATA[Calcium hydroxylapatite, also known as CaHA, is the main ingredient of Radiesse. Radiesse is a water-based material that is injected into the skin. Radiesse belongs to the class of medicines called dermal fillers. Injecting Radiesse into facial skin may give it a firmer, fuller appearance.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=425]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Calcium hydroxylapatite]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Radiesse]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Calcium hydroxylapatite]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Opportunistic Infection and Other Drugs]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Radiesse is a soft-tissue augmentation product composed of smooth calcium hydroxylapatite (CaHA) particles suspended in a water-based gel carrier.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Radiesse was approved by the FDA on December 22, 2006, as a cosmetic dermal filler for use in the long-term correction of facial lipoatrophy associated with antiretroviral treatment in HIV infected people.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Radiesse was approved by the FDA on December 22, 2006, for use as filler material to correct facial lines and wrinkles, such as nasolabial folds. Radiesse is approved for use worldwide in facial plastic and reconstructive surgery.

Other FDA-approved soft-tissue augmentation indications of synthetic CaHA include tissue marking, treatment of vocal cord insufficiency, and treatment of oral-maxillofacial defects. Similar products containing CaHA are approved for the treatment of stress urinary incontinence and are used in products for dental ridge augmentation, bone augmentation, and otology implants.]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Subcutaneous injection.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Single-use syringe containing 0.3, 1, or 1.3 ml of solution with active CaHA particles suspended in each needle in a gel carrier. Radiesse is injected subcutaneously through a very fine needle.]]></drug:dosageform><drug:storage><![CDATA[]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[CaHA is the principal inorganic constituent in human bones and teeth. CaHA in Radiesse is a biocompatible, biodegradable material that is synthetically manufactured to be chemically and biologically identical to the natural substance.

Radiesse contains sterile and nonpyrogenic CaHA microspheres in an aqueous carrier of glycerin, sterile water for injection, and sodium carboxymethylcellulose. After the carrier dissipates in vivo, CaHA particles remain below the skin in the injected area. The active ingredient of Radiesse, CaHA, has been studied extensively in the United States and worldwide; it has been proven safe and effective for various dermal filler uses.

Radiesse is injected subcutaneously to increase skin thickness. Its CaHA microspheres appear in x-rays and CT scans. After Radiesse is injected, the gel carrier dissipates in vivo, and CaHA particles remain at the injection site to provide durable bulking treatment. The CaHA particles act by directly filling space in the soft tissue and by providing a microstructure for tissue infiltration. In addition, Radiesse may promote new collagen binding.

A prospective, open-label study of Radiesse for the treatment of lipoatrophy was conducted in 100 HIV infected patients. The primary endpoint of efficacy and secondary endpoint of safety were evaluated at Months 1, 3, 6, and 12. All patients met the primary endpoint of improved aesthetics at Months 3 and 6, and all patients continued to improve by Month 12.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Radiesse and other products containing CaHA appear safe and well tolerated. The most common adverse effects with Radiesse treatment are redness, bruising, and swelling at the injection site; all of these side effects appear transient and mild.

Mild to moderate echymosis, edema, erythema, pain, and pruritis have occurred in HIV infected patients receiving Radiesse in clinical trials. Severe experiences were of short duration, were expected, and did not affect treatment outcome. The most common other adverse effect was mildly uneven skin contours and irregularities, which resolved with additional injections. No systemic or serious adverse effects were reported that were associated with treatment.

In a study of Radiesse for the treatment of HIV-associated lipoatrophy, no clinically significant events occurred. Although 51% of patients in this study were considered people of color, depth of color did not appear to predict the occurrence of adverse effects. Thus, Radiesse is considered safe for use in people of color.

When Radiesse was studied for the correction of nasolabial folds in 117 patients, 82% of nasolabial folds treated with Radiesse improved after 6 months. This was a significantly greater percentage than with the control, which showed improvement in only 27% of treated folds (p less than 0.0001). No granulomas occurred; the rate of nodule formation was low and was the same in control and treatment arms.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Radiesse is contraindicated for short-term augmentation or restoration. Radiesse should not be used in patients who are allergic to any of its components (sodium carboxymethylcellulose, sterile water for injection, and glycerin).]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[]]></drug:casname><drug:casnumber><![CDATA[]]></drug:casnumber><drug:molecularformula><![CDATA[]]></drug:molecularformula><drug:elementalcomposition><![CDATA[]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[]]></drug:meltingpoint><drug:molecularweight><![CDATA[CaHA particles sized 25 to 45 microns]]></drug:molecularweight><drug:physicaldescription><![CDATA[Flexible, semisolid, cohesive implant.]]></drug:physicaldescription><drug:stability><![CDATA[]]></drug:stability><drug:solubility><![CDATA[]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform" /><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[PMID/15530292 Comite SL, Liu JF, Balasubramanian S, Christian MA. Treatment of HIV-associated facial lipoatrophy with Radiance FN (Radiesse). Dermatol Online J. 2004 Oct 15;10(2):2.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15530292&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16936543 Silvers SL, Eviatar JA, Echavez MI, Pappas AL. Prospective, open-label, 18-month trial of calcium hydroxylapatite (Radiesse) for facial soft-tissue augmentation in patients with human immunodeficiency virus-associated lipoatrophy: one-year durability. Plast Reconstr Surg. 2006 Sep;118(3 Suppl):34S-45S.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16936543&dopt=Abstract]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Calcium hydroxylapatite]]></drug:drugname><drug:companyname><![CDATA[BioForm Medical, Inc.]]></drug:companyname><drug:address1><![CDATA[1875 South Grant St. Suite, #110]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[San Mateo]]></city><drug:state><![CDATA[CA]]></drug:state><drug:zipcode><![CDATA[94103]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(650) 286-4000]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Radiesse]]></drug:drugname><drug:companyname><![CDATA[BioForm Medical, Inc.]]></drug:companyname><drug:address1><![CDATA[1875 South Grant St. Suite, #110]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[San Mateo]]></city><drug:state><![CDATA[CA]]></drug:state><drug:zipcode><![CDATA[94103]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(650) 286-4000]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[January 23, 2007]]></drug:lastupdated></item><item><title><![CDATA[Clarithromycin]]></title><description><![CDATA[Clarithromycin, also known as Biaxin, belongs to the class of medicines known as antibacterials. Antibacterials kill bacteria or stop bacteria from multiplying. Clarithromycin controls the infection and allows the body's immune system to kill the bacteria. Clarithromycin is used to fight many common bacteria that cause sore throat, ear infections, bronchitis, pneumonia, and skin infections. Clarithromycin can also be used to treat some stomach ulcers.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=99]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Clarithromycin]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[kla-RITH-roe-mye-sin]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Biaxin]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Clarithromycin]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Opportunistic Infection and Other Drugs]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Clarithromycin is a semisynthetic macrolide antibiotic. It differs structurally from erythromycin by methylation of a hydroxyl group at position 6 of the lactone ring.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Clarithromycin is used in the prevention and treatment of Mycobacterium avium complex (MAC) disease due to Mycobacterium avium and Mycobacterium intracellular. Clarithromycin was approved by the FDA for treatment of MAC on December 23, 1993, and for the prevention of MAC on October 12, 1995.

The Prevention of Opportunistic Infections Working Group of the U.S. Public Health Service and Infectious Diseases Society of America (USPHS/IDSA) state that HIV infected adults and adolescents with a CD4 count less than 50 cells/mm3 should receive primary chemoprophylaxis against disseminated MAC disease; clarithromycin and azithromycin are the preferred agents. The combination of clarithromycin and rifabutin is no more effective than clarithromycin alone and is associated with a higher rate of adverse effects than either drug alone. This combination should not be used for MAC prophylaxis. In addition to its preventive activity for MAC disease, clarithromycin confers protection against respiratory bacterial infections.

The American Thoracic Society recommends that clarithromycin or azithromycin be used with ethambutol and rifabutin for the treatment of disseminated MAC in HIV infected patients. Limited data from clinical trials indicate that use of ethambutol with clarithromycin may decrease the emergence of clarithromycin-resistant MAC. Adults and adolescents with disseminated MAC should receive lifelong therapy (i.e., secondary prophylaxis, maintenance therapy) unless immune reconstitution occurs as a consequence of highly active antiretroviral therapy (HAART).

Clarithromycin and azithromycin are also the preferred prophylactic agents for disseminated MAC disease in HIV infected children. Prophylaxis should be offered to high-risk children and dosed based on age and CD4 count according to the USPHS/IDSA guidelines. Children with a history of disseminated MAC should be given lifelong prophylaxis to prevent recurrence.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Clarithromycin is indicated in the treatment of acute bacterial exacerbations of chronic bronchitis, otitis media, or acute maxillary sinusitis due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae. It is also indicated in the treatment of pharyngitis or tonsillitis caused by Streptococcus pyogenes and bacterial and community-acquired pneumonia due to Chlamydia pneumoniae, H. influenzae, M. catarrhalis, Mycoplasma pneumoniae, or S. pneumoniae.

Clarithromycin may be used for the treatment of soft tissue infections due to susceptible strains of Staphylococcus aureus or S. pyogenes and as a treatment adjunct for Helicobacter pylori-associated duodenal ulcers.]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Oral.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Film-coated tablets for immediate release containing clarithromycin 250 and 500 mg or for extended release (XL) containing clarithromycin 500 mg.

Oral suspension as granules in sucrose containing 125 and 250 mg per 5 ml.]]></drug:dosageform><drug:storage><![CDATA[Store immediate-release tablets in tight containers at a temperature below 40 C (104 F), preferably between 15 C and 30 C (59 F and 86 F), and protect from light.

Store extended-release tablets between 20 C and 25 C (68 F and 77 F).  Excursions are permitted between 15 C and 30 C (59 F and 86 F). 

Store oral suspension in a well-closed container away from light between 15 C and 30 C (59 F and 86 F).]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Clarithromycin penetrates the cell wall of susceptible organisms and binds to the 50S subunit of the 70S ribosome, inhibiting translocation of aminoacyl transfer-RNA and protein synthesis. Clarithromycin is generally bacteriostatic but may be bactericidal in high concentrations or against highly susceptible organisms.

Clarithromycin is rapidly absorbed from the gastrointestinal (GI) tract following oral administration. The absolute oral bioavailability of clarithromycin is 50% to 55%. However, this underestimates clarithromycin's systemic activity because of the drug's rapid first-pass metabolism to its active metabolite, 14-hydroxyclarithromycin.

Clarithromycin is extensively metabolized in the liver, primarily by oxidative N-demethylation and hydroxylation at the 14 position. At least seven metabolites have been identified, but the principal metabolite, 14-hydroxyclarithromycin, is the only one with significant antibacterial activity. It is as active or only slightly less active than clarithromycin in vitro against most organisms and enhances the antimicrobial activity of clarithromycin against H. influenzae. However, 14-hydroxyclarithromycin was four to seven times less active than clarithromycin against MAC isolates; the clinical importance of this is unknown.

Clarithromycin is stable in gastric acid. The presence of food delays the rate but not the extent of absorption. Clarithromycin is widely distributed into tissues and fluids; high concentrations are found in nasal mucosa, tonsils, and lungs. Serum concentrations are lower than tissue concentrations because of high intracellular concentrations. Protein binding in vitro is 42% to 72% and decreases with increasing serum drug concentrations.

Elimination of clarithromycin is nonlinear and dose dependent. The elimination half-lives of clarithromycin 250 and 500 mg tablets given every 12 hours are 3 to 4 hours and 5 to 7 hours, respectively. The elimination half-life of 14-hydroxyclarithromycin is slightly longer. Time to peak concentration is 1 to 4 hours for conventional tablets and 5 to 8 hours for extended-release tablets. Clarithromycin is eliminated by both renal and nonrenal mechanisms. Hepatic metabolism is extensive and saturable. After a single 250-mg dose of radiolabeled clarithromycin in healthy men, approximately 38% of the dose (18% as clarithromycin) was excreted in the urine and 40% in feces (4% as clarithromycin) over 5 days.

The serum half-life of clarithromycin is prolonged in patients with impaired renal function. Marked increases in peak serum concentration (Cmax), area under the concentration-time curve (AUC), and half-life of clarithromycin and 14-hydroxyclarithromycin have been reported in patients with creatinine clearances less than 30 ml/min. These patients may require dose reduction.

Clarithromycin is in FDA Pregnancy Category C. No adequate and well-controlled studies in pregnant women have been done. In animal studies, clarithromycin has been associated with fetal loss and embryofetal maldevelopment. Clarithromycin should be used during pregnancy only when safer drugs cannot be used or are ineffective. It is not known whether clarithromycin is distributed in human breast milk. However, it is distributed in the milk of lactating animals, and other macrolides are distributed in human milk. Caution should be exercised when clarithromycin is administered to lactating women.

Resistance to macrolide antibiotics usually involves alteration of the antibiotic target site. Resistant bacteria produce an enzyme that leads to methylation of adenine residues in ribosomal RNA and subsequent inhibition of antibiotic ribosomal binding. Erythromycin-resistant organisms are generally resistant to all 14- and 15-membered macrolides because all of the drugs induce the methylase enzyme. Strains of MAC with decreased susceptibility or resistance to clarithromycin have been reported in patients who received the drug for treatment or prevention of MAC infection. MAC isolates resistant to clarithromycin are cross-resistant to azithromycin.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Clarithromycin is generally well tolerated. In clinical studies, most adverse effects were mild and transient; only about 1% of reported effects were described as severe. The most common adverse effects involve the GI tract and include diarrhea, nausea, abnormal taste, dyspepsia, and abdominal discomfort. Limited clinical data indicate that clarithromycin may cause adverse GI effects less frequently than erythromycin.

Pseudomembranous colitis has been reported with clarithromycin use.

Headache is a common adverse effect of clarithromycin therapy.

Allergic reactions ranging from urticaria and mild skin eruptions to rare cases of anaphylaxis and Stevens-Johnson syndrome have occurred. Rare cases of severe hepatic dysfunctions also have been reported. Hepatic dysfunction is usually reversible, but fatalities with clarithromycin use have been reported.

Increased prothrombin time and thrombocytopenia have also been reported with the use of clarithromycin.]]></drug:adverseeventstoxicity><drug:drugandfoodinteractions xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Clarithromycin immediate-release tablets and oral solution may be taken with or without food. Extended-release tablets should be taken with food.

Clarithromycin should be used with caution in patients taking carbamazepine and other medications metabolized by the cytochrome P450 (CYP) enzyme system. Because clarithromycin has been shown to significantly increase the plasma concentrations of these medications, serum concentration should be monitored when coadministered with clarithromycin. Concurrent use of clarithromycin and astemizole is not recommended, as QTc-interval prolongation and torsades de pointes have been reported with concurrent use of astemizole and erythromycin. Cisapride, pimozide, and terfenadine, when used concurrently with clarithromycin, have been associated with cardiac arrhythmias, including QTc-interval prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes. These arrhythmias may be fatal, and concurrent use of clarithromycin with these medications is contraindicated.

Concomitant administration of clarithromycin and antiretroviral agents may alter the pharmacokinetics of both clarithromycin and the antiretroviral agent. Administration of clarithromycin and delavirdine results in a 100% increase in the AUC of clarithromycin but has no effect on delavirdine's pharmacokinetics. Similarly, clarithromycin has no apparent effect on the pharmacokinetics of didanosine. Concurrent use of clarithromycin does increase the Cmax of ritonavir by 12% to 15%; clarithromycin's AUC and Cmax increase by 77% and 31%, respectively. Limited studies have shown that clarithromycin decreases the steady-state AUC of zidovudine by a mean 12% and decreases the Cmax by approximately 41%. This effect is partially offset if the two drugs are given 2 to 4 hours apart. The manufacturer of clarithromycin states that dosage modification is not necessary for concurrent clarithromycin and HAART in patients with normal renal function. However, the clarithromycin dose should be reduced by 50% in patients with creatinine clearance (CrCl) of 30 to 60 ml/min and by 75% in patients with CrCl below 30 ml/min when administered with HAART.

Concurrent use of clarithromycin and rifabutin or rifampin increases the metabolism of clarithromycin. A study of patients with advanced HIV infection demonstrated inhibition of rifabutin metabolism by clarithromycin and induction of clarithromycin metabolism by rifabutin. The AUC of clarithromycin decreased by an average 44% while the AUC of rifabutin increased by an average 99%.

Concurrent administration of warfarin and clarithromycin has been shown to potentiate the effects of warfarin. Prothrombin time should be monitored closely in patients receiving anticoagulants and clarithromycin concurrently.

Serum concentrations of digoxin increase when digoxin is used concurrently with clarithromycin; serum digoxin concentrations should be monitored.

Clarithromycin increases the AUC of theophylline by 17%, and monitoring of theophylline serum concentration is recommended, especially for patients with theophylline concentrations in the upper therapeutic range.]]></drug:drugandfoodinteractions><drug:contraindications xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Clarithromycin is contraindicated in patients with known hypersensitivity to clarithromycin, erythromycin, or any of the macrolide antibiotics. Concomitant administration of clarithromycin with cisapride, pimozide, astemizole, terfenadine, or ergotamine and derivatives is contraindicated.

Clarithromycin should be used with caution in patients with impaired renal function, because the elimination of clarithromycin is significantly reduced, especially in patients with CrCl less than 30 ml/min. The dose of clarithromycin should be halved or the dosing interval should be doubled in these patients.]]></drug:contraindications><drug:chemistry xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:casname><![CDATA[6-O-Methylerythromycin]]></drug:casname><drug:casnumber><![CDATA[81103-11-9]]></drug:casnumber><drug:molecularformula><![CDATA[C38-H69-N-O13]]></drug:molecularformula><drug:elementalcomposition><![CDATA[C61.02%, H9.30%, N1.87%,O27.81%]]></drug:elementalcomposition><drug:boilingpoint><![CDATA[]]></drug:boilingpoint><drug:meltingpoint><![CDATA[217 to 220 C]]></drug:meltingpoint><drug:molecularweight><![CDATA[747.95]]></drug:molecularweight><drug:physicaldescription><![CDATA[White to off-white crystalline powder.]]></drug:physicaldescription><drug:stability><![CDATA[After reconstitution, oral suspension retains potency for 14 days and does not require refrigeration.]]></drug:stability><drug:solubility><![CDATA[Practically insoluble in water and slightly soluble in alcohol at room temperature. Solubility increases with decreasing pH.]]></drug:solubility></drug:chemistry><drug:othernames xmlns:drug="http://www.w3.org/1999/XSL/Transform" /><drug:furtherreadings xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:furtherreading><drug:readingtext><![CDATA[Biaxin Prescribing Information from the FDA Web site <a href="http://www.fda.gov/cder/foi/label/2007/050662s040,050698s022,050775s011lbl.pdf">[PDF]</a>. A more current version may be available on the manufacturer's Web site.]]></drug:readingtext><drug:readingurl><![CDATA[]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/15544511 Bermudex LE, Yamazaki Y. Effects of macrolides and ketolides on mycobacterial infections. Curr Pharm Des. 2004;10(26):3221-8.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15544511&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/16306031 Jacobson MA, Nicolau DP, Sutherland C, Smith A, Aweeka F.  Pharmacokinetics of clarithromycin extended-release (ER) tablets in patients with AIDS. HIV Clin Trials. 2005 Sep-Oct;6(5):246-53.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16306031&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/15336223 Karakousis PC, Moore RD, Chaisson RE. Mycobacterium avium complex in patients with HIV infection in the era of highly active antiretroviral therapy. Lancet Infect Dis. 2004 Sep;4(9):557-65. Review.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=15336223&dopt=Abstract]]></drug:readingurl></drug:furtherreading><drug:furtherreading><drug:readingtext><![CDATA[PMID/17035461 Waller EA, Roy A, Brumble L, Khoor A, Johnson MM, Garland JL.  The expanding spectrum of Mycobacterium avium complex-associated pulmonary disease. Chest. 2006 Oct;130(4):1234-41.]]></drug:readingtext><drug:readingurl><![CDATA[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17035461&dopt=Abstract]]></drug:readingurl></drug:furtherreading></drug:furtherreadings><drug:manufacturerinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:info><drug:drugname><![CDATA[Clarithromycin]]></drug:drugname><drug:companyname><![CDATA[Abbott Laboratories]]></drug:companyname><drug:address1><![CDATA[One Hundred Abbott Park Rd]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Abbott Park]]></city><drug:state><![CDATA[IL]]></drug:state><drug:zipcode><![CDATA[60064-3500]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 633-9110]]></drug:phone></drug:info><drug:info><drug:drugname><![CDATA[Biaxin]]></drug:drugname><drug:companyname><![CDATA[Abbott Laboratories]]></drug:companyname><drug:address1><![CDATA[One Hundred Abbott Park Rd]]></drug:address1><drug:address2><![CDATA[]]></drug:address2><drug:address3><![CDATA[]]></drug:address3><city><![CDATA[Abbott Park]]></city><drug:state><![CDATA[IL]]></drug:state><drug:zipcode><![CDATA[60064-3500]]></drug:zipcode><drug:country><![CDATA[]]></drug:country><drug:phone><![CDATA[(800) 633-9110]]></drug:phone></drug:info></drug:manufacturerinformation><drug:lastupdated xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[January 11, 2008]]></drug:lastupdated></item><item><title><![CDATA[Doxorubicin (liposomal)]]></title><description><![CDATA[Liposomal doxorubicin hydrochloride (HCl), also known as Doxil, belongs to the class of drugs called antineoplastics. Antineoplastics slow or stop the growth of cancer cells.]]></description><guid><![CDATA[http://aidsinfo.nih.gov/DrugsNew/DrugDetailT.aspx?int_id=185]]></guid><drug:drugname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Doxorubicin (liposomal)]]></drug:drugname><drug:pronunciation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[LIP-oh-som-al dox-oh-ROO-bi-sin]]></drug:pronunciation><drug:brandname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Doxil]]></drug:brandname><drug:genericname xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Doxorubicin (liposomal)]]></drug:genericname><drug:drugclass xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Opportunistic Infection and Other Drugs]]></drug:drugclass><drug:drugdescription xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Doxorubicin is an anthracycline glycoside antineoplastic antibiotic produced by Streptomyces peucetius var. caesius.]]></drug:drugdescription><drug:hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Doxorubicin hydrochloride (HCl) encapsulated in polyethylene glycol (PEG)-stabilized liposomes was approved by the FDA on November 17, 1995, for use as first-line therapy for the treatment of advanced AIDS-related Kaposi's sarcoma (KS) disease that has progressed despite prior combination chemotherapy or in patients who are intolerant of such combination therapy. The conventional, nonencapsulated formulations of the drug have also been used in the palliative treatment of AIDS-related KS.]]></drug:hiv-aidsrelateduses><drug:non-hiv-aidsrelateduses xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Liposomal doxorubicin HCl is indicated for the treatment of metastatic ovarian carcinoma that is refractory to both paclitaxel- and platinum-based chemotherapy regimens. Refractory disease is defined as disease that has progressed while the patient is on treatment or within 6 months of completing treatment.]]></drug:non-hiv-aidsrelateduses><drug:dosageinformation xmlns:drug="http://www.w3.org/1999/XSL/Transform"><drug:modeofdelivery><![CDATA[Intravenous.]]></drug:modeofdelivery><drug:dosageform><![CDATA[Doxorubicin HCl (liposomal) for injection at a concentration of 2 mg/ml: in 10-ml sterile, single-use vials that each contain the equivalent of doxorubicin 20 mg and in 30-ml sterile, single-use vials that each contain the equivalent of doxorubicin 50 mg.]]></drug:dosageform><drug:storage><![CDATA[Refrigerate unopened vials between 2 C and 8 C (36 F and 46 F) and protect from freezing. Prolonged freezing may adversely affect liposomal drug products; however, short-term (less than 1 month) freezing does not appear to have a deleterious effect on the drug. When shipped, vials of doxorubicin HCl for injection are packaged with a gel refrigerant (blue ice) to maintain a temperature between 2 C and 8 C (36 F and 46 F).]]></drug:storage></drug:dosageinformation><drug:pharmacology xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Doxorubicin is an anthracycline cytostatic antibiotic with activity against a variety of malignancies, including KS. Both in vitro and in vivo, liposomal doxorubicin has been shown to inhibit KS cell growth. Doxorubicin intercalates between DNA strands, inhibiting topoisomerase II activity and inducing tumor cell DNA fragmentation. Additionally, liposomal doxorubicin induces expression of monocyte chemoattractant protein-1, which results in intralesional recruitment of phagocytic cells in patients with KS. The mechanism by which liposome encapsulation apparently enhances doxorubicin accumulation in AIDS-associated KS is not fully understood, but the passage of liposomal particles through endothelial cell gaps, reported to be present in certain solid tumors and known to be present in KS-like lesions, may contribute to the enhanced accumulation. Once within the tumor, the active ingredient doxorubicin is presumably released locally as the liposomes degrade and become permeable in situ. Doxorubicin-induced apoptosis may be an integral component of the cellular mechanism of action relating to therapeutic effects, toxicities, or both.

Doxorubicin is extremely irritating to tissues and therefore must be administered by intravenous (IV) infusion. Following IV infusion of a single 10- or 20-mg/m2 dose of liposomal doxorubicin HCl in patients with AIDS-related KS, average peak plasma doxorubicin (mostly bound to liposomes) concentrations are 4.33 mcg/ml or 10.1 mcg/ml, respectively; following a 15-minute infusion they are 4.12 mcg/ml; and following a 30-minute infusion, they are 8.34 mcg/ml. Following IV infusion over 15 minutes of a 40-mg/m2 dose of liposomal doxorubicin HCl in patients with AIDS-related KS, peak plasma concentrations averaged 20.1 mcg/ml.

Encapsulation in PEG-stabilized liposomes substantially slows the rate of distribution into the extravascular space. As a result, the liposomally encapsulated drug distributes mainly in intravascular fluid, whereas nonencapsulated drug distributes widely into the extravascular fluids and tissues. Doxorubicin does not cross the blood-brain barrier or achieve a measurable concentration in cerebrospinal fluid. Trace amounts of doxorubicin have been found in fetal mice whose mothers received the drug during pregnancy, and there are limited data to indicate that nonencapsulated doxorubicin crosses the human placenta. Nonencapsulated drug is distributed into milk, and it achieves concentrations that often exceed those in plasma; doxorubicinol (the major metabolite) also distributes into milk.

Liposomal doxorubicin HCl is in FDA Pregnancy Category D. Adequate and well-controlled studies have not been done in pregnant women to assess doxorubicin's effects on fertility and pregnancy. Use of the drug is not recommended during pregnancy. Women of childbearing age should be advised to avoid pregnancy during treatment and, in general, use of contraception is recommended during any cytotoxic drug therapy. Studies to evaluate the carcinogenic potential of liposomal doxorubicin injection have not been performed; however, the active ingredient doxorubicin is carcinogenic and mutagenic in experimental models. Limited in vitro and in vivo assays have shown that the liposome component of liposomal doxorubicin is not mutagenic.

Protein binding of liposomal doxorubicin has not been determined. Plasma concentrations of liposomally encapsulated doxorubicin HCl appear to decline in a biphasic manner. Following IV administration of a single 10- to 40-mg/m2 dose of doxorubicin HCl as a liposomal injection in patients with AIDS-related KS, the initial plasma half-life of doxorubicin averaged 3.76 to 5.2 hours, whereas the terminal elimination half-life averaged 39.1 to 55 hours. Plasma clearance of liposomal doxorubicin HCl appears to be substantially slower than that of nonencapsulated doxorubicin.]]></drug:pharmacology><drug:adverseeventstoxicity xmlns:drug="http://www.w3.org/1999/XSL/Transform"><![CDATA[Adverse effects associated with liposomal doxorubicin HCl use include anemia, asthenia, fever, infusion reactions, leukopenia, neut