Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
Protease Inhibitors (PIs)
(Last updated:11/1/2012; last reviewed:11/1/2012)
Ritonavir (RTV, Norvir)
|Ritonavir (RTV, Norvir)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/
Oral solution (contains 43% alcohol by volume): 80 mg/mL
Capsules: 100 mg
Tablets: 100 mg
RTV as a pharmacokinetic (PK) enhancer:
The major use of RTV is as a PK enhancer of other protease inhibitors used in pediatric patients and in adolescents and adults. The dose of RTV recommended varies and is specific to the drug combination selected. See dosing information for specific protease inhibitors (PIs).
In the unusual situation when RTV is prescribed as sole PI:
- See manufacturer guidelines.
|Selected Adverse Events
- Gastrointestinal (GI) intolerance, nausea, vomiting, diarrhea
- Paresthesias (circumoral and extremities)
- Hyperlipidemia, especially hypertriglyceridemia
- Taste perversion
- Fat maldistribution
- Possible increased bleeding episodes in patients with hemophilia
- Toxic epidermal necrolysis and Stevens-Johnson syndrome
To increase tolerability of RTV oral solution in children:
- Administer RTV with food to increase absorption and reduce GI side effects.
- If RTV is prescribed with didanosine (ddI), administer the drugs 2 hours apart.
- Refrigerate RTV capsules only if the capsules will not be used within 30 days or cannot be stored below 77°F (25°C). RTV tablets are heat stable.
- Do not refrigerate RTV oral solution; store at room temperature (68–77°F or 20–25°C). Shake the solution well before use.
- RTV oral solution has limited shelf life; use within 6 months.
- Patients who have persistent or significant nausea with the capsule may benefit from switching to the tablet. Also, the tablet is smaller than the capsule and thus easier to swallow.
- Mix solution with milk, chocolate milk, or vanilla or chocolate pudding or ice cream.
- Before administration, give a child ice chips, a popsicle, or spoonfuls of partially frozen orange or grape juice concentrate to dull the taste buds, or give peanut butter to coat the mouth.
- After administration, give a child strong-tasting foods such as maple syrup, cheese, or highly flavored chewing gum.
Dosing of RTV in patients with hepatic impairment:
- Cytochrome P (CYP)3A4 and CYP 2D6 inhibitor; CYP3A4 and CYP1A2 inducer.
- RTV is primarily metabolized by the liver. No dosage adjustment is necessary in patients with mild or moderate hepatic impairment. Data are unavailable on RTV dosing for adult or pediatric patients with severe hepatic impairment. Use caution when administering RTV to patients with moderate-to-severe hepatic impairment.
Drug Interactions (see also the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents):
- Metabolism: Ritonavir is extensively metabolized by and is one of the most potent inhibitors of hepatic cytochrome P450 3A (CYP3A). There is potential for multiple drug interactions with ritonavir.
- Before ritonavir is administered, a patient’s medication profile should be carefully reviewed for potential interactions with ritonavir and overlapping toxicities with other drugs.
- Avoid concomitant use of intranasal or inhaled fluticasone. Use caution when prescribing ritonavir with other inhaled steroids because of reports of adrenal insufficiency.1-3
- More common: Nausea, vomiting, diarrhea, headache, abdominal pain, anorexia, circumoral paresthesia, lipid abnormalities.
- Less common (more severe): Exacerbation of chronic liver disease, fat maldistribution.
- Rare: New-onset diabetes mellitus, hyperglycemia, ketoacidosis, exacerbation of pre-existing diabetes mellitus, spontaneous bleeding in hemophiliacs, pancreatitis, and hepatitis (life-threatening in rare cases). Allergic reactions, including bronchospasm, urticaria, and angioedema. Toxic epidermal necrolysis and Stevens-Johnson syndrome have occurred.4
Resistance: Resistance to ritonavir is not clinically relevant when the drug is used as a pharmacokinetic (PK) enhancer of other protease inhibitors (PIs).
Pediatric Use: Ritonavir has been approved by the Food and Drug Administration (FDA) for use in the pediatric population. Use of ritonavir as the sole PI in antiretroviral therapy (ART) in children is not recommended. However, in both children and adults, ritonavir is recommended as a PK enhancer to boost another/second PI in an ART regimen. Ritonavir acts by inhibiting the metabolism of the second (boosted) PI in the regimen, thereby increasing the plasma concentration of the second/boosted PI. Lopinavir/ritonavir, a PI coformulation, has been well studied in children and is a preferred PI for therapy in children (see Lopinavir/Ritonavir). Pediatric dosing regimens including boosted fosamprenavir, tipranavir, darunavir, and atazanavir are available (see individual PIs for more specific information).
Although ritonavir has been well studied, its use in children as a sole PI for therapy is limited because ritonavir is associated with a higher incidence of GI toxicity and has a greater potential for drug-drug interactions than other PIs. Also, ritonavir as a sole PI is associated with a higher risk of virologic failure than efavirenz or lopinavir/ritonavir.5-7 In addition, poor palatability of the liquid preparation and large pill burden with the capsules (adult dose is six capsules or tablets twice daily) limit its use as a sole PI. Concentrations are highly variable in children younger than 2 years, and doses of 350 to 450 mg/m2 twice a day may not be sufficient for long-term suppression of viral replication in this age group.8-19
Full-dose ritonavir has been shown to prolong the PR interval in a study of healthy adults who were given ritonavir at 400 mg twice daily.4 Potentially life-threatening arrhythmias in premature newborn infants treated with lopinavir/ritonavir have been reported; thus, lopinavir/ritonavir should not be used in this group of patients.20,21 Co-administration of ritonavir with other drugs that prolong the PR interval (e.g., macrolides, quinolones, methadone) should be undertaken with caution because it is unknown how co-administering any of these drugs with ritonavir will affect the PR interval. In addition, ritonavir should be used with caution in patients who may be at increased risk of developing cardiac conduction abnormalities, such as those with underlying structural heart disease, conduction system abnormalities, ischemic heart disease, or cardiomyopathy.
- Kedem E, Shahar E, Hassoun G, Pollack S. Iatrogenic Cushing's syndrome due to coadministration of ritonavir and inhaled budesonide in an asthmatic human immunodeficiency virus infected patient. J Asthma. Sep 2010;47(7):830-831. Available at http://www.ncbi.nlm.nih.gov/pubmed/20653496.
- Gray D, Roux P, Carrihill M, Klein M. Adrenal suppression and Cushing's syndrome secondary to ritonavir and budesonide. S Afr Med J. May 2010;100(5):296-297. Available at http://www.ncbi.nlm.nih.gov/pubmed/20460021.
- Frankel JK, Packer CD. Cushing's syndrome due to antiretroviral-budesonide interaction. Ann Pharmacother. Jun 2011;45(6):823-824. Available at http://www.ncbi.nlm.nih.gov/pubmed/21558486.
- Changes to Norvir labeling. AIDS Patient Care STDS. Oct 2008;22(10):834-835. Available at http://www.ncbi.nlm.nih.gov/pubmed/18924248.
- Davies MA, Moultrie H, Eley B, et al. Virologic failure and second-line antiretroviral therapy in children in South Africa--the IeDEA Southern Africa collaboration. J Acquir Immune Defic Syndr. Mar 2011;56(3):270-278. Available at http://www.ncbi.nlm.nih.gov/pubmed/21107266.
- van Zyl GU, van der Merwe L, Claassen M, et al. Protease inhibitor resistance in South African children with virologic failure. Pediatr Infect Dis J. Dec 2009;28(12):1125-1127. Available at http://www.ncbi.nlm.nih.gov/pubmed/19779394.
- Taylor BS, Hunt G, Abrams EJ, et al. Rapid development of antiretroviral drug resistance mutations in HIV-infected children less than two years of age initiating protease inhibitor-based therapy in South Africa. AIDS Res Hum Retroviruses. Sep 2011;27(9):945-956. Available at http://www.ncbi.nlm.nih.gov/pubmed/21345162.
- Mueller BU, Sleasman J, Nelson RP, Jr., et al. A phase I/II study of the protease inhibitor indinavir in children with HIV infection. Pediatrics. Jul 1998;102(1 Pt 1):101-109. Available at http://www.ncbi.nlm.nih.gov/pubmed/9651421.
- Thuret I, Michel G, Chambost H, et al. Combination antiretroviral therapy including ritonavir in children infected with human immunodeficiency. AIDS. Jan 14 1999;13(1):81-87. Available at http://www.ncbi.nlm.nih.gov/pubmed/10207548.
- Nachman SA, Stanley K, Yogev R, et al. Nucleoside analogs plus ritonavir in stable antiretroviral therapy-experienced HIV-infected children: a randomized controlled trial. Pediatric AIDS Clinical Trials Group 338 Study Team. JAMA. Jan 26 2000;283(4):492-498. Available at http://www.ncbi.nlm.nih.gov/pubmed/10659875.
- van Rossum AM, de Groot R, Hartwig NG, Weemaes CM, Head S, Burger DM. Pharmacokinetics of indinavir and low-dose ritonavir in children with HIV-1 infection. AIDS. Sep 29 2000;14(14):2209-2210. Available at http://www.ncbi.nlm.nih.gov/pubmed/11061667.
- Wiznia A, Stanley K, Krogstad P, et al. Combination nucleoside analog reverse transcriptase inhibitor(s) plus nevirapine, nelfinavir, or ritonavir in stable antiretroviral therapy-experienced HIV-infected children: week 24 results of a randomized controlled trial--PACTG 377. Pediatric AIDS Clinical Trials Group 377 Study Team. AIDS Res Hum Retroviruses. Aug 10 2000;16(12):1113-1121. Available at http://www.ncbi.nlm.nih.gov/pubmed/10954886.
- Krogstad P, Lee S, Johnson G, et al. Nucleoside-analogue reverse-transcriptase inhibitors plus nevirapine, nelfinavir, or ritonavir for pretreated children infected with human immunodeficiency virus type 1. Clin Infect Dis. Apr 1 2002;34(7):991-1001. Available at http://www.ncbi.nlm.nih.gov/pubmed/11880966.
- Palacios GC, Palafox VL, Alvarez-Munoz MT, et al. Response to two consecutive protease inhibitor combination therapy regimens in a cohort of HIV-1-infected children. Scandinavian journal of infectious diseases. 2002;34(1):41-44. Available at http://www.ncbi.nlm.nih.gov/pubmed/11874163.
- Yogev R, Lee S, Wiznia A, et al. Stavudine, nevirapine and ritonavir in stable antiretroviral therapy-experienced children with human immunodeficiency virus infection. Pediatr Infect Dis J. Feb 2002;21(2):119-125. Available at http://www.ncbi.nlm.nih.gov/pubmed/11840078.
- Bergshoeff AS, Fraaij PL, van Rossum AM, et al. Pharmacokinetics of indinavir combined with low-dose ritonavir in human immunodeficiency virus type 1-infected children. Antimicrob Agents Chemother. May 2004;48(5):1904-1907. Available at http://www.ncbi.nlm.nih.gov/pubmed/15105157.
- Fletcher CV, Yogev R, Nachman SA, et al. Pharmacokinetic characteristics of ritonavir, zidovudine, lamivudine, and stavudine in children with human immunodeficiency virus infection. Pharmacotherapy. Apr 2004;24(4):453-459. Available at http://www.ncbi.nlm.nih.gov/pubmed/15098798.
- Chadwick EG, Rodman JH, Britto P, et al. Ritonavir-based highly active antiretroviral therapy in human immunodeficiency virus type 1-infected infants younger than 24 months of age. Pediatr Infect Dis J. Sep 2005;24(9):793-800. Available at http://www.ncbi.nlm.nih.gov/pubmed/16148846.
- King JR, Nachman S, Yogev R, et al. Efficacy, tolerability and pharmacokinetics of two nelfinavir-based regimens in human immunodeficiency virus-infected children and adolescents: pediatric AIDS clinical trials group protocol 403. Pediatr Infect Dis J. Oct 2005;24(10):880-885. Available at http://www.ncbi.nlm.nih.gov/pubmed/16220085.
- Lopriore E, Rozendaal L, Gelinck LB, Bokenkamp R, Boelen CC, Walther FJ. Twins with cardiomyopathy and complete heart block born to an HIV-infected mother treated with HAART. AIDS. Nov 30 2007;21(18):2564-2565. Available at http://www.ncbi.nlm.nih.gov/pubmed/18025905.
- McArthur MA, Kalu SU, Foulks AR, Aly AM, Jain SK, Patel JA. Twin preterm neonates with cardiac toxicity related to lopinavir/ritonavir therapy. Pediatr Infect Dis J. Dec 2009;28(12):1127-1129. Available at http://www.ncbi.nlm.nih.gov/pubmed/19820426.