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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Non-Nucleoside Analogue Reverse Transcriptase Inhibitors (NNRTIs)

Nevirapine

(Last updated:February 12, 2014; last reviewed:February 12, 2014)

Nevirapine (NVP, Viramune)

Nevirapine (NVP, Viramune)

For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm

Formulations

Tablets:
immediate-release 200 mg, extended-release (XR) 100 mg and 400 mg
Suspension: 10 mg/mL

Dosing Recommendations

Neonate/Infant Dose (≤14 Days):
  • When used for prevention of perinatal transmission of HIV see Perinatal Guidelines.  
  • Treatment dose is undetermined for infants aged ≤14 days (see Dosing: Special Considerations: Neonates ≤14 Days and Premature Infants).
Pediatric Dose Immediate Release Formulation (>15 Days): 
  • See note below about initiation of therapy.
<8 Years:
  • 200 mg/m2 of body surface area (BSA)/dose (maximum dose of immediate release tablets is 200 mg twice daily). 
≥8 Years: 
  • 120–150 mg/m2 BSA/dose (maximum dose of immediate release tablets is 200 mg twice daily or extended release tablets 400 mg once daily).
  • When adjusting the dose for a growing child, the mg dose need not be decreased as the child reaches age 8 years; rather, the mg dose is left static to achieve the appropriate mg-per-m2 dosage as the child grows, as long as there are no untoward effects.
Note: Nevirapine is initiated at a lower dose and increased in a stepwise fashion to allow induction of cytochrome P450 metabolizing enzymes, which results in increased drug clearance. The occurrence of rash is diminished by this stepwise increase in dose. Initiate therapy with the age-appropriate dose once daily for the first 14 days of therapy. If there is no rash or untoward effect, at 14 days of therapy, increase to the age-appropriate dose administered twice daily. However, in children ≤ 2 years of age some experts initiate nevirapine without a lead-in (see Dosing Considerations: Lead-In Requirement ). The total daily dose should not exceed 400 mg.

Pediatric Dose Extended Release Formulation (>6 Years)
  • Patients >6 years who are already taking immediate release nevirapine twice daily can be switched to nevirapine XR without lead-in dosing as long as plasma RNA is undetectable.

BSA 
Range (m2)
NVP XR (mg) 
0.58–0.83
200 mg once daily (2 x 100 mg)
0.84–1.16
300 mg once daily (3 x 100 mg)
≥1.17
400 mg once daily (1 x 400 mg)

Note: Nevirapine is initiated at a lower dose and increased in a stepwise fashion to allow induction of cytochrome P450 metabolizing enzymes, which results in increased drug clearance. The occurrence of rash is diminished by this stepwise increase in dose. Initiate therapy with the age-appropriate dose once daily for the first 14 days of therapy. If there is no rash or untoward effect, at 14 days of therapy, increase to the age-appropriate dose administered once daily for the XR preparation. The total daily dose should not exceed 400 mg. 

Adolescent/Adult Dose:
  • 200 mg twice daily or 400 mg XR once daily. 
Note: For 200-mg regimen, initiate therapy with 200 mg once daily for the first 14 days and increase to 200 mg twice daily if there is no rash or other untoward effects. For 400-mg XR regimen, initiate therapy with 200-mg immediate-release tablet given once daily for the first 14 days. Increase to 400 mg once daily if there is no rash or other untoward effects. In patients already receiving full-dose immediate-release nevirapine, XR tablets can be used without the 200-mg lead-in period. Patients must swallow nevirapine XR tablets whole. They must not be chewed, crushed, or divided. Patients must never take more than one form of nevirapine at the same time. 

Nevirapine In Combination with Ritonavir-Boosted Lopinavir:

Selected Adverse Events

  • Rash, including Stevens-Johnson syndrome
  • Symptomatic hepatitis, including fatal hepatic necrosis
  • Severe systemic hypersensitivity syndrome with potential for multisystem organ involvement and shock

Special Instructions

  • Can be given without regard to food. 
  • Nevirapine-associated skin rash usually occurs within the first 6 weeks of therapy. If rash occurs during the initial 14 day lead-in period, do not increase dose until rash resolves (see Major Toxicities section).
  • Nevirapine XR tablets must be swallowed whole. They cannot be crushed, chewed, or divided.
  • If nevirapine dosing is interrupted for >14 days, nevirapine dosing should be restarted with once-daily dosing for 14 days, followed by escalation to the full, twice-daily regimen (see Dosing Considerations: Lead-In Requirement ).
  • Most cases of nevirapine -associated hepatic toxicity occur during the first 12 weeks of therapy; frequent clinical and laboratory monitoring, including liver function tests (LFTs), is important during this period. However, about one-third of cases occurred after 12 weeks of treatment, so continued periodic monitoring of LFTs is needed. In some cases, patients presented with nonspecific prodromal signs or symptoms of hepatitis and rapidly progressed to hepatic failure. Patients with symptoms or signs of hepatitis should have LFTs performed. Nevirapine should be permanently discontinued and not restarted in patients who develop clinical hepatitis or hypersensitivity reactions.
  • Shake suspension well and store at room temperature.

Metabolism

  • Metabolized by cytochrome P450 (3A inducer); 80% excreted in urine (glucuronidated metabolites).
  • Dosing of nevirapine in patients with renal failure receiving hemodialysis: An additional dose of nevirapine should be given following dialysis. 
  • Dosing of nevirapine in patients with hepatic impairment: Nevirapine should not be administered to patients with moderate or severe hepatic impairment.

Drug Interactions (See also the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents)

  • Metabolism: Induces hepatic cytochrome P450 including 3A (CYP3A) and 2B6; auto-induction of metabolism occurs in 2 to 4 weeks, with a 1.5- to 2-fold increase in clearance. There is potential for multiple drug interactions. Mutant alleles of CYP2B6 cause increases in nevirapine serum concentration in a similar manner but to a lesser extent than efavirenz. Altered adverse effect profiles related to elevated nevirapine levels have not been documented probably because there are alternative CYP metabolic pathways for nevirapine.1 Please see efavirenz section for further details.
  • Before administration, a patient’s medication profile should be carefully reviewed for potential drug interactions. Nevirapine should not be co-administered to patients receiving atazanavir (with or without ritonavir).

Major Toxicities

Note: These are seen with continuous dosing regimens, not single-dose nevirapine prophylaxis.

  • More common: Skin rash (some severe and requiring hospitalization; some life-threatening, including Stevens-Johnson syndrome and toxic epidermal necrolysis), fever, nausea, headache, and abnormal hepatic transaminases. Nevirapine should be permanently discontinued and not restarted in children or adults who develop severe rash, rash with constitutional symptoms (i.e., fever, oral lesions, conjunctivitis, or blistering), or rash with elevated hepatic transaminases. Nevirapine-associated skin rash usually occurs within the first 6 weeks of therapy. If rash occurs during the initial 14-day lead-in period, do not increase dose until rash resolves. However, the risk of developing nevirapine resistance with extended lead-in dosing is unknown and is a concern that must be weighed against a patient’s overall ability to tolerate the regimen and the current antiviral response. 
  • Less common (more severe): Severe, life-threatening, and in rare cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis, and hepatic failure (these are less common in children than adults). The majority of cases occur in the first 12 weeks of therapy and may be associated with rash or other signs or symptoms of hypersensitivity reaction. Risk factors for nevirapine-related hepatic toxicity in adults include baseline elevation in serum transaminase levels, hepatitis B or hepatitis C infection, female gender, and higher CD4 T lymphocyte (CD4) cell count at time of therapy initiation (CD4 cell count >250 cells/mm3 in adult females and >400 cells/mm3 in adult males). In children, recent results indicate that there is a three-fold increased risk of rash and hepatotoxicity when children initiate nevirapine with a CD4 percentage >15%.2 Hypersensitivity reactions have been reported, including, but not limited to, severe rash or rash accompanied by fever, blisters, oral lesions, conjunctivitis, facial edema, muscle or joint aches, general malaise, and significant hepatic abnormalities. Nevirapine should be permanently discontinued and not restarted in children or adults who develop symptomatic hepatitis, severe transaminase elevations, or hypersensitivity reactions.

Resistance

The International AIDS Society-USA (IAS-USA) maintains a list of updated resistance mutations (see http://www.iasusa.org/resistance_mutations/index.html) and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation (see http://hivdb.stanford.edu/pages/GRIP/NVP.html).

Pediatric Use

Approval
Nevirapine is Food and Drug Administration (FDA) approved for treatment of HIV in children from infancy (aged ≥15 days) onward and remains a mainstay of therapy especially in resource-limited settings. It has been studied in HIV-infected children in combination with nucleoside reverse transcriptase inhibitors (NRTIs) or with NRTIs and a protease inhibitor (PI).3-11 In November 2012 the extended release tablet formulation was FDA-approved for use in children aged ≥6 years.

Efficacy
In infants and children previously exposed to single-dose nevirapine for prevention of perinatal transmission; nevirapine-based, combination antiretroviral therapy (cART) is less likely than ritonavir-boosted lopinavir-based cART to control virus load. In a large randomized clinical trial, P1060, 153 children (mean age 0.7 years) previously exposed to nevirapine for perinatal prophylaxis were treated with zidovudine plus lamivudine plus the randomized addition of nevirapine versus ritonavir-boosted lopinavir. At 24 weeks post-randomization, 24% of children in the zidovudine/lamivudine/nevirapine arm reached a virologic endpoint (virologic failure defined as <1 log decrease in HIV RNA in Weeks 12–24 or HIV RNA >400 copies/mL at Week 24) compared with 7% in the zidovudine/lamivudine/ritonavir-boosted lopinavir, P = 0.0009. When all primary endpoints were considered, including viral failure, death, and treatment discontinuation, the PI arm remained superior because 40% of children in the nevirapine arm met a primary endpoint versus 22% for the ritonavir-boosted lopinavir arm, P = 0.027.12 Enrollment into the comparison study of nevirapine versus LPV/r in children aged 6 to 36 months not previously exposed to nevirapine has reported similar results, suggesting that ritonavir-boosted lopinavir-based therapy is superior to nevirapine-based therapy for infants, regardless of past nevirapine exposure.13 

Extended-release nevirapine (400-mg tablets) was approved by the FDA for use in adult patients based on two trials: VERxVE and TRANxITION. VERxVE14 enrolled treatment-naive adults who received 200 mg of immediate-release nevirapine for 14 days before commencing daily dosing of nevirapine extended release or standard twice-daily dosing of immediate-release tablets. A backbone of tenofovir and emtricitabine was used. TRANxITION enrolled patients already receiving full-dose immediate-release nevirapine and randomized them to receive the extended-release tablets or remain on their current nevirapine regimen. Both studies have shown equivalent efficacy, adverse effect, and CD4 profiles through 144 weeks.15-17 Trial 1100.1518 was an open-label, multiple-dose, non-randomized, crossover trial performed in 85 HIV-1 infected pediatric subjects aged 3 years to <18 years who had received at least 18 weeks of immediate-release nevirapine and had plasma HIV-1 RNA <50 copies per mL prior to trial enrollment. Subjects were stratified according to age (3 to <6 years, 6 to <12 years, and 12 <18 years). Following a 10-day period with immediate-release nevirapine, subjects were treated with nevirapine XR tablets once daily in combination with other antiretrovirals (ARVs) for 10 days, after which steady-state pharmacokinetics were determined. Forty subjects who completed the initial part of the study were enrolled in an optional extension phase of the trial, which evaluated the safety and antiviral activity of nevirapine XR through a minimum of 24 weeks of treatment. Of the 40 subjects who entered the treatment extension phase, 39 completed at least 24 weeks of treatment. After 24 weeks or more of treatment with nevirapine XR, all 39 subjects continued to have plasma HIV-1 RNA less than 50 copies per mL. This dosage form was approved for use in children aged ≥6 years in November 2012.

General Dosing Considerations

Body surface area (BSA) has traditionally been used to guide nevirapine dosing for infants and young children. It is important to avoid under-dosing of nevirapine because a single point mutation in the HIV genome may confer non-nucleoside reverse transcriptase inhibitor resistance to both nevirapine and efavirenz. Younger children (≤8 years of age) have higher apparent oral clearance than older children and require a higher dosage to achieve equivalent drug exposure compared with children aged >8 years.8,9 Because of this, it is recommended that dosing for children younger than age 8 years be 200 mg/m2 of BSA per dose when given twice daily (immediate release tablet maximum dose 200 mg twice daily) or 400 mg/m2 of body surface area per dose when administered once daily as the extended release preparation (maximum dose of the extended release preparation 400 mg/dose once daily). For children aged 8 years and older, the recommended dose is 120 mg/m2 of BSA per dose (maximum dose 200 mg) administered twice daily to a maximum of 400 mg once daily when the extended release preparation is used in children aged ≥6 years. When adjusting the dose in a growing child, the milligram dose need not be decreased (from 200 mg/m2 to 120 mg/m2) as the child reaches 8 years; rather, the milligram dose is left static as long as there are no untoward effects, and the dose is allowed to achieve the appropriate mg/m2 dosage as the child grows. Some practitioners dose nevirapine at 150 mg/m2 of BSA every 12 hours or 300 mg/m2 per dose once daily if using the extended release preparation (maximum of 200 mg per dose twice daily of the immediate release tablets or 400 mg per dose once daily of the extended release tablets) regardless of age, as recommended in the FDA-approved product label.

Dosing Considerations: Lead-In Requirement
One explanation for the poorer performance of nevirapine in the P1060 trial was the potential for under-dosing during the lead-in period. This potential for under-dosing with an increased risk of resistance has led to the re-evaluation of lead-in dosing in children who are naive to nevirapine therapy. Traditional dosing of nevirapine is initiated with an age appropriate dose once daily (200 mg/m2 in infants ≥15 days of age and children <8 years using the immediate release preparations) during the first 2 weeks of treatment to allow for the auto-induction of the liver enzymes CYP3A and CYP2B6, which are involved in nevirapine metabolism. Studies, largely in adult cohorts, previously indicated the potential for greater drug toxicity without this lead-in.18 The CHAPAS-1 Trial19 randomized 211 children to initiate cART with nevirapine without a lead-in (age appropriate dose twice daily of the immediate release preparation) or with a lead-in (age appropriate dose once daily of the immediate release preparation) for 2 weeks followed by standard twice-daily dosing of the immediate release preparation. Children were followed for a median of 92 weeks (68–116), and there was no difference in grade 3 or 4 adverse events between the two groups. The group initiating nevirapine without a lead-in had a statistically significant increase in grade 2 rash, but the majority of subjects were able to continue nevirapine therapy after a brief interruption. CD4 and virologic endpoints were no different through 96 weeks. In a sub-study of this trial, the investigators looked at nevirapine levels 3 to 4 hours after a morning dose of nevirapine after 2 weeks of therapy. For children < 2 years of age, 13% (3/23) initiating at full dose versus 32% (7/22) initiating at half dose had subtherapeutic NVP levels (<3 mg/L) at 2 weeks (p=0.16). There were no rash events in the substudy group aged <2 years and in the parent CHAPAS study there was a strong age effect on rash occurrence (increased risk with increasing age), suggesting that a lead-in dose may not be necessary in young patients.20 Additional trials are in development or are underway to further evaluate the potential of initiating nevirapine therapy without the lead-in dose in treatment-naive children. Reinitiating half-dose nevirapine for another 2 weeks in those children who have interrupted therapy for 7 days or longer has been standard practice; however, given the current understanding of nevirapine resistance, the half-life of the CYP enzymes,21 and the results of CHAPAS-1, the panel recommends restarting full-dose nevirapine in children who interrupt therapy for 14 days or less. 

Dosing: Special Considerations: Neonates ≤14 Days and Premature Infants

For infants aged ≤14 days and for premature infants (until 42 weeks corrected gestational age), pharmacokinetic (PK) data are currently inadequate to formulate an effective complete cART regimen. Although dosing is available for zidovudine and lamivudine, data are inadequate for other classes of cART. Reports of cardiovascular, renal, and central nervous system toxicity associated with ritonavir-boosted lopinavir in young infants preclude the administration of this agent in the first 2 weeks of life. Currently, a study of early treatment is being developed in the International Maternal Pediatric Adolescent AIDS Clinical Trials network; based on PK modeling, an investigational dose of 6 mg/kg administered twice daily for nevirapine in full-term infants will be tested. Providers considering treatment of infants aged <2 weeks or premature infants should contact a pediatric HIV expert for guidance because the decision about whether to treat and what to use will involve weighing the risks and benefits of using unapproved cART dosing, and incorporate case-specific factors such as exposure to ARV prophylaxis. 

References

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  2. Kea C, Puthanakit T, et al. Incidence and risk factors for nevirapine related toxicities among HIV-infected Asian children randomized to starting ART at different CD4%. Abstract MOPE240. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention; July 17-20, 2011, 2011; Rome, Italy.
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  16. Arasteh K, Drulak M, at al. TRANxITION 144-week results: switching virologically stable HIV patients from immediate-release nevirapine (NVP IR) to extended-release NVP (XR). J Int AIDS Soc. 2012;15(6):18344. 
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  19. Mulenga V, Cook A, Walker AS, et al. Strategies for nevirapine initiation in HIV-infected children taking pediatric fixed-dose combination "baby pills" in Zambia: a randomized controlled trial. Clin Infect Dis. Nov 1 2010;51(9):1081-1089. Available at http://www.ncbi.nlm.nih.gov/pubmed/20868279.
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