NEVIVIR

A potent, non-nucleoside reverse transcriptase inhibitor (NNRTI) used in combination with nucleoside analogues for treatment of Human Immunodeficiency Virus Type 1 (HIV-1) infection and AIDS.

Structurally, nevirapine belongs to the dipyridodiazepinone chemical class.

For use in combination with other antiretroviral drugs in the ongoing treatment of HIV-1 infection.

Nevirapine is a non-nucleoside reverse transcriptase inhibitor (nNRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1).

HIV-2 RT and eukaryotic DNA polymerases (such as human DNA polymerases alpha, beta, or sigma) are not inhibited by nevirapine.

Nevirapine is, in general, only prescribed after the immune system has declined and infections have become evident.

It is always taken with at least one other HIV medication such as Retrovir or Videx.

The virus can develop resistance to nevirapine if the drug is taken alone, although even if used properly, nevirapine is effective for only a limited time.

Nevirapine is readily absorbed (greater than 90%) after oral administration in healthy subjects and adults with HIV-1 infection.

The absolute bioavailability in healthy adults following a single dose administration is 93 ± 9% (mean ± SD) for a 50 mg tablet and 91 ± 8% for an oral solution.

Peak plasma nevirapine concentrations of 2 ± 0.4 mcg/mL (7.5 micromolar) were attained by 4 hours following a single 200 mg dose.

Nevirapine tablets and suspension have been shown to be comparably bioavailable and interchangeable at doses up to 200 mg. When the oral tablet is given with a high-fat meal, the extent of absorption is compared to that of the fasted-state.

± 0.09 L/kg Nevirapine is capable of crossing the placenta and is found in breast milk.

In vivo studies in humans and in vitro studies with human liver microsomes have shown that nevirapine is extensively biotransformed via cytochrome P450 3A4 metabolism to several hydroxylated metabolites.

Hover over products below to view reaction partners Nevirapine 12-Hydroxynevirapine 4-carboxynevirapine 12-hydroxynevirapine glucuronide 2-Hydroxynevirapine 2-hydroxynevirapine glucuronide 8-Hydroxynevirapine 8-hydroxynevirapine glucuronide 3-Hydroxynevirapine 3-hydroxynevirapine glucuronide 2-OH-nevirapine 8-OH-nevirapine 3-OH-nevirapine 12-OH-nevirapine.

Thus cytochrome

P450 metabolism, glucuronide conjugation, and urinary excretion of glucuronidated metabolites represent the primary route of nevirapine biotransformation and elimination in humans.

Only a small fraction (<5%) of the radioactivity in urine (representing <3% of the total dose) was made up of parent compound; therefore, renal excretion plays a minor role in elimination of the parent compound.

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Symptoms of overdose include edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonaryinfiltrates, rash, vertigo, vomiting, and weight decrease.

The most common adverse reaction is rash.

• in patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment.

• for use as part of occupational and non-occupational post-exposure prophylaxis (PEP) regimens.

• Patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment.

• Use as part of occupational and non-occupational post-exposure prophylaxis (PEP) regimens, an unapproved use.

• The 14-day lead-in period with immediate-release nevirapine tablets (200 mg once daily) must be strictly followed; it has been demonstrated to reduce the frequency of rash.

• Must be swallowed whole and must not be chewed, crushed, or divided.

• Adult patients must initiate therapy with one 200 mg immediate-release nevirapine tablet once daily for the first 14 days, followed by one 400 mg tablet of nevirapine extended-release tablets once daily.

• Adult patients already on a regimen of immediate-release nevirapine tablets twice daily can be switched to nevirapine extended-release tablets 400 mg once daily without the 14-day lead-in period of immediate-release nevirapine tablets.

• Pediatric patients (ages to less than 18 years with a BSA of 1.17 m 2 or greater) must initiate therapy with immediate-release nevirapine tablets (as 150 mg/m2 of Nevirapine Oral Suspension or as nevirapine tablet) at a dose not to exceed 200 mg per day administered once daily for the first 14 days, followed by nevirapine extended-release tablets 400 mg once daily.

• Pediatric patients with a BSA of 1.17 m 2 or greater already on a regimen of twice daily nevirapine tablets Oral Suspension or immediate-release nevirapine can be switched to nevirapine extended-release tablets 400 mg once daily without the 14-day lead-in period of nevirapine Oral Suspension or immediate-release nevirapine tablets.

• If any patient experiences rash during the 14-day lead-in period with immediate-release nevirapine tablets do not initiate nevirapine extended-release tablets until the rash has resolved.

Do not continue the immediate-release nevirapine tablets lead-in dosing regimen beyond 28 days.

• If dosing is interrupted for greater than 7 days, restart 14-day lead-in dosing. 2.1 General Dosing Considerations Nevirapine extended-release tablets must be swallowed whole and must not be chewed, crushed, or divided.

Pediatric patients should be assessed for their ability to swallow the extended-release tablets before prescribing nevirapine extended-release tablets.

Nevirapine extended-release tablets can be taken with or without food. 2.2 Recommended Dosage in Adult Patients Patients not currently taking immediate-release nevirapine Patients must initiate therapy with one 200-mg tablet of immediate-release nevirapine tablets daily for the first 14 days in combination with other antiretroviral agents.

The 14-day lead-in period with nevirapine tablets 200 mg daily dosing must be strictly followed (the lead-in period has been observed to decrease the incidence of rash), followed by one 400-mg tablet of nevirapine extended-release tablets once daily.

If rash persists beyond the 14-day lead-in period with immediate-release nevirapine tablets, do not begin dosing with nevirapine extended-release tablets.

The lead-in dosing with 200 mg once daily immediate-release nevirapine tablets should not be continued beyond 28 days, at which point an alternative regimen should be sought.

Switching patients from immediate-release nevirapine tablets to nevirapine extended-release tablets Patients already on a regimen of immediate-release nevirapine tablets twice daily in combination with other antiretroviral agents can be switched to nevirapine extended-release tablets 400 mg once daily without the 14-day lead-in period.

Patients already on a regimen of immediate-release nevirapine tablets twice daily who switch to nevirapine extended-release tablets therapy should continue with their ongoing clinical and laboratory monitoring. 2.3 Recommended Dosage in Pediatric Patients Nevirapine extended-release tablet in pediatric patients is dosed based on body surface area (BSA) calculated using the Mosteller formula.

All pediatric patients must initiate therapy with immediate-release nevirapine tablets (as 150 mg/m of Nevirapine Oral Suspension or as nevirapine tablets), at a dose not to exceed 200 mg per day, administered once daily for the first 14 days.

This lead-in period should be used because it has been demonstrated to reduce the frequency of rash.

This lead-in period is not required if the patient is already on a regimen of twice daily immediate-release formulation in combination with other antiretroviral agents.

The recommended oral dosage of nevirapine extended-release tablets for pediatric patients with a BSA of 1.17 m 2 or greater is 400 mg following the lead-in period with immediate-release nevirapine tablets.

The total daily dose should not exceed 400 mg for any patient. formula 2.4 Monitoring of Patients Intensive clinical and laboratory monitoring, including liver enzyme tests, is essential at baseline and during the first 18 weeks of treatment with nevirapine.

The optimal frequency of monitoring during this period has not been established.

Some experts recommend clinical and laboratory monitoring more often than once per month, and in particular, would include monitoring of liver enzyme tests prior to beginning the 14-day lead-in period with immediate-release nevirapine tablets, prior to initiation of nevirapine extended-release tablets, and at two weeks after initiation of nevirapine extended-release tablets therapy.

After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout nevirapine extended-release tablets treatment.

In some cases, hepatic injury has progressed despite discontinuation of treatment.

Patients already on a regimen of immediate-release nevirapine tablets twice daily who switch to nevirapine extended-release tablets once daily should continue with their ongoing clinical and laboratory monitoring. 2.5 Dosage Adjustment Patients with Rash Discontinue nevirapine if a patient experiences severe rash or any rash accompanied by constitutional findings.

Do not initiate therapy with nevirapine extended-release tablets if a patient experiences mild to moderate rash without constitutional symptoms during the 14-day lead-in period of immediate-release nevirapine tablets until the rash has resolved.

The total duration of the once daily lead-in dosing period should not exceed 28 days, at which point an alternative regimen should be sought.

If a clinical (symptomatic) hepatic event occurs, permanently discontinue nevirapine.

Do not restart nevirapine after recovery.

For patients who interrupt nevirapine extended-release tablets dosing for more than 7 days, restart the recommended lead-in dosing with immediate-release nevirapine tablets, using one 200 mg tablet daily for the first 14 days.

Patients with Renal Impairment Patients with

CrCl greater than or equal to 20 mL per min and not requiring dialysis do not require an adjustment in dosing.

The pharmacokinetics of nevirapine have not been evaluated in patients with CrCl less than 20 mL per min. An additional 200 mg dose of immediate-release nevirapine tablets following each dialysis treatment is indicated in patients requiring dialysis.

Nevirapine metabolites may accumulate in patients receiving dialysis; however, the clinical significance of this accumulation is not known.

Nevirapine extended-release tablets have not been studied in patients with renal dysfunction.

Nevirapine extended-release tablets, USP 400 mg are yellow coloured, oval shaped, biconvex tablets debossed with ‘C11’ on one side and plain on the other side.

Nevirapine extended-release tablets are supplied in

Bottles of 30 tablets NDC 33342-238-07 Unit dose blister pack of 100 tablets NDC 33342-238-12 Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .

Store in a safe place out of the reach of children.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to nevirapine during pregnancy.

Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary Available data from the

APR show no difference in the risk of overall major birth defects for nevirapine compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) .

The rate of miscarriage is not reported in the APR.

The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%.

The background risk of birth defects and miscarriage for the indicated population is unknown.

Methodological limitations of the APR include the use of MACDP as the external comparator group.

MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation.

There is a risk for severe hepatic events in pregnant women exposed to nevirapine extended-release tablets.

In animal reproduction studies, no evidence of adverse developmental outcomes was observed following oral administration of nevirapine during organogenesis in the rat and rabbit, at systemic exposures (AUC) to nevirapine approximately equal (rats) and 50% higher (rabbits) than the exposure in humans at the recommended 400 mg daily dose.

Clinical Considerations Maternal adverse reactions

Severe hepatic events, including fatalities, have been reported in pregnant women receiving chronic nevirapine therapy as part of combination treatment of HIV-1 infection.

Regardless of pregnancy status, women with CD4 + cell counts greater than 250 cells/mm3 should not initiate nevirapine unless the benefit outweighs the risk.

It is unclear if pregnancy augments the risk observed in non-pregnant women.

Data Human Data Based on prospective reports to the APR of exposures to nevirapine during pregnancy resulting in live births (including over 1,100 exposed in the first trimester and over 1,500 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.0% (95% CI: 2.1%, 4.1%) and 3.3% (95% CI: 2.4%, 4.3%) following first and second/third-trimester exposure, respectively, to nevirapine-containing regimens, compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP.

Nevirapine was administered orally to pregnant rats (at 0, 12.5, 25, and 50 mg/kg/day), and rabbits (at 0, 30, 100, and 300 mg/kg/day) through organogenesis (on gestation days 7 through and 6 through 18, respectively).

No adverse developmental effects were observed at doses producing systemic exposures (AUC) approximately equivalent to (rats) or approximately 50% higher (rabbits) than human exposure at the recommended daily dose.

In rats, decreased fetal body weights were observed at a maternally toxic dose at an exposure approximately 50% higher than the recommended daily dose.

Nevirapine extended-release tablets are indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in children 6 years of age or older with a BSA of 1.17 m 2 or greater.

The use of nevirapine extended-release tablets for the treatment of HIV-1 infection in pediatric patients to less than 18 years of age is based on pharmacokinetic, safety, and antiviral activity data from an open-label trial with nevirapine extended-release tablets.

The results of this trial were supported by previous demonstration of efficacy in adult patients.

Nevirapine extended-release tablets are not recommended for children less than 6 years of age.

Trial 1100.1518 did not provide sufficient pharmacokinetic data for children to less than 6 years of age to support the use of nevirapine extended-release tablets in this.

Furthermore, nevirapine extended-release tablets are not recommended for children less than 3 years of age because they are not able to swallow tablets.

Clinical studies of nevirapine extended-release tablets did not include sufficient numbers of subjects aged and older to determine whether elderly subjects respond differently from younger subjects.

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.