Nevirapine Suspension

Nevirapine oral suspension is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in adults and pediatric patients 15 days and older [see Clinical Studies (14.1, 14.2)].

Limitations of Use:

Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled trials, nevirapine oral suspension is not recommended to be initiated, unless the benefit outweighs the risk, in:

• adult females with CD4+ cell counts greater than 250 cells/mm3 or
• adult males with CD4+ cell counts greater than 400 cells/mm3[see Warnings and Precautions (5.1)].

Hepatotoxicity and Hepatic Impairment

Severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis and hepatic failure, have been reported in patients treated with nevirapine. In controlled clinical trials, symptomatic hepatic events regardless of severity occurred in 4% (range 0% to 11%) of subjects who received nevirapine and 1% of subjects in control groups.

The risk of symptomatic hepatic events regardless of severity was greatest in the first 6 weeks of therapy. The risk continued to be greater in the nevirapine groups compared to controls through 18 weeks of treatment. However, hepatic events may occur at any time during treatment. In some cases, subjects presented with non­-specific, prodromal signs or symptoms of fatigue, malaise, anorexia, nausea, jaundice, liver tenderness or hepatomegaly, with or without initially abnormal serum transaminase levels. Rash was observed in approximately half of the subjects with symptomatic hepatic adverse events. Fever and flu-like symptoms accompanied some of these hepatic events. Some events, particularly those with rash and other symptoms, have progressed to hepatic failure with transaminase elevation, with or without hyperbilirubinemia, hepatic encephalopathy, prolonged partial thromboplastin time, or eosinophilia. Rhabdomyolysis has been observed in some patients experiencing skin and/or liver reactions associated with nevirapine use. Hepatitis/hepatic failure may be associated with signs of hypersensitivity which can include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction. Patients with signs or symptoms of hepatitis must be advised to discontinue nevirapine and immediately seek medical evaluation, which should include liver enzyme tests. 

The first 18 weeks of therapy with nevirapine are a critical period during which intensive clinical and laboratory monitoring of patients is required to detect potentially life-threatening hepatic events. The optimal frequency of monitoring during this time period has not been established. Some experts recommend clinical and laboratory monitoring more often than once per month, and in particular, include monitoring of liver enzyme tests at baseline, prior to dose escalation and at two weeks post-dose escalation. After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout nevirapine treatment. 

Transaminases should be checked immediately if a patient experiences signs or symptoms suggestive of hepatitis and/or hypersensitivity reaction. Transaminases should also be checked immediately for all patients who develop a rash in the first 18 weeks of treatment. Physicians and patients should be vigilant for the appearance of signs or symptoms of hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness or hepatomegaly. The diagnosis of hepatotoxicity should be considered in this setting, even if transaminases are initially normal or alternative diagnoses are possible [see Dosage and Administration (2.3)].

If clinical hepatitis or transaminase elevations combined with rash or other systemic symptoms occur, permanently discontinue nevirapine. Do not restart nevirapine after recovery. In some cases, hepatic injury progresses despite discontinuation of treatment.

The patients at greatest risk of hepatic events, including potentially fatal events, are women with high CD4+ cell counts. In general, during the first 6 weeks of treatment, women have a 3-fold higher risk than men for symptomatic, often rash-associated, hepatic events (6% versus 2%), and patients with higher CD4+ cell counts at initiation of nevirapine therapy are at higher risk for symptomatic hepatic events with nevirapine. In a retrospective review, women with CD4+ cell counts greater than 250 cells/mm3 had a 12-fold higher risk of symptomatic hepatic adverse events compared to women with CD4+ cell counts less than 250 cells/mm3 (11% versus 1%). An increased risk was observed in men with CD4+ cell counts greater than 400 cells/mm3 (6% versus 1% for men with CD4+ cell counts less than 400 cells/mm3). However, all patients, regardless of gender, CD4+ cell count, or antiretroviral treatment history, should be monitored for hepatotoxicity since symptomatic hepatic adverse events have been reported at all CD4+

cell

counts. Co-infection with hepatitis B or C and/or increased transaminase elevations at the start of therapy with nevirapine are associated with a greater risk of later symptomatic events (6 weeks or more after starting nevirapine) and asymptomatic increases in AST or ALT.

In addition, serious hepatotoxicity (including liver failure requiring transplantation in one instance) has been reported in HIV-1 uninfected individuals receiving multiple doses of nevirapine in the setting of post-exposure prophylaxis (PEP), an unapproved use. Use of nevirapine for occupational and non-occupational PEP is contraindicated [see Contraindications (4)]. 

Increased nevirapine trough concentrations have been observed in some patients with hepatic fibrosis or cirrhosis. Therefore, carefully monitor patients with either hepatic fibrosis or cirrhosis for evidence of drug-induced toxicity. Do not administer nevirapine to patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment [see Contraindications (4), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].

Skin Reactions

Severe and life-threatening skin reactions, including fatal cases, have been reported, occurring most frequently during the first 6 weeks of therapy. These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction including hepatic failure. Rhabdomyolysis has been observed in some patients experiencing skin and/or liver reactions associated with nevirapine use. In controlled clinical trials, Grade 3 and 4 rashes were reported during the first 6 weeks in 2% of nevirapine recipients compared to less than 1% of placebo subjects.

Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, and/or hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction) must permanently discontinue nevirapine and seek medical evaluation immediately. Do not restart nevirapine following severe skin rash, skin rash combined with increased transaminases or other symptoms, or hypersensitivity reaction.

The first 18 weeks of therapy with nevirapine are a critical period during which intensive clinical and laboratory monitoring of patients is required to detect potentially life-threatening skin reactions. The optimal frequency of monitoring during this time period has not been established. Some experts recommend clinical and laboratory monitoring more often than once per month, and in particular, include monitoring of liver enzyme tests at baseline, prior to dose escalation and at two weeks post-dose escalation. After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout nevirapine treatment. In addition, the 14-day lead-in period with nevirapine 200 mg daily dosing has been demonstrated to reduce the frequency of rash [see Dosage and Administration (2.1)].

If patients present with a suspected nevirapine-associated rash, measure transaminases immediately. Permanently discontinue nevirapine in patients with rash-associated transaminase elevations [see Warnings and Precautions (5.1)].

Therapy with nevirapine must be initiated with a 14-day lead-in period of 200 mg per day (150 mg/m2 per day in pediatric patients), which has been shown to reduce the frequency of rash. Discontinue nevirapine if a patient experiences severe rash or any rash accompanied by constitutional findings. Do not increase nevirapine dose to a patient experiencing a mild to moderate rash without constitutional symptoms during the 14-day lead-in period of 200 mg per day (150 mg/m2/day in pediatric patients) until the rash has resolved. The total duration of the once-daily lead-in dosing period must not exceed 28 days at which point an alternative regimen should be sought [see Dosage and Administration (2.4)]. Patients must be monitored closely if isolated rash of any severity occurs. Delay in stopping nevirapine treatment after the onset of rash may result in a more serious reaction.

Women appear to be at higher risk than men of developing rash with nevirapine.

In a clinical trial, concomitant prednisone use (40 mg per day for the first 14 days of nevirapine administration) was associated with an increase in incidence and severity of rash during the first 6 weeks of nevirapine therapy. Therefore, use of prednisone to prevent nevirapine-associated rash is not recommended.

Resistance

Nevirapine must not be used as a single agent to treat HIV-1 or added on as a sole agent to a failing regimen. Resistant virus emerges rapidly when nevirapine is administered as monotherapy. The choice of new antiretroviral agents to be used in combination with nevirapine should take into consideration the potential for cross resistance. When discontinuing an antiretroviral regimen containing nevirapine, the long half-life of nevirapine should be taken into account; if antiretrovirals with shorter half-lives than nevirapine are stopped concurrently, low plasma concentrations of nevirapine alone may persist for a week or longer and virus resistance may subsequently develop [see Microbiology (12.4)].

Drug Interactions

See Table 4 for listings of established and potential drug interactions [see Drug Interactions (7)].

Concomitant use of St. John's wort (Hypericum perforatum) or St. John's wort-containing products and nevirapine is not recommended. Co-administration of St. John’s wort with non-nucleoside reverse transcriptase inhibitors (NNRTIs), including nevirapine, is expected to substantially decrease NNRTI concentrations and may result in sub-optimal levels of nevirapine and lead to loss of virologic response and possible resistance to nevirapine or to the class of NNRTIs. Co-administration of nevirapine and efavirenz is not recommended as this combination has been associated with an increase in adverse reactions and no improvement in efficacy.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including nevirapine. During the initial phase of combination antiretroviral treatment, patients whose immune system responds 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.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.

Fat Redistribution

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.

Pregnancy

Pregnancy Exposure Registry

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 the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) [see Data]. 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 to 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. The 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.

In literature reports, immediate-release nevirapine exposure (Cmin) can be up to 29% lower during pregnancy. However, as this reduction was not found to be clinically meaningful, dose adjustment is not necessary [see Data].

There is a risk for severe hepatic events in pregnant women exposed to nevirapine [see Clinical Considerations]. In animal reproduction studies, no evidence of adverse developmental outcomes were 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 [see Data].

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 [see Warnings and Precautions (5.1)].

Data

Human Data

Based on prospective reports to the APR of over 2600 exposures to nevirapine during pregnancy resulting in live births (including over 1100 exposed in the first trimester), there was no difference between nevirapine and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.8% (95% CI: 1.9 %, 4 %) following first trimester exposure to nevirapine- containing regimens and 3.2% (95% CI: 2.4%, 4.3%) for second/third trimester exposure to nevirapine-containing regimens.

There are several literature reports of chronic administration of immediate-release nevirapine during pregnancy, in which nevirapine pharmacokinetics were compared between pregnancy and postpartum. In these studies, the mean difference in nevirapine Cmin during pregnancy as compared to postpartum ranged from no difference to approximately 29% lower.

Animal Data

Nevirapine was administered orally to pregnant rats (at 0, 12.5, 25, and 50 mg per kg per day), and rabbits (at 0, 30, 100, and 300 mg per kg per day through organogenesis (on gestation days 7 through 16, 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.

Lactation

Risk Summary

The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Published data report that nevirapine is present in human milk [see Data]. There are limited data on the effects of nevirapine on the breastfed infant. There is no information on the effects of nevirapine on milk production. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) serious adverse reactions in nursing infants, mothers should not breastfeed if they are receiving nevirapine.

Data

Based on five publications, immediate-release nevirapine was excreted in breast-milk at median concentrations ranging from 4080 to 6795 ng/mL, and the median maternal breast-milk to maternal plasma concentration ratio range was 59 to 88%. Reported infant nevirapine median plasma concentrations were low, ranging from 734 to 1140 ng/mL. The estimated nevirapine dose of 704 to 682 mcg/kg/day for infants fed exclusively with breast-milk was lower than the daily recommended nevirapine dose for infants. Published literature indicates that rash and hyperbilirubinemia have been seen in infants exposed to nevirapine through breastmilk.

Females and Males of Reproductive Potential

Infertility

Limited human data are insufficient to determine the risk of infertility in humans. Based on results from animal fertility studies conducted in rats, nevirapine may reduce fertility in females of reproductive potential. It is not known if these effects on fertility are reversible [see Nonclinical Toxicology (13.1)].

Pediatric Use

The safety, pharmacokinetic profile, and virologic and immunologic responses of nevirapine have been evaluated in HIV-1 infected pediatric subjects age 3 months to 18 years [see Adverse Reactions (6.2) and Clinical Studies (14.2)].

The safety and pharmacokinetic profile of nevirapine has been evaluated in HIV-1 infected pediatric subjects age 15 days to less than 3 months [see Adverse Reactions (6.2) and Clinical Studies (14.2)].

The most frequently reported adverse events related to nevirapine in pediatric subjects were similar to those observed in adults, with the exception of granulocytopenia, which was more commonly observed in children receiving both zidovudine and nevirapine [see Adverse Reactions (6.2) and Clinical Studies (14.2)].

Geriatric Use

Clinical trials of nevirapine did not include sufficient numbers of subjects aged 65 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.

Renal Impairment

In subjects with renal impairment (mild, moderate or severe), there were no significant changes in the pharmacokinetics of nevirapine. Nevirapine is extensively metabolized by the liver and nevirapine metabolites are extensively eliminated by the kidney. Nevirapine metabolites may accumulate in patients receiving dialysis; however, the clinical significance of this accumulation is not known. No adjustment in nevirapine dosing is required in patients with CrCL greater than or equal to 20 mL per min. The pharmacokinetics of nevirapine have not been evaluated in patients with CrCl less than 20 mL per min. In patients undergoing chronic hemodialysis, an additional 200 mg dose following each dialysis treatment is indicated [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

Hepatic Impairment

Because increased nevirapine levels and nevirapine accumulation may be observed in patients with serious liver disease, do not administer nevirapine to patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment [see Contraindications (4.1), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

There is no known antidote for nevirapine overdosage. Cases of nevirapine overdose at doses ranging from 800 to 1800 mg per day for up to 15 days have been reported. Patients have experienced events including edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, vertigo, vomiting, and weight decrease. All events subsided following discontinuation of nevirapine.

Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Nevirapine is structurally a member of the dipyridodiazepinone chemical class of compounds.

The chemical name of nevirapine is 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido [3,2-b:2',3'-e][1,4] diazepin-6-one. Nevirapine USP is a white to off-white crystalline powder with the molecular weight of 266.30 and the molecular formula C15H14N4O. Nevirapine has the following structural formula:

Nevirapine oral suspension, USP is for oral administration. Each 5 mL of nevirapine oral suspension contains 50 mg of nevirapine (as nevirapine hemihydrate). The suspension also contains the following excipients: carbopol 974PNF, methylparaben, propylparaben, non crystallizing sorbitol solution, sucrose, propylene glycol, polysorbate 80, sodium hydroxide, and purified water.

Mechanism of Action

Nevirapine is an antiretroviral drug [see Microbiology (12.4)].

Pharmacokinetics

Adults

Absorption and Bioavailability

Nevirapine is readily absorbed (greater than 90%) after oral administration in healthy volunteers and in adults with HIV-1 infection. Absolute bioavailability in 12 healthy adults following single-dose administration was 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. Following multiple doses, nevirapine peak concentrations appear to increase linearly in the dose range of 200 to 400 mg/day. Steady-state trough nevirapine concentrations of 4.5 ± 1.9 mcg/mL (17 ± 7 micromolar), (n=242) were attained at 400 mg per day. Nevirapine tablets and suspension have been shown to be comparably bioavailable and interchangeable at doses up to 200 mg. When nevirapine (200 mg) was administered to 24 healthy adults (12 female, 12 male), with either a high-fat breakfast (857 kcal, 50 g fat, 53% of calories from fat) or antacid (Maalox® 30 mL), the extent of nevirapine absorption (AUC) was comparable to that observed under fasting conditions. In a separate trial in HIV-1 infected subjects (n=6), nevirapine steady-state systemic exposure (AUC τ) was not significantly altered by didanosine, which is formulated with an alkaline buffering agent. Nevirapine may be administered with or without food, antacid or didanosine.

Distribution

Nevirapine is highly lipophilic and is essentially nonionized at physiologic pH. Following intravenous administration to healthy adults, the apparent volume of distribution (Vdss) of nevirapine was 1.21 ± 0.09 L/kg, suggesting that nevirapine is widely distributed in humans. Nevirapine readily crosses the placenta and is also found in breast milk [see Use in Specific Populations (8.2)]. Nevirapine is about 60% bound to plasma proteins in the plasma concentration range of 1 to 10 mcg per mL. Nevirapine concentrations in human cerebrospinal fluid (n=6) were 45% (±5%) of the concentrations in plasma; this ratio is approximately equal to the fraction not bound to plasma protein.

Metabolism/Elimination

In vivo trials in humans and in vitro studies with human liver microsomes have shown that nevirapine is extensively biotransformed via cytochrome P450 (oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes suggest that oxidative metabolism of nevirapine is mediated primarily by cytochrome P450 (CYP) isozymes from the CYP3A and CYP2B6 families, although other isozymes may have a secondary role. In a mass balance/excretion trial in eight healthy male volunteers dosed to steady state with nevirapine 200 mg given twice daily followed by a single 50 mg dose of 14C-nevirapine, approximately 91.4 ± 10.5% of the radiolabeled dose was recovered, with urine (81.3 ± 11.1%) representing the primary route of excretion compared to feces (10.1 ± 1.5%). Greater than 80% of the radioactivity in urine was made up of glucuronide conjugates of hydroxylated metabolites. 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 (less than 5%) of the radioactivity in urine (representing less than 3% of the total dose) was made up of parent compound; therefore, renal excretion plays a minor role in elimination of the parent compound.

Nevirapine is an inducer of hepatic cytochrome P450 (CYP) metabolic enzymes 3A and 2B6. Nevirapine induces CYP3A and CYP2B6 by approximately 20 to 25%, as indicated by erythromycin breath test results and urine metabolites. Autoinduction of CYP3A and CYP2B6 mediated metabolism leads to an approximately 1.5- to 2-fold increase in the apparent oral clearance of nevirapine as treatment continues from a single dose to two-to-four weeks of dosing with 200 to 400 mg per day. Autoinduction also results in a corresponding decrease in the terminal phase half-life of nevirapine in plasma, from approximately 45 hours (single dose) to approximately 25 to 30 hours following multiple dosing with 200 to 400 mg per day.

Specific Populations

Renal Impairment

HIV-1 seronegative adults with mild (CrCL 50 to 79 mL per min; n=7), moderate (CrCL 30 to 49 mL per min; n=6), or severe (CrCL less than 30 mL per min; n=4) renal impairment received a single  200 mg dose of nevirapine in a pharmacokinetic trial. These subjects did not require dialysis. The trial included six additional subjects with renal failure requiring dialysis.

In subjects with renal impairment (mild, moderate or severe), there were no significant changes in the pharmacokinetics of nevirapine. However, subjects requiring dialysis exhibited a 44% reduction in nevirapine AUC over a one-week exposure period. There was also evidence of accumulation of nevirapine hydroxy-metabolites in plasma in subjects requiring dialysis. An additional 200 mg dose following each dialysis treatment is indicated [see Dosage and Administration (2.4) and Use in Specific Populations (8.6)].

Hepatic Impairment

In a steady-state trial comparing 46 subjects with mild (n=17; expansion of some portal areas; Ishak Score 1 to 2), moderate (n=20; expansion of most portal areas with occasional portal-to-portal and portal-to-central bridging; Ishak Score 3 to 4), or severe (n=9; marked bridging with occasional cirrhosis without decompensation indicating Child-Pugh A; Ishak Score 5 to 6) fibrosis as a measure of hepatic impairment, the multiple dose pharmacokinetic disposition of nevirapine and its five oxidative metabolites were not altered. However, approximately 15% of these subjects with hepatic fibrosis had nevirapine trough concentrations above 9,000 mcg per mL (2-fold the usual mean trough). Therefore, patients with hepatic impairment should be monitored carefully for evidence of drug-induced toxicity [see Warnings and Precautions (5.1)].

The subjects studied were receiving antiretroviral therapy containing nevirapine 200 mg twice daily for at least 6 weeks prior to pharmacokinetic sampling, with a median duration of therapy of 3.4 years.

In a pharmacokinetic trial where HIV-1 negative cirrhotic subjects with mild (Child-Pugh A; n=6) or moderate (Child-Pugh B; n=4) hepatic impairment received a single 200 mg dose of nevirapine, a significant increase in the AUC of nevirapine was observed in one subject with Child-Pugh B and ascites suggesting that patients with worsening hepatic function and ascites may be at risk of accumulating nevirapine in the systemic circulation. Because nevirapine induces its own metabolism with multiple dosing, this single-dose trial may not reflect the impact of hepatic impairment on multiple-dose pharmacokinetics.

Do not administer nevirapine to patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.7)].

Gender

In the multinational 2NN trial, a population pharmacokinetic substudy of 1077 subjects was performed that included 391 females. Female subjects showed a 13.8% lower clearance of nevirapine than did men. Since neither body weight nor Body Mass Index (BMI) had an influence on the clearance of nevirapine, the effect of gender cannot solely be explained by body size.

Race

An evaluation of nevirapine plasma concentrations (pooled data from several clinical trials) from HIV-1-infected subjects (27 Black, 24 Hispanic, 189 Caucasian) revealed no marked difference in nevirapine steady-state trough concentrations (median Cminss = 4.7 mcg/mL Black, 3.8 mcg/mL Hispanic, 4.3 mcg/mL Caucasian) with long-term nevirapine treatment at 400 mg per day. However, the pharmacokinetics of nevirapine have not been evaluated specifically for the effects of ethnicity.

Black subjects (n=80/group) in Trial 1100.1486 showed approximately 30% to 35% higher trough concentrations than Caucasian subjects (250 to 325 subjects/group) in both immediate-release nevirapine and nevirapine extended-release treatment groups over 96 weeks of treatment at 400 mg per day.

Geriatric Subjects

Nevirapine pharmacokinetics in HIV-1-infected adults do not appear to change with age (range 18 to 68 years); however, nevirapine has not been extensively evaluated in subjects beyond the age of 55 years [see Use in Specific Populations (8.5)].

Pediatric Subjects

Pharmacokinetic data for nevirapine have been derived from two sources: a 48-week pediatric trial in South Africa (BI Trial 1100.1368) involving 123 HIV-1 positive, antiretroviral-naïve subjects aged 3 months to 16 years; and a consolidated analysis of five Pediatric AIDS Clinical Trials Group (PACTG) protocols comprising 495 subjects aged 14 days to 19 years.

BI Trial 1100.1368 studied the safety, efficacy, and pharmacokinetics of a weight-based and a body surface area (BSA)-based dosing regimen of nevirapine. In the weight-based regimen, pediatric subjects up to 8 years of age received a dose of 4 mg/kg once daily for two weeks followed by 7 mg per kg twice daily thereafter. Subjects 8 years and older were dosed 4 mg/kg once daily for two weeks followed by 4 mg/kg twice daily thereafter. In the BSA regimen, all pediatric subjects received 150 mg/m2 once daily for two weeks followed by 150 mg/m2 twice daily thereafter [see Use in Specific Populations (8.4) and Adverse Reactions (6.2)].

Dosing of nevirapine at 150 mg/m2 BID (after a two-week lead-in of 150 mg/m2 QD) produced geometric mean or mean trough nevirapine concentrations between 4 to 6 mcg per mL (as targeted from adult data). In addition, the observed trough nevirapine concentrations were comparable between the two dosing regimens studied (BSA- and weight-based methods).

The consolidated analysis of Pediatric AIDS Clinical Trials Group (PACTG) protocols 245, 356, 366, 377, and 403 allowed for the evaluation of pediatric subjects less than 3 months of age (n=17). The plasma nevirapine concentrations observed were within the range observed in adults and the remainder of the pediatric population, but were more variable between subjects, particularly in the second month of age. For dose recommendations for pediatric patients [see Dosage and Administration (2.2)].

Drug Interactions [see Drug Interactions (7)]

Nevirapine induces hepatic cytochrome P450 metabolic isoenzymes 3A and 2B6. Co-administration of nevirapine and drugs primarily metabolized by CYP3A or CYP2B6 may result in decreased plasma concentrations of these drugs and attenuate their therapeutic effects.

While primarily an inducer of cytochrome P450 3A and 2B6 enzymes, nevirapine may also inhibit this system. Among human hepatic cytochrome P450s, nevirapine was capable in vitro of inhibiting the 10-hydroxylation of (R)-warfarin (CYP3A). The estimated Ki for the inhibition of CYP3A was 270 micromolar, a concentration that is unlikely to be achieved in patients as the therapeutic range is less than 25 micromolar. Therefore, nevirapine may have minimal inhibitory effect on other substrates of CYP3A.

Nevirapine does not appear to affect the plasma concentrations of drugs that are substrates of other CYP450 enzyme systems, such as 1A2, 2D6, 2A6, 2E1, 2C9, or 2C19.

Table 5 (see below) contains the results of drug interaction trials performed with nevirapine and other drugs likely to be co-administered. The effects of nevirapine on the AUC, Cmax, and Cmin of co-administered drugs are summarized.

§ = Cmin below detectable level of the assay

↑ = Increase, ↓ = Decrease, ⇔ = No Effect

a          For information regarding clinical recommendations, see  Drug Interactions (7).

b          Pediatric subjects ranging in age from 6 months to 12 years.

c          Parallel group design; n for nevirapine+lopinavir/ritonavir, n for lopinavir/ritonavir alone.

d          Parallel group design; n=23 for atazanavir/ritonavir + nevirapine, n=22 for atazanavir/ritonavir without nevirapine. Changes in atazanavir PK are relative to atazanavir/ritonavir 300/100 mg alone.

e          Based on between-trial comparison.

f           Based on historical controls.

Because of the design of the drug interaction trials (addition of 28 days of nevirapine therapy to existing HIV-1 therapy), the effect of the concomitant drug on plasma nevirapine steady-state concentrations was estimated by comparison to historical controls.

Administration of rifampin had a clinically significant effect on nevirapine pharmacokinetics, decreasing AUC and Cmax by greater than 50%. Administration of fluconazole resulted in an approximate 100% increase in nevirapine exposure, based on a comparison to historic data [see Drug Interactions (7)]. The effect of other drugs listed in Table 5 on nevirapine pharmacokinetics was not significant. No significant interaction was observed when tipranavir was co-administered with low-dose ritonavir and nevirapine.

Microbiology

Mechanism of Action

Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Nevirapine binds directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site. The activity of nevirapine does not compete with template or nucleoside triphosphates. HIV-2 RT and eukaryotic DNA polymerases (such as human DNA polymerases α, β, γ, or δ) are not inhibited by nevirapine.

Antiviral Activity

The antiviral activity of nevirapine has been measured in a variety of cell lines including peripheral blood mononuclear cells, monocyte-derived macrophages, and lymphoblastoid cell lines. In an assay using human embryonic kidney 293 cells, the median EC50 value (50% inhibitory concentration) of nevirapine was 90 nM against a panel of 2923 wild-type isolates of HIV-1 that were primarily (93%) clade B clinical isolates from the United States. The 99th percentile EC50 value was 470 nM in this trial. The median EC50 value was 63 nM (range 14 to 302 nM, n=29) against clinical isolates of HIV-1 clades A, B, C, D, F, G, and H, and circulating recombinant forms CRF01_AE, CRF02_AG and CRF12_BF. Nevirapine had no antiviral activity in cell culture against group O HIV-1 isolates (n=3) or HIV-2 isolates (n=3) replicating in cord blood mononuclear cells. Nevirapine in combination with efavirenz exhibited strong antagonistic anti-HIV-1 activity in cell culture and was additive to antagonistic with the protease inhibitor ritonavir or the fusion inhibitor enfuvirtide. The anti-HIV-1 activity of nevirapine was not antagonistic in combination with the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir and zidovudine, and the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, saquinavir and tipranavir. The anti-HIV-1 activity of nevirapine was antagonized by the anti-HBV drug adefovir and by the anti-HCV drug ribavirin in cell culture.

Resistance

HIV-1 isolates with reduced susceptibility (100- to 250-fold) to nevirapine emerge in cell culture. Genotypic analysis showed mutations in the HIV-1 RT gene encoding Y181C and/or V106A substitutions depending upon the virus strain and cell line employed. Time to emergence of nevirapine resistance in cell culture was not altered when selection included nevirapine in combination with several other NNRTIs.

Phenotypic and genotypic changes in HIV-1 isolates from treatment-naïve subjects receiving either nevirapine (n=24) or nevirapine and zidovudine (n=14) were monitored in Phase 1 and 2 trials ranging from 1 to 12 weeks or longer. After 1 week of nevirapine monotherapy, isolates from 3/3 subjects had decreased susceptibility to nevirapine in cell culture. One or more of the RT mutations resulting in amino acid substitutions K103N, V106A, V108I, Y181C, Y188C, and G190A were detected in HIV-1 isolates from some subjects as early as 2 weeks after therapy initiation. By week eight of nevirapine monotherapy, 100% of the subjects tested (n=24) had HIV-1 isolates with a greater than 100-fold decrease in susceptibility to nevirapine in cell culture compared to baseline, and had one or more of the nevirapine­-associated RT resistance substitutions. Nineteen of these subjects (80%) had isolates with Y181C substitutions regardless of dose.  

Genotypic analysis of isolates from antiretroviral-naïve subjects experiencing virologic failure (n=71) receiving nevirapine once daily (n=25) or twice daily (n=46) in combination with lamivudine and stavudine (trial 2NN) for 48 weeks showed that isolates from 8/25 and 23/46 subjects, respectively, contained one or more of the following NNRTI resistance-associated substitutions: Y181C, K101E, G190A/S, K103N, V106A/M, V108I, Y188C/L, A98G, F227L, and M230L.

For trial 1100.1486, genotypic analysis was performed for baseline and on-therapy isolates from 23 and 34 subjects who experienced virologic failure in the nevirapine extended-release tablets and immediate-release nevirapine treatment group, respectively. Nevirapine resistance-associated substitutions developed in the on-therapy isolates of 78% (18/23) of the subjects who had virologic failures in the nevirapine extended-release tablets treatment group and 88% (30/34) of the subjects in the immediate-release nevirapine treatment group, respectively. The Y181C nevirapine resistance-associated substitution was found alone or in combination with other nevirapine resistance-associated substitutions (K101E, K103N, V106A, V108I, V179D/E/I, Y188 C/F/H/L/N, G190A, P225H, F227L, M230L) in isolates from 14 subjects failing nevirapine extended-release tablets treatment and 25 subjects failing immediate-release nevirapine treatment. On-therapy isolates from 1 subject in nevirapine extended-release tablets treatment group developed a novel amino acid substitution Y181I and isolates from another subject in the immediate-release nevirapine treatment group developed a novel amino acid substitution Y188N. Phenotypic analysis showed that Y188N and Y181I substitutions conferred 103- and 22-fold reductions in susceptibility to nevirapine, respectively.

Cross-resistance

Rapid emergence of HIV-1 strains which are cross-resistant to NNRTIs has been observed in cell culture. Nevirapine-resistant HIV-1 isolates were cross-resistant to the NNRTIs delavirdine, efavirenz and etravirine.  The Y188N conferred 22- and 7-fold reductions in susceptibility to delavirdine and efavirenz, respectively, but showed no decrease in susceptibility to etravirine. Similarly, the Y181I substitution reduced susceptibility to delavirdine and etravirine 3- and 8-fold, respectively, but did not reduce susceptibility to efavirenz. However, nevirapine-resistant isolates were susceptible to the NRTIs ddI and ZDV. Similarly, ZDV-resistant isolates were susceptible to nevirapine in cell culture.