Nevirapine (Page 5 of 9)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects

Pregnancy Category B.

There are no adequate and well-controlled trials of nevirapine in pregnant women. The Antiretroviral Pregnancy Registry, which has been surveying pregnancy outcomes since January 1989, has not found an increased risk of birth defects following first trimester exposures to nevirapine. The prevalence of birth defects after any trimester exposure to nevirapine is comparable to the prevalence observed in the general population.

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 Boxed Warning].

Nevirapine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Antiretroviral Pregnancy Registry
To monitor maternal-fetal outcomes of pregnant women exposed to nevirapine, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling (800) 258-4263.

Animal Data
No observable teratogenicity was detected in reproductive studies performed in pregnant rats and rabbits. The maternal and developmental no-observable-effect level dosages produced systemic exposures approximately equivalent to or approximately 50% higher in rats and rabbits, respectively, than those seen at the recommended daily human dose (based on AUC). In rats, decreased fetal body weights were observed due to administration of a maternally toxic dose (exposures approximately 50% higher than that seen at the recommended human clinical dose).

8.3 Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. Nevirapine is excreted in breast milk. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving nevirapine.

8.4 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)].

8.5 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.

8.6 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/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)].

8.7 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)].

10 OVERDOSAGE

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.

11 DESCRIPTION

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 is a white to off-white crystalline powder with the molecular weight of 266.30 and the molecular formula C15 H14 N4 O. Nevirapine has the following structural formula:

Chemical structure

Nevirapine Tablets are for oral administration. Each tablet contains 200 mg of nevirapine and the inactive ingredients microcrystalline cellulose, lactose monohydrate, povidone, sodium starch glycolate, silicon dioxide and magnesium stearate.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.3 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/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 (AUCτ) 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 (8.3)]. Nevirapine is about 60% bound to plasma proteins in the plasma concentration range of 1 to 10 mcg/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 14 C-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/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/day.

Specific Populations
Renal Impairment
HIV-1 seronegative adults with mild (CrCL 50 to 79 mL/min; n=7), moderate (CrCL 30 to 49 mL/min; n=6), or severe (CrCL less than 30 mL/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/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/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 (250-325 subjects/group) in both immediate-release nevirapine and extended-release nevirapine 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/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/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 4 (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.

Table 4 Drug Interactions: Changes in Pharmacokinetic Parameters for Co-administered Drug in the Presence of Nevirapine (All interaction trials were conducted in HIV-1 positive subjects)
Co-administered Drug Dose of Co-administered Drug Dose Regimen of nevirapine n % Change of Co-administered Drug Pharmacokinetic Parameters (90% CI)
Antiretrovirals AUC Cmax Cmin
Atazanavir/Ritonavir a,d 300/100 mg QD day 4–13, then 400/100 mg QD, day 14–23 200 mg BID day 1-23. Subjects were treated with nevirapine prior to trial entry. 23 Atazanavir300/100 mg↓42(↓52 to ↓29) Atazanavir300/100 mg↓28(↓40 to ↓14) Atazanavir300/100 mg↓72(↓80 to ↓60)
Atazanavir400/100 mg↓19(↓35 to ↑­2) Atazanavir400/100 mg­↑2(↓15 to ↑­24) Atazanavir400/100 mg↓59(↓73 to ↓40)
Darunavir/Ritonavire 400/100 mg BID 200 mg BID 8 ↑­24(↓3 to ↑57) ↑­40(↑14 to ↑73) ↑­2(↓21 to↑32 )
Didanosine 100-150 mg BID 200 mg QD x 14 days; 200 mg BID x 14 days 18 # # §
Efavirenza 600 mg QD 200 mg QD x 14 days; 400 mg QD x 14 days 17 ↓28(↓34 to ↓14) ↓12(↓23 to ↑­1) ↓32(↓35 to ↓19)
Fosamprenavir 1400 mg BID 200 mg BID. Subjects were treated with nevirapine prior to trial entry. 17 ↓33(↓45 to ↓20) ↓25(↓37 to ↓10) ↓35(↓50 to ↓15)
Fosamprenavir/Ritonavir 700/100 mg BID 200 mg BID. Subjects were treated with nevirapine prior to trial entry 17 ↓11(↓23 to ↑­3) # ↓19(↓32 to ↓4)
Indinavira 800 mg q8H 200 mg QD x 14 days; 200 mg BID x 14 days 19 ↓31(↓39 to ↓22) ↓15(↓24 to ↓4) ↓44(↓53 to ↓33)
Lopinavir a, b 300/75 mg/m2 (lopinavir/ritonavir) b 7 mg/kg or 4 mg/kg QD x 2 weeks; BID x 1 week 12, 15 c ↓22(↓44 to ↑­9) ↓14(↓36 to ↑­16) ↓55(↓75 to ↓19)
Lopinavira 400/100 mg BID (lopinavir/ritonavir) 200 mg QD x 14 days; 200 mg BID >1 year 22, 19 c ↓27(↓47 to ↓2) ↓19(↓38 to ↑­5) ↓51(↓72 to ↓26)
Maraviroc f 300 mg SD 200 mg BID 8 ↑­1(↓35 to ↑55) ↑­54(↓6 to ↑151) #
Nelfinavira Nelfinavir-M8 metabolite 750 mg TID 200 mg QD x 14 days; 200 mg BID x 14 days 23 # # ↓32 (↓50 to ↑­5)
↓62(↓70 to ↓53) ↓59(↓68 to ↓48) ↓66(↓74 to ↓55)
Ritonavir 600 mg BID 200 mg QD x 14 days; 200 mg BID x 14 days 18 # # #
Stavudine 30-40 mg BID 200 mg QD x 14 days; 200 mg BID x 14 days 22 # # §
Zalcitabine 0.125-0.25 mg TID 200 mg QD x 14 days; 200 mg BID x 14 days 6 # # §
Zidovudine 100-200 mg TID 200 mg QD x 14 days; 200 mg BID x 14 days 11 ↓28(↓40 to ↓4) ↓30(↓51 to ↑­14) §
Other Medications AUC Cmax Cmin
Clarithromycina Metabolite 14-OH-clarithromycin 500 mg BID 200 mg QD x 14 days; 200 mg BID x 14 days 15 ↓31(↓38 to ↓24) ↓23(↓31 to ↓14) ↓56(↓70 to ↓36)
↑­42(↑16 to ↑73) ↑­47(↑21 to ↑­80) #
Ethinyl estradiola and Norethindronea 0.035 mg (as Ortho-Novum® 1/35)1 mg (as Ortho- Novum® 1/35) 200 mg QD x 14 days; 200 mg BID x 14 days 10 ↓20(↓33 to ↓3) # §
↓19(↓30 to ↓7) ↓16(↓27 to ↓3) §
Depomedroxyprogesterone acetate 150 mg every 3 months 200 mg QD x 14 days; 200 mg BID x 14 days 32 # # #
Fluconazole 200 mg QD 200 mg QD x 14 days; 200 mg BID x 14 days 19 # # #
Ketoconazolea 400 mg QD 200 mg QD x 14 days; 200 mg BID x 14 days 21 ↓72(↓80 to ↓60) ↓44(↓58 to ↓27) §
Methadonea Individual Subject Dosing 200 mg QD x 14 days; 200 mg BID ≥7 days 9 In a controlled pharmacokinetic trial with 9 subjects receiving chronic methadone to whom steady-state nevirapine therapy was added, the clearance of methadone was increased by 3-fold, resulting in symptoms of withdrawal, requiring dose adjustments in 10 mg segments, in 7 of the 9 subjects. Methadone did not have any effect on nevirapine clearance.
Rifabutina Metabolite 25-O-desacetyl-rifabutin 150 or 300 mg QD 200 mg QD x 14 days; 200 mg BID x 14 days 19 ↑­17(↓2 to ↑40) ↑­28(↑9 to ↑­51) #
↑­24(↓16 to ↑­84) ↑­29(↓2 to ↑­68) ↑­22(↓14to ↑­74)
Rifampina 600 mg QD 200 mg QD x 14 days; 200 mg BID x 14 days 14 ↑­11(↓4 to ↑­28) # §
§ = 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 4 on nevirapine pharmacokinetics was not significant. No significant interaction was observed when tipranavir was co-administered with low-dose ritonavir and nevirapine.

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