PRODUCT MONOGRAPH

Pr

VIRAMUNE(r)

(nevirapine) Tablets, 200 mg

ANTIRETROVIRAL AGENT

NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR WITH ACTIVITY AGAINST

HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 (HIV-1)

Boehringer Ingelheim (Canada) Ltd. 5180 South Service Road Burlington, Ontario

L7L 5H4

Date of Revision: July 18, 2007

Control Number: 113426

For BICL use only: Tracking BPI # 0199-09

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 13 DRUG INTERACTIONS 18 DOSAGE AND ADMINISTRATION 28 OVERDOSAGE 29 ACTION AND CLINICAL PHARMACOLOGY 30 STORAGE AND STABILITY 35 DOSAGE FORMS, COMPOSITION AND PACKAGING 35

PART II: SCIENTIFIC INFORMATION 36

PHARMACEUTICAL INFORMATION 36 CLINICAL TRIALS 37 DETAILED PHARMACOLOGY 38 TOXICOLOGY 40 REFERENCES 41

PART III: CONSUMER INFORMATION. 44

Pr

Viramune(r)

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

• VIRAMUNE (nevirapine) is contraindicated in patients with clinically significant hypersensitivity to any of its components. For a complete listing see the DOSAGE FORMS, COMPOSITION AND PACKAGING sections of the Product Monograph.

• VIRAMUNE should not be administered to patients with severe hepatic dysfunction or pre-treatment AST or ALT > 5X Upper Limit of Normality (ULN).

• VIRAMUNE should not be readministered to patients who have been discontinued for severe rash, rash accompanied by constitutional symptoms, hypersensitivity reactions, or clinical hepatitis due to nevirapine.

• VIRAMUNE should not be readministered in patients who previously had AST or ALT > 5X Upper Limit of Normality (ULN) during nevirapine therapy (see WARNINGS AND PRECAUTIONS).

• VIRAMUNE should not be administered to patients with rare hereditary conditions of galactose intolerance e.g. galactosaemia, the Lapp lactase deficiency or glucose-galactose malabsorption.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

Severe, life-threatening, and in some cases fatal hepatotoxicity, particularly in the first 18 weeks, has been reported in patients treated with VIRAMUNE. Female gender and higher CD4 counts at the initiation of therapy place patients at increased risk of hepatic adverse events (see, General and Hepatic/Biliary/Pancreatic sections below).

Severe, life-threatening skin reactions, including fatal cases, have been reported with VIRAMUNE treatment, occurring almost exclusively during the first 6 weeks of therapy. These have included cases of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and hypersensitivity syndrome characterized by rash, constitutional findings, and organ dysfunction (see ADVERSE REACTIONS). Patients should be carefully monitored

during the first 18 weeks of treatment. 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 VIRAMUNE and seek medical evaluation immediately (see Guidelines for the MANAGEMENT OF RASH EVENTS, WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS).

General

Women and patients with higher CD4 counts are at increased risk of hepatic adverse events. The first 18 weeks of therapy with VIRAMUNE (nevirapine) are a critical period during which intensive monitoring of patients is required to detect potentially life-threatening hepatic events and skin reactions. The optimal frequency of monitoring during this time period has not been established, however it may be prudent to conduct clinical and laboratory monitoring more often than once per month; for example, liver function 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 treatment. The greatest risk of hepatic events and skin reactions occurs in the first 6 weeks of therapy. However, the risk of any hepatic event continues past this period and monitoring should continue at frequent intervals.

Resistant virus emerges rapidly and uniformly when VIRAMUNE is administered as monotherapy. Therefore, VIRAMUNE should always be administered in combination with other antiretroviral agents for the treatment of HIV-1 infection. When discontinuing an antiretroviral regimen containing VIRAMUNE, the longer half-life of nevirapine should be taken into account; if antiretrovirals with shorter half-lives than VIRAMUNE are stopped concurrently, low plasma concentrations of nevirapine alone may persist for a week or longer and virus resistance may subsequently develop. When administering VIRAMUNE as part of a multi-drug antiretroviral treatment regimen, the complete product information for each therapeutic component should be consulted before initiation of treatment. Patients receiving VIRAMUNE or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with associated HIV diseases. VIRAMUNE therapy has not been shown to reduce the risk of horizontal transmission of HIV-1 to others.

Hepatic/Biliary/Pancreatic

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 VIRAMUNE. In some cases, patients presented with non-specific prodromal signs or symptoms of hepatitis and progressed to hepatic failure. These events are often associated with rash. Female gender and higher CD4 counts at the initiation of therapy place patients at greater risk of hepatic adverse events. Based on serious and life- threatening hepatotoxicity observed in controlled and uncontrolled studies, VIRAMUNE should not be initiated in adult females with CD4+ cell counts greater than 250 cells/mm3, including pregnant women receiving chronic treatment for HIV infection, or in adult males with CD4+ cell counts greater than 400 cells/mm3 unless the benefit outweighs the risk. In some cases, hepatic injury has progressed despite discontinuation of treatment. Patients developing signs or symptoms of hepatitis, severe skin reaction or hypersensitivity reactions must discontinue VIRAMUNE and seek medical evaluation immediately. VIRAMUNE should not be restarted following severe hepatic, skin or hypersensitivity reactions.

In clinical trials, the risk of hepatic events regardless of severity was greatest in the first 6 weeks of therapy. The risk continued to be greater in the VIRAMUNE groups compared to controls through 18 weeks of treatment. However, hepatic events may occur at any time during treatment. In some cases, patients 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. Some of these events have progressed to hepatic failure with transaminase elevation, with or without hyperbilirubinemia, prolonged partial thromboplastin time, or eosinophilia. Rash and fever accompanied some of these hepatic events. Patients with signs or symptoms of hepatitis must be advised to discontinue VIRAMUNE and immediately seek medical evaluation, which should include liver function tests. In rare instances rhabdomyolysis has been observed in patients experiencing skin and/or liver reactions associated with VIRAMUNE use. Increased AST or ALT levels and/or co-infection with hepatitis B and C at the start of antiretroviral therapy are associated with a greater risk of hepatic adverse events. In general, women have a three fold higher risk than men for symptomatic, often rash-associated, hepatic events (5.8% versus 2.2%), and patients with higher CD4 counts at initiation of VIRAMUNE therapy are at higher risk for symptomatic hepatic events with VIRAMUNE. In a retrospective review, women with CD4 counts > 250 cells/mm3 had a 12 fold higher risk of symptomatic hepatic adverse events compared to women with CD4 counts < 250 cells/mm3 (11.0% versus 0.9%). An increased risk was also observed in men with CD4 counts > 400 cells/mm3 (6.3% versus 2.3% for men with CD4 counts < 400 cells/mm3). Intensive clinical and laboratory monitoring, including liver function tests, is essential at baseline and during the first 18 weeks of treatment (see WARNINGS, GENERAL). Monitoring should continue at frequent intervals thereafter, depending on the patient's clinical status. Liver function tests should be performed immediately if a patient experiences signs or symptoms suggestive of hepatitis and/or hypersensitivity reaction. Liver function tests should also be obtained 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 hepatic injury should be considered in this setting, even if liver function tests are initially normal or alternative diagnoses are possible (see WARNINGS AND PRECAUTIONS; ADVERSE REACTIONS; and DOSAGE AND ADMINISTRATION). If clinical hepatitis occurs, VIRAMUNE should be permanently discontinued and not restarted after recovery. If either AST or ALT increase to > 5X ULN, VIRAMUNE should be immediately stopped. VIRAMUNE should not be readministered to patients who have been discontinued for severe rash, rash accompanied by constitutional symptoms, hypersensitivity reactions, or clinical hepatitis due to VIRAMUNE (see Guideline for the MANAGEMENT OF HEPATIC EVENTS). In some cases hepatic injury progresses despite the discontinuation of treatment. If AST or ALT is > 2X ULN, liver tests should be monitored more frequently. Asymptomatic elevation of liver enzymes occur frequently in patients infected with HIV and is not necessarily a contraindication to initiating therapy with VIRAMUNE. Asymptomatic GGT elevations are not a contraindication to continuing therapy. VIRAMUNE is extensively metabolised by the liver and nevirapine metabolites are eliminated largely by the kidney. Increased nevirapine levels and nevirapine accumulation may be observed in patients with serious liver disease. Single dose pharmacokinetic results suggest caution should be exercised when VIRAMUNE is administered to patients with moderate hepatic dysfunction. VIRAMUNE should not be administered to patients with severe hepatic dysfunction (see CONTRAINDICATIONS).

Skin

Severe, life-threatening skin reactions, including fatal cases, have been reported with VIRAMUNE treatment, occurring almost exclusively during the first 6 weeks of therapy. These have included cases of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and hypersensitivity syndrome characterized by rash, constitutional findings, and organ dysfunction (see ADVERSE REACTIONS). Patients should be carefully monitored during the first 18 weeks of treatment. 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 VIRAMUNE and seek medical evaluation immediately (see Guidelines for the MANAGEMENT OF RASH EVENTS, WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS).

VIRAMUNE should not be restarted following severe skin rash or hypersensitivity reaction (see Guideline for the MANAGEMENT OF RASH EVENTS). Some of the risk factors for developing serious cutaneous reactions include failure to follow the initial dosing of 200 mg daily during the 14-day lead-in period and delay in stopping the VIRAMUNE treatment after the onset of the initial symptoms.

Therapy with VIRAMUNE must be initiated with a 14-day lead-in period of 200 mg/day which has been shown to reduce the frequency of rash. If rash is observed during this lead-in period, dose escalation should not occur until the rash has resolved (see Guideline for the MANAGEMENT OF RASH EVENTS, and DOSAGE AND ADMINISTRATION) Patients should be monitored closely if an isolated rash of any severity occurs. If patients present with a suspected VIRAMUNE-associated rash, liver function tests should be performed. Patients with rash-associated AST or ALT elevations should be permanently discontinued from VIRAMUNE. In rare instances rhabdomyolysis has been observed in patients experiencing skin and/or liver reactions associated with VIRAMUNE use. Women appear to be at higher risk than men of developing rash with VIRAMUNE. In a clinical trial, the concomitant use of prednisone was associated with an increase in the incidence and severity of rash during the first 6 weeks of VIRAMUNE therapy. Therefore, the use of prednisone to prevent VIRAMUNE-associated rash is not recommended.

Post-Exposure Prophylaxis

VIRAMUNE is not recommended for post-exposure prophylaxis

. In the setting of post- exposure prophylaxis, an unapproved use, serious hepatotoxicity, including one instance of liver failure requiring transplantation, and serious skin rash including Stevens-Johnson syndrome, have been reported in HIV-uninfected individuals receiving multiple doses of VIRAMUNE in combination with other antiretroviral agents.

Carcinogenesis and Mutagenesis

In long-term carcinogenicity studies, the incidence of hepatocellular adenomas and carcinomas in mice increased at all doses in males and at the two high doses in females. In rats an increase in hepatocellular adenomas was seen in males at all doses and in females at the high dose. The systemic exposure (based on AUCs) at all doses in the two animal studies were lower than that measured in humans at the recommended daily dose. In genetic toxicology assays, nevirapine showed no evidence of mutagenic activity in a battery of in vitro and in vivo assays including microbial assays for gene mutation (Ames test in Salmonella strains and E. coli), mammalian cell gene mutation (HGRPT) assays in Chinese hamster ovary (CHO) cell line, cytogenetic assays using a CHO cell line and mouse bone marrow micronucleus assay following oral administration. In reproductive toxicology studies, evidence of impaired fertility was seen in female rats at doses providing systemic exposure, based on AUC, approximately equivalent to that observed following a human clinical dosage of 400 mg/day.

Renal

VIRAMUNE is extensively metabolised by the liver and nevirapine metabolites are eliminated largely by the kidney. In renal dysfunction, a single dose study suggested that patients with a creatinine clearance >= 20 mL/min do not require an adjustment in VIRAMUNE dosing (see PHARMACOKINETICS, subsection Special Populations).

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.

Immune Reconstitution

During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as MAC, CMV, PCP and TB), which may necessitate further evaluation and treatment.

Special Populations

Pregnant Women:

VIRAMUNE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. There have been no adequate and well-controlled studies of nevirapine in pregnant women, nor are there reports of infants born to women who conceived while receiving nevirapine chronic dosing in clinical trials.

Antiretroviral Pregnancy Registry:

To monitor maternal-fetal outcomes of pregnant women exposed to VIRAMUNE, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263 or 910-256-0238.

Nursing Women:

It is currently recommended that HIV-1 infected women should not breast feed infants regardless of the use of antiretroviral agents, to avoid post-natal transmission of HIV-1. Preliminary results from a pharmacokinetic study (ACTG 250) of 10 HIV-1-infected pregnant women who were administered a single oral dose of 100 or 200 mg VIRAMUNE at a median of hours before delivery, indicated that nevirapine readily crosses the placenta and is found in breast milk (breast milk samples taken from 3 out of 10 mothers).

Pediatrics (< 15 years of age):

Safety and effectiveness of VIRAMUNE in HIV-1-infected pediatric patients younger than 15 years of age have not been established. Nevirapine is metabolized more rapidly in pediatric patients than in adults.

Geriatrics (> 65 years of age)

:

Clinical studies of VIRAMUNE 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.

Ethnic Origin:

An evaluation of nevirapine plasma concentrations (pooled data from several clinical trials) from HIV-1-infected patients (27 Black, 24 Hispanic, 189 Caucasian) revealed no marked difference in nevirapine steady-state trough concentrations (median Cminss= 4.7 ug/mL Black, 3.8 ug/mL Hispanic, 4.3 ug/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.

Gender:

In general, women have a three fold higher risk than men for symptomatic, often rash-associated, hepatic events (5.8% versus 2.2%), and patients with higher CD4 counts at initiation of VIRAMUNE therapy are at higher risk for symptomatic hepatic events with VIRAMUNE. In a retrospective review, women with CD4 counts > 250 cells/mm3 had a 12 fold higher risk of symptomatic hepatic adverse events compared to women with CD4 counts < 250 cells/mm3 (11.0% versus 0.9%). An increased risk was also observed in men with CD4 counts > 400 cells/mm3 (6.3% versus 2.3% for men with CD4 counts < 400 cells/mm3) (see ADVERSE REACTIONS).

DRUG INTERACTIONS

Serious Drug Interactions

• See Table 4 for the changes in pharmacokinetic parameters of co-administered drugs

• See Table 5 for drugs that require an alteration in dose or regimen

• See Table 6 for drugs that may need a dose adjustment

Overview

Cytochrome P450 Nevirapine induces hepatic cytochrome P450 metabolic isoenzymes 3A4 and 2B6. Co- administration of VIRAMUNE and drugs primarily metabolized by CYP3A4 or CYP2B6 may result in decreased plasma concentrations of these drugs and attenuate their therapeutic effects. 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 contains the results of drug interaction studies performed with VIRAMUNE and other drugs likely to be co-administered. The effects of VIRAMUNE on the AUC, Cmax, and Cmin of co-administered drugs are summarized. To measure the full potential pharmacokinetic interaction effect following induction, patients on the concomitant drug at steady state were administered 28 days of VIRAMUNE (200 mg daily for 14 days followed by 200 mg BID for 14 days) followed by a steady state reassessment of the concomitant drug. Clinical comments about possible dosage modifications based on these pharmacokinetic changes are listed in Table 2. The data in Tables 4 and 5 are based on the results of drug interaction studies conducted in HIV- 1 seropositive subjects unless otherwise indicated. In addition to established drug interactions, there may be potential pharmacokinetic interactions between nevirapine and other drug classes that are metabolized by the cytochrome P450 system. These potential drug interactions are listed in Table 6. Although specific drug interaction studies in HIV-1 seropositive subjects have not been conducted for the classes of drugs listed in Table 6, additional clinical monitoring may be warranted when co-administering these drugs.

TABLE 4: DRUG INTERACTIONS: CHANGES IN PHARMACOKINETIC PARAMETERS FOR CO-ADMINISTERED DRUG IN THE PRESENCE OF VIRAMUNE (ALL INTERACTION STUDIES WERE CONDUCTED IN HIV-1 POSITIVE PATIENTS)

SS = Cmin below detectable level of the assay

| = Increase, | = Decrease, = = No Effect

a

For information regarding clinical recommendations see Table 5

b

Pediatric subjects ranging in age from 6 months to 12 years

c

Parallel group design; n for VIRAMUNE +lopinavir/ritonavir, n for lopinavir/ritonavir alone

Because of the design of the drug interaction trials (addition of 28 days of VIRAMUNE therapy to existing HIV 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 (Table 5). The effect of other drugs listed in Table 4 on nevirapine pharmacokinetics was not significant. The in vitro interaction between nevirapine and the antithrombotic agent warfarin is complex. As a result, when giving these drugs concomitantly, plasma warfarin levels may change with the potential for increases in coagulation time. When warfarin is co-administered with nevirapine, anticoagulation levels should be monitored frequently.

TABLE 5: ESTABLISHED DRUG INTERACTIONS: ALTERATION IN DOSE OR REGIMEN MAY BE RECOMMENDED BASED ON DRUG INTERACTION STUDIES (SEE TABLE 4 FOR MAGNITUDE OF INTERACTION)

a

Based on reports of narcotic withdrawal syndrome in patients treated with nevirapine and methadone concurrently, and evidence of decreased plasma concentrations of methadone.

TABLE 6: POTENTIAL DRUG INTERACTIONS: USE WITH CAUTION, DOSE ADJUSTMENT OF CO-ADMINISTERED DRUG MAY BE NEEDED DUE TO POSSIBLE DECREASE IN CLINICAL EFFECT

Nucleoside Reverse Transcriptase Inhibitors

No dosage adjustments are required when VIRAMUNE is taken in combination with ZDV, ddI or ddC. In a subset of patients (n=6) who were administered nevirapine 400 mg/day and ddI on a background of ZDV therapy, nevirapine produced a significant decline of 32% in ZDV AUC and a non-significant decline of 27% in ZDV Cmax. When the ZDV data were pooled from two studies (n=33) in which HIV-1 infected patients received VIRAMUNE 400 mg/day either alone or in combination with 200-300 mg/day ddI or 0.375 to 0.75 mg/day ddC on a background of ZDV therapy, nevirapine produced a non-significant decline of 13% in ZDV AUC and a non- significant increase of 5.8% in ZDV Cmax. Paired data suggest that ZDV had no effect on the steady-state pharmacokinetics of nevirapine. In one crossover study, nevirapine had no effect on the steady-state pharmacokinetics of either ddI (n=18) or ddC (n=6). Results from a 36 day study in HIV infected patients (n=25) administered VIRAMUNE, nelfinavir (750 mg tid) and stavudine (30-40 mg, bid) showed no statistically significant changes in the AUC or Cmax of stavudine. Furthermore, a population pharmacokinetic study of 90 patients assigned to receive lamivudine with VIRAMUNE or placebo revealed no changes to lamivudine apparent clearance and volume of distribution, suggesting no induction effect of VIRAMUNE on lamivudine clearance.

Lamivudine

A population pharmacokinetic study of 90 patients assigned to receive lamivudine with VIRAMUNE or placebo revealed no changes to lamivudine apparent clearance and volume of distribution, suggesting no induction effect of VIRAMUNE on lamivudine clearance.

Protease Inhibitors

In the following four studies, nevirapine was given 200 mg once daily for two weeks followed by 200 mg twice daily for 14 days:

Ritonavir

No dosage adjustments are required when nevirapine is taken in combination with ritonavir. Results from a clinical trial (n=18) with HIV infected patients administered nevirapine and ritonavir (600 mg b.i.d. [using a gradual dose escalation regimen]) indicated that their co- administration leads to no significant change in ritonavir or nevirapine plasma concentrations.

Indinavir

Results from a clinical trial (n=19) with HIV infected patients administered nevirapine and indinavir (800 mg q8h) indicated that their co-administration leads to a 31% mean decrease (p<0.01) in indinavir AUC and a 44% mean decrease in indinavir Cmin (p<0.01). There was no significant change in nevirapine plasma levels. No definitive clinical conclusions have been reached regarding the potential impact of co-administration of nevirapine and indinavir. A dose increase of indinavir to 1000 mg q8h may be considered when indinavir is given with nevirapine 200 mg b.i.d. ; however, there are no data currently available to establish that the short term or long term safety or antiviral activity of indinavir 1000 mg q8h with nevirapine 200 mg b.i.d. will differ from that of indinavir 800 mg q8h with nevirapine 200 mg b.i.d.

Saquinavir

Results from a clinical trial (n=23) with HIV infected patients administered nevirapine and saquinavir (hard gelatine capsules; 600 mg t.i.d.) indicated that their co-administration leads to a mean reduction of 38% (p=0.041) in saquinavir AUC and no significant change in nevirapine plasma levels. The reduction in saquinavir levels due to this interaction may further reduce the plasma levels of saquinavir which are achieved with the hard gelatine capsule formulation. The clinical significance of this interaction is not known. Coadministration did not affect the pharmacokinetics of nevirapine.

Nelfinavir

Results from a 28 day study in HIV infected patients (n=23) administered VIRAMUNE, nelfinavir (750 mg t.i.d.) showed no statistically significant changes in nelfinavir pharmacokinetic parameters after the addition of VIRAMUNE. Mean nelfinavir Cmin decreased by 32%. Compared to historical controls VIRAMUNE levels appeared to be unchanged. The major metabolite of nelfinavir (M8) which has comparable activity to the parent compound, however, has a 62% mean decrease in AUC with a 59% decrease in Cmax and 66% decrease in Cmin. The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established.

Lopinavir / ritonavir

In HIV positive adults, nevirapine used in combination with lopinavir/ritonavir 400/100 mg (3 capsules) twice daily resulted in a decline in the mean lopinavir AUC of approximately 27% and mean Cmin by 51%. Although the clinical relevance of this observation has not been fully established, an increase in the dose of lopinavir/ritonavir to 533/133 mg (4 capsules) twice daily with food is recommended in combination with nevirapine. Results from a pharmacokinetic study in paediatric patients were consistent with the findings in adults. During nevirapine co-administration, mean lopinavir AUC decreased by approximately 22 % and mean lopinavir Cmin by 55 %. In children 6 months to 12 years of age, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to < 15 kg; 11/2.75 mg/kg for those 15 to 45 kg; and up to a maximum dose of 533/133 mg for those > 45 kg twice daily when used in combination with nevirapine, particularly for patients in whom reduced susceptibility to lopinavir/ritonavir is suspected.

Oral Contraceptives

Nevirapine 200 mg b.i.d. was co-administered with a single dose of an oral contraceptive containing ethinyl estradiol (17-a EE) 0.035mg and norethindrone (NET) 1.0 mg (Ortho- Novum(r) 1/35). Compared to plasma concentrations observed prior to nevirapine administration, AUC for 17a-EE was decreased by 20 % (AUC point estimate 0.80; 90 % confidence interval 0.67-0.97) after 28 days of nevirapine dosing. There was a significant reduction in EE mean resident time and half-life. There was also a reduction in mean AUC for NET by 19 % (point estimate 0.81 HC; 0.70-0.93), without changes in mean resident time or half-life. The magnitude of the effect suggests that the dose of the oral contraceptive could be adjusted to allow adequate treatment for indications other than contraception (e.g., endometriosis), if used with nevirapine. However, the risk of oral contraceptive failure is a possibility if estrogen/progesterone-containing oral contraceptives are used. Other means of contraception (such as barrier methods) are recommended, when nevirapine is administered to women of child-bearing potential. For other therapeutic uses requiring hormonal regulation, the therapeutic effect in patients being treated with nevirapine should be monitored.

Methadone

There have been reports of narcotic withdrawal symptoms in patients receiving methadone treatment concomitantly with VIRAMUNE. Methadone-maintained patients beginning VIRAMUNE therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. In two pharmacokinetic studies of HIV-infected patients (n=8 and n=20) the effects of VIRAMUNE on the pharmacokinetics of methadone were determined. In the presence of nevirapine, steady state plasma methadone concentrations have been shown to be reduced by 42% at Cmax and by up to 60% in extent of methadone exposure (AUC).

CYP Isozyme Inducers

Rifampin

In an open label study (n=14), rifampin produced a significant lowering of nevirapine AUC (-58%), Cmax (-50%) and Cmin (-68%) compared to historical data. In contrast, the effects of VIRAMUNE on the steady state pharmacokinetics of rifampin resulted in no significant change in rifampin Cmax and AUC. Rifampin and nevirapine should, therefore, not be used concomitantly and physicians wanting to use rifampin for treatment of mycobacterial infections in those patients taking nevirapine should consider rifabutin instead (see WARNINGS AND PRECAUTIONS).

Rifabutin

In an open label pharmacokinetic study (n=19) the concomitant administration of rifabutin following full induction with nevirapine resulted in a 17% increase in the steady-state AUC, a 28% increase in Cmax, and a 7% increase in Cmin of rifabutin. There was also an increase in the 25-O-desacetyl-rifabutin metabolite exposure in extent (AUC increase by 24%) and rate (Cmax increase by 29%). Therefore, caution should be used in concomitant administration with nevirapine. In the same study, rifabutin administration resulted in an apparent significant increase in systemic clearance of nevirapine by 9% compared to historical controls.

CYP Isozyme Inhibitors

Ketoconazole

Administration of nevirapine 200 mg b.i.d. with ketoconazole 400 mg q.d. resulted in a significant reduction by 72 % in ketoconazole AUC and by 44 % in ketoconazole Cmax. In the same study [n=21], ketoconazole administration resulted in a 15-28% increase in the plasma levels of nevirapine compared to historical controls. Ketoconazole and nevirapine should not be given concomitantly. The effects of nevirapine on itraconazole are not known.

Fluconazole

Co-administration of fluconazole and nevirapine resulted in approximately 100% increase in nevirapine exposure compared with historical data where nevirapine was administered alone. Because of the risk of increased exposure to nevirapine, caution should be exercised if the medicinal products are given concomitantly and patients should be monitored closely. Fluconazole may only be added to a stable nevirapine containing regimen when the benefits clearly outweigh the risks. There was no clinically relevant effect of nevirapine on fluconazole.

Clarithromycin

Results of a VIRAMUNE-clarithromycin drug-drug interaction study (n=15) resulted in a significant reduction in clarithromycin AUC (-31%), Cmax (-23%) and Cmin (- 56%) but a significant increase in AUC (42%) and Cmax (47%) of the active metabolite 14-OH clarithromycin. There was a significant increase in the nevirapine Cmin (28%) and a non- significant increase in nevirapine AUC (26%) and Cmax (24%). Alternative therapy to clarithromycin should be considered when treating a patient for mycobacterium avium- intracellulare complex, as the active metabolite is not effective in this instance.

Other Drugs Metabolized By CYP3A

Biotransformation of nevirapine involves extensive cytochrome P450 metabolism (CYP3A>CYP2B6) and glucuronidation with maximal induction occurring within 2-4 weeks of initiating multiple-dose therapy. Available data on the potential interaction between nevirapine and other drugs that are extensively metabolized by CYP3A are limited and preliminary; therefore, careful monitoring of the therapeutic effectiveness of CYP3A-metabolized drugs is recommended when taken in combination with nevirapine.

In Vitro

Studies

Studies using human liver microsomes indicated that the formation of nevirapine hydroxylated metabolites was not affected by the presence of dapsone, rifabutin, rifampin and trimethoprim/sulphamethoxazole. Ketoconazole and erythromycin significantly inhibited the formation of nevirapine hydroxylated metabolites.

Drug-Herb Interactions

St. John's Wort Concomitant use of VIRAMUNE and St. John's wort (hypericum perforatum) or St. John's wort-containing products is not recommended. Co-administration of non-nucleoside reverse transcriptase inhibitors including VIRAMUNE, with St. John's wort is expected to decrease NNRTI concentrations and may result in sub-optimal levels of VIRAMUNE and lead to loss of virologic response and possible resistance to VIRAMUNE or to the class of NNRTIs.

Drug-Lifestyle Interactions

Occupational Hazards: Psychomotor Performance:

There are no specific studies assessing psychomotor performance in patients using VIRAMUNE. Somnolence has been reported in association with VIRAMUNE therapy; if this occurs during VIRAMUNE administration, patients should be advised to refrain from driving a motor vehicle or operating potentially hazardous machinery.

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

The recommended dose for VIRAMUNE (nevirapine) is one 200 mg tablet daily for the first 14 days (this lead-in period should be used because it has been found to lessen the frequency of rash), followed by one 200 mg tablet twice daily, as part of a multi-drug antiretroviral treatment regimen. The manufacturer's recommended dosage and monitoring for the concomitantly administered antiretroviral therapy should be used.

Dosing Considerations

Monitoring of Patients

Intensive clinical and laboratory monitoring, including liver function tests, is essential at baseline and during the first 18 weeks of treatment with VIRAMUNE. The optimal frequency of monitoring during this period has not been established, however it may be prudent to conduct clinical and laboratory monitoring more often than once per month; for example, liver function 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 VIRAMUNE treatment (see WARNINGS AND PRECAUTIONS).

VIRAMUNE should be discontinued if patients experience severe rash or a rash accompanied by constitutional findings (see WARNINGS AND PRECAUTIONS). Patients experiencing rash during the 14-day lead-in period of 200 mg/day should not have their VIRAMUNE dose increased until the rash has resolved (see WARNINGS AND PRECAUTIONS).

VIRAMUNE administration should be interrupted in patients experiencing moderate or severe liver function test abnormalities (> 5X ULN) (excluding GGT), until the liver function test elevations have returned to baseline. VIRAMUNE may then be restarted at the lead-in dose of 200 mg/day. Increasing the daily dose to 200 mg twice daily (400 mg/day) should be done with caution, after extended observation. Patients should be aware that this may not prevent serious adverse reactions. VIRAMUNE should be permanently discontinued if moderate or severe liver function test abnormalities recur (see WARNINGS AND PRECAUTIONS).

Patients with Renal Impairment

In End Stage Renal Disease (ESRD) appropriate doses of VIRAMUNE with respect to safety and efficacy have not been established. Subjects with ESRD requiring dialysis exhibited a 43.5% reduction in VIRAMUNE AUC over a one week exposure period with an accumulation of nevirapine hydroxy-metabolites in plasma. An additional 200 mg dose of VIRAMUNE following each dialysis treatment is recommended in patients requiring dialysis. In renal dysfunction, a single dose study suggested that patients with a creatinine clearance >= 20 mL/min do not require an adjustment in VIRAMUNE dosing.

Patients with Hepatic Impairment

Patients with mild hepatic impairment do not require an adjustment in VIRAMUNE dosing; however, caution should be exercised when VIRAMUNE is administered to patients with moderate hepatic impairment. VIRAMUNE should not be administered to patients with severe hepatic dysfunction.

Patients with Lactose Intolerance

VIRAMUNE tablets contain 636 mg of lactose per maximum recommended daily dose. Patients with rare hereditary conditions of galactose intolerance e.g. galactosaemia, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Missed Dose

Patients who miss a dose should take it as soon as they remember and then continue as before. Do not double the next dosage. Patients who interrupt VIRAMUNE dosing for more than 7 days should restart the recommended dosing, using one 200 mg tablet daily for the first 14 days (lead-in) followed by one 200 mg tablet twice daily.

OVERDOSAGE

There is no known antidote for VIRAMUNE (nevirapine) overdosage. The use of activated charcoal may be helpful. Cases of VIRAMUNE overdose at doses ranging from 800 to 6000 mg per day for up to 15 days have been reported. Patients have experienced edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, vertigo, vomiting, increase in transaminases, and weight decrease. All subsided following discontinuation of VIRAMUNE. In one case, a patient accidentally ingested VIRAMUNE 1200 mg daily for three days, and then 1800 mg for a fourth day. The patient suffered fever, generalized rash, nausea, vomiting, headache, chills, and facial swelling, and was admitted to hospital for 5 days. The event resolved without sequelae. In another case, a patient ingested 9 tablets of VIRAMUNE (1800 mg) per day for 10 days. The patient presented with rash (erythema nodosum), pulmonary infiltrate, and bilateral edema of hands and feet. He was hospitalized for 2 weeks during which time he was aggressively diuresed. The events resolved over 3 weeks. No acute toxicities or sequelae were reported for one patient who ingested 800 mg of VIRAMUNE for one day.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

VIRAMUNE (nevirapine) is a highly selective, non-nucleoside reverse transcriptase inhibitor (NNRTI) of Human Immunodeficiency Virus Type 1 (HIV-1). The enzymatic activity of reverse transcriptase (RT) is required for replication of HIV. Nevirapine binds directly to RT and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site. The inhibitory activity of nevirapine is not competitive with respect to template or nucleoside triphosphates. Reverse transcriptase from HIV-2 and eukaryotic DNA polymerases (such as human DNA polymerases a, b, g, or d) are not inhibited by nevirapine.

Pharmacodynamics

Nevirapine is a non-nucleoside RT inhibitor which exhibits selective antiviral activity against HIV-1. Nevirapine inhibits the replication of a wide variety of HIV-1 strains in a number of cellular assays. HIV-1 isolates exhibiting reduced susceptibility to nevirapine were selected in cell culture experiments and during in vivo clinical studies. The in vitro 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 recent studies using human cord blood lymphocytes and human embryonic kidney 293 cells, EC50 values (50% inhibitory concentration) ranged from 14->400 nM against laboratory and clinical isolates of HIV-1. Some isolates of HIV-1 group M clade A demonstrated reduced susceptibility to nevirapine in vitro. The antiviral activity of nevirapine against HIV-1, group M, clade E is unknown. Nevirapine exhibited antiviral activity in vitro against group M HIV-1 isolates from clades A, B, C, D, F, G, and H, and circulating recombinant forms (CRF), CRF01_AE, CRF02_AG and CRF12_BF (median EC50 value of 63 nM). Nevirapine had no antiviral activity in vitro against isolates from group O HIV-1 and HIV-2. Some isolates of HIV-1 group M clade A demonstrated reduced susceptibility to nevirapine in vitro. The antiviral activity of nevirapine against HIV-1, group M, clade E is unknown. Nevirapine in combination with efavirenz exhibited a strong antagonistic anti-HIV-1 activity in vitro and was additive to antagonistic with the protease inhibitor ritonavir or the fusion inhibitor enfuvirtide. Nevirapine exhibited additive to synergistic anti-HIV-1 activity in combination with the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, saquinavir and tipranavir, and the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir and zidovudine. The anti-HIV-1 activity of nevirapine was antagonized by the anti-HBV drug adefovir and by the anti-HCV drug ribavirin in vitro.

Resistance

HIV isolates with reduced susceptibility (100-250 fold) to nevirapine emerge in vitro. Genotypic analysis showed mutations in the HIV-1 RT gene Y181C and/or V106A depending upon the virus strain and cell line employed. Time to emergence of nevirapine resistance in vitro was not altered when selection included nevirapine in combination with several other NRTI's. Phenotypic or genotypic changes in HIV-1 isolates from treatment-naive patients treated with either nevirapine (n=24) or nevirapine and ZDV (n=14) were monitored in Phase I/II trials over 1 to >= 12 weeks. After 1 week of nevirapine monotherapy, isolates from 3/3 patients had decreased susceptibility to nevirapine in vitro; one or more of the RT mutations at amino acid positions 103, 106, 108, 181, 188, and 190 were detected in some patients as early as 2 weeks after therapy initiation. By week eight of nevirapine monotherapy, 100% of the patients tested (n=24) had HIV isolates with a > 100 fold decrease in susceptibility to nevirapine in vitro compared to baseline, and had one or more of the nevirapine-associated RT resistance mutations; 19 of 24 patients (80%) had isolates with a position 181 mutation regardless of dose. The prevalence of phenotypic drug resistance was assessed in 60 patients with a viral rebound after they received a protease inhibitor (PI) or nevirapine containing regimen. Resistance testing was done within 36 weeks of viral rebound classified as a subsequent increase to >500 copies/mL following an initial viral load decrease to <500 copies/mL or a viral rebound of >= 0.5 log10 following an initial drop of >= 1.0 log10. In total, 88.9% given nevirapine had strains with reduced susceptibility to the drug. Overall, 46 patients (76.7%) harboured a strain resistant to >= 1 drug of their initial PI or nevirapine containing regimen. Of 53 patients who remained on treatment at the time of the study (40 had switched to a different combination from that at baseline), 6 harboured isolates susceptible to all drugs they had ever received. Genotypic analysis of isolates from antiretroviral naive patients with virologic rebound (n=71) receiving nevirapine once daily (n=25) or twice daily (n=46) in combination with lamivudine and stavudine (study 2NN) for 48 weeks showed that isolates from 8/25 and 23/46 patients, respectively, contained one or more of the following NNRTI resistance-associated mutations: Y181C, K101E, G190A/S, K103N, V106A/M, V108I, Y188C/L, A98G, F227L and M230L.

Cross-Resistance

Rapid emergence of HIV strains which are cross-resistant to NNRTI's has been observed in vitro. Data on cross-resistance between the NNRTI nevirapine and nucleoside analogue RT inhibitors are very limited. In four patients, ZDV-resistant isolates tested in vitro retained susceptibility to nevirapine and in six patients, nevirapine-resistant isolates were susceptible to ZDV and ddI. One case of double resistance to ZDV and nevirapine including transmission has been reported. Cross-resistance between nevirapine and HIV protease inhibitors is unlikely because the enzyme targets involved are different. Cross-resistance among the currently registered NNRTIs is broad. Some genotypic resistance data indicate that in most patients failing NNRTIs, viral strains express cross-resistance to the other NNRTIs. The currently available data do not support sequential use of NNRTIs. Nevirapine must not be used as a single agent to treat HIV or added on as a sole agent to a failing regimen. As with all other non-nucleoside reverse transcriptase inhibitors, 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.

Absorption

Nevirapine is readily absorbed (>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 the 50 mg tablet and 91.8% for the oral solution. Peak plasma nevirapine concentrations of 2 +- 0.4 ug/mL are 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 ug/mL (17 +- 7 uM), (n=242) were attained at 400 mg/day. When VIRAMUNE (200 mg) was administered to 24 healthy adults (12 male, 12 female), with either a high fat breakfast (857 kcal, 50 g fat, 53% of calories from fat) or antacid (Maalox(r) 30 mL), the extent of nevirapine absorption (AUC) was comparable to that observed under fasting conditions. In a separate study in HIV-1-infected patients (n=6), nevirapine steady-state systemic exposure (AUCt) was not significantly altered by ddI, which is formulated with an alkaline buffering agent. VIRAMUNE may be administered with or without food, antacid or ddI.

Distribution

Nevirapine is highly lipophilic and is essentially nonionized at physiologic pH. Animal studies have shown that nevirapine is widely distributed to nearly all tissues and readily crosses the blood-brain barrier. Following intravenous administration in healthy adults, the apparent volume of distribution (Vdss) of nevirapine was 1.21 +- 0.09 L/kg, suggesting that nevirapine also is widely distributed in humans. Nevirapine is approximately 57-61% bound to plasma proteins in the plasma concentration range of 1-10 ug/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

In vivo studies in humans and in vitro studies with human liver microsomes have shown that nevirapine is extensively biotransformed via cytochrome P-450 (oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes suggest that oxidative metabolism of nevirapine is mediated primarily by cytochrome P-450 isozymes from the CYP3A4 and CYP2B6 families, although other isozymes may have a secondary role. In a mass balance/excretion study in eight healthy male volunteers dosed to steady state with nevirapine 200 mg b.i.d. followed by a single dose of 50 mg 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 P-450 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 of nevirapine plays a minor role in elimination of the parent compound.

Excretion

Nevirapine is an inducer of hepatic cytochrome P450 (CYP) metabolic enzymes 3A4 and 2B6. Nevirapine induces CYP3A4 and CYP2B6 by approximately 20-25%, as indicated by erythromycin breath test results and urine metabolites. Autoinduction of CYP3A4 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 200-400 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 25-30 hours following multiple dosing with 200-400 mg/day.

Special Populations and Conditions

Pediatrics:

Safety and effectiveness of VIRAMUNE in HIV-1 infected pediatric patients younger than 15 years of age has not been established.

Age:

Nevirapine pharmacokinetics in HIV-1-infected adult males and females do not appear to change with age (range 18-68 years); however, nevirapine has not been extensively evaluated in patients beyond the age of 65 years. Nevirapine is metabolized more rapidly in pediatric patients than in adults.

Gender:

In one Phase I study in healthy volunteers (15 females, 15 males), the weight-adjusted apparent volume of distribution (Vdss/F) of nevirapine was higher in the female subjects (1.54 L/kg) compared to the males (1.38 L/kg), suggesting that nevirapine was distributed more extensively in the female subjects. However, this difference was offset by a slightly shorter terminal-phase half-life in the females resulting in no significant gender difference in nevirapine oral clearance (24.6+-7.7 mL/kg/hr in females vs. 19.9+-3.9 mL/kg/hr in males after single dose) or plasma concentrations following either single- or multiple-dose administration(s). An evaluation of nevirapine plasma concentrations (pooled data from several clinical trials) from HIV-1-infected patients (37 females, 205 males) revealed no clinically significant difference in nevirapine steady-state trough concentrations (median Cminss = 4.6 ug/mL females, 4.2 ug/mL males) with long-term nevirapine treatment at 400 mg/day.

Race:

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

Hepatic Insufficiency:

The single-dose pharmacokinetics of VIRAMUNE have been compared in 10 subjects with hepatic impairment and 8 subjects with normal hepatic function. Overall, the results suggest that mild to moderate hepatic impairment had no significant effect on the pharmacokinetics of VIRAMUNE. However, the pharmacokinetics of VIRAMUNE in one subject with a Child-Pugh score of 8 and moderate to severe ascites suggests that patients with worsening hepatic function may be at risk of accumulating nevirapine in the systemic circulation (see DOSAGE AND ADMINISTRATION). In a 200 mg nevirapine single dose pharmacokinetic study of HIV-negative patients with mild and moderate hepatic impairment, a significant increase in the AUC of nevirapine was observed in one patient with moderate hepatic impairment and ascites suggesting that patients with worsening hepatic function and ascites may be at risk of accumulating nevirapine in the systemic circulation.

Renal Insufficiency:

The single dose pharmacokinetics of VIRAMUNE have been compared in 23 subjects with either mild (50 <= Clcr < 80 mL/min), moderate (30 <= Clcr < 50 mL/min) or severe (Clcr < 30 mL/min) renal impairment or end stage renal disease (ESRD) requiring dialysis and 8 subjects with normal renal function (CLcr > 80 mL/min). Renal impairment (mild, moderate and severe) resulted in no significant change in the pharmacokinetics of VIRAMUNE. Subjects with ESRD requiring dialysis exhibited a 43.5% reduction in VIRAMUNE AUC over a one week exposure period with an accumulation of nevirapine hydroxy-metabolites in plasma (see DOSAGE AND ADMINISTRATION).

STORAGE AND STABILITY

Solid substance stability studies have shown nevirapine bulk drug to be extremely stable. Tablets are packaged in bottles of 60 tablets and should be stored at 15oC - 30oC (59oF - 86oF). The bottles should be kept tightly closed.

DOSAGE FORMS, COMPOSITION AND PACKAGING

VIRAMUNE (nevirapine) 200 mg tablets are white, oval, biconvex tablets, 9.3 x. 19.1 mm. One side is embossed with "54 193", with a single bisect separating the "54" and "193". The opposite side has a single bisect. Each tablet contains 200 mg of nevirapine and the non-medicinal ingredients: colloidal silicon dioxide, lactose, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. Tablets are packaged in bottles of 60 tablets. The bottles should be kept tightly closed.