VIRAMUNE is the brand name for nevirapine, 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 C15H14N4O. Nevirapine has the following structural formula:

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

VIRAMUNE Oral Suspension is for oral administration. Each 5 mL of VIRAMUNE suspension contains 50 mg of nevirapine (as nevirapine hemihydrate). The suspension also contains the following excipients: carbomer 934P, methylparaben, propylparaben, sorbitol, sucrose, polysorbate 80, sodium hydroxide and purified water.

VIRAMUNE is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection. This indication is based on one principal clinical trial (BI 1090) that demonstrated prolonged suppression of HIV-RNA and two smaller supportive studies, one of which (BI 1046) is described below.

Additional important information regarding the use of VIRAMUNE for the treatment of HIV-1 infection:

• • 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 or in adult males with CD4+ cell counts greater than 400 cells/mm³ unless the benefit outweighs the risk [see Boxed Warning and WARNINGS and PRECAUTIONS].
• •The 14-day lead-in period with VIRAMUNE 200 mg daily dosing has been demonstrated to reduce the frequency of rash [see DOSAGE AND ADMINISTRATION and WARNINGS and PRECAUTIONS].
• If rash persists beyond the 14 day lead-in period, do not dose escalate to 200 mg twice daily. The 200 mg once daily dosing regimen should not be continued beyond 28 days at which point an alternative regimen should be sought.

Adults

The recommended dose for VIRAMUNE is one 200 mg tablet daily for the first 14 days, followed by one 200 mg tablet twice daily, in combination with other antiretroviral agents. The lead-in period has been observed to decrease the incidence of rash. For concomitantly administered antiretroviral therapy, the recommended dosage and monitoring should be followed.

Pediatric Patients

The recommended oral dose for pediatric patients 15 days and older is 150 mg/m² once daily for 14 days followed by 150 mg/m² twice daily thereafter. The total daily dose should not exceed 400 mg for any patient.

Mosteller Formula: BSA (m2) = √Height (cm) x Wt (kg)/3600

Table 1: Calculation of the Volume of VIRAMUNE Oral Suspension (50 mg/5 mL) Required for Pediatric Dosing Based on Body Surface and a Dose of 150 mg/m²

BSA range (m2)	Volume (mL)
0.06 - 0.12	1.25
0.12 - 0.25	2.5
0.25 - 0.42	5
0.42 - 0.58	7.5
0.58 - 0.75	10
0.75 - 0.92	12.5
0.92 - 1.08	15
1.08 - 1.25	17.5
1.25+	20

VIRAMUNE suspension should be shaken gently prior to administration. It is important to administer the entire measured dose of suspension by using an oral dosing syringe or dosing cup. An oral dosing syringe is recommended, particularly for volumes of 5 mL or less. If a dosing cup is used, it should be thoroughly rinsed with water and the rinse should also be administered to the patient.

Monitoring of Patients

Intensive clinical and laboratory monitoring, including liver enzyme tests, is essential at baseline and during the first 18 weeks of treatment with VIRAMUNE. The optimal frequency of monitoring during this period has not been established. Some experts recommend clinical and laboratory monitoring more often than once per month, and in particular, would include monitoring of liver enzyme tests 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]. In some cases, hepatic injury has progressed despite discontinuation of treatment.

Dosage Adjustment

Patients with Rash

VIRAMUNE should be discontinued if a patient experiences severe rash or any rash accompanied by constitutional findings [see Boxed Warning, WARNINGS and PRECAUTIONS, and Patient Counseling Information]. A patient experiencing mild to moderate rash without constitutional symptoms during the 14-day lead-in period of 200 mg/day (150 mg/m²/day in pediatric patients) should not have their VIRAMUNE dose increased until the rash has resolved [see WARNINGS and PRECAUTIONS and Patient Counseling Information]. The total duration of the once daily lead-in dosing period should not exceed 28 days at which point an alternative regimen should be sought.

Patients with Hepatic Events

If a clinical (symptomatic) hepatic event occurs, VIRAMUNE should be permanently discontinued. Do not restart VIRAMUNE after recovery [see WARNINGS and PRECAUTIONS].

Patients with Dose Interruption

Patients who interrupt VIRAMUNE dosing for more than 7 days should restart the recommended dosing, using one 200 mg tablet daily (150mg/m²/day in pediatric patients) for the first 14 days (lead-in) followed by one 200 mg tablet twice daily (150 mg/m² twice daily for pediatric patients).

Patients on Dialysis

An additional 200 mg dose of VIRAMUNE following each dialysis treatment is indicated in patients requiring dialysis. Nevirapine metabolites may accumulate in patients receiving dialysis; however, the clinical significance of this accumulation is not known [see CLINICAL PHARMACOLOGY]. Patients with CrCL ≥ 20 mL/min do not require an adjustment in VIRAMUNE dosing.

Dosage Forms And Strengths

Tablets: 200 mg, white, oval, biconvex, tablets embossed with 54 193 on one side

Oral suspension: 50 mg/5 mL, white to off-white oral suspension

Storage And Handling

VIRAMUNE tablets, 200 mg, are white, oval, biconvex tablets, 9.3 mm 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.

VIRAMUNE Tablets are supplied in bottles of 60 (NDC 0597-0046-60).

VIRAMUNE oral suspension is a white to off-white preserved suspension containing 50 mg nevirapine (as nevirapine hemihydrate) in each 5 mL. VIRAMUNE suspension is supplied in plastic bottles with child-resistant closures containing 240 mL of suspension (NDC 0597-0047-24).

Storage

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°- 86°F) [see USP Controlled Room Temperature]. Store in a safe place out of the reach of children.

Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877, USA. Rev: June 2008. FDA rev date: 6/24/2008

Clinical Trials in Adults

The most serious adverse reactions associated with VIRAMUNE are hepatitis, hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions. Hepatitis/hepatic failure may be isolated or associated with signs of hypersensitivity which may 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 [see Boxed Warning and WARNINGS and PRECAUTIONS].

Hepatic Reaction

In controlled clinical trials, symptomatic hepatic events regardless of severity occurred in 4.0% (range 0% to 11.0%) of patients who received VIRAMUNE and 1.2% of patients in control groups. Female gender and higher CD4 counts ( > 250 cells/mm³ in women and > 400 cells/mm³ in men) place patients at increased risk of these events [see Boxed Warning and WARNINGS and PRECAUTIONS].

Asymptomatic transaminase elevations (AST or ALT > 5X ULN) were observed in 5.8% (range 0% to 9.2%) of patients who received VIRAMUNE and 5.5% of patients in control groups. Co-infection with hepatitis B or C and/or increased transaminase elevations at the start of therapy with VIRAMUNE are associated with a greater risk of later symptomatic events (6 weeks or more after starting VIRAMUNE) and asymptomatic increases in AST or ALT.

Liver enzyme abnormalities (AST, ALT, GGT) were observed more frequently in patients receiving VIRAMUNE than in controls (see Table 3).

Skin Reaction

The most common clinical toxicity of VIRAMUNE is rash, which can be severe or life-threatening [ see Boxed Warning and WARNINGS and PRECAUTIONS]. Rash occurs most frequently within the first 6 weeks of therapy. Rashes are usually mild to moderate, maculopapular erythematous cutaneous eruptions, with or without pruritus, located on the trunk, face and extremities. In controlled clinical trials (Trials 1037, 1038, 1046, and 1090), Grade 1 and 2 rashes were reported in 13.3% of patients receiving VIRAMUNE compared to 5.8% receiving placebo during the first 6 weeks of therapy. Grade 3 and 4 rashes were reported in 1.5% of VIRAMUNE recipients compared to 0.1% of subjects receiving placebo. Women tend to be at higher risk for development of VIRAMUNE associated rash [see Boxed Warning and WARNINGS and PRECAUTIONS].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Treatment related, adverse experiences of moderate or severe intensity observed in > 2% of patients receiving VIRAMUNE in placebo-controlled trials are shown in Table 2.

Table 2: Percentage of Patients with Moderate or Severe Drug Related Events in Adult Placebo Controlled Trials

	Trial 10901		Trials 1037,1038, 10462
	VIRAMUNE	Placebo	VIRAMUNE	Placebo
	(n=1121)	(n=1128)	(n=253)	(n=203)
Median exposure (weeks)	58	52	28	28
Any adverse event	14.5%	11.1%	31.6%	13.3%
Rash	5.1	1.8	6.7	1.5
Nausea	0.5	1.1	8.7	3.9
Granulocytopenia	1.8	2.8	0.4	0
Headache	0.7	0.4	3.6	0.5
Fatigue	0.2	0.3	4.7	3.9
Diarrhea	0.2	0.8	2.0	0.5
Abdominal pain	0.1	0.4	2.0	0
Myalgia	0.2	0	1.2	2.0
1Back ground therapy included 3TC for all patients and combinations of NRTIs and PIs. Patients had CD4+ cell counts < 200 cells/mm3. 2Back ground therapy included ZDV and ZDV+ddI; VIRAMUNE monotherapy was administered in some patients. Patients had CD4+ cell count ≥ 200 cells/mm3.

Laboratory Abnormalities

Liver enzyme test abnormalities (AST, ALT) were observed more frequently in patients receiving VIRAMUNE than in controls (Table 3). Asymptomatic elevations in GGT occur frequently but are not a contraindication to continue VIRAMUNE therapy in the absence of elevations in other liver enzyme tests. Other laboratory abnormalities (bilirubin, anemia, neutropenia, thrombocytopenia) were observed with similar frequencies in clinical trials comparing VIRAMUNE and control regimens (see Table 3).

Table 3: Percentage of Adult Patients with Laboratory Abnormalities

Laboratory Abnormality	Trial 10901		Trials 1037, 1038, 10462
	VIRAMUNE	Placebo	VIRAMUNE	Placebo
	(n=1121)	(n=1128)	(n=253)	(n=203)
Blood Chemistry
SGPT (ALT) >250 U/L	5.3	4.4	14.0	4.5
SGOT (AST) >250 U/L	3.7	2.5	7.6	1.5
Bilirubin >2.5 mg/dL	1.7	2.2	1.7	1.5
Hematology
Hemoglobin <8.0 g/dL	3.2	4.1	0	0
Platelets <50,000/mm3	1.3	1.0	0.4	1.5
Neutrophils <750/mm3	13.3	13.5	3.6	1.0
1 Background therapy included 3TC for all patients and combinations of NRTIs and PIs. Patients had CD4+ cell counts < 200 cells/mm3. 2 Background therapy included ZDV and ZDV+ddI; VIRAMUNE monotherapy was administered in some patients. Patients had CD4+ cell count ≥ 200 cells/mm3.

Clinical Trials in Pediatric Patients

Adverse events were assessed in BI Trial 1100.1032 (ACTG 245), a double-blind, placebo-controlled trial of VIRAMUNE (n = 305) in which pediatric patients received combination treatment with VIRAMUNE. In this trial two patients were reported to experience Stevens-Johnson syndrome or Stevens-Johnson/toxic epidermal necrolysis transition syndrome. Safety was also assessed in trial BI 1100.882 (ACTG 180) an open-label trial of VIRAMUNE (n=37) in which patients were followed for a mean duration of 33.9 months (range: 6.8 months to 5.3 years, including long-term follow-up in 29 of these patients in trial BI 1100.892). The most frequently reported adverse events related to VIRAMUNE in pediatric patients were similar to those observed in adults, with the exception of granulocytopenia, which was more commonly observed in children receiving both zidovudine and VIRAMUNE. Cases of allergic reaction, including one case of anaphylaxis, were also reported.

The safety of VIRAMUNE was also examined in BI Trial 1100.1368, an open-label, randomized clinical study performed in South Africa in which 123 HIV-1 infected treatment naïve patients between 3 months and 16 years of age received combination treatment with VIRAMUNE oral suspension, lamuvidine and zidovudine for 48 weeks [see Use In Specific Populations and CLINICAL PHARMACOLOGY]. Rash (all causality) was reported in 21% of the patients, 4 (3%) of whom discontinued drug due to rash. All 4 patients experienced the rash early in the course of therapy ( < 4 weeks) and resolved upon nevirapine discontinuation. Other clinically important adverse events (all causality) include neutropenia (8.9%), anemia (7.3%) and hepatotoxicity (2.4%) [see Use in Special Populations and Clinical Studies].

Safety information on use of VIRAMUNE in combination therapy in pediatric patients 2 weeks to < 3 months of age was assessed in 36 patients from the BI 1100.1222 (PACTG 356) study. No unexpected safety findings were observed although granulocytopenia was reported more frequently in this age group compared to the older pediatric age groups and adults.

Post-Marketing Surveillance

In addition to the adverse events identified during clinical trials, the following adverse reactions have been identified during post-approval use of VIRAMUNE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: fever, somnolence, drug withdrawal [see DRUG INTERACTIONS], redistribution/accumulation of body fat [see WARNINGS and PRECAUTIONS]

Gastrointestinal: vomiting

Liver and Biliary: jaundice, fulminant and cholestatic hepatitis, hepatic necrosis, hepatic failure

Hematology: anemia, eosinophilia, neutropenia

Musculoskeletal: arthralgia, rhabdomyolysis associated with skin and/or liver reactions

Neurologic: paraesthesia

Skin and Appendages: allergic reactions including anaphylaxis, angioedema, bullous eruptions, ulcerative stomatitis and urticaria have all been reported. In addition, hypersensitivity syndrome and hypersensitivity reactions with rash associated with constitutional findings such as fever, blistering, oral lesions, conjunctivitis, facial edema, muscle or joint aches, general malaise, fatigue or significant hepatic abnormalities [see WARNINGS and PRECAUTIONS] plus one or more of the following: hepatitis, eosinophilia, granulocytopenia, lymphadenopathy and/or renal dysfunction have been reported with the use of VIRAMUNE.

In post-marketing surveillance anemia has been more commonly observed in children although development of anemia due to concomitant medication use cannot be ruled out.

Nevirapine is principally metabolized by the liver via the cytochrome P450 isoenzymes, 3A and 2B6. Nevirapine is known to be an inducer of these enzymes. As a result, drugs that are metabolized by these enzyme systems may have lower than expected plasma levels when co-administered with nevirapine.

The specific pharmacokinetic changes that occur with co-administration of nevirapine and other drugs are listed in CLINICAL PHARMACOLOGY, Table 5. Clinical comments about possible dosage modifications based on established drug interactions are listed in Table 4. 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 additi on 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 also listed in Table 4. Although specific drug interaction studies in HIV-1 seropositive subjects have not been conducted for some classes of drugs listed in Table 4, additional clinical monitoring may be warranted when co-administering these drugs.

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 4: Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed due to Drug Interaction Established Drug Interactions: See CLINICAL PHARMACOLOGY, Table 5 for Magnitude of Interaction.

Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
Clarithromycin	↓Clarithromycin ↑14-OH clarithromycin	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Efavirenz	Efavirenz	Appropriate doses for this combination are not established.
Ethinyl estradiol and Norethindrone	↓Ethinyl estradiol ↓Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.
Fluconazole	Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Indinavir	Indinavir	Appropriate doses for this combination are not established, but an increase in the dosage of indinavirmay be required.
Ketoconazole	Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Lopinavir/Ritonavir	Lopinavir	KALETRA 400/100 mg tablets can be used twice-daily in combination with nevirapine with no dose adjustment in antiretroviral-naïve patients.
		A dose increase of KALETRA tablets to 600/150 mg (3 tablets) twice daily may be considered when usedin combination with nevirapine in treatment experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence).
		A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine.
		In children 6 months to 12 years of age, consideration should be given to increasing the dose oflopinavir/ritonavir to 13/3.25 mg/kg for those 7 to < 15kg; 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 twicedaily when used in combination with nevirapine, particularly for patients in whom reduced susceptibility to lopinavir/ritonavir is suspected.
Methadone	↓Methadone	Methadone levels were decreased; increased dosagesmay be required to prevent symptoms of opiate withdrawal. Methadone maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Nelfinavir	↓Nelfinavir M8 Metabolite ↓Nelfinavir Cmin	The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, hasnot been established.
Rifabutin	Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high inter subject variability, however, some patients may experience large increases in rifabutin exposure and may be athigher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin	↓Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasmaconcentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected withtuberculosis and using a nevirapine containing regimenmay use rifabutin instead.
Saquinavir	Saquinavir	Appropriate doses for this combination are not established, but an increase in the dosage of saquinavirmay be required.
Potential Drug Interactions:
Drug Class	Examples of Drugs
Antiarrhythmics	Amiodarone, disopyramide, lidocaine	Plasma Concentrations May Be Decreased
Anticonvulsants	Carbamazepine, clonazepam, ethosuximide	Plasma Concentrations May Be Decreased
Antifungals	Itraconazole	Plasma Concentrations May Be Decreased
Calcium channel blockers	Diltiazem, nifedipine, verapamil	Plasma Concentrations May Be Decreased
Cancer chemotherapy	Cyclophosphamide	Plasma Concentrations May Be Decreased
Ergot alkaloids	Ergotamine	Plasma Concentrations May Be Decreased
Immunosuppressants	Cyclosporin, tacrolimus, sirolimus	Plasma Concentrations May Be Decreased
Motility agents	Cisapride	Plasma Concentrations May Be Decreased
Opiate agonists	Fentanyl	Plasma Concentrations May Be Decreased
Antithrombotics	Warfarin	Plasma Concentrations May Be Increased. Potential effect on anticoagulation. Monitoring ofanticoagulation levels is recommended.

Included as part of the PRECAUTIONS section.

The most serious adverse reactions associated with VIRAMUNE are hepatitis/hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions. 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.

The first 18 weeks of therapy with VIRAMUNE are a critical period during which intensive clinical and laboratory 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. Some experts recommend clinical and laboratory monitoring more often than once per month, and in particular, would 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 VIRAMUNE treatment. In addition, the 14-day lead-in period with VIRAMUNE 200 mg daily dosing has been demonstrated to reduce the frequency of rash [ see DOSAGE AND ADMINISTRATION].

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 VIRAMUNE. In controlled clinical trials, symptomatic hepatic events regardless of severity occurred in 4% (range 0% to 11.0%) of patients who received VIRAMUNE and 1.2% of patients 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 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. Rash was observed in approximately half of the patients 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 VIRAMUNE use. Patients with signs or symptoms of hepatitis must be advised to discontinue VIRAMUNE and immediately seek medical evaluation, which should include liver enzyme tests.

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 Boxed Warning, DOSAGE AND ADMINISTRATION and Patient Counseling Information].

If clinical hepatitis or transaminase elevations combined with rash or other systemic symptoms occur, VIRAMUNE should be permanently discontinued. Do not restart VIRAMUNE 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 counts. In general, during the first 6 weeks of treatment, 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 observed in men with CD4 counts > 400 cells/mm³ (6.3% versus 1.2% for men with CD4 counts < 400 cells/mm³). However, all patients, regardless of gender, CD4 count, or antiretroviral treatment history, should be monitored for hepatotoxicity since symptomatic hepatic adverse events have been reported at all CD4 counts. Co-infection with hepatitis B or C and/or increased transaminase elevations at the start of therapy with VIRAMUNE are associated with a greater risk of later symptomatic events (6 weeks or more after starting VIRAMUNE) and asymptomatic increases in AST or ALT.

In addition, serious hepatotoxicity (including liver failure requiring transplantation in one instance) has been reported in HIV-uninfected individuals receiving multiple doses of VIRAMUNE in the setting of post-exposure prophylaxis, an unapproved use.

Increased nevirapine trough concentrations have been observed in some patients with hepatic fibrosis or cirrhosis. Therefore, patients with either hepatic fibrosis or cirrhosis should be monitored carefully for evidence of drug induced toxicity. Nevirapine should not be administered to patients with moderate or severe (Child Pugh Class B or C, respectively) hepatic impairment [see CONTRAINDICATIONS, Use in Specific Populations and CLINICAL PHARMACOLOGY].

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 VIRAMUNE use. In controlled clinical trials, Grade 3 and 4 rashes were reported during the first 6 weeks in 1.5% of VIRAMUNE recipients compared to 0.1% 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 VIRAMUNE and seek medical evaluation immediately [see Boxed Warning and Patient Counseling Information]. Do not restart VIRAMUNE following severe skin rash, skin rash combined with increased transaminases or other symptoms, or hypersensitivity reaction.

If patients present with a suspected VIRAMUNE-associated rash, transaminases should be measured immediately. Patients with rash-associated transaminase elevations should be permanently discontinued from VIRAMUNE [see WARNINGS and PRECAUTIONS].

Therapy with VIRAMUNE must be initiated with a 14-day lead-in period of 200 mg/day (150mg/m²/day in pediatric patients), which has been shown to reduce the frequency of rash. VIRAMUNE should be discontinued if a patient experiences severe rash or any rash accompanied by constitutional findings. A patient experiencing a mild to moderate rash without constitutional symptoms during the 14-day lead-in period of 200 mg/day (150 mg/m²/day in pediatric patients) should not have their VIRAMUNE dose increased until the rash has resolved. The total duration of the once daily lead-in dosing period should not exceed 28 days at which point an alternative regimen should be sought [see DOSAGE AND ADMINISTRATION]. Patients should be monitored closely if isolated rash of any severity occurs. Delay in stopping VIRAMUNE 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 VIRAMUNE.

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

Resistance

VIRAMUNE must not be used as a single agent to treat HIV 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 VIRAMUNE, the long 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 [see CLINICAL PHARMACOLOGY].

Drug Interactions

See Table 4 for listings of established and potential drug interactions [see DRUG INTERACTIONS].

Concomitant use of St. John's wort (Hypericum perforatum) or St. John's wort containing products and VIRAMUNE is not recommended. Co-administration of St. John's (NNRTIs), including VIRAMUNE, is expected to substantially decrease NNRTI concentrations andwort with non-nucleoside reverse transcriptase inhibitors 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.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including VIRAMUNE. 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 (PCP), or tuberculosis), which may necessitate further evaluation and 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.

Patient Counseling Information

See FDA-Approved Medication Guide

The Medication Guide provides written information for the patient, and should be dispensed with each new prescription and refill.

Hepatotoxicity and Skin Reactions

Patients should be informed of the possibility of severe liver disease or skin reactions associated with VIRAMUNE that may result in death. Patients developing signs or symptoms of liver disease or severe skin reactions should be instructed to discontinue VIRAMUNE and seek medical attention immediately, including performance of laboratory monitoring. Symptoms of liver disease include fatigue, malaise, anorexia, nausea, jaundice, acholic stools, liver tenderness or hepatomegaly. Symptoms of severe skin or hypersensitivity reactions include rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema and/or hepatitis.

Intensive clinical and laboratory monitoring, including liver enzymes, is essential during the first 18 weeks of therapy with VIRAMUNE to detect potentially life- threatening hepatotoxicity and skin reactions. However, liver disease can occur after this period, therefore monitoring should continue at frequent intervals throughout VIRAMUNE treatment. Extra vigilance is warranted during the first 6 weeks of therapy, which is the period of greatest risk of hepatic events and skin reactions. Patients with signs and symptoms of hepatitis should discontinue VIRAMUNE and seek medical evaluation immediately. If VIRAMUNE is discontinued due to hepatotoxicity, do not restart it. Patients, particularly women, with increased CD4+ cell count at initiation of VIRAMUNE therapy ( > 250 cells/mm³ in women and > 400 cells/mm³ in men) are at substantially higher risk for development of symptomatic hepatic events, often associated with rash. Patients should be advised that co­infection with hepatitis B or C and/or increased transaminases at the start of therapy with VIRAMUNE are associated with a greater risk of later symptomatic events (6 weeks or more after starting VIRAMUNE) and asymptomatic increases in AST or ALT [see Boxed Warning and WARNING and PRECAUTIONS].

The majority of rashes associated with VIRAMUNE occur within the first 6 weeks of initiation of therapy. Patients should be instructed that if any rash occurs during the two-week lead-in period, the VIRAMUNE dose should not be escalated until the rash resolves. The total duration of the once daily lead-in dosing period should not exceed 28 days at which point an alternative regimen may need to be started. Any patient experiencing a rash should have their liver enzymes (AST, ALT) evaluated immediately. Patients with severe rash or hypersensitivity reactions should discontinue VIRAMUNE immediately and consult a physician. VIRAMUNE should not be restarted following severe skin rash or hypersensitivity reaction. Women tend to be at higher risk for development of VIRAMUNE associated rash [ see Boxed Warning and WARNING and PRECAUTIONS].

Administration

Patients should be informed to take VIRAMUNE every day as prescribed. Patients should not alter the dose without consulting their doctor. If a dose is missed, patients should take the next dose as soon as possible. However, if a dose is skipped, the patient should not double the next dose. Patients should be advised to report to their doctor the use of any other medications.

Patients should be informed that VIRAMUNE therapy has not been shown to reduce the risk of transmission of HIV-1 to others through sexual contact or blood contamination. The long-term effects of VIRAMUNE are unknown at this time.

VIRAMUNE is not a cure for HIV-1 infection; patients may continue to experience illnesses associated with advanced HIV-1 infection, including opportunistic infections. Patients should be advised to remain under the care of a physician when using VIRAMUNE.

Drug Interactions

VIRAMUNE may interact with some drugs, therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. John's wort [see WARNING and PRECAUTIONS and DRUG INTERACTIONS].

Contraceptives

Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking VIRAMUNE, since VIRAMUNE may lower the plasma levels of these medications. Additionally, when oral contraceptives are used for hormonal regulation during VIRAMUNE therapy, the therapeutic effect of the hormonal therapy should be monitored [see DRUG INTERACTIONS].

Methadone

VIRAMUNE may decrease plasma concentrations of methadone by increasing its hepatic metabolism. Narcotic withdrawal syndrome has been reported in patients treated with VIRAMUNE and methadone concomitantly. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly [see DRUG INTERACTIONS].

Fat Redistribution

Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long term health effects of these conditions are not known at this time [see WARNINGS and PRECAUTIONS].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies in mice and rats were carried out with nevirapine. Mice were dosed with 0, 50, 375 or 750 mg/kg/day for two years. Hepatocellular adenomas and carcinomas were increased at all doses in males and at the two high doses in females. In studies in which rats were administered nevirapine at doses of 0, 3.5, 17.5 or 35 mg/kg/day for two years, 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 200 mg BID dose. The mechanism of the carcinogenic potential is unknown. However, in genetic toxicology assays, nevirapine showed no evidence of mutagenic or clastogenic activity in a battery of in vitro and in vivo studies. These included microbial assays for gene mutation (Ames: Salmonella strains and E. coli), mammalian cell gene mutation assay (CHO/HGPRT), cytogenetic assays using a Chinese hamster ovary cell line and a mouse bone marrow micronucleus assay following oral administration. Given the lack of genotoxic activity of nevirapine, the relevance to humans of hepatocellular neoplasms in nevirapine treated mice and rats is not known. 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 provided with the recommended clinical dose of VIRAMUNE.

Use In Specific Populations

Pregnancy

Teratogenic Effects, Pregnancy Category B.

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).

There are no adequate and well-controlled studies of VIRAMUNE 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 VIRAMUNE therapy as part of combination treatment of HIV infection. Regardless of pregnancy status women with CD4 counts > 250 cells/mm³ should not initiate VIRAMUNE unless the benefit outweighs the risk. It is unclear if pregnancy augments the risk observed in non-pregnant women [see Boxed Warning].

VIRAMUNE 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 VIRAMUNE, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling (800) 258-4263.

Nursing Mothers

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

Pediatric Use

The safety, pharmacokinetic profile, and virologic and immunologic responses of VIRAMUNE have been evaluated in HIV-infected pediatric patients age 3 months to 18 years [ see ADVERSE REACTIONS and Clinical Studies]. The safety and pharmacokinetic profile of VIRAMUNE has been evaluated in HIV-infected pediatric patients age 15 days to < 3 months [see ADVERSE REACTIONS and Clinical Studies].

The most frequently reported adverse events related to VIRAMUNE in pediatric patients were similar to those observed in adults, with the exception of granulocytopenia, which was more commonly observed in children receiving both zidovudine and VIRAMUNE [(see ADVERSE REACTIONS and Clinical Studies].

Geriatric Use

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.

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 ≥ 20 mL/min. In patients undergoing chronic hemodialysis, an additional 200 mg dose following each dialysis treatment is indicated [ see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

Hepatic Impairment

Because increased nevirapine levels and nevirapine accumulation may be observed in patients with serious liver disease, do not administer VIRAMUNE to patients with moderate or severe (Child Pugh Class B or C, respectively) hepatic impairment [see CONTRAINDICATIONS, WARNINGS and PRECAUTIONS, and CLINICAL PHARMACOLOGY].

There is no known antidote for VIRAMUNE overdosage. Cases of VIRAMUNE 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 VIRAMUNE.

VIRAMUNE is contraindicated in patients with moderate or severe (Child Pugh Class B or C, respectively) hepatic impairment [see WARNINGS and PRECAUTIONS and Use in Specific Populations].

Mechanism of Action

Nevirapine is an antiviral drug.

Pharmacokinetics

Adults

Absorption and Bioavailability

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 a 50 mg tablet and 91 ± 8% for an oral solution. Peak plasma nevirapine concentrations of 2 ± 0.4 µg/mL (7.5 µM) 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 µg/mL (17 ± 7 µM), (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 VIRAMUNE (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 study in HIV-1 infected patients (n=6), nevirapine steady-state systemic exposure (AUCτ) was not significantly altered by didanosine, which is formulated with an alkaline buffering agent. VIRAMUNE 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]. Nevirapine is about 60% bound to plasma proteins in the plasma concentration range of 1-10 µg/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 studies 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 study 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 ( < 5%) of the radioactivity in urine (representing < 3% of the total dose) was made up of parent compound; therefore, renal excretion plays a minor role in elimination of the parent compound.

Nevirapine is an inducer of hepatic cytochrome P450 (CYP) metabolic enzymes 3A and 2B6. Nevirapine induces CYP3A and CYP2B6 by approximately 20-25%, 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 200-400 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

Renal Impairment

HIV seronegative adults with mild (CrCL 50-79 mL/min; n=7), moderate (CrCL 30-49 mL/min; n=6), or severe (CrCL < 30 mL/min; n=4) renal impairment received a single 200 mg dose of nevirapine in a pharmacokinetic study. These subjects did not require dialysis. The study 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 and Use in Specific Populations].

Hepatic Impairment

In a steady state study comparing 46 patients with mild (n=17; expansion of some portal areas; Ishak Score 1-2), moderate (n=20; expansion of most portal areas with occasional portal-to-portal and portal-to-central bridging; Ishak Score 3-4), or severe (n=9; marked bridging with occasional cirrhosis without decompensation indicating Child-Pugh A; Ishak Score 5-6) 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 patients with hepatic fibrosis had nevirapine trough concentrations above 9,000 ƒÊg/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]. The patients studied were receiving antiretroviral therapy containing Viramune 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 study where HIV-negative cirrhotic patients 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 patient 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 study may not reflect the impact of hepatic impairment on multiple dose pharmacokinetics.

Do not administer nevirapine to c patients with moderate or severe (Child Pugh Class B or C, respectively) hepatic impairment [see CONTRAINDICATIONS, WARNINGS and PRECAUTIONS, and Use in Specific Populations].

Gender

In the multinational 2NN study, a population pharmacokinetic substudy of 1077 patients was performed that included 391 females. Female patients 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 patients (27 Black, 24 Hispanic, 189 Caucasian) revealed no marked difference in nevirapine steady-state trough concentrations (median C_minss = 4.7 µg/mL Black, 3.8 µg/mL Hispanic, 4.3 µg/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.

Geriatric Patients

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

Pediatric Patients

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 patients aged 3 months to 16 years; and a consolidated analysis of five Pediatric AIDS Clinical Trials Group (PACTG) protocols comprising 495 patients 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 patients 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. Patients 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 patients received 150 mg/m² once daily for two weeks followed by 150 mg/m² twice daily thereafter [see Use in Specific Populations and ADVERSE REACTIONS]. 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 4-6 µg/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 patients 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 patients, particularly in the second month of age. For dose recommendations for pediatric patients see DOSAGE AND ADMINISTRATION.

Drug Interactions

[see DRUG INTERACTIONS]

Nevirapine induces hepatic cytochrome P450 metabolic isoenzymes 3A and 2B6. Co-administration of VIRAMUNE 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 µM, a concentration that is unlikely to be achieved in patients as the therapeutic range is < 25 µM. Therefore, ne virapine 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 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 QD for 14 days followed by 200 mg BID for 14 days) followed by a steady state reassessment of the concomitant drug.

Table 5: 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)

Co-administered Drug	Dose of Co­administered Drug	Dose Regimen of VIRAMUNE	n	% Change of Co-administered Drug Pharmacokinetic Parameters (90% CI)
Antiretrovirals				AUC	Cmax	Cmin
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)
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)
Lopinavira, b	300/75 mg/m2 (lopinavir/ritonavir)b	7 mg/kg or 4 mg/kg QD x 2 weeks; BID x 1 week	12,15c	↓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	22,19c	↓27 (↓47 to ↑2)	↓19 (↓38 to ↑5)	↓51 (↓72 to ↓26)
Nelfinavira	750 mg TID	200 mg QD x 14 days; 200 mg BID x 14 days	23	⇔	⇔	↓32 (↓50 to ↑5)
Nelfinavir-M8 metabolite				↓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	⇔	⇔	⇔
Saquinavira	600 mg TID	200 mg QD x 14 days; 200 mg BID x 21 days	23	↓38 (↓47 to ↓11)	↓32 (↓44 to ↓6)	§
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	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)
Metabolite 14-OH­clarithromycin				↑42 (↑16 to ↑73)	↑47 ( ↑21 to ↑80)	⇔
Ethinyl estradiola	0.035 mg (as Ortho-Novum® 1/35)	200 mg QD x 14 days; 200 mg BID x 14 days	10	↓20 (↓33 to ↓3)	⇔	§
and
Norethindronea	1 mg (as Ortho-Novum® 1/35)			↓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 Patient Dosing	200 mg QD x 14 days; 200 mg BID ≥ 7 days	9	In a controlled pharmacokinetic study with 9 patients 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 patients. Methadone did not have any effect on nevirapine clearance.
Rifabutina	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)	⇔
Metabolite25-O-desacetyl­ rifabutin				↑24 (↓16 to ↑84)	↑29 (↓2 to ↑68)	↑22 (↓14 to ↑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 aFor information regarding clinical recommendations see DRUG INTERACTIONS. bPediatric subjects ranging inage from 6 months to 12 years cParallel group design; n for VIRAMUNE + lopinavir/ritonavir, n forlopinavir/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 [see DRUG INTERACTIONS]. 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 recent studies using human cord blood lymphocytes and human embryonic kidney 293 cells, EC50 values (50% inhibitory concentration) ranged from 14-302 nM against laboratory and clinical isolates of HIV-1. Nevirapine exhibited antiviral activity in cell culture 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 cell culture against group O HIV-1 isolates or HIV-2 isolates. 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. 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 cell culture.

Resistance

HIV-1 isolates with reduced susceptibility (100-250-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 patients receiving either nevirapine (n=24) or nevirapine and ZDV (n=14) were monitored in Phase 1 and 2 trials over 1 to 12 weeks. After 1 week of nevirapine monotherapy, isolates from 3/3 patients 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 patients as early as 2 weeks after therapy initiation. By week eight of nevirapine monotherapy, 100% of the patients tested (n=24) had HIV-1 isolates with a > 100-fold decrease in susceptibility to nevirapine in cell culture compared to baseline, and had one or more of the nevirapine-associated RT resistance mutations. Nineteen of these patients (80%) had isolates with Y181C substitutions regardless of dose.

Genotypic analysis of isolates from antiretroviral naïve patients experiencing virologic failure (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 substitutions: Y181C, K101E, G190A/S, K103N, V106A/M, V108I, Y188C/L, A98G, F227L and M230L.

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 and efavirenz. However, nevirapine-resistant isolates were susceptible to the NRTI's ddI and ZDV. Similarly, ZDV-resistant isolates were susceptible to nevirapine in cell culture.

Animal Toxicology and/or Pharmacology

Animal studies have shown that nevirapine is widely distributed to nearly all tissues and readily crosses the blood-brain barrier.

Clinical Studiess

Clinical Studies in Adults

Trial BI 1090, was a placebo-controlled, double-blind, randomized trial in 2249 HIV-1 infected patients with < 200 CD4+ cells/mm³ at screening. Initiated in 1995, BI 1090 compared treatment with VIRAMUNE + lamivudine + background therapy versus lamivudine + background therapy in NNRTI naïve patients. Treatment doses were VIRAMUNE, 200 mg daily for two weeks followed by 200 mg twice daily or placebo, and lamivudine 150 mg twice daily. Other a ntiretroviral agents were given at approved doses. Initial background therapy (in addition to lamivudine) was one NRTI in 1309 patients (58%), two or more NRTIs in 771 (34%), and PIs and NRTIs in 169 (8%). The patients (median age 36.5 years, 70% Caucasian, 79% male) had advanced HIV infection, with a median baseline CD4+ cell count of 96 cells/mm³ and a baseline HIV RNA of 4.58 log₁₀ copies/mL (38,291 copies/mL). Prior to entering the trial, 45% had previously experienced an AIDS-defining clinical event. Eighty-nine percent had antiretroviral treatment prior to entering the trial. BI 1090 was originally designed as a clinical endpoint study. Prior to unblinding the trial, the primary endpoint was changed to proportion of patients with HIV RNA < 50 copies/mL and not previously failed at 48 weeks. Treatment response and outcomes are shown in Table 6.

Table 6: BI 1090 Outcomes through 48 weeks

Outcome	VIRAMUNE (N=1121)%	Placebo (N=1128) %
Responders at 48 weeks: HIV RNA <50 copies/mL	18.0	1.6
Treatment Failure	82.0	98.4
Never suppressed viral load	44.6	66.4
Virologic failure after response	7.2	4.3
CDC category C event or death	9.6	11.2
Added antiretroviral therapy1 while <50 copies/mL	5.0	0.9
Discontinued trial therapy due to AE	7.0	5.9
Discontinued trial <48 weeks2	8.5	9.8
1including change to open-label nevirapine 2includes withdrawal of consent, lost to follow-up, non-compliance withprotocol, other administrative reasons

The change from baseline in CD4+ cell count through one year of therapy was significantly greater for the VIRAMUNE group compared to the placebo group for the overall study population (64 cells/mm³ vs 22 cells/mm³, respectively), as well as for patients who entered the trial as treatment naïve or having received only ZDV (85 cells/mm³ vs 25 cells/mm³, respectively).

At two years into the study, 16% of subjects on VIRAMUNE had experienced class C CDC events as compared to 21% of subjects on the control arm.

Trial BI 1046 (INCAS) was a double-blind, placebo-controlled, randomized, three arm trial with 151 HIV-1 infected patients with CD4+ cell counts of 200-600 cells/mm³ at baseline. BI 1046 compared treatment with VIRAMUNE+zidovudine+didanosine to VIRAMUNE+zidovudine and zidovudine + didanosine. Treatment doses were VIRAMUNE at 200 mg daily for two weeks followed by 200 mg twice daily or placebo, zidovudine at 200 mg three times daily, and didanosine at 125 or 200 mg twice daily (depending on body weight). The patients had mean baseline HIV RNA of 4.41 log 10 copies/mL (25,704 copies/mL) and mean baseline CD4+ cell count of 376 cells/mm³. The primary endpoint was the proportion of patients with HIV-RNA < 400 copies/mL and not previously failed at 48 weeks. The virologic responder rates at 48 weeks were 45% for patients treated with VIRAMUNE+zidovudine+didanosine, 19% for patients treated with zidovudine+didanosine, and 0% for patients treated with VIRAMUNE+zidovudine.

CD4+ cell counts in the VIRAMUNE+ZDV+ddI group increased above baseline by a mean of 139 cells/mm³ at one year, significantly greater than the increase of 87 cells/mm³ in the ZDV+ddI patients. The VIRAMUNE+ZDV group mean decreased by 6 cells/mm³ below baseline.

Clinical Studies in Pediatric Patients

The pediatric safety and efficacy of VIRAMUNE was examined in BI Trial 1100.1368, an open-label, randomized clinical study performed in South Africa in which 123 HIV-1 infected treatment naïve patients between 3 months and16 years of age received VIRAMUNE oral suspension for 48 weeks. Patients were divided into 4 age groups (3 months to < 2 years, 2 to < 7 years, 7 to < 12 years, and 12 to 16 years) and randomized to receive one of two VIRAMUNE doses, determined by 2 different dosing methods [body surface area (150mg/m²) and weight-based dosing (4 or 7mg/kg)] in combination with zidovudine and lamivudine [see ADVERSE REACTIONS, Use in Specific Population, and CLINICAL PHARMACOLOGY]. The total daily dose of VIRAMUNE did not exceed 400 mg in either regimen. There were 66 patients in the body surface area (BSA) dosing group and 57 patients in the weight-based (BW) dosing group.

Baseline demographics included: 49% male; 81% Black and 19% Caucasian; 4% had previous exposure to ARVs. Patients had a median baseline HIV RNA of 5.45 log₁₀ copies/mL and a median baseline CD4 cell count of 527 cells/mm³ (range 37-2279). One hundred and five (85%) completed the 48 weeks period while 18 (15%) discontinued prematurely. Of the patients who discontinued prematurely, 9 (7%) discontinued due to adverse reactions and 3 (2%) discontinued due to virologic failure. Overall the proportion of patients who achieved and maintained an HIV RNA < 400 copies/mL at 48 weeks was 47% (58/123).

For dose recommendations for pediatric patients see DOSAGE AND ADMINISTRATION

MEDICATION GUIDE

VIRAMUNE®
(VIH-rah-mune) Tablets

VIRAMUNE® Oral Suspension

Generic name: nevirapine tablets and oral suspension

Read this Medication Guide before you start taking VIRAMUNE and each time you get a refill because there may be new information. This information does not take the place of talking with your doctor. You and your doctor should discuss VIRAMUNE when you start taking your medicine and at regular checkups. You should stay under a doctor's care while using VIRAMUNE. You should consult with your doctor before making any changes to your medications, except in any of the special circumstances described below regarding rash or liver problems.

What is the most important information I should know about VIRAMUNE?

Patients taking VIRAMUNE may develop severe liver disease or skin reactions that can cause death. The risk of these reactions is greatest during the first 18 weeks of treatment, but these reactions also can occur later.

Liver Reactions

Any patient can experience liver problems while taking VIRAMUNE. However, women and patients who have higher CD4 counts when they begin VIRAMUNE treatment have a greater chance of developing liver damage. Women with CD4 counts higher than 250 cells/mm³ are at the greatest risk of these events. If you are a woman with CD4 > 250 cells/mm³ or a man with CD4 > 400 cells/mm³ you should not begin taking VIRAMUNE unless you and your doctor have decided that the benefit of doing so outweighs the risk. Liver problems are often accompanied by a rash.

Patients starting VIRAMUNE with abnormal liver tests and patients with hepatitis B or C have a greater chance of developing further increases in liver tests after starting VIRAMUNE and throughout therapy.

In rare cases liver problems have led to liver failure and can lead to a liver transplant or death. Therefore, if you develop any of the following symptoms of liver problems stop taking VIRAMUNE and call your doctor right away:

general ill feeling or "flu-like" symptoms tiredness nausea (feeling sick to your stomach) lack of appetite yellowing of your skin or whites of your eyes

dark urine (tea colored) pale stools (bowel movements) pain, ache, or sensitivity to touch on your right side below your ribs

Your doctor should check you and do blood tests often to check your liver function during the first 18 weeks of therapy. Checks for liver problems should continue regularly during treatment with VIRAMUNE.

Skin Reactions

Skin rash is the most common side effect of VIRAMUNE. Most rashes occur in the first 6 weeks of treatment. In a small number of patients, rash can be serious and result in death. Therefore, if you develop a rash with any of the following symptoms stop using VIRAMUNE and call your doctor right away:

general ill feeling or "flu-like" symptoms fever muscle or joint aches conjunctivitis (red or inflamed eyes, like "pink eye") any of the symptoms of liver problems discussed above

blisters mouth sores swelling of your face tiredness

If your doctor tells you to stop treatment with VIRAMUNE because you have experienced the serious liver or skin reactions described above, never take VIRAMUNE again.

These are not all the side effects of VIRAMUNE. See the section "What are the possible side effects of VIRAMUNE?" for more information. Tell your doctor if you have any side effects from VIRAMUNE.

What is VIRAMUNE?

VIRAMUNE is a medicine used to treat Human Immunodeficiency Virus (HIV), the virus that causes AIDS (