FDA Label for Viramune

Warning: Life-Threatening (Including Fatal) Hepatotoxicity And Skin Reactions

HEPATOTOXICITY:

Severe, life-threatening, and in some cases fatal hepatotoxicity, particularly in the first 18 weeks, has 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⁺ cell counts at initiation of therapy place patients at increased risk; women with CD4⁺ cell counts >250 cells/mm³, including pregnant women receiving VIRAMUNE in combination with other antiretrovirals for the treatment of HIV-1 infection, are at the greatest risk. However, hepatotoxicity associated with VIRAMUNE use can occur in both genders, all CD4⁺ cell counts and at any time during treatment. Patients with signs or symptoms of hepatitis, or with increased transaminases combined with rash or other systemic symptoms, must discontinue VIRAMUNE and seek medical evaluation immediately [see Warnings and Precautions (5.1)].

SKIN REACTIONS:

Severe, life-threatening skin reactions, including fatal cases, have occurred in patients treated with VIRAMUNE. These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction. Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions must discontinue VIRAMUNE and seek medical evaluation immediately. Transaminase levels should be checked immediately for all patients who develop a rash in the first 18 weeks of treatment. The 14-day lead-in period with VIRAMUNE 200 mg daily dosing has been observed to decrease the incidence of rash and must be followed [see Warnings and Precautions (5.2)].

MONITORING:

Patients must be monitored intensively during the first 18 weeks of therapy with VIRAMUNE to detect potentially life-threatening hepatotoxicity or skin reactions. Extra vigilance is warranted during the first 6 weeks of therapy, which is the period of greatest risk of these events. Do not restart VIRAMUNE following severe hepatic, skin or hypersensitivity reactions. In some cases, hepatic injury has progressed despite discontinuation of treatment.

1     Indications And Usage

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-1 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 (5.1)].
  
  
• 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 (2.4) and Warnings and Precautions (5.2)].
  
  
• 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.

2.1   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 manufacturer’s recommended dosage and monitoring should be followed.

2.2   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.

Formula Image - image1

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.

2.3   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 (5)]. In some cases, hepatic injury has progressed despite discontinuation of treatment.

2.4   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 (5.2), and Patient Counseling Information (17.1)]. 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 (5.2) and Patient Counseling Information (17.1)]. 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 (5.1)].

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 (150 mg/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 (12.3)]. Patients with CrCL ≥20 mL/min do not require an adjustment in VIRAMUNE dosing.

3   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

4   Contraindications

VIRAMUNE is contraindicated in patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment [see Warnings and Precautions (5.1) and Use in Specific Populations (8.7)].

5   Warnings And Precautions

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 (2.1)].

5.1   Hepatotoxicity And Hepatic Impairment

Severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis and hepatic failure, have been reported in patients treated with 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 (2.3), and Patient Counseling Information (17.1)].

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⁺ cell 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⁺ cell counts at initiation of VIRAMUNE therapy are at higher risk for symptomatic hepatic events with VIRAMUNE. In a retrospective review, women with CD4⁺ cell counts >250 cells/mm³ had a 12-fold higher risk of symptomatic hepatic adverse events compared to women with CD4⁺ cell counts <250 cells/mm³ (11.0% versus 0.9%). An increased risk was observed in men with CD4⁺ cell counts >400 cells/mm³ (6.3% versus 1.2% for men with CD4⁺ cell counts <400 cells/mm³). However, all patients, regardless of gender, CD4⁺ cell count, or antiretroviral treatment history, should be monitored for hepatotoxicity since symptomatic hepatic adverse events have been reported at all CD4⁺ cell counts. Co-infection with hepatitis B or C and/or increased transaminase elevations at the start of therapy with 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-1 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 (4), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].

5.2   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 (17.1)]. 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 (5.1)].

Therapy with VIRAMUNE must be initiated with a 14-day lead-in period of 200 mg/day (150 mg/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 (2.4)]. 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.

5.3   Resistance

VIRAMUNE must not be used as a single agent to treat HIV-1 or added on as a sole agent to a failing regimen. Resistant virus emerges rapidly when nevirapine is administered as monotherapy. The choice of new antiretroviral agents to be used in combination with nevirapine should take into consideration the potential for cross resistance. When discontinuing an antiretroviral regimen containing 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 (12.4)].

5.4   Drug Interactions

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

Concomitant use of St. John's wort (Hypericum perforatum) or St. John's wort-containing products and VIRAMUNE is not recommended. Co-administration of St. John’s wort with non-nucleoside reverse transcriptase inhibitors (NNRTIs), including VIRAMUNE, is expected to substantially 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. Co-administration of VIRAMUNE and efavirenz is not recommended as this combination has been associated with an increase in adverse reactions and no improvement in efficacy.

5.5   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.

5.6   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.

6.1   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 (5.1, 5.2)].

6.2   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, lamivudine and zidovudine for 48 weeks [see Use In Specific Populations (8.4) and Clinical Pharmacology (12.3)]. 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 Specific Populations (8.4) and Clinical Studies (14.2)].

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.

6.3   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 (7)], redistribution/accumulation of body fat [see Warnings and Precautions (5.6)]
•  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 (5.1)] 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.

7   Drug Interactions

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 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 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.

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-1 infection. Regardless of pregnancy status, women with CD4⁺ cell 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.

8.3   Nursing Mothers

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

8.4   Pediatric Use

The safety, pharmacokinetic profile, and virologic and immunologic responses of VIRAMUNE have been evaluated in HIV-1 infected pediatric patients age 3 months to 18 years [see Adverse Reactions (6.2) and Clinical Studies (14.2)]. The safety and pharmacokinetic profile of VIRAMUNE has been evaluated in HIV-1 infected pediatric patients age 15 days to <3 months [see Adverse Reactions (6.2) and Clinical Studies (14.2)].

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 (6.2) and Clinical Studies (14.2)].

8.5   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.

8.6   Renal Impairment

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

8.7   Hepatic Impairment

Because increased nevirapine levels and nevirapine accumulation may be observed in patients with serious liver disease, do not administer VIRAMUNE to patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment [see Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

10   Overdosage

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.

11   Description

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:

Chemical Structure - viramune structure

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.

12.1   Mechanism Of Action

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

Mechanism Of Action

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

Antiviral Activity

The antiviral activity of nevirapine has been measured in a variety of cell lines including peripheral blood mononuclear cells, monocyte-derived macrophages, and lymphoblastoid cell lines. In an assay using human embryonic kidney 293 cells, the median EC₅₀ value (50% inhibitory concentration) of nevirapine was 90 nM against a panel of 2923 isolates of HIV-1 that were primarily (93%) clade B clinical isolates from the United States. The 99^th percentile EC₅₀ value was 470 nM in this study. The median EC₅₀ value was 63 nM (range 14-302 nM, n=29) against clinical isolates of HIV-1 clades A, B, C, D, F, G, and H, and circulating recombinant forms CRF01_AE, CRF02_AG and CRF12_BF. Nevirapine had no antiviral activity in cell culture against group O HIV-1 isolates (n=3) or HIV-2 isolates (n=3) replicating in cord blood mononuclear cells. Nevirapine in combination with efavirenz exhibited strong antagonistic anti-HIV-1 activity in cell culture and was additive to antagonistic with the protease inhibitor ritonavir or the fusion inhibitor enfuvirtide. 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- to 250-fold) to nevirapine emerge in cell culture. Genotypic analysis showed mutations in the HIV-1 RT gene encoding Y181C and/or V106A substitutions depending upon the virus strain and cell line employed. Time to emergence of nevirapine resistance in cell culture was not altered when selection included nevirapine in combination with several other NNRTIs.

Phenotypic and genotypic changes in HIV-1 isolates from treatment-naïve 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 substitutions. 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 NRTIs ddI and ZDV. Similarly, ZDV-resistant isolates were susceptible to nevirapine in cell culture.

13.1   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 was 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.

13.2   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.

14.1   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 antiretroviral 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-1 infection, with a median baseline CD4⁺ cell count of 96 cells/mm³ and a baseline HIV-1 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-1 RNA <50 copies/mL and not previously failed at 48 weeks. Treatment response and outcomes are shown in Table 6.

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-1 RNA of 4.41 log₁₀ 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-1 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.

14.2   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 and 16 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 (150 mg/m²) and weight-based dosing (4 or 7 mg/kg)] in combination with zidovudine and lamivudine [see Adverse Reactions (6.2), Use in Specific Populations (8.4), and Clinical Pharmacology (12.3)]. 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-1 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-week 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-1 RNA <400 copies/mL at 48 weeks was 47% (58/123).

For dose recommendations for pediatric patients [see Dosage and Administration (2.2)].

16   How Supplied/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.

Dispense in tight container as defined in the USP/NF.

VIRAMUNE oral suspension is a white to off-white preserved suspension containing 50 mg nevirapine (as nevirapine hemihydrate) in each 5 mL.

They are supplied by State of Florida DOH Central Pharmacy as follows:

17   Patient Counseling Information

See MEDICATION GUIDE

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

A Medication Guide is supplied as a tear-off following the full prescribing information.

ATTENTION PHARMACISTS: Detach "Medication Guide" and dispense with the product.

17.1   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 co-infection 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 Warnings and Precautions (5.1)].

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 Warnings and Precautions (5.2)].

17.2   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.

17.3   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 Warnings and Precautions (5.4) and Drug Interactions (7)].

17.4   Contraceptives

Hormonal methods of birth control, other than depomedroxy-progesterone acetate (DMPA), 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 (7)].

17.5   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 (7)].

17.6   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 (5.6)].