Nevirapine

Nevirapine tablet is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in adults and pediatric patients 15 days and older . Limitations of Use: Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled trials, nevirapine tablet is not recommended to be initiated, unless the benefit outweighs the risk, in: adult females with CD4 + cell counts greater than 250 cells/mm 3 or adult males with CD4 + cell counts greater than 400 cells/mm 3 . Nevirapine tablet is an NNRTI indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in adults and pediatric patients 15 days and older. Limitations of Use: Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled trials, nevirapine tablet is not recommended to be initiated, unless the benefit outweighs the risk, in: adult females with CD4 + cell counts greater than 250 cells/mm 3 adult males with CD4 + cell counts greater than 400 cells/mm 3 ( 1 , 5.1 )

The 14-day lead-in period must be strictly followed; it has been demonstrated to reduce the frequency of rash. ( 2.4 , 5.2 ) If any patient experiences rash during the 14-day lead-in period, do not increase dose until the rash has resolved. Do not continue the lead-in dosing regimen beyond 28 days. If dosing is interrupted for greater than 7 days, restart 14-day lead-in dosing. Adults (≥16 yrs) Pediatric Patients* (≥15 days) First 14 days 200 mg once daily 150 mg/m 2 once daily After 14 days 200 mg twice daily 150 mg/m 2 twice daily *Total daily dose should not exceed 400 mg for any patient.

2.1Adult Patients The

recommended dose for nevirapine 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 14-day lead-in period with nevirapine 200 mg daily dosing must be strictly followed as the lead-in period has been observed to decrease the incidence of rash . 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.

For concomitantly administered antiretroviral therapy, the manufacturer’s recommended dosage and monitoring should be followed.

2.2Pediatric Patients The

recommended oral dose for pediatric patients 15 days and older is 150 mg/m 2 once daily for 14 days followed by 150 mg/m 2 twice daily thereafter. The total daily dose should not exceed 400 mg for any patient. nevirapine-img.jpg

2.3Monitoring of Patients Intensive

clinical and laboratory monitoring, including liver enzyme tests, is essential at baseline and during the first 18 weeks of treatment with nevirapine. 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 nevirapine treatment . In some cases, hepatic injury has progressed despite discontinuation of treatment.

2.4Dosage Adjustment Patients with Rash Discontinue

nevirapine if a patient experiences severe rash or any rash accompanied by constitutional findings . Do not increase nevirapine dose if a patient experiences mild to moderate rash without constitutional symptoms during the 14-day lead-in period of 200 mg/day (150 mg/m 2 /day in pediatric patients) 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. Patients with Hepatic Events If a clinical (symptomatic) hepatic event occurs, permanently discontinue nevirapine. Do not restart nevirapine after recovery . Patients with Dose Interruption For patients who interrupt nevirapine dosing for more than 7 days, restart the recommended dosing, using one 200 mg tablet daily (150 mg/m 2 /day in pediatric patients) for the first 14 days (lead-in) followed by one 200 mg tablet twice daily (150 mg/m 2 twice daily for pediatric patients).

Patients with Renal Impairment Patients with CrCl greater than or equal to 20 mL per min do not require an adjustment in nevirapine dosing. The pharmacokinetics of nevirapine have not been evaluated in patients with CrCl less than 20 mL per min. An additional 200 mg dose of nevirapine 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 .

Monitor patients for immune reconstitution syndrome and fat redistribution. ( 5.5 , 5.6 )

5.1Hepatotoxicity and Hepatic Impairment Severe,

life-threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis and hepatic failure, have been reported in patients treated with nevirapine. In controlled clinical trials, symptomatic hepatic events regardless of severity occurred in 4% (range 0% to 11%) of subjects who received nevirapine and 1% of subjects in control groups. The risk of symptomatic hepatic events regardless of severity was greatest in the first 6 weeks of therapy.

The risk continued to be greater in the nevirapine groups compared to controls through 18 weeks of treatment. However, hepatic events may occur at any time during treatment. In some cases, subjects presented with non­-specific, prodromal signs or symptoms of fatigue, malaise, anorexia, nausea, jaundice, liver tenderness or hepatomegaly, with or without initially abnormal serum transaminase levels.

Rash was observed in approximately half of the subjects with symptomatic hepatic adverse events. Fever and flu-like symptoms accompanied some of these hepatic events. Some events, particularly those with rash and other symptoms, have progressed to hepatic failure with transaminase elevation, with or without hyperbilirubinemia, hepatic encephalopathy, prolonged partial thromboplastin time, or eosinophilia.

Rhabdomyolysis has been observed in some patients experiencing skin and/or liver reactions associated with nevirapine use. Hepatitis/hepatic failure may be associated with signs of hypersensitivity which can include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction. Patients with signs or symptoms of hepatitis must be advised to discontinue nevirapine and immediately seek medical evaluation, which should include liver enzyme tests.

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

After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout nevirapine treatment. Transaminases should be checked immediately if a patient experiences signs or symptoms suggestive of hepatitis and/or hypersensitivity reaction. Transaminases should also be checked immediately for all patients who develop a rash in the first 18 weeks of treatment.

Physicians and patients should be vigilant for the appearance of signs or symptoms of hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness or hepatomegaly. The diagnosis of hepatotoxicity should be considered in this setting, even if transaminases are initially normal or alternative diagnoses are possible . If clinical hepatitis or transaminase elevations combined with rash or other systemic symptoms occur, permanently discontinue nevirapine. Do not restart nevirapine after recovery.

In some cases, hepatic injury progresses despite discontinuation of treatment. The patients at greatest risk of hepatic events, including potentially fatal events, are women with high CD4 + cell counts. In general, during the first 6 weeks of treatment, women have a 3-fold higher risk than men for symptomatic, often rash-associated, hepatic events (6% versus 2%), and patients with higher CD4 + cell counts at initiation of nevirapine therapy are at higher risk for symptomatic hepatic events with nevirapine.

In a retrospective review, women with CD4 + cell counts greater than 250 cells/mm 3 had a 12-fold higher risk of symptomatic hepatic adverse events compared to women with CD4 + cell counts less than 250 cells/mm 3 (11% versus 1%). An increased risk was observed in men with CD4 + cell counts greater than 400 cells/mm 3 (6% versus 1% for men with CD4 + cell counts less than 400 cells/mm 3 ). However, all patients, regardless of gender, CD4 + cell count, or antiretroviral treatment history, should be monitored for hepatotoxicity since symptomatic hepatic adverse events have been reported at all CD4 + cell counts.

Co-infection with hepatitis B or C and/or increased transaminase elevations at the start of therapy with nevirapine are associated with a greater risk of later symptomatic events (6 weeks or more after starting nevirapine) and asymptomatic increases in AST or ALT. In addition, serious hepatotoxicity (including liver failure requiring transplantation in one instance) has been reported in HIV-1 uninfected individuals receiving multiple doses of nevirapine in the setting of post-exposure prophylaxis (PEP), an unapproved use. Use of nevirapine for occupational and non-occupational PEP is contraindicated . Increased nevirapine trough concentrations have been observed in some patients with hepatic fibrosis or cirrhosis. Therefore, carefully monitor patients with either hepatic fibrosis or cirrhosis for evidence of drug-induced toxicity.

Do not administer nevirapine to patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment .

5.2Skin Reactions Severe and

life-threatening skin reactions, including fatal cases, have been reported, occurring most frequently during the first 6 weeks of therapy. These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction including hepatic failure. Rhabdomyolysis has been observed in some patients experiencing skin and/or liver reactions associated with nevirapine use.

In controlled clinical trials, Grade 3 and 4 rashes were reported during the first 6 weeks in 2% of nevirapine recipients compared to less than 1% of placebo subjects. Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, and/or hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction) must permanently discontinue nevirapine and seek medical evaluation immediately. Do not restart nevirapine following severe skin rash, skin rash combined with increased transaminases or other symptoms, or hypersensitivity reaction.

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

After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout nevirapine treatment. In addition, the 14-day lead-in period with nevirapine 200 mg daily dosing has been demonstrated to reduce the frequency of rash . If patients present with a suspected nevirapine-associated rash, measure transaminases immediately. Permanently discontinue nevirapine in patients with rash-associated transaminase elevations . Therapy with nevirapine must be initiated with a 14-day lead-in period of 200 mg per day (150 mg/m 2 per day in pediatric patients), which has been shown to reduce the frequency of rash.

Discontinue nevirapine if a patient experiences severe rash or any rash accompanied by constitutional findings. Do not increase nevirapine dose to a patient experiencing a mild to moderate rash without constitutional symptoms during the 14-day lead-in period of 200 mg per day (150 mg/m 2 /day in pediatric patients) until the rash has resolved . The total duration of the once-daily lead-in dosing period must not exceed 28 days at which point an alternative regimen should be sought . Patients must be monitored closely if isolated rash of any severity occurs. Delay in stopping nevirapine treatment after the onset of rash may result in a more serious reaction.

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

5.3Resistance Nevirapine

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

When discontinuing an antiretroviral regimen containing nevirapine, the long half-life of nevirapine should be taken into account; if antiretrovirals with shorter half-lives than nevirapine are stopped concurrently, low plasma concentrations of nevirapine alone may persist for a week or longer and virus resistance may subsequently develop .

5.4Drug Interactions See Table

4 for listings of established and potential drug interactions . Concomitant use of St. John's wort ( Hypericum perforatum ) or St. John's wort-containing products and nevirapine is not recommended. Co-administration of St. John’s wort with non-nucleoside reverse transcriptase inhibitors (NNRTIs), including nevirapine, is expected to substantially decrease NNRTI concentrations and may result in sub-optimal levels of nevirapine and lead to loss of virologic response and possible resistance to nevirapine or to the class of NNRTIs.

Co­-administration of nevirapine and efavirenz is not recommended as this combination has been associated with an increase in adverse reactions and no improvement in efficacy.

5.5Immune Reconstitution Syndrome Immune

reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including nevirapine. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.6Fat 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.

Nevirapine is contraindicated: in patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment . for use as part of occupational and non-occupational post-exposure prophylaxis (PEP) regimens . Patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment. ( 4 , 5.1 , 8.7 ) Use as part of occupational and non-occupational post-exposure prophylaxis (PEP) regimens, an unapproved use. ( 4 , 5.1 )

8.1Pregnancy Pregnancy Exposure Registry There

is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to nevirapine during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Available data from the APR show no difference in the risk of overall major birth defects for nevirapine compared with the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) . The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15 to 20%. The background risk of birth defects and miscarriage for the indicated population is unknown.

Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation. In literature reports, immediate-release nevirapine exposure (C min ) can be up to 29% lower during pregnancy.

However, as this reduction was not found to be clinically meaningful, dose adjustment is not necessary . There is a risk for severe hepatic events in pregnant women exposed to nevirapine . In animal reproduction studies, no evidence of adverse developmental outcomes was observed following oral administration of nevirapine during organogenesis in the rat and rabbit, at systemic exposures (AUC) to nevirapine approximately equal (rats) and 50% higher (rabbits) than the exposure in humans at the recommended 400 mg daily dose . Clinical Considerations Maternal adverse reactions Severe hepatic events, including fatalities, have been reported in pregnant women receiving chronic nevirapine therapy as part of combination treatment of HIV-1 infection. Regardless of pregnancy status, women with CD4 + cell counts greater than 250 cells/mm 3 should not initiate nevirapine unless the benefit outweighs the risk. It is unclear if pregnancy augments the risk observed in non-pregnant women . Data Human Data Based on prospective reports to the APR of exposures to nevirapine during pregnancy resulting in live births (including over 1100 exposed in the first trimester and over 1500 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.0% (95% CI: 2.1 %, 4.1%) and 3.3% (95% CI: 2.4%, 4.3%) following first and second/third trimester exposure, respectively, to nevirapine-containing regimens, compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. There are several literature reports of chronic administration of immediate-release nevirapine during pregnancy, in which nevirapine pharmacokinetics were compared between pregnancy and postpartum.

In these studies, the mean difference in nevirapine C min during pregnancy as compared to postpartum ranged from no difference to approximately 29% lower. Animal Data Nevirapine was administered orally to pregnant rats (at 0, 12.5, 25, and 50 mg per kg per day) and rabbits (at 0, 30, 100, and 300 mg per kg per day) through organogenesis (on gestation days 7 through 16, and 6 through 18, respectively). No adverse developmental effects were observed at doses producing systemic exposures (AUC) approximately equivalent to (rats) or approximately 50% higher (rabbits) than human exposure at the recommended daily dose.

In rats, decreased fetal body weights were observed at a maternally toxic dose at an exposure approximately 50% higher than the recommended daily dose.

The most common adverse reaction is rash. In adults, the incidence of rash is 15% versus 6% with placebo, with Grade 3/4 rash occurring in 2% of subjects. In pediatric subjects the incidence of rash (all causality) was 21%. To report SUSPECTED ADVERSE REACTIONS, contact Micro Labs USA, Inc. at 1-855-839-8195 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials Experience 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 clinical practice. Clinical Trial Experience in Adult Patients The most serious adverse reactions associated with nevirapine 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 . Hepatic Reaction In controlled clinical trials, symptomatic hepatic events regardless of severity occurred in 4% (range 0% to 11%) of subjects who received nevirapine and 1% of subjects in control groups.

Female gender and higher CD4 + cell counts (greater than 250 cells/mm 3 in women and greater than 400 cells/mm 3 in men) place patients at increased risk of these events . Asymptomatic transaminase elevations (AST or ALT greater than 5X ULN) were observed in 6% (range 0% to 9%) of subjects who received nevirapine and 6% of subjects in control groups. Co-infection with hepatitis B or C and/or increased transaminase elevations at the start of therapy with nevirapine are associated with a greater risk of later symptomatic events (6 weeks or more after starting nevirapine) and asymptomatic increases in AST or ALT. Liver enzyme abnormalities (AST, ALT, GGT) were observed more frequently in subjects receiving nevirapine than in controls . Skin Reaction The most common clinical toxicity of nevirapine is rash, which can be severe or life-threatening . 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% of subjects receiving nevirapine compared to 6% receiving placebo during the first 6 weeks of therapy. Grade 3 and 4 rashes were reported in 2% of nevirapine recipients compared to less than 1% of subjects receiving placebo. Women tend to be at higher risk for development of nevirapine-associated rash . Treatment-related, adverse experiences of moderate or severe intensity observed in greater than 2% of subjects receiving nevirapine in placebo-controlled trials are shown in Table 2.

Table 2 Percentage of Subjects with Moderate or Severe Drug-Related Events in Adult Placebo-Controlled Trials Trial 1090 1 Trials 1037, 1038, 1046 2 Nevirapine (n=1121) Placebo (n=1128) Nevirapine (n=253) Placebo (n=203) Median exposure (weeks) 58 52 28 28 Any adverse event 15% 11% 32% 13% Rash 5 2 7 2 Nausea 1 1 9 4 Granulocytopenia 2 3 <1 0 Headache 1 <1 4 1 Fatigue <1 <1 5 4 Diarrhea <1 1 2 1 Abdominal pain <1 <1 2 0 Myalgia <1 0 1 2 1 Background therapy included 3TC for all subjects and combinations of NRTIs and PIs. Subjects had CD4 + cell counts less than 200 cells/mm 3 . 2 Background therapy included ZDV and ZDV+ddI; nevirapine monotherapy was administered in some subjects. Subjects had CD4 + cell count greater than or equal to 200 cells/mm 3 . Laboratory Abnormalities Liver enzyme test abnormalities (AST, ALT) were observed more frequently in subjects receiving nevirapine than in controls (Table 3).

Asymptomatic elevations in GGT occur frequently but are not a contraindication to continue nevirapine 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 nevirapine and control regimens . Table 3 Percentage of Adult Subjects with Laboratory Abnormalities Trial 1090 1 Trials 1037, 1038, 1046 2 Nevirapine Placebo Nevirapine Placebo Laboratory Abnormality (n=1121) (n=1128) (n=253) (n=203) Blood Chemistry SGPT (ALT) >250 U/L 5 4 14 4 SGOT (AST) >250 U/L 4 3 8 2 Bilirubin >2.5 mg/dL 2 2 2 2 Hematology Hemoglobin <8.0 g/dL 3 4 0 0 Platelets <50,000/mm 3 1 1 <1 2 Neutrophils <750/mm 3 13 14 4 1 1 Background therapy included 3TC for all subjects and combinations of NRTIs and PIs. Subjects had CD4 + cell counts less than 200 cells/mm 3 . 2 Background therapy included ZDV and ZDV+ddI; nevirapine monotherapy was administered in some subjects.

Subjects had CD4 + cell count greater than or equal to 200 cells/mm 3 . Clinical Trial Experience in Pediatric Patients Adverse events were assessed in BI Trial 1100.1032 (ACTG 245), a double-blind, placebo-controlled trial of nevirapine (n=305) in which pediatric subjects received combination treatment with nevirapine. In this trial two subjects 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 nevirapine (n=37) in which subjects 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 subjects in trial BI 1100.892).

The most frequently reported adverse events related to nevirapine in pediatric subjects were similar to those observed in adults, with the exception of granulocytopenia, which was more commonly observed in children receiving both zidovudine and nevirapine. Cases of allergic reaction, including one case of anaphylaxis, were also reported. The safety of nevirapine was also examined in BI Trial 1100.1368, an open-label, randomized clinical trial performed in South Africa in which 123 HIV-1 infected treatment-naïve subjects between 3 months and 16 years of age received combination treatment with lamivudine and zidovudine for 48 weeks . Rash (all causality) was reported in 21% of the subjects, 4 (3%) of whom discontinued drug due to rash.

All 4 subjects experienced the rash early in the course of therapy (less than 4 weeks) and resolved upon nevirapine discontinuation. Other clinically important adverse events (all causality) include neutropenia (9%), anemia (7%), and hepatotoxicity (2%) . Safety information on use of nevirapine in combination therapy in pediatric subjects 2 weeks to less than 3 months of age was assessed in 36 subjects from the BI 1100.1222 (PACTG 356) trial. 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.

6.2Postmarketing Experience In

addition to the adverse events identified during clinical trials, the following adverse reactions have been identified during post-approval use of nevirapine. 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 , redistribution/accumulation of body fat Gastrointestinal: vomiting Liver and Biliary: jaundice, fulminant and cholestatic hepatitis, hepatic necrosis, hepatic failure Hematology: anemia, eosinophilia, neutropenia Investigations: decreased serum phosphorus 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, drug reaction with eosinophilia and systemic symptoms (DRESS) plus one or more of the following: hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and/or renal dysfunction have been reported. 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.