nevirapine er 400 mg tablet generic viramune xr

Uses

Treatment of HIV Infection

Nevirapine is used in conjunction with other antiretroviral agents for treatment of human immunodeficiency virus type 1 (HIV-1) infection, in adults, adolescents, and pediatric patients.

Because adults with high pretreatment CD4 T-cell counts are at increased risk for serious and life-threatening hepatotoxicity, nevirapine should not be initiated in women with pretreatment CD4 T-cell counts exceeding 250 cells/mm or in men with CD4 T-cell counts exceeding 400 cells/mm unless potential benefits outweigh risks.(See Cautions: Hepatic Effects.)

Nevirapine generally has been used in HIV nonnucleoside reverse transcriptase inhibitor-based (NNRTI-based) regimens that include nevirapine and 2 HIV nucleoside reverse transcriptase inhibitors (NRTIs).

The most appropriate antiretroviral regimen cannot be defined for each clinical scenario and selection of specific antiretroviral agents for use in such regimens should be individualized based on information regarding antiretroviral potency, potential rate of development of resistance, known toxicities, and potential for pharmacokinetic interactions as well as virologic, immunologic, and clinical characteristics of the patient. For information on the general principles and guidelines for use of antiretroviral therapy, including specific recommendations for initial therapy in antiretroviral-naive patients and recommendations for changing antiretroviral regimens,

Antiretroviral-naive Adults

The US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents states that nevirapine is not recommended for initial treatment regimens in antiretroviral-naive adults and adolescents. Nevirapine is no longer recommended for initial regimens because it has been associated with more serious toxicities than other NNRTIs and many other preferable options are available. These experts state that patients who are already receiving and tolerating a suppressive regimen that includes nevirapine may continue to receive the drug.(See Antiretroviral-experienced Adults under Uses: Treatment of HIV Infection.)

Study BI 1046

Safety and efficacy of nevirapine (200 mg once daily for the initial 2 weeks, then 200 mg every 12 hours) have been evaluated in conjunction with zidovudine (200 mg 3 times daily) with or without didanosine (125 or 200 mg twice daily) for initial antiretroviral therapy in a randomized, double-blind study in treatment-naive (had not previously received antiretroviral therapy) adults (study BI 1046). Study BI 1046 included 151 adults (median age 36 years) with baseline CD4 T-cell counts of 200-600 cells/mm (mean 376 cells/mm) and mean baseline plasma HIV-1 RNA levels of 4.41 log₁₀ copies/mL (25,704 copies/mL). Patients were randomized to receive a 3-drug regimen of zidovudine, didanosine, and nevirapine or a 2-drug regimen of zidovudine and didanosine or zidovudine and nevirapine.

The primary endpoint was the proportion of patients with plasma HIV-1 RNA levels less than 400 copies/mL and not previously failed at 48 weeks. At 48 weeks, the virologic response rate was 45% in those receiving the 3-drug regimen (zidovudine, didanosine, and nevirapine), 19% for those receiving zidovudine and didanosine, and 0% in those receiving nevirapine and zidovudine. The mean increase in CD4 T-cell count above baseline was 139 cells/mm in those receiving the 3-drug regimen compared with 87% in those receiving zidovudine and didanosine.

Study 1100.1486

Safety and efficacy of nevirapine extended-release tablets were evaluated in an ongoing, randomized, double-blind, double-dummy, phase 3 trial in antiretroviral-naive adults (85% male, 75% white, 20% black, 29% from North America) who received a regimen of nevirapine immediate-release tablets (200 mg once daily) for 14 days with 2 NRTIs (tenofovir and emtricitabine) and were then randomized to continue therapy with nevirapine immediate-release tablets (200 mg twice daily) or switch to nevirapine extended-release tablets (400 mg once daily) with the same background regimen of 2 NRTIs (study 1100.1486; VERxVE). At baseline, the mean plasma HIV RNA level was 4.7 log₁₀ copies/mL and the mean CD4 T-cell count was 228 cells/mm; approximately 66% of patients had baseline plasma HIV RNA levels of 100,000 copies/mL or lower. At 96 weeks, 67% of those receiving immediate-release nevirapine and 69% of those receiving extended-release nevirapine had plasma HIV RNA levels less than 50 copies/mL and the mean change from baseline in CD4 T-cell count, adjusted for baseline HIV viral load stratum, was 222 or 244 cells/mm, respectively.

Antiretroviral-experienced Adults

Study BI 1090

Nevirapine has been evaluated for use in conjunction with other antiretroviral agents in adults with advanced HIV-1 infection (study BI 1090). This study was a placebo-controlled, double-blind, randomized study that included 2,249 adults (median age 36.5 years, 79% male, 70% white, median baseline CD4 T-cell count 96 cells/mm, median baseline plasma HIV-1 RNA level 4.58 log₁₀ copies/mL [38,291 copies/mL]; 89% had previously received antiretroviral therapy). Patients were randomized to receive nevirapine (200 mg once daily for 2 weeks, then 200 mg twice daily) and lamivudine (150 mg twice daily) with a background antiretroviral regimen or lamivudine with a background regimen; the background regimen was one NRTI (58%), 2 or more NRTIs (34%), or HIV protease inhibitors (PIs) and NRTIs (8%). Prior to study entry, 45% of patients had previously experienced an AIDS-defining clinical event.

At 48 weeks, 18% of those receiving a regimen that included nevirapine had plasma HIV-1 RNA levels less than 50 copies/mL compared with 2% of those not receiving the NNRTI. At 1 year, the change from baseline CD4 T-cell count for the overall trial population was 64 cells/mm in those receiving nevirapine compared with 22 cells/mm in those not receiving the drug. At 2 years, 16% of those receiving nevirapine had experienced events classified as US Centers for Disease Control (CDC) class C events compared to 21% of those in the control arm.

Study 1100.1526

Safety and efficacy of switching from nevirapine immediate-release tablets to nevirapine extended-release tablets was evaluated in an ongoing open-label, phase 3 trial in antiretroviral-experienced adults with HIV-1 RNA levels less than 50 copies/mL (approximately 50% had been receiving immediate-release nevirapine for at least 3 years; approximately 50% were receiving a background regimen of tenofovir and emtricitabine and the remaining patients were receiving abacavir [or zidovudine]) and lamivudine. Patients were randomized (2:1 ratio) to switch to nevirapine extended-release tablets (400 mg once daily) or continue therapy with nevirapine immediate-release tablets (200 mg twice daily) with their current background regimen of 2 NRTIs (study 1100.1526; TRANxITION). At 48 weeks after randomization, 93% of those receiving extended-release tablets and 91% of those receiving immediate-release tablets continued to have plasma HIV-1 RNA levels less than 50 copies/mL.

Pediatric Patients

Nevirapine is used in conjunction with other antiretroviral agents for treatment of HIV-1 infection in children 15 days of age or older (oral suspension or immediate-release tablets). Alternatively, nevirapine extended-release tablets may be used in pediatric patients 6 years of age or older.

For initial treatment in HIV-infected pediatric patients, the HHS Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children recommends a PI or NNRTI with 2 NRTIs. These experts state that nevirapine in conjunction with 2 NRTIs is an alternative (not a preferred) regimen for initial treatment in pediatric patients 15 days of age or older. The preferred regimen for initial treatment in pediatric patients 14 days of age and older is the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) in conjunction with 2 NRTIs. In children younger than 3 years of age, there is some evidence that nevirapine regimens are associated with a higher risk of virologic failure compared with lopinavir/ritonavir regimens; in children 3 years of age or older, NNRTI-based regimens that include nevirapine are associated with a higher incidence of toxicity than NNRTI-based regimens that include efavirenz.

Nevirapine should not be used in postpubertal or adolescent girls with CD4 T-cell counts exceeding 250 cells/mm or adolescent boys with CD4 T-cell counts exceeding 400 cells/mm, unless benefits clearly outweigh risks.(See Cautions: Hepatic Effects.)

For further information on treatment of HIV infection in pediatric patients,

Study BI 1100.1368

Safety and efficacy of nevirapine have been evaluated in an open-label, randomized study in treatment-naive children 3 months to 16 years of age with HIV-1 infection (49% male, 81% black, 19% white, median baseline plasma HIV-1 RNA level 5.45 log₁₀ copies/mL, median baseline CD4 T-cell count 527 cells/mm, 4% previously received antiretroviral therapy). Children received nevirapine oral suspension (dose based on body surface area or body weight; maximum 400 mg daily) in conjunction with lamivudine and zidovudine. At 48 weeks, 47% of patients had plasma HIV-1 RNA levels less than 400 copies/mL.

Safety and efficacy of nevirapine have been evaluated in an open-label, phase 1 or 2 study that included 8 HIV-infected children 2-16 months of age who were treatment-naive. These pediatric patients received a 3-drug regimen of oral zidovudine (180 mg/m given every 8 hours), oral didanosine (120 mg/m given every 12 hours), and nevirapine (120 mg/m given once daily for 28 days, then 200 mg/m given every 12 hours). Plasma HIV-1 RNA levels were reduced at least 96% (a decrease of 1.5 log₁₀ copies/mL) in 7 of 8 patients within 2-4 weeks of initiating therapy and, at 6 months, were still below baseline levels in 5 of 6 infants whose treatment started when they were 4 months of age or younger; the regimen was well tolerated in all patients.

Study 1100.1518

Nevirapine extended-release tablets were evaluated in an open-label, nonrandomized, crossover trial in 85 HIV-infected pediatric patients 3 to less than 18 years of age who had received at least 18 weeks of immediate-release nevirapine and had plasma HIV-1 RNA levels less than 50 copies/mL (55% female, 93% black, approximately 84% from Africa, median baseline CD4 T-cell count 925 cells/mm [range 207-2057 cells/mm]). Following a 10-day period of treatment with immediate-release nevirapine, patients were switched to extended-release nevirapine in conjunction with other antiretrovirals. After 10 days of treatment with the extended-release preparation, steady-state pharmacokinetics were determined and 40 of the initial study patients were enrolled in an optional extension phase of the trial to evaluate safety and antiretroviral activity of extended-release nevirapine. At 24 weeks, 39 of these patients continued to have plasma HIV-1 RNA levels less than 50 copies/mL and 1 patient had discontinued the drug because of an adverse reaction. When the 39 patients were stratified according to age, median CD4 T-cell counts in those 3 to less than 6 years, 6 to less than 12 years, and 12 to less than 18 years of age were 1113, 853, and 682 cells/mm, respectively. These CD4 T-cell counts were similar to those observed at baseline.

Prevention of Perinatal HIV Transmission

Nevirapine is used for prevention of perinatal HIV transmission.

In the US, multiple-drug antiretroviral regimens are considered the standard of care for treatment of HIV infection in pregnant women and for prevention of perinatal HIV transmission. The HHS Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission states that all pregnant HIV-infected women in the US should receive multiple-drug antiretroviral therapy, regardless of the woman's plasma HIV RNA level or CD4 T-cell count. In addition, to decrease the risk of perinatal HIV transmission, the HHS panel states that pregnant HIV-infected women with plasma HIV-1 RNA levels exceeding 1000 copies/mL (or with unknown HIV RNA levels) near the time of delivery should receive an intrapartum IV zidovudine prophylaxis regimen and all neonates born to HIV-infected women (HIV-exposed neonates) should receive an oral or IV zidovudine prophylaxis regimen. In certain situations (e.g., infant born to a woman who did not receive antepartum or intrapartum antiretrovirals or received only intrapartum antiretrovirals), a 3-dose nevirapine prophylaxis regimen is recommended in the neonate in addition to the usual 6-week neonatal zidovudine prophylaxis regimen. Combined antepartum, intrapartum, and neonatal antiretroviral prophylaxis is recommended since this strategy reduces perinatal HIV transmission by several mechanisms, including lowering maternal antepartum viral load and providing pre- and postexposure prophylaxis in the infant. Maternal and neonatal regimens recommended for prevention of perinatal HIV transmission in the US may differ from those used in other countries (e.g., resource-limited countries).

Various other nevirapine regimens have been used alone or in conjunction with other antiretrovirals for prevention of perinatal HIV transmission in limited-resource areas (e.g., sub-Saharan Africa), including single-dose intrapartum/neonatal nevirapine regimens (e.g., a single nevirapine dose given to the mother at the onset of labor and a single nevirapine dose given to the neonate within 72 hours after birth) and 6-week neonatal nevirapine regimens. The HHS panel states that single-dose nevirapine regimens (either alone or in addition to the usual intrapartum/neonatal zidovudine regimens) are not recommended in the US for women receiving the recommended antenatal antiretroviral prophylaxis because such regimens do not appear to provide additional efficacy in reducing perinatal HIV transmission.

The HHS panel states that, for US patients, decisions to include additional antiretrovirals for prophylaxis with the recommended intrapartum and neonatal zidovudine prophylaxis regimens should be made in consultation with a pediatric HIV specialist (preferably before delivery) and should be accompanied by maternal counseling regarding the potential risks and benefits. These experts also state that, because safety and dosage data are not available, use of antiretrovirals other than zidovudine and nevirapine cannot be recommended for prophylaxis in premature HIV-exposed neonates.

For information on the risk of perinatal transmission of HIV and some additional information regarding recommendations for use of antiretroviral agents for prevention of perinatal HIV transmission, In addition, clinicians can consult the National Perinatal HIV Hotline at 888-448-8765 for information regarding antiretroviral treatment of pregnant HIV-infected women and their infants and prevention of perinatal HIV transmission.

Dosage and Administration

Administration

Nevirapine is administered orally without regard to food.

Nevirapine conventional (immediate-release) tablets and oral suspension are used in adults, adolescents, and pediatric patients 15 days of age or older.

Nevirapine extended-release tablets are used in adults, adolescents, and pediatric patients 6 years of age or older.

Nevirapine therapy is initiated using a low dosage of immediate-release nevirapine for the first 14 days since this appears to reduce the frequency of rash. Nevirapine extended-release tablets should not be used during the initial 14 days of nevirapine therapy. Patients not currently receiving nevirapine may receive the extended-release tablets after a lead-in period of 14 days of low dosage of immediate-release nevirapine. Patients already receiving usual dosage of immediate-release nevirapine may be switched to the extended-release tablets without the 14-day lead-in period.

If mild to moderate rash without constitutional symptoms occurs during the initial 14-day period of low dosage of immediate-release nevirapine, dosage should not be increased until the rash has resolved. The low dosage should not be continued for longer than 28 days; if the rash has not resolved by day 28, nevirapine should be discontinued and an alternative antiretroviral agent selected.

If nevirapine therapy has been interrupted for more than 7 days for any reason and reinitiation of the drug is not contraindicated, the manufacturer states that the drug should be restarted using the recommended low initial dosage of immediate-release nevirapine for the first 14 days.

If signs or symptoms of severe skin 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, occur at any time during nevirapine therapy, the drug should be discontinued and should not be reinitiated. If nevirapine therapy is discontinued because of hepatitis or transaminase elevations associated with rash or other systemic symptoms, the drug should be permanently discontinued and not reinitiated after recovery.(See Cautions: Precautions and Contraindications.)

Extended-release Tablets

Nevirapine extended-release tablets should be swallowed whole; the tablets must not be chewed, crushed, or divided.

When considering use of nevirapine extended-release tablets in a child 6 years of age or older, the child should be assessed for their ability to swallow tablets.

Oral Suspension

Nevirapine oral suspension should be shaken gently prior to administration of each dose. The entire measured dose of suspension should be administered using an oral dosing syringe or, alternatively, a dosing cup. The oral 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.

Dosage

Adult Dosage

Treatment of HIV Infection

The usual initial dosage of nevirapine immediate-release tablets for treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults is 200 mg once daily for the first 14 days of therapy (lead-in period of low dosage). Dosage should then be increased to 200 mg twice daily in patients who do not experience rash or liver function test abnormalities with the lower dosage.

The usual dosage of nevirapine extended-release tablets for treatment of HIV-1 infection in adults is 400 mg once daily, initiated after immediate-release nevirapine. Patients not currently receiving nevirapine should receive a lead-in period of low dosage of immediate-release nevirapine (200 mg once daily for 14 days) before being switched to the once-daily regimen of extended-release tablets. Patients already receiving a twice-daily regimen of usual dosage of immediate-release nevirapine may be switched to the extended-release tablets without the 14-day lead-in period.

A low initial dosage should be used the first time nevirapine is initiated and whenever nevirapine therapy has been interrupted for more than 7 days.(See Dosage and Administration: Administration.)

Pediatric Dosage

Dosage of nevirapine in pediatric patients is based on body surface area (BSA) calculated using the Mosteller formula.

Treatment of HIV Infection

For treatment of HIV-1 infection in children 15 days of age or older, the usual initial dosage of nevirapine oral suspension or immediate-release tablets is 150 mg/m once daily for the first 14 days of therapy (lead-in period of low dosage). Dosage should then be increased to 150 mg/m twice daily in patients who do not experience rash or liver function test abnormalities with the lower dosage. Dosage should not exceed 400 mg daily.

When extended-release nevirapine tablets are used for treatment of HIV-1 infection in children 6 years to less than 18 years of age, those not currently receiving immediate-release nevirapine should be given nevirapine oral suspension or immediate-release tablets in a dosage of 150 mg/m once daily (up to 200 mg daily) for 14 days (lead-in period of low dosage) before being switched to the recommended dosage of nevirapine extended-release tablets. After the lead-in period, pediatric patients 6 years of age or older with BSA 0.58-0.83 m should receive 200 mg once daily, those with BSA 0.84-1.16 m should receive 300 mg once daily, and those with BSA 1.17 m or greater should receive 400 mg once daily. Dosage should not exceed 400 mg daily.

Some experts suggest that children younger than 8 years of age require a higher nevirapine dosage for treatment of HIV-1 infection than those 8 years of age or older. When immediate-release nevirapine is used, these experts recommend that children younger than 8 years of age receive a dosage of 200 mg/m twice daily (up to 200 mg twice daily) and that those 8 years of age or older receive a dosage of 120-150 mg/m twice daily (up to 200 mg twice daily). If extended-release tablets are used in those 6 to less than 8 years of age, these experts recommend 400 mg/m once daily (up to 400 mg once daily).

Some experts state that adolescents can receive the usual adult dosage of nevirapine.(See Adult Dosage under Dosage and Administration: Dosage.)

A low initial dosage should be used the first time nevirapine is initiated and whenever nevirapine therapy has been interrupted for more than 7 days.(See Dosage and Administration: Administration.)

Prevention of Maternal-Fetal Transmission of HIV

For prevention of perinatal HIV transmission in neonates born to HIV-infected women who received no antiretroviral therapy prior to and/or during labor, the US Department of Health and Human Services (HHS) Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission recommends a 3-dose neonatal regimen of immediate-release nevirapine initiated as soon as possible after delivery in addition to the usual 6-week neonatal zidovudine prophylaxis regimen.(See Uses: Prevention of Perinatal HIV Transmission.)

These HIV-exposed neonates should receive 3 doses of oral nevirapine during the first week of life (first dose given within 48 hours of birth, second dose given 48 hours after first dose, third dose given 96 hours after second dose). Neonates with birth weight of 1.5-2 kg should receive 8 mg of nevirapine oral suspension for each of the 3 doses; neonates with birth weight greater than 2 kg should receive 12 mg of nevirapine oral suspension for each of the 3 doses.

Dosage in Renal and Hepatic Impairment

Renal Impairment

Modification of the usual dosage of nevirapine is not necessary in patients with creatinine clearances of 20 mL/minute or greater not requiring dialysis. However, because nevirapine is removed by dialysis, an additional 200-mg dose of immediate-release nevirapine should be administered following each dialysis treatment. Although nevirapine metabolites may accumulate in patients receiving dialysis, the clinical importance of this accumulation is unknown. The pharmacokinetics of nevirapine have not been evaluated in those with creatinine clearances less than 20 mL/minute.

Nevirapine extended-release tablets have not been studied in patients with renal impairment.

Hepatic Impairment

Data are insufficient to date to determine the appropriate dosage of nevirapine in patients with mild hepatic impairment (Child-Pugh Class A); some experts state that dosage adjustments are not necessary in these patients. Nevirapine is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh Class B or C).(See Cautions: Precautions and Contraindications.)

Nevirapine extended-release tablets have not been studied in patients with hepatic impairment.

Cautions

The most frequently reported adverse effects in patients receiving nevirapine are rash, nausea, headache, fatigue, and abnormal liver function test results. Serious adverse reactions reported in patients receiving nevirapine include hepatitis, hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions. Hepatitis/hepatic failure may be associated with signs of hypersensitivity, including 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 impairment.

Adverse effects reported with nevirapine extended-release tablets are similar to those reported with conventional (immediate-release) nevirapine tablets.

Hepatic Effects

Severe, life-threatening (and in some cases fatal) hepatotoxicity, including fulminant and cholestatic hepatitis (e.g., transaminase elevations with or without hyperbilirubinemia, prolonged partial thromboplastin time, or eosinophilia), hepatic necrosis, and hepatic failure, have been reported in patients receiving nevirapine. Although clinical presentation varied, frequently occurring features included nonspecific prodromal signs and symptoms of fatigue, malaise, anorexia, nausea, jaundice, liver tenderness, and/or hepatomegaly, with or without initially abnormal serum transaminase concentrations; rash was observed in 50% of patients with symptomatic hepatic events. A diagnosis of hepatotoxicity should be considered even if liver function tests are initially normal or alternative diagnoses are possible. Some events, especially those with rash and other symptoms, have progressed over several days to hepatic failure with transaminase elevation, with or without hyperbilirubinemia, hepatic encephalopathy, prolonged partial thromboplastin time, and/or eosinophilia. These events may occur at any time during treatment. While the risk of hepatic events is greatest during the first 6 weeks of therapy, substantial risk continues through the first 18 weeks of therapy.

Patients with signs and symptoms of hepatitis must seek immediate medical attention, have serum transaminase concentrations measured, and be advised to discontinue nevirapine as soon as possible. If nevirapine is discontinued because of hepatitis or transaminase elevations associated with rash or other systemic symptoms, the drug should be permanently discontinued and not reinitiated.

Asymptomatic increases in serum AST or ALT (more than 5 times the upper limit of normal) have occurred in 6% of patients receiving nevirapine and in 6% of those in control groups. In clinical studies, symptomatic hepatic events (regardless of severity) occurred in 4% of patients receiving regimens that included nevirapine and in 1% of those in the control group. Women, including pregnant women, appear to be at higher risk of nevirapine-associated hepatic events than men. Symptomatic hepatic events (usually associated with rash) have been observed in 6% of women and in 2% of men during the first 6 weeks of treatment with a nevirapine-containing regimen.

In a clinical study in antiretroviral-naive patients who received initial treatment with nevirapine immediate-release tablets for 14 days and were then randomized to continue treatment with immediate-release tablets or be switched to nevirapine extended-release tablets, the incidence of any hepatic event was 9% in the immediate-release group and 6% in the extended-release group; the incidence of symptomatic hepatic events (anorexia, jaundice, vomiting) was 3 and 2%, respectively. Overall the incidence of symptomatic events in study patients was similar among men and women.

While all patients with higher CD4 T-cell counts prior to initiation of therapy with nevirapine are at increased risk for symptomatic hepatic events, the patients at highest risk are women with high CD4 T-cell counts at baseline. Symptomatic hepatic events were observed in 11% of women with CD4 T-cell counts exceeding 250 cells/mm at baseline and in 6% of men with CD4 T-cell counts exceeding 400 cells/mm at baseline.

Increased serum concentrations of AST or ALT prior to initiation of antiretroviral therapy and/or coinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV) are associated with a greater risk of later symptomatic hepatic adverse effects (i.e., events that occur 6 or more weeks after initiation of nevirapine therapy) and asymptomatic increases in serum transaminase concentrations.

Serious hepatotoxicity has been reported in individuals not infected with HIV who received multiple doses of nevirapine as part of a 2- or 3-drug regimen for postexposure prophylaxis following occupational or nonoccupational exposure to HIV. Adverse hepatic effects in these individuals have included end-stage liver failure requiring transplantation, clinical hepatitis (e.g., jaundice, fever, nausea, vomiting, abdominal pain, and/or hepatomegaly), and elevated serum ALT and AST concentrations without clinical hepatitis. Nevirapine is contraindicated for and should not be included in regimens used for postexposure prophylaxis of HIV infection following occupational or nonoccupational exposure to the virus.

Asymptomatic elevations in serum γ-glutamyltransferase (GGT, γ-glutamyltranspeptidase, GGTP) have been reported frequently in patients receiving nevirapine. Nevirapine therapy may be continued in patients who have asymptomatic elevations of GGT without elevations in other liver enzymes.

Dermatologic and Sensitivity Reactions

The most frequently reported adverse reaction in patients receiving nevirapine is rash. Rash reported in patients receiving nevirapine usually is mild to moderate, consists of maculopapular erythematous cutaneous eruptions (with or without pruritus), and is located on the trunk, face, and extremities. In controlled studies, 13 or 6% of patients receiving nevirapine or placebo, respectively, experienced a mild to moderate rash (grade 1 or 2) during the first 6 weeks of therapy and 2% or less than 1% of patients receiving nevirapine or placebo, respectively, experienced a serious rash (grade 3 or 4). Women appear to be at higher risk of nevirapine-associated rash than men.

Severe and life-threatening skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction including hepatic failure, also have occurred in patients receiving nevirapine. Fatalities have been reported. There have been postmarketing reports of anaphylaxis, drug reaction with eosinophilia and systemic symptoms (DRESS), angioedema, bullous eruptions, ulcerative stomatitis, and urticaria.

Most cases of rash (including severe, life-threatening skin reactions and fatalities) have occurred within the first 4-6 weeks of nevirapine therapy. Initiating nevirapine therapy using a low dosage during the first 14 days of therapy appears to reduce the frequency of rash and is recommended for all patients.(See Dosage and Administration.) Risk factors for developing serious cutaneous reactions include failure to follow the low dosage regimen during the first 14 days of therapy and delay in discontinuing nevirapine after the onset of initial symptoms.

In a clinical study in antiretroviral-naive patients who received initial treatment with nevirapine immediate-release tablets for 14 days and were then randomized to continue treatment with immediate-release tablets or be switched to nevirapine extended-release tablets, the incidence of severe or life-threatening rash considered to be related to nevirapine was 1% in patients during the lead-in phase and also was 1% in patients subsequently randomized to immediate-release or to extended-release tablets.

Concomitant use of prednisone during the first 14 days of therapy in an attempt to prevent nevirapine-associated rash is not recommended. In a clinical trial of nevirapine immediate-release tablets, concomitant use of prednisone (40 mg daily during the first 14 days of nevirapine administration) was associated with an increased incidence and severity of rash during the first 6 weeks of nevirapine therapy.

Management of patients who develop rash while receiving nevirapine should be based on the type and severity of symptoms. Serum transaminase concentrations should be immediately evaluated in any patient experiencing rash, especially during the first 18 weeks of therapy. If signs or symptoms of severe skin 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, occur during nevirapine therapy, the drug should be discontinued and should not be reinitiated. Delay in discontinuing nevirapine after onset of rash may result in a more severe reaction. If nevirapine is discontinued because of severe skin rash, skin rash combined with increased serum transaminase concentrations or other symptoms, or hypersensitivity reaction, the drug should be permanently discontinued and not reinitiated. While nevirapine therapy generally can be continued in patients with mild or moderate rash (e.g., erythema, pruritus, diffuse erythematous macular or maculopapular rash), dosage should not be increased until the rash has resolved. Mild to moderate rash resolves within 2 weeks in about 50% of patients and within 1 month in about 75% of patients; these patients may be treated symptomatically with antihistamines, antipyretics, and/or nonsteroidal anti-inflammatory agents.

GI Effects

Adverse GI effects, including nausea, diarrhea, vomiting, abdominal pain, and ulcerative stomatitis, have been reported in patients who received nevirapine in conjunction with other antiretroviral agents.

Adipogenic Effects

Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (''buffalo hump''), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance, has been reported in patients receiving antiretroviral agents. The mechanisms responsible for these adipogenic effects and the long-term consequences of these effects are unknown. A causal relationship has not been established.

Immune Reconstitution Syndrome

An inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii]) has occurred in patients who have responded to initial antiretroviral therapy.

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barre syndrome) have been reported to occur in the setting of immune reconstitution; the time to onset is more variable and can occur many months after initiation of antiretroviral therapy.

Other Adverse Effects

Other adverse effects reported in patients receiving nevirapine include headache, fatigue, somnolence, paresthesia, arthralgia, rhabdomyolysis associated with dermatologic and/or hepatic events, myalgia, neutropenia, thrombocytopenia, granulocytopenia, and decreased hemoglobin.

Precautions and Contraindications

Nevirapine is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).

Nevirapine is contraindicated for and should not be used in regimens used for postexposure prophylaxis of HIV following occupational or nonoccupational exposure to the virus.(See Cautions: Hepatic Effects.)

Hepatotoxicity and Skin Reactions

Intensive clinical and laboratory monitoring, including liver enzyme tests, is essential at baseline and during the initial 18 weeks of nevirapine therapy to detect potentially life-threatening skin reactions and hepatotoxicity. Extra vigilance is required during the first 6 weeks of therapy since this is the period of greatest risk.

The optimum frequency of monitoring during this period has not been established, but some clinicians recommend clinical and laboratory monitoring more often than once monthly and, in particular, recommend liver function tests at baseline, prior to dosage escalation, and at 2 weeks after dosage escalation. Although severe liver disease occurs most frequently during the first 6 weeks of therapy, liver disease can occur after this period. Therefore, clinical and laboratory monitoring should continue at frequent intervals throughout nevirapine therapy. Serum transaminase concentrations should be determined immediately whenever a patient experiences rash or signs or symptoms suggestive of hepatitis and/or hypersensitivity reactions during nevirapine therapy.

Nevirapine is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh class B or C). Because severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis, and hepatic failure, has occurred in patients receiving nevirapine, clinicians and patients should be vigilant for the appearance of signs or symptoms of hepatitis (e.g., fatigue, malaise, anorexia, nausea, jaundice, bilirubinemia, acholic stools, liver tenderness, hepatomegaly).(See Cautions: Hepatic Effects.) Patients should be advised to seek immediate medical attention and have serum transaminase concentrations measured and to discontinue the drug as soon as possible if signs or symptoms of hepatitis develop. A diagnosis of hepatotoxicity should be considered in this setting, even if liver function test results are initially normal or alternative diagnoses are possible. If nevirapine is discontinued because of hepatitis or transaminase elevations associated with rash or other systemic symptoms, the drug should not be reinitiated. Patients also should be advised that increased liver function test results and/or a history of HBV or HCV infection and CD4 T-cell counts exceeding 250 cells/mm in women or 400 cells/mm in men prior to initiation of antiretroviral therapy are associated with an increased risk of hepatic events with nevirapine; women also may be at higher risk of these events.

Severe and life-threatening skin reactions (e.g., Stevens-Johnson syndrome; toxic epidermal necrolysis; hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction including hepatic failure), including some fatalities, have occurred in patients receiving nevirapine, usually during the first 6 weeks of therapy. Nevirapine should be immediately discontinued and not reinitiated in any patient who develops 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. Delay in discontinuing nevirapine after onset of rash may result in a more severe reaction.

Patients receiving nevirapine should be warned of the signs and symptoms of nevirapine skin reactions and directed to immediately discontinue the drug and seek medical evaluation if severe rash, rash accompanied by other symptoms, or hypersensitivity occurs. Patients also should be instructed that if any rash occurs during the first 14 days of nevirapine therapy, dosage of the drug should not be increased until the rash has resolved.

If nevirapine is discontinued because of severe skin rash, skin rash combined with increased serum transaminase concentrations or other symptoms, or hypersensitivity reaction, the drug should be permanently discontinued and not reinitiated.

Other Precautions

Patients should be advised 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 as yet unknown.(See Cautions: Adipogenic Effects.)

Concomitant use of nevirapine and some other drugs may result in drug interactions, and patients should be instructed to inform their clinician of their use of other drugs, including prescription and nonprescription drugs or dietary or herbal supplements such as St. John's wort.(See Drug Interactions.)

Nevirapine in conjunction with other antiretroviral agents is not a cure for HIV infection, and opportunistic infections and other complications associated with HIV disease may still occur. Patients receiving nevirapine should be under close clinical observation by clinicians experienced in treatment of diseases associated with HIV infection, and patients should be advised to seek medical care if any clinically important change in their health status occurs.

Patients should be advised that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others. Patients should continue to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never share personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reuse or share needles.

Nevirapine should always be administered in conjunction with other antiretroviral agents and should not be used alone for treatment of HIV infection. Although nevirapine used in conjunction with other antiretroviral agents appears to be well tolerated, patients should be monitored closely for adverse effects. The usual precautions and contraindications of the other antiretrovirals in the regimen should be considered.

The effect of nevirapine therapy on subsequent therapy with certain other HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs) remains to be determined.(See Resistance: Cross-resistance.)

Pediatric Precautions

Safety, pharmacokinetic profile, and efficacy of nevirapine immediate-release tablets and oral suspension have been evaluated in pediatric patients 3 months to 18 years of age. Safety and pharmacokinetic profile of nevirapine oral suspension have been evaluated in pediatric patients 15 days to less than 3 months of age.

Nevirapine extended-release tablets can be used for treatment of HIV-1 infection in children 6 years of age or older based on pharmacokinetic, safety, and antiretroviral activity data from an open-label trial evaluating the drug in pediatric patients 3 to less than 18 years of age and efficacy data from adults. The extended-release tablets are not recommended in pediatric patients 3 to less than 6 years of age because pharmacokinetic data are insufficient to support use in this age group; the tablets are not recommended in those less than 3 years of age because of inability to swallow tablets.

A 3-dose regimen of immediate-release nevirapine is recommended for prevention of perinatal HIV transmission in neonates born to HIV-infected women who received no antiretroviral therapy prior to and/or during labor.(See Uses: Prevention of Perinatal HIV Transmission.)

The most frequently reported adverse effects in children were similar to those observed in adults; however, granulocytopenia occurred more frequently in children than in adults. Stevens-Johnson syndrome or Stevens-Johnson/toxic epidermal necrolysis transition syndrome has occurred rarely in children receiving nevirapine. Rash, allergic reaction, including anaphylaxis, also have been reported. Anemia has been observed in children during postmarketing surveillance; whether anemia was due to nevirapine or concomitant drug therapy has not been determined. Nevirapine generally has been well tolerated when used in neonates.

Geriatric Precautions

Clinical studies of nevirapine to date have not included sufficient numbers of adults 65 years of age or older to determine whether geriatric individuals respond differently to the drug than younger adults. In general, dosage for geriatric patients should be selected carefully since these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Mutagenicity and Carcinogenicity

Nevirapine was not mutagenic or clastogenic in a variety of in vitro and in vivo assays, including microbial assays for gene mutation (Ames test in Salmonella and Escherichia coli), mammalian cell gene mutation assays (Chinese hamster ovary [CHO] cells/HGPRT), cytogenetic assays using a CHO cell line, and a mouse bone marrow micronucleus assay.

Long-term carcinogenicity studies in mice using nevirapine dosages of 0, 50, 375, or 750 mg/kg daily for 2 years revealed an increased incidence of hepatocellular adenomas and carcinomas at all dosages in males and at the 2 highest dosages in females. In similar studies in rats using nevirapine dosages of 0, 3.5, 17.5, or 35 mg/kg daily for 2 years, there was an increase in hepatocellular adenomas at all dosages in males and at the highest dosage in females. The mechanism of the carcinogenic potential is unknown. Systemic exposure (based on AUC) in these rodents was lower than that measured in humans receiving a dosage of 200 mg twice daily. Given the lack of genotoxic activity of nevirapine, the relevance to humans of the hepatocellular neoplasms reported in nevirapine-treated mice and rats is unknown.

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rats and rabbits using nevirapine have not revealed evidence of teratogenicity. In rats, a decrease in fetal body weight occurred at nevirapine dosages approximately 50% higher than those associated with the recommended human dosage based on area under the concentration-time curve (AUC). The maternal and developmental nonobservable-effect level dosages in rats and rabbits produced systemic exposures approximately equivalent to or approximately 50% higher, respectively, than those seen at the recommended daily human dosage based on AUC.

To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral agents, including nevirapine, the Antiretroviral Pregnancy Registry was established through the collaboration of antiretroviral manufacturers and an advisory committee of practitioners. Clinicians are encouraged to contact the registry at 800-258-4263 or http://www.APRegistry.com to report cases of prenatal exposure to antiretroviral agents.

Data obtained through the Antiretroviral Pregnancy Registry to date do not indicate an increased risk for congenital abnormalities among infants born to women exposed to nevirapine during the first trimester. The prevalence of congenital abnormalities observed in infants born to women exposed to nevirapine during pregnancy was similar to that observed in the general population.

The manufacturer states that there are no adequate and controlled studies to date using nevirapine in pregnant women, and the drug should be used during pregnancy only if the potential benefits justify the potential risks to the fetus.

The HHS Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission states that nevirapine in conjunction with 2 NRTIs is considered an alternative NNRTI-based regimen for initial treatment in antiretroviral-naive pregnant women with baseline CD4 T-cell counts less than 250 cells/mm. Women (including pregnant women) with baseline CD4 T-cell counts exceeding 250 cells/mm appear to be at higher risk of nevirapine-associated symptomatic and potentially fatal rash and hepatic toxicity. The HHS panel states that nevirapine should be used as part of initial regimens in pregnant women with pretreatment CD4 T-cell counts of 250 cells/mm or greater only if potential benefits clearly outweigh risks. If nevirapine is initiated in such women, caution is recommended.(See Cautions: Precautions and Contraindications.) Nevirapine may be continued in women who become pregnant while receiving a suppressive nevirapine-based regimen, regardless of their CD4 T-cell count, as long as the drug is tolerated.

Fertility

In reproduction studies in female rats, there was evidence of impaired fertility at doses providing systemic exposure approximately equivalent to that provided by the usually recommended human dosage based on AUC.

Lactation

Nevirapine is distributed into milk. Following administration of a single 100- or 200-mg dose of nevirapine to pregnant women several hours before delivery, postpartum concentrations of the drug in milk have been reported to be 25-122% of maternal serum concentrations.

Because of the risk of transmission of HIV to an uninfected infant through breast milk, the CDC and other experts recommend that HIV-infected women not breast-feed infants, regardless of antiretroviral therapy. Therefore, because of the potential for HIV transmission and the potential for serious adverse effects from nevirapine if the drug were distributed into milk, women should be instructed not to breast-feed while they are receiving nevirapine.

Drug Interactions

The following drug interactions are based on studies using nevirapine conventional (immediate-release) tablets and are expected to also apply to nevirapine extended-release tablets.

Drugs Affected or Metabolized by Hepatic Microsomal Enzymes

Metabolism of nevirapine is mediated in part by the cytochrome P-450 (CYP) 3A4 and 2B6 isoenzymes, and plasma nevirapine concentrations may be decreased by concomitant use of drugs that induce these isoenzymes (e.g., rifabutin, rifampin) or may be increased by concomitant use of drugs that inhibit these isoenzymes (e.g., cimetidine, macrolides). In addition, nevirapine is an inducer of CYP3A4 and CYP2B6 and may alter the pharmacokinetics of drugs metabolized by these isoenzymes (e.g., HIV protease inhibitors). While principally an inducer of CYP3A4 and CYP2B6, nevirapine may also inhibit these enzymes; however, the drug may have only a minimal inhibitory effect on other substrates of CYP3A4 at therapeutic concentrations.

Nevirapine does not appear to affect plasma concentrations of drugs that are substrates of other CYP isoenzymes (e.g., 1A2, 2D6, 2A6, 2E1, 2C9, 2C19).

Antifungal Agents

Fluconazole

Nevirapine and fluconazole should be used concomitantly with caution and patients closely monitored for nevirapine-associated adverse effects. Because of a possible increased risk of hepatotoxicity, some experts suggest that an alternative antiretroviral agent be considered in patients receiving fluconazole.

Concomitant use of fluconazole and nevirapine does not appear to affect plasma concentrations or area under the concentration-time curve (AUC) of the antifungal agent; however, based on comparison with historical data, concomitant use results in about a 100% increase in nevirapine exposure.

Itraconazole

Itraconazole and nevirapine should not be used concomitantly since plasma concentrations of the antifungal may be decreased and antifungal efficacy may be reduced. If the drugs are used concomitantly, plasma concentrations of itraconazole should be monitored and dosage of the antifungal adjusted accordingly.

Ketoconazole

Ketoconazole and nevirapine should not be used concomitantly since plasma concentrations of the antifungal may be decreased and antifungal efficacy may be reduced.

Concomitant use of ketoconazole (400 mg once daily) and nevirapine (200 mg once daily for 2 weeks followed by 200 mg twice daily for 2 weeks) in HIV-infected patients decreased ketoconazole peak plasma concentrations and AUC by 44 and 72%, respectively.

Voriconazole

Concomitant use of voriconazole and nevirapine may result in decreased voriconazole concentrations and increased nevirapine concentrations. If the drugs are used concomitantly, patients should be monitored for adverse effects or toxicity and clinical response to voriconazole and/or plasma concentrations of the antifungal should be monitored.

Antimalarial Agents

Concomitant use of the fixed combination of artemether and lumefantrine (artemether/lumefantrine) and nevirapine decreases the AUC of artemether and the active metabolite of artemether (dihydroartemisinin) and may increase the AUC of lumefantrine. Although the clinical importance of this interaction is unknown, patients should be closely monitored for antimalarial efficacy and lumefantrine toxicity.

Antimycobacterial Agents

Bedaquiline

Concomitant use of bedaquiline and nevirapine does not affect the AUC of bedaquiline. Dosage adjustments are not necessary if bedaquiline and nevirapine are used concomitantly.

Rifabutin

Nevirapine and rifabutin should be used concomitantly with caution. Some experts state that dosage adjustments are unnecessary if the drugs are used concomitantly.

Concomitant use of rifabutin and nevirapine results in a 28% increase in peak plasma concentrations and 17% increase in the AUC of rifabutin and similar increases in plasma concentrations and AUC of its major metabolite. However, because of interindividual variability, some patients may experience large increases in rifabutin exposure and may be at higher risk of rifabutin toxicity.

Rifampin

Concomitant use of rifampin and nevirapine is not recommended.

Concomitant administration of rifampin and nevirapine results a greater than 50% decrease in nevirapine peak plasma concentration and AUC; peak plasma concentrations of rifampin are unaffected bit the AUC of rifampin is increased 11%.

Rifapentine

Concomitant use of rifapentine and nevirapine is not recommended. HIV-infected tuberculosis patients treated with rifapentine have a higher rate of tuberculosis relapse than those treated with other rifamycin-based tuberculosis regimens; an alternative antimycobacterial agent is recommended in these patients.

Antineoplastic Agents

Concomitant use of nevirapine and cyclophosphamide is predicted to result in decreased plasma concentrations of the antineoplastic agent. Appropriate dosages for concomitant use of cyclophosphamide and nevirapine have not been established.

Antiretroviral Agents

HIV Entry and Fusion Inhibitors

Maraviroc

Concomitant use of maraviroc and nevirapine does not affect the AUC of maraviroc. If nevirapine is used with maraviroc in a regimen that does not include an HIV PI or other potent CYP3A inhibitor, the recommended maraviroc dosage is 300 mg twice daily. If nevirapine is used with maraviroc in a regimen that includes a PI (except ritonavir-boosted tipranavir), the recommended maraviroc dosage is 150 mg twice daily.

There is no in vitro evidence of antagonistic antiretroviral effects between maraviroc and nevirapine.

HIV Integrase Inhibitors (INSTIs)

Dolutegravir

Concomitant use of nevirapine and dolutegravir may decrease plasma dolutegravir concentrations. Nevirapine and dolutegravir should not be used concomitantly; data are insufficient to make dosage recommendations.

There is no in vitro evidence of antagonistic antiretroviral effects between dolutegravir and nevirapine.

Elvitegravir and Cobicistat

Concomitant use of the fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (EVG/COBI/TDF/FTC) and nevirapine may result in altered concentrations of elvitegravir, cobicistat, and/or nevirapine. EVG/COBI/TDF/FTC should not be used concomitantly with nevirapine.

Raltegravir

Some experts state that dosage adjustments are not necessary if raltegravir is used concomitantly with nevirapine.

There is in vitro evidence of additive to synergistic antiretroviral effects between raltegravir and nevirapine.

HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Nevirapine should not be used concomitantly with other NNRTIs (delavirdine, efavirenz, etravirine, rilpivirine).

Concomitant use of efavirenz and nevirapine results in a 12% decrease in peak plasma concentrations and a 28% decrease in the AUC of efavirenz. An increased incidence of adverse effects and no improvement in efficacy have been reported when these NNRTIs were used concomitantly. Appropriate dosages for concomitant use of efavirenz and nevirapine with respect to safety and efficacy have not been established.

Concomitant use of nevirapine and delavirdine, etravirine, or rilpivirine may result in altered plasma concentrations of the drugs.

HIV Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Results of in vitro studies indicate that the antiretroviral effects of nevirapine and some NRTIs (e.g., abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zidovudine) may be additive or synergistic against HIV-1.

Didanosine

Concomitant use of didanosine and nevirapine does not appear to affect the pharmacokinetics of either drug.

Stavudine

Concomitant use of stavudine (30-40 mg twice daily) and nevirapine (200 mg once daily for 14 days, then 200 mg twice daily for 14 days) does not have a clinically important effect on peak plasma concentrations or AUC of stavudine.

Zidovudine

Concomitant use of zidovudine and nevirapine results in a 28 and 30% decrease in zidovudine peak plasma concentrations and AUC, respectively.

HIV Protease Inhibitors (PIs)

Results of in vitro studies indicate that the antiretroviral effects of nevirapine and some HIV PIs (e.g., amprenavir [active metabolite of fosamprenavir], atazanavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir) may be additive to synergistic against HIV-1. There is no in vitro evidence of antagonistic antiretroviral effects between nevirapine and atazanavir or darunavir.

Atazanavir

Concomitant use of atazanavir or ritonavir-boosted atazanavir with nevirapine results in decreased atazanavir plasma concentrations and AUC and increased nevirapine concentrations and AUC.

Atazanavir (with or without low-dose ritonavir) and nevirapine should not be used concomitantly.

Darunavir

Concomitant use of ritonavir-boosted darunavir and nevirapine results in increased plasma concentrations and AUC of darunavir and nevirapine.

Ritonavir-boosted darunavir and nevirapine can be used concomitantly without dosage adjustments.

Fosamprenavir

Concomitant use of nevirapine and fosamprenavir (without low-dose ritonavir) results in a 33% decrease in the AUC of amprenavir (active metabolite of fosamprenavir) and a 29% increase in the AUC of nevirapine. Concomitant use of nevirapine with a twice-daily regimen of ritonavir-boosted fosamprenavir results in an 11% decrease in amprenavir AUC and 14% increase in nevirapine AUC.

Usual nevirapine dosage can be used concomitantly with a twice-daily regimen of ritonavir-boosted fosamprenavir (fosamprenavir 700 mg twice daily and ritonavir 100 mg twice daily). Concomitant use of nevirapine with a once-daily regimen of ritonavir-boosted fosamprenavir has not been studied.

Concomitant use of fosamprenavir (without low-dose ritonavir) and nevirapine is not recommended.

Indinavir

Concomitant use of nevirapine (200 mg once daily for 14 days, then 200 mg every 12 hours for 14 days) and indinavir (800 mg every 8 hours) decreased peak plasma concentrations and AUC of indinavir by 15 and 31%, respectively.

Appropriate dosages for concomitant use of nevirapine and indinavir with respect to safety and efficacy have not been established.

Lopinavir

Concomitant use of nevirapine and the fixed combination containing lopinavir and ritonavir (lopinavir/ritonavir) results in decreased lopinavir plasma concentrations and AUC.

A once-daily regimen of lopinavir/ritonavir should not be used in patients receiving nevirapine.

If a twice-daily regimen of lopinavir/ritonavir is used in patients receiving nevirapine, an increased lopinavir/ritonavir dosage is recommended. Dosage depends on the lopinavir/ritonavir preparation used (tablets, oral solution) and clinical characteristics of the patient. (For specific dosage recommendations,

Nelfinavir

Appropriate dosages for concomitant use of nelfinavir and nevirapine with respect to safety and efficacy have not been established.

In one study, concomitant use of nevirapine (200 mg once daily for 14 days, followed by 200 mg twice daily for 14 days) and nelfinavir (750 mg 3 times daily for 36 days) did not affect nelfinavir peak plasma concentrations or AUC, but resulted in a 32% decrease in trough plasma concentrations of the drug and a 62-66% decrease in plasma concentrations and AUC of the major nelfinavir metabolite (M8).

Ritonavir

Concomitant use of ritonavir and nevirapine in a limited number of HIV-infected patients did not result in clinically important changes in ritonavir plasma concentrations or AUC.

Saquinavir

Appropriate dosages for concomitant use of ritonavir-boosted saquinavir and nevirapine with respect to safety and efficacy have not been established.

Concomitant use of saquinavir and nevirapine results in decreased saquinavir concentrations and AUC, but does not have a clinically important effect on nevirapine concentrations. Concomitant use of ritonavir-boosted saquinavir and nevirapine has not been evaluated.

Tipranavir

Concomitant use of nevirapine and ritonavir-boosted tipranavir does not result in clinically important effects on nevirapine concentrations; the effect of concomitant use on tipranavir pharmacokinetics is unknown.

Some experts state that dosage adjustments are not necessary if nevirapine and ritonavir-boosted tipranavir are used concomitantly.

Cardiovascular Agents

Antiarrhythmic Agents

Concomitant use of nevirapine and antiarrhythmic agents (e.g., amiodarone, disopyramide, lidocaine) may result in decreased plasma concentrations of the antiarrhythmic agent. Appropriate dosages for concomitant use of these antiarrhythmic agents and nevirapine have not been established.

Antilipemic Agents

Lovastatin

Concomitant use of lovastatin and nevirapine may result in decreased plasma concentrations of the statin. If lovastatin is used concomitantly with nevirapine, lovastatin dosage should be titrated based on lipid response and should not exceed the maximum recommended dosage. Lovastatin should be avoided if nevirapine is used in a regimen that includes a ritonavir-boosted PI.

Pitavastatin

Data are not available regarding concomitant use of pitavastatin and nevirapine, but clinically important interactions are not expected and dosage adjustments are not needed.

Simvastatin

Concomitant use of simvastatin and nevirapine may result in decreased plasma concentrations of the statin. If simvastatin is used concomitantly with nevirapine, simvastatin dosage should be titrated based on lipid response and should not exceed the maximum recommended dosage. Simvastatin should be avoided if nevirapine is used in a regimen that includes a ritonavir-boosted PI.

Calcium-channel Blocking Agents

Concomitant use of nevirapine and calcium-channel blocking agents (diltiazem, nifedipine, verapamil) may result in decreased plasma concentrations of these agents. Appropriate dosages for concomitant use of these calcium-channel blocking agents and nevirapine have not been established. If nevirapine is used concomitantly, dosage of the calcium-channel blocking agent should be titrated based on clinical response.

CNS Agents

Benzodiazepines

Data are not available regarding concomitant use of alprazolam and nevirapine; if the drugs are used concomitantly, some experts suggest that patients be monitored for therapeutic effectiveness of the benzodiazepine.

Opiate Agonists

Buprenorphine

Concomitant use of buprenorphine and nevirapine does not result in a clinically important pharmacokinetic interaction; dosage adjustments are not necessary if the drugs are used concomitantly.

Fentanyl

Concomitant use of fentanyl and nevirapine may decrease plasma concentrations of the opiate agonist. Appropriate dosages for concomitant use of fentanyl and nevirapine have not been established.

Methadone

There have been reports of opiate withdrawal and subtherapeutic or decreased serum methadone concentrations following initiation of nevirapine therapy in individuals who were receiving long-term methadone treatment for opiate addiction; nevirapine concentrations are not affected.

Individuals receiving concomitant nevirapine and methadone therapy should be informed of this potential interaction and closely monitored for signs of opiate withdrawal when nevirapine therapy is initiated; an increase in methadone maintenance dosage may be necessary. If methadone dosage is increased during nevirapine therapy, patients should be monitored for methadone overdosage when the antiretroviral agent is discontinued.

Anticonvulsants

Concomitant use of nevirapine and anticonvulsants (carbamazepine, clonazepam, ethosuximide, phenobarbital, phenytoin) may result in decreased plasma concentrations of the anticonvulsant and nevirapine. Nevirapine and these anticonvulsants should be used concomitantly with caution. Anticonvulsant and nevirapine concentrations and antiretroviral response should be monitored; alternatively, use of another anticonvulsant can be considered.

Corticosteroids

Concomitant use of dexamethasone and nevirapine may result in decreased nevirapine concentrations. If dexamethasone and nevirapine are used concomitantly, antiretroviral response should be monitored; an alternative corticosteroid should be considered for long-term therapy.

Concomitant use of prednisone (40 mg daily) during the first 14 days of nevirapine therapy is not recommended since it has been associated with an increased incidence and severity of rash during the first 6 weeks of nevirapine therapy.(See Cautions: Dermatologic and Sensitivity Reactions.)

Ergot Alkaloids and Derivatives

Concomitant use of nevirapine and ergot alkaloids (e.g., dihydroergotamine, ergotamine, methylergonovine) is predicted to result in decreased plasma concentrations of the ergot alkaloid. Appropriate dosages for concomitant use of ergotamine and nevirapine have not been established.

If methylergonovine maleate (Methergine) is used to treat postpartum hemorrhage in a woman receiving nevirapine, additional uterotonic agents may be needed since nevirapine potentially could decrease methylergonovine concentrations resulting in an inadequate treatment effect.

Estrogens/Progestins

Concomitant use of nevirapine and an oral contraceptive containing 0.035 mg of ethinyl estradiol and 1 mg of norethindrone decreased the AUC of both hormones by about 20%.

Concomitant use of nevirapine and medroxyprogesterone acetate (150 mg given IM every 3 months) did not affect concentrations of the contraceptive.

Oral contraceptives or other hormonal methods of birth control (other than medroxyprogesterone acetate) should not be used as the sole method of contraception in women receiving nevirapine since the antiretroviral agent may decrease concentrations of the hormones. An alternative or additional methods of birth control is recommended in patients receiving hormonal contraceptives and nevirapine.

If oral contraceptives are used for hormonal regulation during nevirapine therapy, the therapeutic effect of the hormonal therapy should be monitored.

GI Drugs

Results of a study in 24 healthy adults indicate that concomitant use of a single 200-mg dose of immediate-release nevirapine and 30 mL of an antacid (Maalox) does not affect the extent of absorption (AUC) of the antiretroviral agent. Immediate-release nevirapine may be administered with antacids.

Concomitant use of nevirapine and cisapride is predicted to result in decreased plasma concentrations of cisapride. Appropriate dosages for concomitant use of cisapride and nevirapine have not been established.

HCV Antivirals

HCV Protease Inhibitors

Boceprevir

Concomitant use of boceprevir and nevirapine may decrease plasma boceprevir concentrations. Boceprevir and nevirapine should not be used concomitantly since boceprevir efficacy may be decreased.

Simeprevir

Concomitant use of simeprevir and nevirapine is expected to decrease simeprevir concentrations. Simeprevir and nevirapine should not be used concomitantly.

Telaprevir

Concomitant use of telaprevir and nevirapine may decrease telaprevir concentrations and increase nevirapine concentrations. Telaprevir and nevirapine should not be used concomitantly since telaprevir efficacy may be decreased and risk of nevirapine-associated adverse effects may be increased.

Immunosuppressive Agents

Concomitant use of nevirapine and immunosuppressive agents such as cyclosporine, tacrolimus, or sirolimus is predicted to result in decreased plasma concentrations of these agents. Appropriate dosages for concomitant use of these immunosuppressive agents and nevirapine have not been established. If nevirapine is used concomitantly with one of these immunosuppressive agents, increased dosage of the immunosuppressive agent may be necessary. Therapeutic drug monitoring of the immunosuppressive agent is recommended; consultation with a specialist may be necessary.

Macrolides

Concomitant use of clarithromycin and nevirapine has resulted in decreased clarithromycin concentrations and AUC and increased concentrations and AUC of its major metabolite (14-hydroxyclarithromycin). Because the clarithromycin metabolite has reduced activity against Mycobacterium avium complex (MAC), overall activity of the drug against this organism may be altered. Therefore, patients receiving nevirapine and clarithromycin concomitantly should be monitored for efficacy of the macrolide or an alternative to clarithromycin (e.g., azithromycin) should be used for treatment or prophylaxis of MAC.

Phosphodiesterase Type 5 Inhibitors

Data are not available regarding concomitant use of avanafil and nevirapine; concomitant use is not recommended.

Quinupristin and Dalfopristin

Although specific studies are not available, it is possible that concomitant use of nevirapine and quinupristin and dalfopristin may result in increased nevirapine plasma concentrations since quinupristin and dalfopristin is a potent inhibitor of CYP3A4.

Warfarin

Concomitant use of nevirapine and warfarin is predicted to alter warfarin plasma concentrations resulting in increased or decreased effects of the anticoagulant. The in vitro interaction between nevirapine and warfarin is complex. The INR should be closely monitored in patients receiving nevirapine and warfarin concomitantly and warfarin dosage adjusted accordingly.

Dietary and Herbal Supplements

St. John's Wort (Hypericum perforatum)

Concomitant use of St. John's wort (Hypericum perforatum) and nevirapine is not recommended since such use is expected to result in suboptimal antiretroviral concentrations and may be associated with loss of virologic response and development of resistance. St. John's wort is an extract of hypericum and contains at least 7 different components that may contribute to its pharmacologic effects, including hypericin, pseudohypericin, and hyperforin. There is evidence that hypericum extracts can induce several different CYP isoenzymes, including CYP3A4 and CYP1A2, and also may induce the p-glycoprotein transport system. Therefore, it has been recommended that concomitant use of St. John's wort and HIV PIs or NNRTIs metabolized by CYP isoenzymes be avoided. For further information on drug interactions between St. John's wort and drugs metabolized by CYP isoenzymes,

Pharmacokinetics

The pharmacokinetics of nevirapine have been studied in healthy adults, adults with human immunodeficiency virus type 1 (HIV-1) infection, and pediatric patients 14 days of age and older with HIV-1 infection. Studies to date have not revealed clinically important race-related differences in the pharmacokinetics of nevirapine. Studies in adults 18-68 years of age have not revealed any age-related differences in the pharmacokinetics of nevirapine; however, pharmacokinetics of the drug have not been extensively studied to date in geriatric adults older than 55-65 years of age.

The pharmacokinetics of nevirapine in pregnant women generally are similar to that reported in nonpregnant adults; dosage adjustments are not recommended during pregnancy.

Immediate-release tablets containing nevirapine and the oral suspension containing nevirapine hemihydrate are bioequivalent and can be used interchangeably at doses up to 200 mg.

Bioavailability of 400 mg of nevirapine administered as extended-release tablets relative to 400 mg administered as conventional (immediate-release) tablets is approximately 75%.

Absorption

Following oral administration of nevirapine immediate-release tablets or oral suspension in healthy or HIV-infected adults, the drug is readily (more than 90%) absorbed. Absolute bioavailability of nevirapine in 12 healthy adults was 93% following administration of a single 50-mg immediate-release tablet or 91% following administration of an oral solution of the drug. Peak plasma nevirapine concentrations average 2 mcg/mL and are attained within 4 hour after a single 200-mg dose in adults. Following multiple doses, peak plasma nevirapine concentrations appear to increase linearly in the dosage range of 200-400 mg daily. Nevirapine dosage of 400 mg daily resulted in steady-state trough plasma concentrations of 4.5 mcg/mL.

Following oral administration of a single 400-mg dose of nevirapine as an extended-release tablet in healthy adults, mean peak plasma concentrations were 2.06 mcg/mL and were attained at a median of approximately 24 hours. In a multiple-dose study in adults with HIV-1 infection who were switched from nevirapine immediate-release tablets to nevirapine extended-release tablets given under fasting conditions, the mean area under the concentration-time curve (AUC) and trough plasma concentrations after 19 days of the extended-release preparation were 82 mcg&bul;hr/mL and 2.92 mcg/mL, respectively.

Following oral administration of multiple doses of nevirapine 150 mg/m twice daily as the immediate-release oral suspension in HIV-infected pediatric patients, trough plasma concentrations averaged 4-6 mcg/mL. In HIV-infected children 6 to less than 18 years of age who were switched to nevirapine extended-release tablets after at least 18 weeks of immediate-release nevirapine, overall mean systemic nevirapine exposure with the extended-release preparation was similar to that reported for the immediate-release preparation. At steady state, the observed geometric mean ratios of extended-release nevirapine to immediate-release nevirapine were approximately 97% for trough plasma concentrations and 94% for AUCs; the ratio for peak plasma concentrations was lower and consistent with the once-daily extended-release preparation.

In 8 neonates who had serum nevirapine concentrations of 141-768 ng/mL at birth as the result of distribution across the placenta from their HIV-infected mothers who had received single 200-mg doses of the drug 3-7 hours prior to delivery (see Pharmacokinetics: Distribution), administration of a single 2-mg/kg dose of nevirapine to the neonates 48-78 hours after birth resulted in peak neonatal serum concentrations of 1355 ng/mL (range: 644-1607 ng/mL) at 2-24 hours after the dose. Serum nevirapine concentrations in these neonates 7 days after birth were estimated to be 215 ng/mL (range: 112-275 ng/mL) based on extrapolation from the concentration-time plots and the elimination rate constant.

Food

Results of a study in 24 healthy adults indicate that when 200 mg of nevirapine as immediate-release tablets is administered with a high-fat meal (857 kcal, 50 g fat, 53% of calories from fat), the extent of absorption (AUC) is comparable to that observed under fasting conditions.

When nevirapine extended-release tablets were administered under fed conditions, the mean nevirapine AUC and trough plasma concentrations at steady state were 96.7 mcg&bul;hr/mL and 3.15 mcg/mL, respectively. The bioavailability of 400 mg of nevirapine as extended-release tablets relative to 400 mg of the drug given as immediate-release tablets under fasted and fed conditions was 80 and 94%, respectively. The difference in bioavailability of nevirapine extended-release tablets under fasted or fed conditions is not considered clinically important.

Distribution

Distribution of nevirapine into body tissues and fluids has not been fully characterized; however, animal studies indicate that the drug is widely distributed into most tissues. Nevirapine is highly lipophilic and is essentially nonionized at physiologic pH.

Following IV administration in healthy adults, the apparent volume of distribution of nevirapine is 1.21 L/kg, suggesting that the drug is widely distributed in humans.

In a study in 12 HIV-infected men receiving nevirapine in conjunction with lamivudine or stavudine, nevirapine was distributed into semen in concentrations that were approximately 60% of concurrent plasma concentrations.

Results of a study in 6 individuals indicate that nevirapine is distributed into CSF in concentrations that are 45% of concurrent plasma concentrations; this ratio is approximately equal to the fraction of the drug not bound to plasma proteins.

At plasma concentrations of 1-10 mcg/mL, nevirapine is approximately 60% bound to plasma proteins.

Nevirapine readily crosses the placenta in humans. In a limited number of HIV-infected pregnant women who received a single 100- or 200-mg oral dose of nevirapine 0.9-10.5 hours prior to delivery, cord blood concentrations of nevirapine were 74-123% of maternal serum concentrations and peak serum concentrations of the drug in the neonates of these women averaged 862 ng/mL (range: 257-1031 ng/mL) or 925 ng/mL (range: 62-2030 ng/mL), respectively. In pregnant HIV-infected women who received a regimen of nevirapine (200 mg once daily for 2 weeks followed by 200 mg twice daily), zidovudine, and lamivudine during the second and third trimester, cord blood concentrations (at delivery) and neonatal serum concentrations (24 hours after birth) of nevirapine were 76 and 60%, respectively, of maternal serum concentrations (at delivery). These neonatal concentrations were lower than those reported in neonates whose mothers received a single nevirapine dose during labor, possibly as the result of hepatic enzyme induction in the neonate after placental transfer.

Nevirapine is distributed into human milk. Following administration of a single 100- or 200-mg dose of nevirapine to pregnant women several hours before delivery, postpartum, concentrations of the drug in milk were 25-122% of maternal serum concentrations.

Elimination

Nevirapine is extensively converted in vivo to several hydroxylated metabolites via cytochrome P-450 (CYP) oxidative metabolism. In vitro studies using human liver microsomes indicate that metabolism of nevirapine is mediated principally by CYP3A4, but other isoenzymes may also play a role in metabolism of the drug.

There is evidence that nevirapine induces CYP3A4 and CYP2B6 enzymes resulting in autoinduction of its own metabolism. The pharmacokinetics of autoinduction are characterized by an approximately 1.5- to 2-fold increase in the apparent oral clearance of nevirapine as treatment continues from a single dose to 2-4 weeks of dosing at a dosage of 200-400 mg daily. Autoinduction also results in a corresponding decrease in the terminal phase half-life of nevirapine in plasma from approximately 45 hours with a single dose to approximately 25-30 hours following multiple dosing using a dosage of 200-400 mg daily in adults.

In a study in 8 healthy adults who received 200 mg once daily for 2 weeks followed by 200 mg twice daily for 2 weeks to reach steady state and then received a single 50-mg dose of radiolabeled nevirapine, approximately 81% of the radiolabeled dose was recovered in urine and approximately 10% was recovered in feces over a period of 10 days. More than 80% of the radioactivity in urine consisted of glucuronide conjugates of hydroxylated metabolites. Therefore, CYP metabolism, glucuronide conjugation, and urinary excretion of glucuronidated metabolites represent the principal route of biotransformation and elimination of nevirapine in humans. Less than 5% of the radioactivity in urine (representing less than 3% of the total dose) consisted of unchanged drug.

Results of a study in a limited number of HIV-negative adults with mild, moderate, or severe renal impairment indicate that there are no clinically important changes in the pharmacokinetics of a single dose of nevirapine as immediate-release tablets in adults with impaired renal function. However, adults undergoing dialysis have a 44% reduction in the AUC of nevirapine after 1 week of nevirapine therapy; treatment and accumulation of the hydroxy metabolites of the drug also may occur. In an HIV-infected adult with end-stage renal failure on continuous ambulatory peritoneal dialysis who was receiving a regimen of nevirapine immediate-release tablets (200 mg twice daily), nelfinavir (1250 mg twice daily), and zidovudine (250 mg twice daily), peak and trough plasma concentrations of nevirapine were 4.7 and 2.6 mcg/mL, respectively, and the AUC_0-12 was 46.6 mcg&bul;hr/mL. The drug was removed by peritoneal dialysis, and concentrations in peritoneal dialysis fluid were approximately 50% of plasma concentrations.

Disposition of nevirapine was not altered in HIV-infected adults with mild, moderate, or severe hepatic fibrosis who received multiple doses of nevirapine immediate-release tablets (nevirapine 200 mg twice daily for at least 6 weeks); however, approximately 15% of these individuals had nevirapine trough concentrations that were twofold higher than the usual mean trough concentrations.

In a limited study in HIV-negative adults with mild or moderate hepatic impairment who received a single 200-mg dose of nevirapine as immediate-release tablets, most patients had no clinically important change in the pharmacokinetics of the drug. However, in one patient with moderate hepatic impairment (Child-Pugh Class B) and ascites, there was an increase in the AUC of nevirapine. Because nevirapine induces its own metabolism with multiple doses, a single-dose study may not reflect the impact of hepatic impairment on multiple-dose pharmacokinetics.

Nevirapine extended-release tablets have not been studied in patients with renal or hepatic impairment.

In a population substudy, women had a 13.8% lower clearance of nevirapine than men. These results could not be explained by body weight or body mass index differences between men and women.