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Nevirapine

Class: HIV Nonnucleoside Reverse Transcriptase Inhibitors
- Reverse Transcriptase Inhibitors
VA Class: AM800
Chemical Name: 11-Cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b: 2′,3′-e)[1,4]diazepin-6-one
Molecular Formula: C15H14N4O
CAS Number: 129618-40-2
Brands: Viramune

Medically reviewed by Drugs.com on Aug 3, 2021. Written by ASHP.

Warning

    Hepatotoxicity
  • Severe, life-threatening (and in some cases fatal) hepatotoxicity reported, particularly during first 18 weeks of therapy. In some cases, patients presented with nonspecific prodromal signs or symptoms of hepatitis and progressed to hepatic failure; these events often associated with rash. Patients with higher CD4+ T-cell counts at initiation of therapy and women are at increased risk. Women with CD4+ T-cell counts >250 cells/mm3 (including pregnant women receiving nevirapine with other antiretrovirals for treatment of HIV-1 infection) are at greatest risk, but hepatotoxicity can occur in both genders, all CD4+ T-cell counts, and at any time during treatment. Patients with signs or symptoms of hepatitis or with increased serum aminotransferase (transaminase) concentrations in conjunction with rash or other systemic symptoms must discontinue nevirapine and immediately seek medical evaluation.

  • Contraindicated for postexposure prophylaxis of HIV following occupational or nonoccupational exposures; hepatic failure reported in patients without HIV infection receiving nevirapine for postexposure prophylaxis.

    Skin Reactions
  • Severe, life-threatening skin reaction, including fatal cases, reported. Reactions include Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction. Patients with signs or symptoms of severe skin reactions or hypersensitivity must discontinue nevirapine and immediately seek medical evaluation. Immediately measure serum transaminase concentrations if rash occurs during first 18 weeks of nevirapine therapy.

  • Must be initiated using a lead-in 14-day period of low dosage of conventional (immediate-release) nevirapine (200 mg once daily in adults) since this decreases the incidence of rash.

    Monitoring
  • Must monitor patients intensively during first 18 weeks of therapy to detect potential life-threatening hepatotoxicity or skin reactions. Extra vigilance warranted during first 6 weeks, the period of greatest risk.

  • Do not restart nevirapine following clinical hepatitis, elevated transaminase concentrations combined with rash or other systemic symptoms, or following severe rash or hypersensitivity reactions.

Introduction

Antiretroviral; HIV nonnucleoside reverse transcriptase inhibitor (NNRTI).

Uses for Nevirapine

Treatment of HIV Infection

Treatment of HIV-1 infection in adults, adolescents, and pediatric patients; usually used in conjunction with 2 HIV nucleoside reverse transcriptase inhibitors (NRTIs).

Because of increased risk of potentially life-threatening hepatotoxicity, do not initiate in females (including postpubertal girls and adolescents) with pretreatment CD4+ T-cell counts >250/mm3 or in males (including adolescent boys) with CD4+ T-cell counts >400/mm3 unless potential benefits clearly outweigh risks. (See Hepatic Effects under Cautions.)

For initial treatment in antiretroviral-naive adults or adolescents, experts state nevirapine not recommended since it is associated with serious and potentially fatal toxicity (e.g., hepatic events and severe rash, including Stevens-Johnson syndrome and toxic epidermal necrolysis) and did not meet noninferiority criteria when compared to efavirenz.

For initial treatment in antiretroviral-naive pediatric patients, experts state that nevirapine and 2 NRTIs is an alternative (not preferred) regimen in those >14 days and <3 years of age.

Experts state that nevirapine and 2 NRTIs is the regimen of choice for initial treatment in neonates <14 days of age when HIV infection confirmed. Consultation with an expert in pediatric HIV infection recommended; unclear whether initiation of antiretroviral treatment within first 14 days of life improves outcome compared with initiation at >14 days of age. If used, consider changing to fixed-combination lopinavir and ritonavir (lopinavir/ritonavir) and 2 NRTIs when infant is 14 days of age with postmenstrual age at least 42 weeks (i.e., time elapsed since first day of mother’s last menstrual period to birth plus time elapsed after birth).

Prevention of Perinatal HIV Transmission

Prophylaxis in neonates born to HIV-infected women for prevention of perinatal HIV transmission; used in conjunction with zidovudine.

Empiric HIV therapy in neonates born to HIV-infected women for prevention of perinatal HIV transmission; used in 3-drug empiric regimen (zidovudine, lamivudine, and nevirapine) in neonates at highest risk of HIV acquisition.

Pregnant HIV-infected women: Multiple-drug antiretroviral regimens are standard of care in the US for treatment of HIV infection in pregnant women and for prevention of perinatal HIV transmission. In addition, to further decrease risk of perinatal HIV transmission, experts recommend that all pregnant HIV-infected women with plasma HIV-1 RNA levels >1000 copies/mL (or unknown HIV-1 RNA levels) near delivery receive an intrapartum IV zidovudine prophylaxis regimen initiated at the onset of labor (or 3 hours before scheduled cesarean delivery) and continued until delivery (unless contraindicated).

HIV-exposed neonates: Experts recommend that all neonates born to HIV-infected women (HIV-exposed neonates) receive an antiretroviral regimen (either prophylaxis or empiric HIV therapy) initiated as soon as possible after birth (preferably within 6–12 hours) and continued through 4–6 weeks of age. Select antiretroviral prophylaxis regimen or empiric HIV therapy regimen based on likelihood of perinatal HIV transmission. HIV-exposed neonates at low risk of perinatal HIV acquisition (i.e., infants born to women who were receiving a recommended multiple-drug antiretroviral regimen during pregnancy with sustained viral suppression near delivery and no concerns related to maternal adherence to the treatment regimen) may receive a 4-week zidovudine prophylaxis regimen used alone. HIV-exposed neonates at higher risk of HIV acquisition (e.g., those born to HIV-infected women who did not receive antepartum or intrapartum antiretrovirals, received only intrapartum antiretrovirals, or received antepartum and intrapartum antiretrovirals with suboptimal viral suppression near delivery) should receive a 2-drug prophylaxis regimen (6-week zidovudine prophylaxis and 3-dose nevirapine prophylaxis). Alternatively, those at highest risk can receive a 3-drug empiric HIV therapy regimen (zidovudine, lamivudine, and nevirapine).

Maternal and neonatal regimens recommended for prevention of perinatal HIV transmission in the US may differ from those used in other countries.

Consult 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.

Nevirapine Dosage and Administration

Administration

Oral Administration

Administer orally with or without food.

Conventional (immediate-release) tablets and oral suspension: Use in adults, adolescents, and pediatric patients ≥15 days of age.

Extended-release tablets: Use in adults, adolescents, and pediatric patients ≥6 years of age.

Extended-release Tablets

Extended-release tablets: Swallow whole; do not chew, crush, or divide.

When considering use in a child ≥6 years of age, assess child for ability to swallow tablets.

Oral Suspension

Shake suspension gently prior to each dose.

Administer using calibrated dosing syringe (especially for volumes <5 mL). Alternatively, administer using dosing cup; rinse cup with water and administer the rinse to the patient.

Dosage

Available as nevirapine (immediate-release tablets, extended-release tablets) and nevirapine hemihydrate (oral suspension); dosage expressed in terms of nevirapine.

Initiate therapy using a low dosage of immediate-release nevirapine for first 14 days since this appears to reduce frequency of rash. Do not use extended-release tablets during initial 14 days of nevirapine therapy.

If mild to moderate rash without constitutional symptoms occurs during initial 14-day period of low dosage of immediate-release nevirapine, do not increase dosage until rash resolves. Do not continue initial low dosage beyond 28 days; if rash does not resolve by day 28, discontinue nevirapine and select alternative therapy.

If nevirapine therapy has been interrupted for >7 days for any reason and is not contraindicated, restart using the recommended low initial dosage of immediate-release nevirapine for first 14 days.

Pediatric Patients

Dosage usually based on body surface area (BSA) calculated using Mosteller formula. Investigational dosage based on weight has been recommended in certain neonates.

Treatment of HIV Infection
Oral

Neonates <14 days of age: If gestational age 34 to <37 weeks, experts recommend 4 mg/kg twice daily from birth to 1 week of age, then 6 mg/kg twice daily beginning at 1 week of age. If gestational age ≥37 weeks, experts recommend 6 mg/kg twice daily.

Neonates, infants, and children ≥15 days of age (oral suspension or immediate-release tablets): Manufacturer recommends 150 mg/m2 once daily for first 14 days of therapy (lead-in period of low dosage), followed by 150 mg/m2 twice daily.

Children 6 to <18 years of age (extended-release nevirapine): Manufacturer recommends 200 mg once daily if BSA 0.58–0.83 m2, 300 mg once daily if BSA 0.84–1.16 m2, or 400 mg once daily if BSA ≥1.17 m2. If not already receiving nevirapine, use oral suspension or immediate-release tablets for lead-in period of low dosage (150 mg/m2 once daily [up to 200 mg daily]) for first 14 days, then switch to extended-release tablets.

Experts suggest that infants and children 1 month to <8 years of age require higher dosage than those ≥8 years of age. When immediate-release nevirapine used, these experts recommend 200 mg/m2 once daily for 14 days (lead-in period of low dosage) followed by 200 mg/m2 twice daily (up to 200 mg twice daily) in those 1 month to <8 years of age and 120–150 mg/m2 once daily for 14 days (lead-in period of low dosage) followed by 120–150 mg/m2 twice daily (up to 200 mg twice daily) in those ≥8 years of age. Some experts suggest lead-in period of low dosage not needed in pediatric patients ≤2 years of age.

Adolescents: Experts state usual adult dosage can be used. (See Adults under Dosage and Administration.)

Prevention of Perinatal HIV Transmission†
Prophylaxis in Neonates Born to HIV-infected Women†
Oral

Neonates at higher risk of HIV acquisition: 3 nevirapine doses (nevirapine oral suspension) during first week of life initiated as soon as possible after delivery in addition to usual 6-week neonatal zidovudine prophylaxis regimen.

Give first nevirapine dose within 48 hours of birth, second dose 48 hours after first dose, and third dose 96 hours after second dose.

Birth weight 1.5–2 kg: Experts recommend 8 mg of nevirapine for each of the 3 doses.

Birth weight >2 kg: Experts recommend 12 mg of nevirapine for each of the 3 doses.

Empiric HIV Therapy in Neonates Born to HIV-infected Women†
Oral

Recommended empiric HIV therapy regimen consists of zidovudine, lamivudine, and nevirapine initiated as soon as possible after birth (within 6–12 hours); used in HIV-exposed neonates considered at highest risk of HIV acquisition. (See Prevention of Perinatal HIV Transmission under Uses.)

Gestational age 34 to <37 weeks: Experts recommend 4 mg/kg of nevirapine twice daily from birth to 1 week of age, then 6 mg/kg twice daily beginning at 1 week of age.

Gestational age ≥37 weeks: Experts recommend 6 mg/kg of nevirapine twice daily.

Optimal duration of empiric HIV therapy in HIV-exposed neonates unknown. Many experts recommend that 3-drug empiric regimen be continued for 6 weeks; others discontinue nevirapine and/or lamivudine if results of neonate's HIV nucleic acid amplification test (NAAT) are negative, but recommend continuing zidovudine for 6 weeks.

Consult National Perinatal HIV Hotline at 888-448-8765 for information regarding selection of antiretrovirals, including dosage considerations, for prevention of perinatal HIV transmission.

Adults

Treatment of HIV Infection
Oral

Immediate-release tablets: 200 mg once daily for first 14 days (lead-in period of low dosage), followed by 200 mg twice daily.

Extended-release tablets: 400 mg once daily, initiated after immediate-release nevirapine. In those not currently receiving nevirapine, use lead-in period of low dosage of immediate-release tablets (200 mg once daily for 14 days) then switch to extended-release tablets 400 mg once daily. In those already receiving twice-daily regimen of usual dosage of immediate-release nevirapine, switch to extended-release tablets 400 mg once daily (without 14-day lead-in period).

Prescribing Limits

Pediatric Patients

Treatment of HIV Infection
Oral

Children ≥15 days of age (oral suspension or immediate-release tablets): Dosage based on BSA (maximum 400 mg daily).

Children 6 to <18 years of age (extended-release nevirapine): Dosage based on BSA (maximum 400 mg daily).

Special Populations

Hepatic Impairment

Treatment of HIV Infection
Oral

Immediate-release nevirapine: Data insufficient to make dosage recommendation in patients with mild hepatic impairment (Child-Pugh class A); some experts state dosage adjustments not necessary. Contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).

Extended-release tablets: Not studied in patients with hepatic impairment. Contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).

Renal Impairment

Treatment of HIV Infection
Oral

Immediate-release nevirapine: Dosage adjustments not needed in patients with Clcr ≥20 mL/minute not undergoing dialysis. Administer additional 200-mg dose of immediate-release nevirapine after each dialysis treatment.

Extended-release tablets: Not studied in patients with renal impairment.

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Cautions for Nevirapine

Contraindications

  • Moderate or severe hepatic impairment (Child-Pugh class B or C).

  • Do not use for postexposure prophylaxis following occupational exposure to HIV (PEP) or for postexposure prophylaxis following nonoccupational exposure to HIV (nPEP). (See Hepatic Effects under Cautions.)

Warnings/Precautions

Sensitivity Reactions

Dermatologic and Sensitivity Reactions

Severe, life-threatening skin reactions (including some fatalities) reported. Anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous eruptions, ulcerative stomatitis, urticaria, drug reaction with eosinophilia and systemic symptoms (DRESS), and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction (including hepatic failure) reported.

Patients with signs or symptoms of severe skin or hypersensitivity reactions (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 immediate medical evaluation.

Must be initiated using low dosage of immediate-release nevirapine for first 14 days (200 mg once daily in adults or 150 mg/m2 once daily in pediatric patients); this lead-in period of low dosage reduces frequency of rash. If mild to moderate rash without constitutional symptoms occurs during initial 14 days, dosage should not be increased until rash resolves. Do not continue initial low dosage beyond 28 days; discontinue nevirapine and select alternative therapy.

Monitor closely if isolated rash of any severity occurs.

Risk factors for severe cutaneous reactions include failure to follow recommended initial low dosage during first 14 days and delay in discontinuing nevirapine after onset of initial symptoms.

Women appear to be at higher risk of developing rash than men.

Prednisone not recommended for prevention of nevirapine-associated rash. (See Specific Drugs under Interactions.)

Do not restart nevirapine following hypersensitivity reaction, severe rash, or rash in conjunction with increased serum transaminase concentrations or other systemic symptoms.

Patient Monitoring

Serious adverse effects include hepatitis, hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions reported.

Intensive monitoring required during first 18 weeks of therapy to detect potentially life-threatening hepatic events and skin reactions; extra vigilance warranted during first 6 weeks (period of greatest risk). Optimum frequency of monitoring during this period not established; some experts recommend clinical and laboratory monitoring more often than once monthly and liver function tests at baseline, prior to dosage escalation, and 2 weeks after dosage escalation.

Continue frequent clinical and laboratory monitoring after initial 18-week period and throughout nevirapine therapy.

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, reported. Hepatic events can occur at any time during therapy. Risk of hepatic events (regardless of severity) greatest during the first 6 weeks of therapy; substantial risk continues through 18 weeks of therapy.

Some patients present with 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 observed in 50% of those with symptomatic hepatic adverse events. Fever and flu-like symptoms accompany some of these hepatic events. Some events, particularly those with rash or other symptoms, have progressed to hepatic failure with serum transaminase elevation, with or without hyperbilirubinemia, hepatic encephalopathy, prolonged partial thromboplastin time, and/or eosinophilia.

Patients with higher CD4 counts and women are at increased risk of hepatic events. Women with CD4 counts >250 cells/mm3, including pregnant women receiving long-term treatment for HIV infection, are at considerably higher risk of these events. Increased liver enzymes and/or HBV or HCV infection associated with increased risk.

Serious hepatotoxicity reported in individuals not infected with HIV who received nevirapine as part of a multiple-drug regimen for postexposure prophylaxis following occupational or nonoccupational exposure to HIV. Do not use in HIV postexposure prophylaxis regimens following occupational or nonoccupational exposure to the virus.

Intensive clinical and laboratory monitoring essential. (See Patient Monitoring under Cautions.)

Consider possibility of hepatotoxicity if there are signs or symptoms of hepatitis (e.g., fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness or hepatomegaly), even if liver function tests are initially normal or alternative diagnosis is possible.

Hepatic injury has progressed despite discontinuation of nevirapine in some patients.

Patients with signs and symptoms of hepatitis must seek immediate medical attention, have liver function tests performed (serum transaminase concentrations), and be advised to discontinue nevirapine as soon as possible. If nevirapine is discontinued because of hepatitis or increased serum transaminase concentrations associated with rash or other systemic symptoms, it should be permanently discontinued and not reinitiated.

Interactions

Concomitant use with certain drugs not recommended (e.g., St. John’s wort). (See Specific Drugs under Interactions.)

Adipogenic Effects

Possible redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, breast enlargement, and general cushingoid appearance. Mechanisms and long-term consequences of fat redistribution unknown; causal relationship not established.

Immune Reconstitution Syndrome

During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii]); this may necessitate further evaluation and treatment.

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

Specific Populations

Pregnancy

Antiretroviral Pregnancy Registry (APR) at 800-258-4263 or [Web].

Available data from the APR do not indicate an increased risk for overall major birth defects among infants born to women who received nevirapine during pregnancy compared with US background rate for major birth defects.

Experts states that nevirapine in conjunction with 2 NRTIs not recommended for initial treatment in antiretroviral-naive pregnant women because of greater potential for adverse events, complex lead-in dosage regimen, and low barrier for HIV resistance.

Severe hepatic events, including fatalities, reported in HIV-infected pregnant women receiving long-term nevirapine therapy as part of multiple-drug antiretroviral treatment. Because of risk of potentially life-threatening hepatotoxicity, do not initiate nevirapine in pregnant women with pretreatment CD4+ T-cell counts >250/mm3 unless potential benefits clearly outweigh risks. If initiated in such women, caution recommended. (See Hepatic Effects under Cautions.)

May be continued if tolerated in women who become pregnant, regardless of CD4+ T-cell count.

Fertility

Evidence of impaired fertility in female rats at exposure level approximately equivalent to that provided by usually recommended human dosage. Human data insufficient to determine risk of infertility in patients receiving nevirapine.

Advise females with reproductive potential that, based on results from fertility studies in rats, nevirapine may impair fertility and it is not known whether effects on fertility are reversible.

Lactation

Distributed into milk.

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.

Pediatric Use

Immediate-release tablets and oral suspension: Safety and pharmacokinetics evaluated in children 15 days to <3 months of age. Safety, pharmacokinetics, and efficacy evaluated in children 3 months to 18 years of age.

Extended-release nevirapine: Can be used in children ≥6 years of age based on pharmacokinetic, safety, and antiretroviral activity data in pediatric patients 3 to <18 years of age and efficacy data from adults. Not recommend in those 3 to <6 years of age because of insufficient pharmacokinetic data in this age group; not recommended in those <3 years of age because of inability to swallow tablets.

Immediate-release nevirapine recommended by some experts for initial treatment of confirmed HIV infection in certain neonates <14 days of age (see Treatment of HIV Infection under Uses). Also recommended for prophylaxis or empiric HIV therapy for perinatal HIV transmission in certain neonates <14 days of age (see Prevention of Perinatal HIV Transmission under Uses).

Adverse effects reported in children generally similar to those reported in adults; granulocytopenia reported more frequently in children than adults. Stevens-Johnson syndrome or Stevens-Johnson/toxic epidermal necrolysis transition syndrome reported rarely. Allergic reactions, including anaphylaxis, also reported.

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Hepatic Impairment

Carefully monitor those with hepatic impairment (e.g., those with hepatic fibrosis or cirrhosis) for toxicity.

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

Renal Impairment

Modification of usual dosage of immediate-release nevirapine dosage forms not necessary in patients with Clcr ≥20 mL/minute not requiring dialysis; additional dose of immediate-release nevirapine necessary following dialysis. Pharmacokinetics not evaluated in those with Clcr <20 mL/minute. (See Renal Impairment under Dosage and Administration.)

Extended-release tablets not studied in patients with renal impairment.

Common Adverse Effects

Rash, nausea, headache, fatigue, abnormal liver function test results. Adverse effects reported with extended-release tablets similar to those reported with immediate-release tablets.

Interactions for Nevirapine

Metabolized by CYP3A and CYP2B6.

Inhibits CYP3A and CYP2B6.

Induces CYP3A and CYP2B6.

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

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions likely with drugs that are inhibitors, inducers, or substrates of CYP3A or 2B6 with possible alteration in metabolism of nevirapine and/or other drug.

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).

Specific Drugs

Drug

Interaction

Comments

Abacavir

No in vitro evidence of antagonistic antiretroviral effects

Antacids (Maalox)

No effect on nevirapine absorption

Immediate-release nevirapine may be administered with antacids

Antiarrhythmic agents (amiodarone, disopyramide, lidocaine)

Possible decreased antiarrhythmic agent concentrations

Appropriate dosages for concomitant use not established

Anticoagulants

Apixaban, rivaroxaban: Possible decreased anticoagulant concentrations

Betrixaban, dabigatran, edoxaban: Altered anticoagulant concentrations not expected

Warfarin: Possible altered warfarin concentrations and increased or decreased anticoagulant effects

Apixaban, rivaroxaban: Consider alternative therapy

Betrixaban, dabigatran, edoxaban: Dosage adjustments not needed

Warfarin: Closely monitor INR; adjust warfarin dosage accordingly

Anticonvulsants (carbamazepine, clonazepam, eslicarbazepine, ethosuximide, phenobarbital, phenytoin)

Carbamazepine, clonazepam, phenobarbital, phenytoin: Possible decreased anticonvulsant concentrations

Eslicarbazepine: Possible decreased nevirapine concentrations

Ethosuximide: Possible decreased ethosuximide and nevirapine concentrations

Carbamazepine, clonazepam, phenobarbital, phenytoin: Use concomitantly with caution; monitor anticonvulsant and nevirapine concentrations and antiretroviral response; alternatively, consider different anticonvulsant

Eslicarbazepine: Monitor antiretroviral response and consider monitoring nevirapine concentrations; alternatively, consider different anticonvulsant or different antiretroviral

Ethosuximide: Use concomitantly with caution; monitor ethosuximide concentrations and antiretroviral response

Antidiabetic agents

Canagliflozin, dapagliflozin, empagliflozin, sitagliptin: Altered antidiabetic agent concentrations not expected

Linagliptin, saxagliptin: Possible decreased antidiabetic agent concentrations

Canagliflozin, dapagliflozin, empagliflozin, sitagliptin: Dosage adjustments not needed

Linagliptin, saxagliptin: Monitor glycemic control

Antifungals, azoles

Fluconazole: Increased nevirapine concentrations; no effect on fluconazole concentrations; possible increased risk of hepatotoxicity

Isavuconazonium (prodrug of isavuconazole): Possible decreased isavuconazole concentrations

Itraconazole: Possible decreased itraconazole concentrations and reduced antifungal efficacy

Ketoconazole: Possible decreased ketoconazole concentrations and reduced antifungal efficacy

Posaconazole: Possible increased nevirapine concentrations

Voriconazole: Possible decreased voriconazole concentrations and increased nevirapine concentrations

Fluconazole: Use concomitantly with caution; closely monitor for nevirapine adverse effects; consider alternative antiretroviral

Isavuconazonium: Antifungal dosage adjustment may be needed; consider monitoring isavuconazole concentrations and antifungal response

Itraconazole: Concomitant use not recommended; if used, monitor itraconazole concentrations and adjust itraconazole dosage accordingly

Ketoconazole: Concomitant use not recommended

Posaconazole: Monitor for nevirapine-associated adverse effects

Voriconazole: Monitor frequently for adverse effects or toxicity and response to voriconazole; monitor voriconazole plasma concentrations

Antimalarial agents

Fixed combination of artemether and lumefantrine (artemether/lumefantrine): Decreased AUC of artemether and active metabolite of artemether (dihydroartemisinin); possible altered (increased or decreased) AUC of lumefantrine

Artemether/lumefantrine: Clinical importance unknown; monitor for antimalarial efficacy and lumefantrine toxicity

Antimycobacterials (rifabutin, rifampin, rifapentine)

Bedaquiline: No effect on bedaquiline AUC

Rifabutin: Increased rifabutin concentrations (high intersubject variability, some patients may experience large increases in rifabutin exposure); decreased nevirapine concentrations

Rifampin: Decreased nevirapine concentrations

Rifapentine: Possible decreased nevirapine concentrations

Bedaquiline: Dosage adjustments not needed

Rifabutin: Use concomitantly with caution; dosage adjustment not needed

Rifampin: Concomitant use not recommended

Rifapentine: Concomitant use not recommended

Antiplatelet agents

Clopidogrel, prasugrel: Altered antiplatelet agent concentrations not expected

Ticagrelor: Decreased ticagrelor concentrations expected

Clopidogrel, prasugrel: Dosage adjustments not needed

Ticagrelor: Some experts state consider alternative therapy

Antipsychotics (lurasidone, olanzapine, pimozide, quetiapine, thioridazine)

Lurasidone, pimozide, quetiapine, thioridazine: Possible decreased antipsychotic concentrations

Olanzapine: Altered olanzapine concentrations not expected

Lurasidone, pimozide, quetiapine, thioridazine: Monitor for antipsychotic effects

Olanzapine: Dosage adjustments not needed

Atazanavir

Ritonavir-boosted atazanavir: Decreased atazanavir concentrations and AUC; increased nevirapine concentrations and AUC

Cobicistat-boosted atazanavir: Possible decreased atazanavir and cobicistat concentrations

Unboosted atazanavir: Possible decreased atazanavir concentrations

No in vitro evidence of antagonistic antiretroviral effects

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Concomitant use contraindicated

Avanafil

Possible decreased avanafil concentrations

May need to increase avanafil dosage based on clinical effects

Benzodiazepines

Alprazolam, diazepam: Possible decreased benzodiazepine concentrations

Alprazolam, diazepam: Monitor for therapeutic effectiveness of the benzodiazepine

Buprenorphine

Sublingual or buccal buprenorphine: No clinically important pharmacokinetic interactions

Buprenorphine implants: Data not available

Sublingual or buccal buprenorphine: Dosage adjustments not needed

Buprenorphine implants: If nevirapine initiated, clinical monitoring recommended

Bupropion

Decreased bupropion AUC

Titrate bupropion dosage based on clinical response

Calcium-channel blocking agents (diltiazem, nifedipine, verapamil)

Possible decreased concentrations of the calcium-channel blocking agent

Appropriate dosages for concomitant use not established; if used concomitantly, titrate dosage of calcium-channel blocking agent based on clinical response

Cisapride

Possible decreased cisapride concentrations

Appropriate dosages for concomitant use not established

Corticosteroids

Dexamethasone: Possible decreased nevirapine concentrations

Prednisone: Concomitant use during first 14 days of nevirapine has been associated with increased incidence and severity of rash during first 6 weeks of nevirapine

Dexamethasone: Monitor antiretroviral response; consider alternative corticosteroid for long-term therapy

Prednisone: Concomitant use not recommended

Cyclophosphamide

Possible decreased cyclophosphamide concentrations

Appropriate dosages for concomitant use not established

Daclatasvir

Decreased daclatasvir concentrations

Use daclatasvir dosage of 90 mg once daily

Darunavir

Ritonavir-boosted darunavir: Increased darunavir concentrations and AUC; increased nevirapine concentrations and AUC

Cobicistat-boosted darunavir: Decreased darunavir and cobicistat concentrations

No in vitro evidence of antagonistic antiretroviral effects

Ritonavir-boosted darunavir: Dosage adjustment not needed if used concomitantly with nevirapine

Cobicistat-boosted darunavir: Do not use concomitantly

Dasabuvir, ombitasvir, paritaprevir, and ritonavir

Fixed combination of dasabuvir, ombitasvir, paritaprevir, and ritonavir (dasabuvir/ombitasvir/paritaprevir/ritonavir) or fixed combination of ombitasvir, paritaprevir, and ritonavir (ombitasvir/paritaprevir/ritonavir) copackaged with dasabuvir (ombitasvir/paritaprevir/ritonavir with dasabuvir): Possible decreased HCV antiviral concentrations

Dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination) or ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged): Do not use concomitantly

Delavirdine

Possible altered delavirdine concentrations

Do not use concomitantly

Didanosine

No effect on nevirapine or didanosine pharmacokinetics

No in vitro evidence of antagonistic antiretroviral effects

Dolutegravir

Possible decreased dolutegravir concentrations

No in vitro evidence of antagonistic antiretroviral effects

Do not use concomitantly; data insufficient to make dosage recommendations

Dutasteride

Possible decreased dutasteride concentrations

Monitor and adjust dutasteride dosage if needed

Efavirenz

Decreased efavirenz concentrations and AUC; increased incidence of adverse effects and no improvement in efficacy

Do not use concomitantly; appropriate dosages for concomitant use with respect to safety and efficacy not established

Elbasvir and grazoprevir

Fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir): Decreased elbasvir and grazoprevir concentrations expected

Elbasvir/grazoprevir: Do not use concomitantly

Elvitegravir and cobicistat

Fixed combination of elvitegravir, cobicistat, emtricitabine, and either tenofovir alafenamide (EVG/c/FTC/TAF) or tenofovir disoproxil fumarate (EVG/FTC/TDF): Possible altered (increased or decreased) concentrations of elvitegravir, cobicistat, and/or nevirapine

EVG/c/FTC/TAF, EVG/c/FTC/TDF: Do not use concomitantly with nevirapine

Emtricitabine

No in vitro evidence of antagonistic antiretroviral effects

Ergot alkaloids (dihydroergotamine, ergotamine, methylergonovine)

Possible decreased concentrations of the ergot alkaloid; possible inadequate treatment effects

Ergotamine: Appropriate dosages for concomitant use not established

If methylergonovine used to treat postpartum hemorrhage in a woman receiving nevirapine, additional uterotonic agents may be needed

Estrogens and progestins

Drospirenone, medroxyprogesterone, progesterone: Possible decreased concentrations of the progestin

Estradiol, conjugated estrogens: Possible decreased estrogen concentrations

Implants containing etonogestrel or levonorgestrel: No effect on progestin concentrations

Oral contraceptives containing ethinyl estradiol and norethindrone: Decreased ethinyl estradiol and norethindrone AUC; does not appear to affect pregnancy rates in HIV-infected women

Drospirenone, medroxyprogesterone, progesterone: Monitor and use lowest effective progestin dosage to achieve clinical effects

Estradiol, conjugated estrogens: Monitor and use lowest effective estrogen dosage to achieve clinical effects

Implants containing etonogestrel or levonorgestrel: Dosage adjustments not needed

Oral contraceptives containing ethinyl estradiol and norethindrone: Dosage adjustments not needed

Etravirine

Possible altered etravirine concentrations

Do not use concomitantly

Fentanyl

Possible decreased fentanyl concentrations

Appropriate dosages for concomitant use not established

Finasteride

Possible decreased finasteride concentrations

Monitor and adjust finasteride dosage if needed

Fosamprenavir

Fosamprenavir (without low-dose ritonavir): Decreased amprenavir (active metabolite of fosamprenavir) AUC and increased nevirapine AUC

Ritonavir-boosted fosamprenavir (twice-daily regimen): Decreased amprenavir AUC and increased nevirapine AUC

Ritonavir-boosted fosamprenavir (once-daily regimen): Concomitant use with nevirapine not studied

No in vitro evidence of antagonistic antiretroviral effects

Fosamprenavir (without low-dose ritonavir): Concomitant use with nevirapine not recommended

Ritonavir-boosted fosamprenavir (twice-daily regimen): Use usual nevirapine dosage with fosamprenavir 700 mg twice daily and ritonavir 100 mg twice daily

Glecaprevir and pibrentasvir

Fixed combination of glecaprevir and pibrentasvir (glecaprevir/pibrentasvir): Possible decreased glecaprevir and pibrentasvir concentrations

Glecaprevir/pibrentasvir: Do not use concomitantly

Goserelin

Altered goserelin concentrations not expected

HMG-CoA reductase inhibitors (statins)

Atorvastatin: Possible decreased atorvastatin concentrations

Lovastatin, simvastatin: Possible decreased concentrations of the statin

Pitavastatin, rosuvastatin: Altered statin concentrations not expected

Atorvastatin: Adjust statin dosage based on lipid response and do not exceed maximum recommended statin dosage

Lovastatin, simvastatin: Adjust statin dosage based on lipid response and do not exceed maximum recommended statin dosage; avoid lovastatin and simvastatin if nevirapine used in a regimen that includes a ritonavir-boosted PI

Pitavastatin, rosuvastatin: Dosage adjustments not needed

Immunosuppressive agents

Cyclosporine, everolimus, sirolimus, tacrolimus: Possible decreased concentrations of immunosuppressive agent

Cyclosporine, everolimus, sirolimus, tacrolimus: Appropriate dosages for concomitant use not established; therapeutic drug monitoring of the immunosuppressive agent recommended and consultation with a specialist may be needed

Indinavir

Decreased indinavir concentrations and AUC; no clinically important change in nevirapine pharmacokinetics

No in vitro evidence of antagonistic antiretroviral effects

Appropriate dosages for concomitant use with respect to safety and efficacy not established

Lamivudine

No in vitro evidence of antagonistic antiretroviral effects

Ledipasvir and sofosbuvir

Fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir): Clinically important interactions not expected

Ledipasvir/sofosbuvir: Dosage adjustments not needed

Leuprolide

Altered leuprolide concentrations not expected

Lopinavir and ritonavir

Fixed combination of lopinavir and ritonavir (lopinavir/ritonavir): Decreased lopinavir concentrations and AUC

Lopinavir/ritonavir (once-daily regimen): Not recommended with nevirapine

Lopinavir/ritonavir (twice-daily regimen): Increased lopinavir/ritonavir dosage recommended; dosage depends on lopinavir/ritonavir preparation used (tablets, oral solution) and clinical characteristics of the patient

Macrolides

Clarithromycin: Decreased clarithromycin concentration and increased 14-hydroxyclarithromycin concentration; possible increased nevirapine AUC

Monitor for efficacy of the macrolide or use an alternative (e.g., azithromycin) for treatment or prophylaxis of MAC

Maraviroc

No effect on maraviroc AUC

No in vitro evidence of antagonistic antiretroviral effects

Recommended maraviroc dosage is 300 mg twice daily when used with nevirapine, provided regimen does not include a PI or other potent CYP3A inhibitor; recommended maraviroc dosage is 150 mg twice daily if used with nevirapine in a regimen that includes a PI (except ritonavir-boosted tipranavir)

Methadone

Decreased methadone concentrations; no change in nevirapine concentrations

Opiate withdrawal reported

Consider need to increase methadone dosage

Nefazodone

Decreased nefazodone concentrations expected; possible increased nevirapine concentrations

Monitor for nefazodone therapeutic effects and titrate antidepressant dosage as needed; also monitor for nevirapine-associated adverse effects

Nelfinavir

No effect on nelfinavir peak concentrations or AUC; decreased nelfinavir trough concentrations and substantially decreased concentrations and AUC of major nelfinavir metabolite (M8).

No in vitro evidence of antagonistic antiretroviral effects

Appropriate dosages for concomitant use with respect to safety and efficacy not established

Quinupristin and dalfopristin

Possible increased nevirapine concentrations

Raltegravir

No in vitro evidence of antagonistic antiretroviral effects

Dosage adjustments not necessary

Rilpivirine

Possible altered rilpivirine concentrations

Do not use concomitantly

Ritonavir

No clinically important pharmacokinetic interactions

St. John’s wort (Hypericum perforatum)

Decreased nevirapine concentrations; possible loss of virologic response and increased risk of nevirapine resistance

Concomitant use contraindicated

Saquinavir

Ritonavir-boosted saquinavir: Concomitant use not evaluated

No in vitro evidence of antagonistic antiretroviral effects

Ritonavir-boosted saquinavir: Appropriate dosages for concomitant use with respect to safety and efficacy not established

Sildenafil

Possible decreased sildenafil concentrations

May need to increase sildenafil dosage based on clinical effects

Simeprevir

Decreased simeprevir concentrations expected

Do not use concomitantly

Sofosbuvir and velpatasvir

Fixed combination of sofosbuvir and velpatasvir (sofosbuvir/velpatasvir): Decreased velpatasvir concentrations expected

Sofosbuvir/velpatasvir: Do not use concomitantly

Sofosbuvir, velpatasvir, and voxilaprevir

Fixed combination of sofosbuvir, velpatasvir, and voxilaprevir (sofosbuvir/velpatasvir/voxilaprevir): Decreased velpatasvir and voxilaprevir concentrations expected

Sofosbuvir/velpatasvir/voxilaprevir: Do not use concomitantly

Spironolactone

Altered spironolactone concentrations not expected

SSRIs

Citalopram, escitalopram: Possible decreased SSRI concentrations

Fluoxetine, fluvoxamine, paroxetine: Altered SSRI concentrations not expected

Citalopram, escitalopram: Titrate SSRI dosage based on clinical response

Fluoxetine, fluvoxamine, paroxetine: Dosage adjustments not needed

Stavudine

No clinically important effect on stavudine concentrations or AUC

No in vitro evidence of antagonistic antiretroviral effects

Tadalafil

Possible decreased tadalafil concentrations

May need to increase tadalafil dosage based on clinical effects

Tenofovir

No in vitro evidence of antagonistic antiretroviral effects

Testosterone

Possible decreased testosterone concentrations

Monitor for testosterone effects and adjust testosterone dosage if needed

Tipranavir

Ritonavir-boosted tipranavir: No clinically important effect on nevirapine concentrations; altered tipranavir concentrations not expected

No in vitro evidence of antagonistic antiretroviral effects

Ritonavir-boosted tipranavir: Experts state dosage adjustments not needed

Trazodone

Possible decreased trazodone concentrations

Monitor for trazodone therapeutic effects and titrate trazodone dosage as needed

Vardenafil

Possible decreased vardenafil concentrations

May need to increase vardenafil dosage based on clinical effects

Zidovudine

Decreased zidovudine concentrations

No in vitro evidence of antagonistic antiretroviral effects

Nevirapine Pharmacokinetics

Absorption

Bioavailability

Immediate-release nevirapine: Well absorbed from GI tract; absolute bioavailability is 91–93%. Peak plasma concentrations attained within 4 hours.

Extended-release tablets: Peak plasma concentrations attained at a median of approximately 24 hours after dose.

Commercially available immediate-release tablets and oral suspension are bioequivalent at dose ≤200 mg.

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

Food

Food does not appear to affect absorption of immediate-release tablets.

Difference in bioavailability of nevirapine extended-release tablets under fasted or fed conditions not considered clinically important.

Special Populations

Immediate-release nevirapine in children: Steady-state trough concentrations similar to concentrations in adults receiving recommended dosage.

Extended-release tablets in children 6 to <18 years: Overall mean systemic nevirapine exposure after switch from immediate-release to extended-release nevirapine similar to that reported with immediate-release.

Immediate-release nevirapine in pregnant women: Pharmacokinetics generally similar to that reported in nonpregnant adults; dosage adjustments not recommended during pregnancy.

Immediate-release tablets in patients with mild, moderate, or severe renal impairment: Pharmacokinetics not altered. AUC decreased in individuals requiring dialysis. Accumulation of nevirapine metabolites noted in individuals requiring dialysis.

Immediate-release tablets in patients with mild to moderate hepatic impairment: Pharmacokinetics not altered in most patients; trough concentrations twofold higher in 15% of patients with hepatic fibrosis. Increased nevirapine AUC noted in 1 patient with moderate hepatic impairment (Child-Pugh class B) and ascites.

Extended-release tablets: Not studied in pregnant women or in patients with hepatic or renal impairment.

Distribution

Extent

Distributed into CSF; concentrations in CSF are 45% of concurrent plasma concentrations.

Crosses placenta; distributed into human milk and semen.

Plasma Protein Binding

60%.

Elimination

Metabolism

Metabolized by CYP3A and CYP2B6.

Elimination Route

Excreted in urine (81%) mainly as glucuronide conjugates of hydroxylase metabolites and in feces (10%).

Half-life

45 hours after a single dose and 25–30 hours after multiple doses.

Special Populations

Clearance greater in children than adults.

Stability

Storage

Oral

Tablets

Conventional (immediate-release): 25°C (may be exposed to 15–30°C).

Extended-release: 25°C (may be exposed to 15–30°C).

Suspension

25°C (may be exposed to 15–30°C).

Actions and Spectrum

  • Pharmacologically related to other NNRTIs (e.g., delavirdine, efavirenz, etravirine, rilpivirine); differs structurally from these drugs; also differs pharmacologically and structurally from other currently available antiretrovirals.

  • Active against HIV-1; inactive against HIV-2.

  • Nevirapine inhibits replication of HIV-1 by interfering with viral RNA- and DNA-directed polymerase activities of reverse transcriptase.

  • HIV-1 with reduced susceptibility to nevirapine have been selected in vitro and have emerged during therapy with the drug.

  • Strains of HIV-1 resistant to nevirapine may be cross-resistant to some other NNRTIs.

  • Cross-resistance between nevirapine and NRTIs unlikely since the drugs bind at difference sites on reverse transcriptase and have difference mechanisms of action. Cross-resistance between nevirapine and HIV protease inhibitors (PIs) unlikely since the drugs have different target enzymes and mechanisms of action.

Advice to Patients

  • Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician. Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.

  • Importance of using in conjunction with other antiretrovirals— not for monotherapy.

  • Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.

  • Advise patients 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. Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never sharing personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reusing or sharing needles.

  • Importance of reading patient information provided by the manufacturer.

  • If a dose is missed, the next dose should be taken as soon as possible. If a dose is skipped, do not take a double dose to make up for the missed dose.

  • Possibility of severe liver disease or skin reactions (potentially fatal). Importance of discontinuing nevirapine and seeking immediate medical attention if signs or symptoms of liver disease (fatigue, malaise, anorexia, nausea, jaundice, acholic stools, liver tenderness, hepatomegaly) or severe skin or hypersensitivity reactions (rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis) occur.

  • Need for intensive clinical and laboratory monitoring, including liver enzymes, during first 18 weeks of therapy (especially first 6 weeks) and importance of frequent monitoring throughout nevirapine treatment.

  • Risk of rash, especially during first 6 weeks of therapy. If rash occurs during first 2 weeks of therapy, do not increase nevirapine dosage and do not switch to extended-release tablets until rash resolves.

  • Redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.

  • Advise patients to immediately contact a clinician if they have any signs or symptoms of infection since inflammation from previous infections may occur soon after antiretroviral therapy is initiated.

  • To avoid overdosage, do not use immediate-release nevirapine (tablets or oral suspension) and extended-release nevirapine (tablets) concomitantly.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Advise HIV-infected women not to breast-feed.

  • Importance of advising patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Nevirapine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

200 mg*

Nevirapine Tablets

Viramune (scored)

Boehringer Ingelheim

Tablets, extended-release

100 mg*

Nevirapine Extended-release Tablets

Viramune XR

Boehringer Ingelheim

400 mg*

Nevirapine Extended-release Tablets

Viramune XR

Boehringer Ingelheim

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Nevirapine Hemihydrate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Suspension

50 mg (of nevirapine) per 5 mL*

Nevirapine Oral Suspension

Viramune

Boehringer Ingelheim

AHFS DI Essentials™. © Copyright 2021, Selected Revisions August 13, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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