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Viramune

Generic Name: Nevirapine
Class: Nonnucleoside 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

Warning(s)

  • Severe, life-threatening (and in some cases fatal) hepatotoxicity reported, particularly during first 18 weeks of therapy.1 234 In some cases, patients presented with nonspecific prodromal signs or symptoms of hepatitis and progressed to hepatic failure; these events often associated with rash.1 234 Patients with higher CD4+ T-cell counts at initiation of therapy and women are at increased risk.1 234 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. 1 234 Patients with signs or symptoms of hepatitis or with increased serum transaminase concentrations in conjunction with rash or other systemic symptoms must discontinue nevirapine and immediately seek medical evaluation.1 234

  • Contraindicated for occupational and nonoccupational postexposure prophylaxis of HIV;1 234 hepatic failure reported in patients without HIV infection receiving nevirapine for postexposure prophylaxis.1 234

  • Severe, life-threatening skin reaction, including fatal cases, reported.1 234 Reactions include Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction.1 234 Patients with signs or symptoms of severe skin reactions or hypersensitivity must discontinue nevirapine and immediately seek medical evaluation.1 234 Immediately measure serum transaminase concentrations if rash occurs during first 18 weeks of nevirapine therapy.1 234

  • 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.1 234

  • Must monitor patients intensively during first 18 weeks of therapy to detect potential life-threatening hepatotoxicity or skin reactions.1 234 Extra vigilance warranted during first 6 weeks, the period of greatest risk.1 234

  • Do not restart nevirapine following clinical hepatitis, elevated transaminase concentrations combined with rash or other systemic symptoms, or following severe rash or hypersensitivity reactions.1 234

Introduction

Antiretroviral; nonnucleoside reverse transcriptase inhibitor (NNRTI).1 21 200 234

Uses for Viramune

Treatment of HIV Infection

Treatment of HIV-1 infection in conjunction with other antiretrovirals.1 234

Because of increased risk of potentially life-threatening hepatotoxicity, do not initiate in women with pretreatment CD4+ T-cell counts >250/mm3 or in men with CD4+ T-cell counts >400/mm3 unless potential benefits clearly outweigh risks.1 96 200 234 (See Hepatic Effects under Cautions.)

An acceptable (not preferred or alternative) NNRTI when NNRTI-based regimens are used for initial treatment in antiretroviral-naive adults and adolescents.200

Slideshow: Flashback: FDA Drug Approvals 2013

Nevirapine and 2 NRTIs is an alternative (not preferred) regimen for initial treatment in antiretroviral-naive pediatric patients.201

Prevention of Perinatal HIV Transmission

Prophylaxis in neonates born to HIV-infected women;202 used as part of a multiple-drug neonatal prophylaxis regimen.202

Multiple-drug antiretroviral regimens are considered the standard of care in the US for treatment of HIV infection in pregnant women and for prevention of perinatal HIV transmission.202 In addition, to decrease risk of perinatal HIV transmission, all pregnant HIV-infected women in the US should receive intrapartum IV zidovudine prophylaxis regimen and all neonates born to HIV-infected women should receive a 6-week zidovudine prophylaxis regimen.202

In situations when an HIV-infected woman received no antiretrovirals prior to and/or during labor, a multiple-drug prophylaxis regimen should be initiated in the neonate as soon as possible after birth.202 In the US, experts recommend that such neonates receive a 2-drug prophylaxis regimen consisting of 3 doses of nevirapine given during the first week of life in addition to the usual 6-week zidovudine regimen.202

Decisions regarding use of multiple-drug neonatal prophylaxis regimens in situations associated with increased risk of perinatal HIV transmission should be made in consultation with a pediatric HIV specialist.202

Clinicians can 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.202

Maternal and neonatal regimens recommended for prevention of perinatal HIV transmission in the US may differ from those used in other countries.202

Viramune Dosage and Administration

Administration

Oral Administration

Administer orally with or without food.1 234

Conventional (immediate-release) tablets and oral suspension (Viramune): Used in adults, adolescents, and pediatric patients ≥3 months of age.1

Extended-release tablets (Viramune XR): Used in adults; safety and efficacy not established in pediatric patients.234

Tablets

Extended-release tablets: Swallow whole; must not be chewed, crushed, or divided.234

Oral Suspension

Shake suspension gently prior to each dose.1

Administer using calibrated dosing syringe (especially for volumes <5 mL).1 Alternatively, administer using dosing cup; rinse cup with water and administer the rinse to the patient.1

Dosage

Available as nevirapine (immediate-release tablets, extended-release tablets) and nevirapine hemihydrate (oral suspension); dosage expressed in terms of nevirapine.1 234

Initiate therapy using a low dosage of immediate-release nevirapine for first 14 days since this appears to reduce frequency of rash.1 48 49 67 234 Do not use extended-release tablets during initial 14 days of nevirapine therapy.234

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 has resolved.1 234 Do not continue initial low dosage beyond 28 days; if rash does not resolve by day 28, discontinue nevirapine and select alternative therapy.1 234

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.1 234

Pediatric Patients

Treatment of HIV Infection
Oral

Children ≥15 days of age (immediate-release nevirapine): 150 mg/m2 once daily for first 14 days of therapy (lead-in period of low dosage), followed by 150 mg/m2 twice daily.1

Some experts suggest 200 mg/m2 twice daily in those <8 years of age and 120–150 mg/m2 (up to 200 mg) twice daily in those ≥8 years of age.201

Prevention of Perinatal HIV Transmission
Multiple-drug Neonatal Prophylaxis
Oral

Neonate born to an HIV-infected woman who received no antiretrovirals prior to and/or during labor: 3 nevirapine doses (immediate-release nevirapine) during first week of life (first dose within 48 hours of birth, second dose 48 hours after first dose, third dose 96 hours after second dose) in addition to usual 6-week neonatal zidovudine prophylaxis regimen.202 If birth weight 1.5–2 kg, use 8 mg of nevirapine for each dose; if birth weight >2 kg, use 12 mg of nevirapine for each dose.202

Consultation with pediatric HIV specialist recommended when making decisions regarding use of multiple-drug neonatal prophylaxis regimens.202

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.1 200

Extended-release tablets: 400 mg once daily, initiated after immediate-release nevirapine.234 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.234 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).234

Prescribing Limits

Pediatric Patients

Treatment of HIV Infection
Oral

Children ≥15 days of age: Dosage based on body surface area (maximum 400 mg daily).1

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);1 some experts state dosage adjustments not necessary.200 Do not use in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).1 234

Extended-release tablets: Not studied in patients with hepatic impairment.234

Renal Impairment

Treatment of HIV Infection
Oral

Immediate-release nevirapine: Dosage adjustment not needed in patients with Clcr ≥20 mL/minute.1 234 Administer additional 200-mg dose of immediate-release nevirapine after each dialysis treatment.1

Extended-release tablets: Not studied in patients with renal impairment.234

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1 234

Cautions for Viramune

Contraindications

  • Moderate or severe hepatic impairment (Child-Pugh class B or C).1 234

  • Do not use as part of postexposure prophylaxis of HIV following occupational or nonoccupational exposures.1 234 (See Hepatic Effects under Cautions.)

Warnings/Precautions

Sensitivity Reactions

Skin Reactions

Severe, life-threatening skin reaction (including some fatalities) reported.1 234 Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction (including hepatic failure) reported.1 234

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.1 234

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.1 234 If mild to moderate rash without constitutional symptoms occurs during initial 14 days, dosage should not be increased until rash resolves.1 234 Do not continue initial low dosage beyond 28 days; discontinue nevirapine and select alternative therapy.1 234

Monitor closely if isolated rash of any severity occurs.1 234

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.1 234

Women appear to be at higher risk of developing rash than men.1 234

Prednisone not recommended for prevention of nevirapine-associated rash.1 234 (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.1 234

Patient Monitoring

Serious adverse effects include hepatitis, hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions reported.1

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).1 234 Optimum frequency not established;1 clinical and laboratory monitoring more often than once monthly and liver function tests at baseline, 2 weeks after initiation, 2 weeks after dosage escalation, and then once monthly for first 18 weeks recommended.200

Continue frequent clinical and laboratory monitoring after initial 18-week period.1 234

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.1 234 Hepatic events can occur at any time during therapy.1 234 Risk of hepatic events (regardless of severity) greatest during the first 6 weeks of therapy; substantial risk continues through 18 weeks of therapy.1 234

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.1 Rash observed in 50% of those with symptomatic hepatic adverse events.1 234 Fever and flu-like symptoms accompany some of these hepatic events.1 234 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.1 86 234

Patients with higher CD4 counts and women are at increased risk of hepatic events.1 234 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.1 234 Increased liver enzymes and/or HBV or HCV infection associated with increased risk.1 234

Intensive clinical and laboratory monitoring essential.1 234 (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.1 234

Hepatic injury has progressed despite discontinuation of nevirapine in some patients.1 234

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.1 86 234 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.1 86 234

Interactions

Concomitant use with certain drugs is not recommended (e.g., St. John’s wort).1 234 (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.1 234

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 jiroveci [formerly P. carinii]); this may necessitate further evaluation and treatment.1 101 234

Specific Populations

Pregnancy

Category B.1 234

Antiretroviral Pregnancy Registry at 800-258-4263 or .1 202 234 Pregnancy registry data to date do not indicate an increased risk for congenital abnormalities among infants born to women who received nevirapine during pregnancy compared with general population.1 234

Manufacturer states use during pregnancy only if potential benefits justify risks to the fetus.1

Some experts state nevirapine is the preferred NNRTI for use in multiple-drug antiretroviral regimens in antiretroviral-naive pregnant women with baseline CD4+ T-cell counts <250/mm3.202

Because of risk of potentially life-threatening hepatotoxicity, do not initiate nevirapine in adult women, including pregnant women, with pretreatment CD4+ T-cell counts >250/mm3 unless potential benefits clearly outweigh risks.1 96 200 (See Hepatic Effects under Cautions.)

May be continued if tolerated in women who become pregnant, regardless of CD4+ T-cell count.202

Lactation

Distributed into milk.1 58 65 234

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.1 202 234

Pediatric Use

Safety, pharmacokinetics, and efficacy of immediate-release tablets and oral suspension evaluated in children 3 months to 18 years of age.1 Safety and pharmacokinetics of oral suspension assessed in children 15 days to <3 months of age.1

For prevention of perinatal HIV transmission, a 3-dose regimen of immediate-release nevirapine has been recommended for neonates born to HIV-infected women who received no antiretroviral therapy prior to and/or during labor.202 (See Prevention of Perinatal HIV Transmission under Uses.)

Safety and efficacy of extended-release tablets not established in pediatric patients.234

Adverse effects reported in children generally similar to those reported in adults; granulocytopenia reported more frequently in children than adults.1 Stevens-Johnson syndrome or Stevens-Johnson/toxic epidermal necrolysis transition syndrome reported rarely.1 Allergic reactions, including anaphylaxis, also reported.1

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.1 234

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1 234

Hepatic Impairment

Carefully monitor those with hepatic impairment (e.g., those with hepatic fibrosis or cirrhosis) for toxicity.1

Contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).1 234

Extended-release tablets not studied in patients with hepatic impairment.234

Renal Impairment

Modification of usual dosage of immediate-release nevirapine not necessary in patients with Clcr ≥20 mL/minute;1 234 additional dose of immediate-release nevirapine necessary following dialysis.1 234 (See Renal Impairment under Dosage and Administration.)

Extended-release tablets not studied in patients with renal impairment.234

Common Adverse Effects

Rash, nausea, headache, fatigue, abnormal liver function test results.1 234 Adverse effects reported with extended-release tablets similar to those reported with immediate-release tablets.234

Interactions for Viramune

Metabolized by CYP3A and CYP2B6.1

Inhibits CYP3A and CYP2B6.1

Induces CYP3A and CYP2B6.1

The following drug interactions are based on studies using nevirapine immediate-release tablets and are expected to also apply to extended-release tablets;1 234 studies not performed to date using extended-release tablets.234

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.1 47

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).1

Specific Drugs

Drug

Interaction

Comments

Abacavir

In vitro evidence of additive to synergistic antiretroviral effects1 27

Antacids (Maalox)

No effect on absorption of nevirapine1

Antiarrhythmic agents (amiodarone, disopyramide, lidocaine)

Possible decreased antiarrhythmic agent concentrations1

Clinical monitoring recommended1

Anticoagulants, oral (warfarin)

Possible altered warfarin concentrations and increased or decreased anticoagulant effects1 200

Closely monitor INR; adjust warfarin dosage accordingly1 200

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

Possible decreased anticonvulsant concentrations1 200

Monitor anticonvulsant and nevirapine concentrations and antiretroviral response;200 alternatively, consider different anticonvulsant200

Antifungals, azoles

Fluconazole: Increased nevirapine concentrations;1 no effect on fluconazole concentrations;1 possible increased risk of hepatotoxicity200

Itraconazole: Possible decreased itraconazole concentrations1

Ketoconazole: Possible decreased ketoconazole concentrations and reduced antifungal efficacy1 200

Voriconazole: Possible decreased voriconazole concentrations and increased nevirapine concentrations200

Fluconazole: Use concomitantly with caution;1 closely monitor for nevirapine adverse effects;1 200 consider alternative antiretroviral200

Itraconazole: Concomitant use not recommended;1 if used, monitor itraconazole concentrations and adjust itraconazole dosage accordingly200

Ketoconazole: Concomitant use not recommended1 200

Voriconazole: Monitor frequently for adverse effects or toxicity and response to voriconazole; monitor voriconazole plasma concentrations200

Antimycobacterials (rifabutin, rifampin, rifapentine)

Rifabutin: Increased rifabutin concentrations (high intersubject variability, some patients may experience large increases in rifabutin exposure); decreased nevirapine concentrations1

Rifampin: Decreased nevirapine concentrations1 200

Rifabutin: Use concomitantly with caution;1 200 dosage adjustment not needed200

Rifampin: Concomitant use not recommended200

Rifapentine: Concomitant use not recommended200

Atazanavir

Ritonavir-boosted atazanavir: Decreased atazanavir concentrations and AUC; increased nevirapine concentrations and AUC1 200 203

In vitro evidence of additive to synergistic antiretroviral effects;1 no in vitro evidence of antagonistic antiretroviral effects203

Atazanavir (with or without low-dose ritonavir): Do not use concomitantly1 200 203

Benzodiazepines

Alprazolam: Data not available200

Alprazolam: Monitor for therapeutic effectiveness of the benzodiazepine200

Buprenorphine

No clinically important pharmacokinetic interactions200

Dosage adjustments not needed200

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

Possible decreased concentrations of the calcium-channel blocking agent1 200

Titrate dosage of calcium-channel blocking agent based on clinical response200

Cisapride

Possible decreased cisapride concentrations1

Clinical monitoring recommended1

Corticosteroids

Dexamethasone: Possible decreased nevirapine concentrations200

Prednisone: Concomitant use during first 14 days of nevirapine has been associated with increased incidence and severity of rash during first 6 weeks of nevirapine1 234

Dexamethasone: Monitor antiretroviral response;200 consider alternative corticosteroid for long-term therapy200

Cyclophosphamide

Possible decreased cyclophosphamide concentrations1

Clinical monitoring recommended1

Darunavir

Ritonavir-boosted darunavir: Increased darunavir concentrations and AUC;1 200 204 increased nevirapine concentrations and AUC200 204

Ritonavir-boosted darunavir: Dosage adjustment not needed if used concomitantly with nevirapine200 204

Delavirdine

Not studied200

Do not use concomitantly1 200

Didanosine

No effect on nevirapine or didanosine pharmacokinetics1

In vitro evidence of additive to synergistic antiretroviral effects1 27

Efavirenz

Decreased efavirenz concentrations and AUC;1 increased incidence of adverse effects and no improvement in efficacy1

Do not use concomitantly1 200

Emtricitabine

In vitro evidence of additive to synergistic antiretroviral effects1

Ergot alkaloids (dihydroergotamine, ergonovine, ergotamine, methylergonovine)

Possible decreased concentrations of the ergot alkaloid1

Clinical monitoring recommended1

Estrogens/Progestins

Oral contraceptives: Decreased ethinyl estradiol and norethindrone concentrations1

Medroxyprogesterone acetate (Depo-Provera Contraceptive): No effect on concentrations of the contraceptive1

Do not use hormonal contraceptives (other than medroxyprogesterone acetate) as sole method of contraception;1 use alternative or additional contraceptive measures1 200

Oral contraceptives used for hormonal regulation: Monitor for therapeutic effects of the hormonal therapy1

Etravirine

Possible decreased etravirine concentrations200

Do not use concomitantly1 200

Fentanyl

Possible decreased fentanyl concentrations1

Clinical monitoring recommended1

Fosamprenavir

Fosamprenavir (without low-dose ritonavir): Decreased amprenavir (active metabolite of fosamprenavir) AUC and increased nevirapine AUC1 205

Ritonavir-boosted fosamprenavir (twice-daily regimen): Decreased amprenavir AUC and increased nevirapine AUC1 205

Ritonavir-boosted fosamprenavir (once-daily regimen): Concomitant use with nevirapine not studied205

In vitro evidence of additive antiretroviral effects205

Fosamprenavir (without low-dose ritonavir): Concomitant use with nevirapine not recommended1 205

RItonavir-boosted fosamprenavir (twice-daily regimen): Use usual nevirapine dosage with fosamprenavir 700 mg twice daily and ritonavir 100 mg twice daily1 205

HMG-CoA reductase inhibitors (statins)

Lovastatin or simvastatin: Possible decreased concentrations of the statin200

Lovastatin or simvastatin: Titrate statin dosage based on lipid response; do not exceed maximum recommended statin dosage;200 avoid statin if nevirapine used in a regimen that includes a ritonavir-boosted PI200

Immunosuppressive agents

Possible decreased concentrations of cyclosporine, sirolimus, or tacrolimus1

Clinical monitoring recommended1

Indinavir

Decreased indinavir concentrations and AUC; no clinically important change in nevirapine pharmacokinetics1

In vitro evidence of additive to synergistic antiretroviral effects1

Appropriate dosages for concomitant use with respect to safety and efficacy not established1 206

Lamivudine

In vitro evidence of additive to synergistic antiretroviral effects1 27

Lopinavir/ritonavir

Decreased lopinavir concentrations and AUC1 207

Lopinavir/ritonavir (once-daily regimen): Not recommended with nevirapine207

Lopinavir/ritonavir (twice-daily regimen): Increased lopinavir/ritonavir dosage recommended;1 207 dosage depends on lopinavir/ritonavir preparation used (tablets, oral solution) and clinical characteristics of the patient207

Macrolides

Clarithromycin: Decreased clarithromycin concentration and increased 14-hydroxyclarithromycin concentration1 200

Monitor for efficacy of the macrolide or use an alternative (e.g., azithromycin) for treatment or prophylaxis of MAC1 200

Maraviroc

Increased maraviroc concentrations, but no effect on maraviroc AUC200

No in vitro evidence of antagonistic antiretroviral effects224

Recommended maraviroc dosage is 300 mg twice daily when used with nevirapine, provided regimen does not include a PI or other potent CYP3A inhibitor;200 224 recommended maraviroc dosage is 150 mg twice daily if used with nevirapine in a regimen that includes a PI (except ritonavir-boosted tipranavir)200 224

Methadone

Decreased methadone concentrations;1 no change in nevirapine concentrations200

Opiate withdrawal reported200

Consider need to increase methadone dosage1 200

Nelfinavir

No effect on nelfinavir peak concentrations or AUC;1 decreased nelfinavir trough concentrations and substantially decreased concentrations and AUC of major nelfinavir metabolite (M8).1

In vitro evidence of synergistic antiretroviral effects1

Appropriate dosages for concomitant use with respect to safety and efficacy not established1 208

Quinupristin and dalfopristin

Possible increased nevirapine concentrations77

Raltegravir

In vitro evidence of additive to synergistic antiretroviral effects225

Rilpivirine

Possible decreased rilpivirine concentrations200

Do not use concomitantly1 208

Ritonavir

No clinically important pharmacokinetic interaction1

Saquinavir

Decreased saquinavir concentrations; no change in nevirapine pharmacokinetics200

Ritonavir-boosted saquinavir: Concomitant use not evaluated1

In vitro evidence of additive to synergistic antiretroviral effects1

Ritonavir-boosted saquinavir: Appropriate dosages for concomitant use with respect to safety and efficacy not established1 200

St. John’s wort (Hypericum perforatum)

Decreased nevirapine concentrations; possible loss of virologic response and increased risk of nevirapine resistance1 78 79 200

Concomitant use not recommended1 78 200

Stavudine

No clinically important effect on stavudine concentrations or AUC1

In vitro evidence of additive to synergistic antiretroviral effects1 27

Tenofovir

In vitro evidence of additive to synergistic antiretroviral effects1

Tipranavir

Ritonavir-boosted tipranavir: No clinically important effect on nevirapine concentrations;1 200 211 effect on tipranavir pharmacokinetics unknown200

In vitro evidence of additive antiretroviral effects211

Ritonavir-boosted tipranavir: Some experts state dosage adjustments not needed200

Zidovudine

Decreased zidovudine concentrations1

In vitro evidence of additive to synergistic antiretroviral effects1 27

Viramune Pharmacokinetics

Absorption

Bioavailability

Immediate-release nevirapine: Well absorbed from GI tract; absolute bioavailability is 91–93%.1 75 Peak plasma concentrations attained within 4 hours.1

Extended-release tablets: Peak plasma concentrations attained at a median of approximately 24 hours after an oral dose.234

Steady-state trough concentrations in adults similar to concentrations in children receiving the recommended dosage.1

Commercially available immediate-release tablets and oral suspension are bioequivalent at dose ≤200 mg.1

Bioavailability of 400 mg of nevirapine as extended-release tablets relative to 400 mg as immediate-release tablets is approximately 75%.234

Food

Food does not appear to affect absorption of immediate-release tablets.1

Difference in bioavailability of nevirapine extended-release tablets under fasted or fed conditions not considered clinically important.234

Special Populations

Pharmacokinetics in pregnant women is similar to that reported in nonpregnant adults.202

Immediate-release tablets: Pharmacokinetics not altered in patients with mild, moderate, or severe renal impairment.1 AUC decreased in individuals requiring dialysis.1 Accumulation of nevirapine metabolites noted in individuals requiring dialysis.1

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

Extended-release tablets: Not studied in patients with hepatic or renal impairment.234

Distribution

Extent

Distributed into CSF; concentrations in CSF are 45% of concurrent plasma concentrations.1

Crosses placenta;1 65 distributed into human milk58 65 1 and semen.88

Plasma Protein Binding

60%.1

Elimination

Metabolism

Metabolized by CYP3A and CYP2B6.1

Elimination Route

Excreted in urine (81%) mainly as glucuronide conjugates of hydroxylase metabolites and in feces (10%).1

Half-life

45 hours after a single dose and 25–30 hours after multiple doses.1

Special Populations

Clearance greater in children than adults.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1 234

Suspension

25°C (may be exposed to 15–30°C).1

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.1 21

  • Active against HIV-1; inactive against HIV-2.1 3 22 71

  • Nevirapine inhibits replication of HIV-1 by interfering with viral RNA- and DNA-directed polymerase activities of reverse transcriptase.1 3

  • HIV-1 with reduced susceptibility to nevirapine have been selected in vitro and have emerged during therapy with the drug.1 3 5 21 22

  • Strains of HIV-1 resistant to nevirapine may be cross-resistant to some other NNRTIs.1 28 42

  • Cross-resistance between nevirapine and nucleoside reverse transcriptase inhibitors (NRTIs) unlikely since the drugs bind at difference sites on reverse transcriptase and have difference mechanisms of action.1 Cross-resistance between nevirapine and HIV protease inhibitors (PIs) unlikely since the drugs have different target enzymes and mechanisms of action.1

Advice to Patients

  • Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.1 234 Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1 234

  • Importance of using in conjunction with other antiretrovirals— not for monotherapy.1 234

  • Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.1 234

  • 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.200 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.1 234 200

  • Importance of reading patient information provided by the manufacturer.1 234

  • If a dose is missed, the next dose should be taken as soon as possible.1 234 If a dose is skipped, do not take a double dose to make up for the missed dose.1 234

  • Possibility of severe liver disease or skin reactions (potentially fatal).1 234 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.1 234

  • 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.1 234

  • Risk of rash, especially during first 6 weeks of therapy.1 234 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.1 234

  • Redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.1 234

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products.1 234

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 234 Advise HIV-infected women not to breast-feed.1 234

  • Importance of advising patients of other important precautionary information.1 234 (See Cautions.)

Preparations

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

Nevirapine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

200 mg

Viramune (scored)

Boehringer Ingelheim

Tablets, extended-release

400 mg

Viramune XR

Boehringer Ingelheim

Nevirapine Hemihydrate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Suspension

50 mg (of nevirapine) per 5 mL

Viramune

Boehringer Ingelheim

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Viramune 200MG Tablets (BOEHRINGER INGELHEIM): 60/$606.99 or 180/$1,781.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 11, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

References

1. Boehringer Ingelheim. Viramune (nevirapine) tablets and oral suspension prescribing information. Ridgefield, CT; 2011 Nov.

2. Havlir D, Cheeseman SH, McLaughlin M et al. High-dose nevirapine: Safety, pharmacokinetics, and antiviral effect in patients with human immunodeficiency virus infection. J Infect Dis. 1995; 171:537-45. [IDIS 346014] [PubMed 7533197]

3. Richman D, Rosenthal AS, Skoog M et al. BI-RG-587 is active against zidovudine- resistant human immunodeficiency virus type 1 and synergistic with zidovudine. Antimicrob Agents Chemother. 1991; 35:305-8. [PubMed 1708976]

4. Cheeseman SH, Havlir D, McLaughlin MM et al. Phase I/II evaluation of nevirapine alone and in combination with zidovudine for infection with human immunodeficiency virus. J Acquir Immune Defic Syndr Hum Retrovirol. 1995; 8:141-51. [PubMed 7530585]

5. Kohlstaedt LA, Wang J, Friedman JM et al. Crystal structure at 3.5 resolution of HIV- 1 reverse transcriptase complexed with an inhibitor. Science. 1992; 256:1783-90. [PubMed 1377403]

6. D’Aquila RT, Hughes MD, Johnson VA et al. Nevirapine, zidovudine, and didanosine compared with zidovudine and didanosine in patients with HIV-1 infection. Ann Intern Med. 1996; 124:1019-30. [IDIS 366146] [PubMed 8633815]

9. Merrill DP, Moonis M, Chou TC et al. Lamivudine or stavudine in two- and three-drug combinations against human immunodeficiency virus type 1 replication in vitro. J Infect Dis. 1996; 173:355-64. [IDIS 362747] [PubMed 8568296]

13. Montaner JSG, Reiss P, Cooper D et al. A randomized, double-blind trial comparing combinations of nevirapine, didanosine, and zidovudine for HIV-infected patients: the INCAS trial. JAMA. 1998; 279:930-7. [IDIS 401578] [PubMed 9544767]

16. Reviewers’ comments (personal observations) on saquinavir.

20. Luzuriaga K, Bryson Y, Krogstad P et al. Combination treatment with zidovudine, didanosine, and nevirapine in infants with human immunodeficiency virus infection. N Engl J Med. 1997; 336:1343-9. [IDIS 385528] [PubMed 9134874]

21. Spence RA, Kati WM, Anderson KS et al. Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors. Science. 1995; 267:988-93. [PubMed 7532321]

22. Merluzzi VJ, Hargrave KD, Labadia M et al. Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor. Science. 1990; 250:1411-13. [PubMed 1701568]

24. Anon. Boehringer Ingleheim Viramune for combination use will be on the market by end of July; interaction studies with protease inhibitors part of Phase IV. F-D-C Rep. 1996; July 1: T&G 7-8.

27. Zhu QY, Scarborough A, Polsky B et al. Drug combinations and effect parameters of zidovudine, stavudine, and nevirapine in standardized drug-sensitive and resistant HIV type 1 strains. AIDS Res Hum Retroviruses. 1996; 12:507-17. [PubMed 8679306]

28. Byrnes VW, Sardana VV, Schleif WA et al. Comprehensive mutant enzyme and viral variant assessment of human immunodeficiency virus type 1 reverse transcriptase resistance to nonnucleoside inhibitors. Antimicrob Agents Chemother. 1993; 27:1576-9.

42. Moyle GJ. Resistance to antiretroviral compounds: implications for the clinical management of HIV infection. Immunol Infect Dis. 1995; 5:170-82.

43. Imrie A, Beveridge A, Genn W et al. Transmission of human immunodeficiency virus type 1 resistant to nevirapine. J Infect Dis. 1997; 175:1502-6. [IDIS 387319] [PubMed 9180194]

46. Meyers MW. Dear doctor letter regarding ongoing pharmacokinetic interaction trials with nevirapine and the protease inhibitors saquinavir, indinavir and ritonavir. Ridgefield, CT: Boehringer Ingelheim; 1996 Sept 23.

47. Meyers MW. Dear investigator letter regarding VIRAMUNE in combination with protease inhibitors. Ridgefield, CT: Boehringer Ingelheim; 1996 Nov 20.

48. Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT: Personal communication.

49. Roxane Laboratories, Inc. Management of rash associated with Viramune (nevirapine). Ridgefield, CT; 1996 Sept.

58. Musoke P, Guay LA, Bagenda D et al. A phase I/II study of the safety and pharmacokinetics of nevirapine in HIV-1-infected pregnant Ugandan women and their neonates (HIVNET 006). AIDS. 1999; 13:479-86. [PubMed 10197376]

59. Guay LA, Musoke p, Fleming T et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet. 1999; 354:795-802. [IDIS 431671] [PubMed 10485720]

60. Marseille E, Kahn JG, Mmiro F et al. Cost effectiveness of single-dose nevirapine regimen for mothers and babies to decrease vertical HIV-1 transmission in sub-Saharan Africa. Lancet. 1999; 354:803-9. [IDIS 431672] [PubMed 10485721]

61. National Institute of Allergy and Infectious Diseases. HIVNET 012: questions and answers. News release. 1999 July 8.

65. Mirochnick M, Fenton T, Gagnier P et al. Pharmacokinetics of nevirapine in human immunodeficiency virus type 1-infected pregnant women and their neonates. J Infect Dis. 1998; 178:368-74. [IDIS 408897] [PubMed 9697716]

66. Warren KJ, Boxwell DE, Kim NY et al. Nevirapine-associated Stevens-Johnson syndrome. Lancet. 1998; 351:567. [IDIS 400433] [PubMed 9492778]

67. Barner A, Myers M. Nevirapine and rashes. Lancet. 1998; 351:1133. [IDIS 402958] [PubMed 9660609]

69. Altice FL, Friedland GH, Cooney EL. Nevirapine induced opiate withdrawal among injection drug users with HIV infection receiving methadone. AIDS. 1999; 13:957-62. [PubMed 10371177]

70. Heelon MW, Meade LB. Methadone withdrawal when starting an antiretroviral regimen including nevirapine. Pharmacotherapy. 1999; 19:471-2. [IDIS 423886] [PubMed 10212021]

71. Witvrouw M, Pannecouque C, Van Laethem K et al. Activity of non-nucleoside reverse transcriptase inhibitors against HIV-2 and SIV. AIDS. 1999; 13:1477-83. [PubMed 10465070]

72. Centers for Disease Control and Prevention. Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: principles of therapy and revised recommendations. MMWR Recomm Rep. 1998; 47(No. RR-20).

73. Centers for Disease Control and Prevention. Notice to readers: updated guidelines for the use of rifabutin or rifampin for the treatment and prevention of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. MMWR Morb Mortal Wkly Rep. 2000; 49:185-9. [IDIS 441965] [PubMed 11795500]

74. Riska P, Lamson M, MacGregor T et al. Disposition and biotransformation of the antiretroviral drug nevirapine in humans. Drug Metab Dispos. 1999; 27:895-901. [IDIS 436541] [PubMed 10421616]

75. Lamson MJ, Sabo JP, MacGregor TR et al. Single dose pharmacokinetics and bioavailability of nevirapine in healthy volunteers. Biopharm Drug Dispos. 1999; 20:285-91. [IDIS 442239] [PubMed 10701699]

76. Taylor S, Little J, Halifax K et al. Pharmacokinetics of nelfinavir and nevirapine in a patient with end-stage renal failure on continuous ambulatory, peritoneal dialysis. J Antimicrob Chemother. 2000; 45:716-7. [IDIS 447296] [PubMed 10797104]

77. Rhone-Poulenc Rorer Pharmaceuticals Inc. Synercid I.V. (quinupristin and dalfopristin) prescribing information. Collegeville, PA; 1999 Jul.

78. Lumpkin MM, Alpert A. Risk of drug interactions with St John’s wort and indinavir and other drugs. FDA Public Health Advisory. 2000 Feb 10. From FDA website.

79. Piscitelli SC, Burstein AH, Chaitt D et al. Indinavir concentrations and St John’s wort. Lancet. 2000; 355:547-8. [IDIS 440260] [PubMed 10683007]

80. Johne A, Brockmoller J, Bauer S et al. Pharmacokinetic interaction of digoxin with an herbal extract from St John’s wort (Hypericum perforatum). Clin Pharmacol Ther. 1999; 66:338-45. [IDIS 435511] [PubMed 10546917]

81. Ruschitzka F, Meier PJ, Turina M et al. Acute heart transplant rejection due to Saint John’s wort. Lancet. 2000; 355:548-9. [IDIS 440261] [PubMed 10683008]

82. Taylor GP, Lyall EGH, Back D et al. Pharmacological implications of lengthened in-utero exposure to nevirapine. Lancet. 2000; 355:2134-5. [IDIS 448351] [PubMed 10902630]

84. American Thoracic Society (ATS) and Centers for Disease Control and Prevention (CDC). Targeted tuberculin testing and treatment of latent tuberculosis infections. Am J Respir Crit Care Med. 2000; 161:S221-47.

85. Krogstad P, Lee S, Johnson G et al. Nucleoside-analogue reverse-transcriptase inhibitors plus nevirapine, nelfinavir, or ritonavir for pretreated children infected with human immunodeficiency virus type 1. Clin Infect Dis. 2002; 34:991-1001. [IDIS 480417] [PubMed 11880966]

86. Roxane Laboratories, Inc. Important drug warning re. severe, life-threatening and fatal cases of hepatotoxicity with Viramune. Ridgefield, CT; 2000 Nov.

87. Anon. Serious adverse events attributed to nevirapine regimens for postexposure prophylaxis after HIV exposures: worldwide, 1997-2000. MMWR Morb Mortal Wkly Rep. 2001; 49:1153-6. [PubMed 11198946]

88. Taylor S, van Heeswijk RP, Hoetelmans RM et al. Concentrations of nevirapine, lamivudine and stavudine in semen of HIV-1-infected men. AIDS. 2000; 14:1979-84. [PubMed 10997403]

91. Yogev R, Lee S, Wiznia A et al. Stavudine, nevirapine and ritonavir in stable antiretroviral therapy-experienced children with human immunodeficiency virus infection. Pediatr Infect Dis J. 2002; 21:119-25. [IDIS 477734] [PubMed 11840078]

92. Coovadia HM, Brown ER, Fowler MG et al. Efficacy and safety of an extended nevirapine regimen in infant children of breastfeeding mothers with HIV-1 infection for prevention of postnatal HIV-1 transmission (HPTN 046): a randomised, double-blind, placebo-controlled trial. Lancet. 2012; 379:221-8. [PubMed 22196945]

96. US Food and Drug Administration. FDA public health advisory for neveripine (Viramune). 2005 Jan 19. From FDA web site.

101. Lipman M, Breen R. Immune reconstitution inflammatory syndrome in HIV. Curr Opin Infect Dis. 2006; 19:20-5. [PubMed 16374213]

199. Center for Disease Control and Prevention. Updated U.S. public health service guidelines for the management of occupational exposures to HIV and recommendations for postexposure prophylaxis. MMWR Morb Mortal Wkly Rep. 2005; 54(No. RR-9):1-17. [PubMed 15647722]

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (April 18, 2012). Updates may be available at HHS AIDS Information (AIDSinfo) website.

201. Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in pediatric HIV infection (August 11, 2011). Updates may be available at HHS AIDS Information (AIDSinfo) website.

202. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States (September 14, 2011). Updates may be available at HHS AIDS Information (AIDSinfo) website.

203. Bristol-Myers Squibb. Reyataz (atazanavir sulfate) capsules prescribing information. Princeton, NJ; 2012 Mar.

204. Janssen. Prezista (darunavir) oral suspension and tablets prescribing information. Titusville, NJ; 2012 Jun.

205. ViiV Healthcare. Lexiva (fosamprenavir calcium) tablets and oral suspension prescribing information. Research Triangle Park, NC; 2012 Feb.

206. Merck Sharp & Dohme. Crixivan (indinavir sulfate) capsules prescribing information. Whitehouse Station, NJ; 2012 Apr.

207. Abbott Laboratories. Kaletra (lopinavir/ritonavir) tablets and oral solution prescribing information. North Chicago, IL; 2012 Feb.

208. ViiV Healthcare. Viracept (nelfinavir mesylate) tablets and oral powder prescribing information. Research Triangle Park, NC; 2012 Apr.

211. Boehringer Ingelheim. Aptivus (tipranavir) capsules and oral solution prescribing information. Ridgefield, CT; 2012 Apr.

224. ViiV Healthcare. Selzentry (maraviroc) tablets prescribing information. Research Triangle Park, NC; 2011 Nov.

225. Merck Sharp & Dohme. Isentress (raltegravir) film-coated tablets and chewable tablets prescribing information. Whitehouse Station, NJ; 2012 Apr.

226. Tibotec Therapeutics. Edurant (rilpivirine) tablets prescribing information. Raritan, NJ; 2011 May.

234. Boehringer Ingelheim. Viramune XR (nevirapine) extended-release tablets prescribing information. Ridgefield, CT; 2011 Nov.

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