Nevirapine

Pronunciation

(ne VYE ra peen)

U.S. Brand Names

Viramune®

Synonyms

NVP

Generic Available

Canadian Brand Names

Viramune®

Use

In combination therapy with other antiretroviral agents for the treatment of HIV-1

Restrictions

A patient medication guide has been developed and should be dispensed with each new prescription or refill.

Pregnancy Risk Factor

Pregnancy Implications

Nevirapine crosses the placenta. Pharmacokinetics are not altered during pregnancy and dose adjustment is not needed. The Perinatal HIV Guidelines Working Group recommends nevirapine as the NNRTI for use during pregnancy. When used to prevent perinatal transmission in women who do not need therapy for their own health, use is not recommended if CD4⁺ lymphocyte counts >250/mm³ (monitor for liver toxicity during first 18 weeks of therapy). It may also be used in combination with zidovudine in HIV-infected women who are in labor, but have had no prior antiretroviral therapy, in order to reduce the maternal-fetal transmission of HIV. Health professionals are encouraged to contact the antiretroviral pregnancy registry to monitor outcomes of pregnant women exposed to antiretroviral medications (1-800-258-4263 or www.APRegistry.com).

Lactation

Enters breast milk/contraindicated

Contraindications

Hypersensitivity to nevirapine or any component of the formulation

Warnings/Precautions

Severe hepatotoxic reactions may occur (fulminant and cholestatic hepatitis, hepatic necrosis) and, in some cases, have resulted in hepatic failure and death. Intensive monitoring is required during the initial 18 weeks of therapy to detect potentially life-threatening dermatologic, hypersensitivity, and hepatic reactions. The greatest risk of these reactions is within the initial 6 weeks of treatment. Patients with a history of chronic hepatitis (B or C) or increased baseline transaminase levels may be at increased risk of hepatotoxic reactions. Female gender and patients with increased CD4⁺ cell counts may be at substantially greater risk of hepatic events (often associated with rash). Therapy should not be started with elevated CD4⁺ cell counts unless the benefit of therapy outweighs the risk of serious hepatotoxicity (adult females: CD4⁺ cell counts >250 cells/mm³ ; adult males: CD4⁺ cell counts >400 cells/mm³ ).

Severe life-threatening skin reactions (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, hypersensitivity reactions with rash and organ dysfunction) have occurred. Nevirapine must be initiated with a 14-day lead-in dosing period to decrease the incidence of adverse effects.

If a severe dermatologic or hypersensitivity reaction occurs, or if signs and symptoms of hepatitis occur, nevirapine should be permanently discontinued. These may include a severe rash, or a rash associated with fever, blisters, oral lesions, conjunctivitis, facial edema, muscle or joint aches, general malaise, hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction.

Consider alteration of antiretroviral therapies if disease progression occurs while patients are receiving nevirapine. Safety and efficacy have not been established in neonates.

Adverse Reactions

Note: Potentially life-threatening nevirapine-associated adverse effects may present with the following symptoms: Abrupt onset of flu-like symptoms, abdominal pain, jaundice, or fever with or without rash; may progress to hepatic failure with encephalopathy. Skin rash is present in ~50% of cases.

Percentages of adverse effects vary by clinical trial:

>10%:

Dermatologic: Rash (grade 1/2: 13%; grade 3/4: 1.5%) is the most common toxicity; occurs most frequently within the first 6 weeks of therapy; women may be at higher risk than men

Hepatic: ALT >250 U/L (5% to 14%); symptomatic hepatic events (4%, range: up to 11%) are more common in women, women with CD4⁺ cell counts >250 cells/mm³ , and men with CD4⁺ cell counts >400 cells/mm³

1% to 10%:

Central nervous system: Headache (1% to 4%), fatigue (up to 5%)

Gastrointestinal: Nausea (<1% to 9%), abdominal pain (<1% to 2%), diarrhea (up to 2%)

Hepatic: AST >250 U/L (4% to 8%); co-infection with hepatitis B or C and/or increased liver function tests at the beginning of therapy are associated with a greater risk of asymptomatic transaminase elevations (ALT or AST >5 times ULN: 6%, range: up to 9%) or symptomatic events occurring 6 weeks after beginning treatment

Postmarketing and/or case reports: Allergic reactions, anaphylaxis, anemia, angioedema, arthralgia, blisters, bullous eruptions, conjunctivitis, eosinophilia, facial edema, fever, fulminant and cholestatic hepatitis, granulocytopenia, hepatic failure, hepatic necrosis, hypersensitivity syndrome, jaundice, lymphadenopathy, malaise, neutropenia, oral lesions, paresthesia, redistribution/accumulation of body fat, renal dysfunction, Stevens-Johnson syndrome, somnolence, toxic epidermal necrolysis, ulcerative stomatitis, urticaria, vomiting

Overdosage/Toxicology

Edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, vertigo, and weight loss have been reported following large doses.

Drug Interactions

Substrate of CYP2B6 (minor), 2D6 (minor), 3A4 (major); Inhibits CYP1A2 (weak), 2D6 (weak), 3A4 (weak); Induces CYP2B6 (strong), 3A4 (strong)

Antiarrhythmics (includes amiodarone, disopyramide, lidocaine): Serum concentration/effects may be decreased by nevirapine.

Anticonvulsants (includes carbamazepine, clonazepam, ethosuximide): Serum concentration/effects may be decreased by nevirapine.

Calcium channel blockers: Serum concentration may be decreased by nevirapine.

Cimetidine may decrease the metabolism of nevirapine, potentially increasing levels/toxicity.

Clarithromycin: Serum concentration may be decreased by nevirapine; an alternative antimicrobial agent should be considered.

Cyclophosphamide: Serum concentration may be decreased by nevirapine.

CYP2B6 substrates: Nevirapine may decrease the levels/effects of CYP2B6 substrates. Example substrates include bupropion, efavirenz, promethazine, selegiline, and sertraline

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of nevirapine. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 substrates: Nevirapine may decrease the levels/effects of CYP3A4 substrates. Example substrates include benzodiazepines, calcium channel blockers, clarithromycin, cyclosporine, erythromycin, estrogens, mirtazapine, nateglinide, nefazodone, protease inhibitors, tacrolimus, and venlafaxine

Efavirenz: Serum concentration may be decreased by nevirapine; specific adjustments not established

Immunosuppressants: Serum concentration may be decreased by nevirapine.

Ketoconazole: Nevirapine may inhibit ketoconazole absorption. Ketoconazole may inhibit metabolism of nevirapine. Avoid concurrent use.

Methadone: Plasma concentrations may be reduced by nevirapine. Acute withdrawal symptoms have been reported; monitor

Oral contraceptives: Nevirapine may decrease the clinical effect of oral contraceptives; recommend alternative form or additional method of contraception

Prednisone: Concurrent administration of prednisone for the initial 14 days of nevirapine therapy was associated with an increased incidence and severity of rash.

Protease inhibitors: Nevirapine may decrease serum concentrations of some protease inhibitors (AUC of indinavir, lopinavir, nelfinavir, and saquinavir may be decreased - no effect noted with ritonavir), specific dosage adjustments have not been recommended; no adjustment recommended for ritonavir, unless in combination with lopinavir (Kaletra™).

Rifampin, rifabutin: May decrease nevirapine concentrations; rifabutin concentrations may be increased by nevirapine; avoid concurrent use.

St John's wort: Concurrent use may reduce serum concentrations/efficacy of nevirapine. May lead to treatment failure and/or drug resistance. Avoid concurrent use.

Warfarin: Therapeutic effects may be increased; monitor.

Ethanol/Nutrition/Herb Interactions

Herb/Nutraceutical: Nevirapine serum concentration may be decreased by St John's wort; avoid concurrent use.

Stability

Store at room temperature

Mechanism of Action

As a non-nucleoside reverse transcriptase inhibitor, nevirapine has activity against HIV-1 by binding to reverse transcriptase. It consequently blocks the RNA-dependent and DNA-dependent DNA polymerase activities including HIV-1 replication. It does not require intracellular phosphorylation for antiviral activity.

Pharmacodynamics/Kinetics

Absorption: >90%

Distribution: Widely; Vd: 1.2-1.4 L/kg; CSF penetration approximates 40% to 50% of plasma

Protein binding, plasma: 60%

Metabolism: Extensively hepatic via CYP3A4 (hydroxylation to inactive compounds); may undergo enterohepatic recycling

Half-life elimination: Decreases over 2- to 4-week time with chronic dosing due to autoinduction (ie, half-life = 45 hours initially and decreases to 25-30 hours)

Time to peak, serum: 2-4 hours

Excretion: Urine (~81%, primarily as metabolites, <3% as unchanged drug); feces (~10%)

Dosage

Oral:

Children 2 months to <8 years: Initial: 4 mg/kg/dose once daily for 14 days; increase dose to 7 mg/kg/dose every 12 hours if no rash or other adverse effects occur; maximum dose: 200 mg/dose every 12 hours

Children 8 years: Initial: 4 mg/kg/dose once daily for 14 days; increase dose to 4 mg/kg/dose every 12 hours if no rash or other adverse effects occur; maximum dose: 200 mg/dose every 12 hours

Note: Alternative pediatric dosing (unlabeled): 120-200 mg/m² every 12 hours; this dosing has been proposed due to the fact that dosing based on mg/kg may result in an abrupt decrease in dose at the 8th birthday, which may be inappropriate.

Adults: Initial: 200 mg once daily for 14 days; maintenance: 200 mg twice daily (in combination with an additional antiretroviral agent)

Note: If patient experiences a rash during the 14-day lead-in period, dose should not be increased until the rash has resolved. Discontinue if severe rash, or rash with constitutional symptoms, is noted. If therapy is interrupted for >7 days, restart with initial dose for 14 days. Use of prednisone to prevent nevirapine-associated rash is not recommended. Permanently discontinue if symptomatic hepatic events occur.

Dosage adjustment in renal impairment:

Clcr 20 mL/minute: No adjustment required

Hemodialysis: An additional 200 mg dose is recommended following dialysis.

Dosage adjustment in hepatic impairment: Avoid use in patients with moderate-to-severe hepatic impairment. Permanently discontinue if symptomatic hepatic events occur.

Administration

Oral: May be administered with or without food; may be administered with an antacid or didanosine; shake suspension gently prior to administration

Monitoring Parameters

Liver function tests should be monitored at baseline, and intensively during the first 18 weeks of therapy (optimal frequency not established, some practitioners recommend more often than once a month, including prior to dose escalation, and at 2 weeks following dose escalation), then periodically throughout therapy; observe for CNS side effects. Assess/evaluate AST/ALT in any patients with a rash. Permanently discontinue if patient experiences severe rash, constitutional symptoms associated with rash, rash with elevated AST/ALT, or clinical hepatitis, Mild-to-moderate rash without AST/ALT elevation may continue treatment per discretion of prescriber. If mild-to-moderate urticarial rash, do not restart if treatment is interrupted.

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. This is not a cure for HIV and has not been shown to reduce the risk of transmitting HIV to others. The long-term effects of use are not known. Take as directed, with food. If unable to swallow tablets whole, the tablet may be dissolved in water or crushed in food. Shake suspension gently prior to use. Use oral syringe for volumes of 5 mL or less. When using dosing cups, rinse cup with water and drink. If you miss a dose, take as soon as possible and return to regular schedule (never take a double dose). Frequent blood tests may be required with prolonged therapy. May cause diarrhea (buttermilk, boiled milk, or yogurt may help); or headache (consult prescriber for approved analgesic). If rash develops, stop medicine and contact prescriber immediately. Report fever, blisters, facial edema, muscle or joint pain, general malaise, respiratory difficulty, persistent diarrhea or nausea, or pain or irritation in eyes. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Consult prescriber for appropriate barrier contraceptives (nevirapine may decrease the effectiveness of oral contraceptives) to reduce risk of transmitting infection and possible pregnancy. Do not breast-feed.

Additional Information

Potential compliance problems, frequency of administration, and adverse effects should be discussed with patients before initiating therapy to help prevent the emergence of resistance. Early virologic failure was observed with tenofovir and didanosine delayed release capsules, plus either efavirenz or nevirapine; use caution in treatment-naive patients with high baseline viral loads.

Anesthesia and Critical Care Concerns/Other Considerations

Nevirapine has a mechanism of action different than nucleoside analogues and protease inhibitors. Potential compliance problems, frequency of administration, and adverse effects should be discussed with patients before initiating therapy to help prevent the emergence of resistance.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Ulcerative stomatitis and oral lesions.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

None reported

Mental Health: Effects on Psychiatric Treatment

Neutropenia is common; avoid clozapine and carbamazepine

Dosage Forms

Suspension, oral: 50 mg/5 mL (240 mL)

Tablet: 200 mg

References

D'Aquila RT, Hughes MD, Johnson VA, et al, "Nevirapine, Zidovudine, and Didanosine Compared With Zidovudine and Didanosine in Patients With HIV-1 Infection. A Randomized, Double-Blind, Placebo-Controlled Trial. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group Protocol 241 Investigators," Ann Intern Med , 1996, 124(12):1019-30.

"Guidelines for the Use of Antiretroviral Agents in HIV-infected Adults and Adolescents, Panel on Clinical Practices for Treatment of HIV Infection," October 29, 2004. Available at: http://www.aidsinfo.nih.gov.

Hammer SM, Kessler HA, and Saag MS, "Issues in Combination Antiretroviral Therapy: A Review," J Acquir Immune Defic Syndr , 1994, 7(Suppl 2):24-35.

Havlir DV and Lange JM, "New Antiretrovirals and New Combinations," AIDS , 1998, 12(Suppl A):165-74.

Hilts AE and Fish DN, "Dosage Adjustment of Antiretroviral Agents in Patients With Organ Dysfunction," Am J Health Syst Pharm , 1998, 55:2528-33.

Mueller BU, Sei S, Anderson B, et al, "Comparison of Virus Burden in Blood and Sequential Lymph Node Biopsy Specimens From Children Infected With Human Immunodeficiency Virus," J Pediatr , 1996, 129(3):410-8.

"Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States," December 17, 2004. Available at: http://www.aidsinfo.nih.gov.

Weverling GJ, Lange JM, Jurriaans S, et al, "Alternative Multidrug Regimen Provides Improved Suppression of HIV-1 Replication Over Triple Therapy," AIDS , 1998, 12(11):F117-22.

Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children, "Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection," November 30, 2004. Available at: http://www.aidsinfo.nih.gov.

International Brand Names

Ciplanevimune® (CO); Filide® (AR); Nevimune® (IN); Neviralea® (AR); Nevirapina® (BR); Viramune® (AR, AT, AU, BE, BR, CA, CH, CL, CO, CY, DE, DK, EG, ES, FI, FR, GB, HK, HR, HU, ID, IE, IL, IT, JO, KW, LB, MT, MX, MY, NL, NO, NZ, PL, PT, RO, RU, SE, SG, TH, TR, TW, YU)

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