nevirapine (Rx)

>10%

Diarrhea (15-20%)

Rash (15-20%)

Headache (11%)

Neutropenia (10-11%)

Fever (8-11%)

1-10%

Ulcerative stomatitis (4%)

Increased LFTs (2-4%)

Abdominal pain (2%)

Paresthesia (2%)

Nausea

Anemia

Peripheral neuropathy

Myalgia

Frequency Not Defined

Potentially fatal hepatotoxicity (fulminant hepatitis, cholestatic hepatitis, hepatic failure, hepatic necrosis)

Stevens-Johnson syndrome

Toxic epidermal necrolysis

Rhabdomyolysis

Postmarketing Reports

Body as a whole: Fever, somnolence, drug withdrawal, redistribution/accumulation of body fat

Gastrointestinal: Vomiting

Liver and biliary: Jaundice, fulminant and cholestatic hepatitis, hepatic necrosis, hepatic failure

Hematology: Anemia, eosinophilia, neutropenia Investigations: decreased serum phosphorus

Investigations: Decreased serum phosphorus

Musculoskeletal: Arthralgia, rhabdomyolysis associated with skin and/or liver reactions

Neurologic: Paraesthesia

Skin and appendages: Allergic reactions including anaphylaxis, angioedema, bullous eruptions, ulcerative stomatitis and urticaria have all been reported; hypersensitivity syndrome and hypersensitivity reactions with rash associated with constitutional findings (eg, fever, blistering, oral lesions, conjunctivitis, facial edema, muscle or joint aches, general malaise, fatigue, or significant hepatic abnormalities, drug reaction with eosinophilia and systemic symptoms [DRESS])

Contraindications

Hypersensitivity

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

Coadministration with drugs (eg, CYP inducers) where significant decreases in nevirapine plasma concentrations may occur, which may result in loss of virologic response and possible resistance and cross-resistance to other NNRTIs

Use as part of postexposure prophylaxis (PEP) regimens

Cautions

Do not restart therapy following severe skin rash, skin rash combined with increased transaminases or other symptoms, or hypersensitivity reaction

Risk of severe, life threatening skin reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity

Discontinue if severe rash or any rash accompanied by constitutional findings occurs

Risk of immune reconstitution syndrome if used in combination with other antiretroviral drugs

Redistribution/accumulation of body fat may occur (cushingoid appearance)

Limited human data are insufficient to determine risk of infertility in humans; based on results from animal fertility studies conducted in rats, therapy may reduce fertility in females of reproductive potential; not known if these effects on fertility are reversible

Risk of hepatotoxicity

• Rhabdomyolysis reported in some patients experiencing skin and/or liver reactions associated with therapy; hepatitis/hepatic failure may be associated with signs of hypersensitivity which can include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction; patients with signs or symptoms of hepatitis must be advised to discontinue therapy and immediately seek medical evaluation, which should include liver enzyme tests
• The first 18 weeks of therapy are a critical period during which intensive clinical and laboratory monitoring of patients is required to detect potentially life-threatening hepatic events; some experts recommend clinical and laboratory monitoring more often than once per month, and in particular, include monitoring of liver enzyme tests at baseline, prior to dose escalation and at two weeks post-dose escalation; after initial 18-week period, frequent clinical and laboratory monitoring should continue throughout treatment
• Hepatic injury may progress despite treatment discontinuation
• Female gender and higher CD4 are higher risk factors

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to nevirapine during pregnancy; healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263

Available data from the APR show no difference in risk of overall major birth defects for nevirapine compared with background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP); rate of miscarriage is not reported in the APR

Severe hepatic events, including fatalities, reported in pregnant women receiving chronic therapy as part of combination treatment of HIV-1 infection; regardless of pregnancy status, women with CD4+ cell counts greater than 250 cells/mm3 should not initiate therapy unless benefit outweighs risk; it is unclear if pregnancy augments risk observed in non-pregnant women

Lactation

The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers in the United States not breastfeed infants to avoid risking postnatal transmission of HIV-1 infection; published data report that nevirapine is present in human milk; there are limited data on effects of nevirapine on breastfed infant; there is no information on effects of nevirapine on milk production; because of potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) serious adverse reactions in nursing infants, mothers should not breastfeed if they are receiving therapy; published literature indicates that rash and hyperbilirubinemia have been seen in infants exposed to nevirapine through breastmilk

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI); activity against HIV-1 by binding to reverse transcriptase, and thereby blocking RNA- and DNA-dependent DNA polymerase actions including HIV-1 replication

Does not require intracellular phosphorylation for activity

Absorption

Bioavailability: >90%

Peak Plasma: 2-4 hr

Distribution

Distributed widely; crosses placenta; enters breast milk; CSF penetration approximates 50% of plasma

Protein Bound: 50-60%

Vd: 1.2-1.4 L/kg

Metabolism

Extensively hepatic via CYP3A4 (hydroxylation to inactive compounds)

May undergo enterohepatic recycling

Elimination

Half-life: Decreases over 2-4 wk with chronic dosing due to autoinduction (ie, half-life initially 45 hr and decreases to 23 hr)

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

Oral Administration

Shake suspension gently and administer entire measured dose

5 mL or less: Use oral syringe

Extended-release tablets should be swallowed whole; do not chew, crush, or split

May take with or without food