Nevirapine

Trade Names:
Viramune
- Tablets 200 mg
- Solution, oral 50 mg/mL (as hemihydrate)

Pharmacology

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NNRTI of HIV-1. Binds directly to reverse transcriptase and blocks the RNA-dependent and DNA-dependent DNA polymerase activities.

Pharmacokinetics

Absorption

Nevirapine oral absorption is more than 90%, bioavailability is 93% (tablets) and 91% (oral solution), T _max is 4 h, and C _max is approximately 2 mcg/mL.

Distribution

Nevirapine crosses the placenta and is found in breast milk. Protein binding is approximately 60% and is highly lipophilic and widely distributed. Nevirapine Vd is 1.21 L/kg (IV), and CSF approximates 45% of concentration in plasma.

Metabolism

Extensively metabolized by CYP isozymes. In vitro studies indicated that metabolism is primarily by CYP2B6 and CYP3A4.

Elimination

Nevirapine is eliminated in urine (81.3%) and feces (10.1%). Less than 3% of the parent compound is excreted in urine. Autoinduction results in a decrease of the half-life from 45 h (single dose) to approximately 25 to 30 h (multiple doses).

Special Populations

No change in pharmacokinetics in patients with mild, moderate, or severe renal impairment.

Pharmacokinetics do not appear to change within the range of 18 to 68 yr of age.

Cl is 13.8% lower in women than men.

Pharmacokinetics have not been fully evaluated; however, no difference in steady-state trough levels were found based on ethnicity.

Indications and Usage

In combination with other antiretroviral agents for treatment of HIV-1 infection.

Contraindications

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

Dosage and Administration

PO 200 mg daily for 14 days. Total daily dose not to exceed 400 mg.

PO 200 mg twice daily in combination with other antiretroviral agents.

PO 150 mg/m ² once daily for 14 days followed by 150 mg/m ² twice daily thereafter (max, 400 mg daily).

PO An additional 200 mg following each dialysis.

General Advice

• Tablets and oral suspension are interchangeable on a mg-to-mg basis at doses of up to 200 mg.
• Administer without regard to meals. Administer with food if GI upset occurs.
• Shake suspension before measuring dose. Administer dose using oral dosing syringe or dosing cup. If using dosing cup, thoroughly rinse dosing cup with water and administer rinse water to patient.
• Therapy should be discontinued in patients experiencing severe rash or any rash accompanied by constitutional findings.
• Patients experiencing mild to moderate rash without constitutional symptoms during the 14-day lead-in period should not have their dose increased until the rash resolves. The duration of the lead-in dosing period should not exceed 28 days, at which time an alternative regimen should be sought.
• Permanently discontinue nevirapine if a symptomatic hepatic event occurs. Do not restart after recovery.

Storage/Stability

Store tablets and oral suspension at 59° to 86°F.

Drug Interactions

Plasma levels may be decreased by nevirapine.

Clarithromycin concentrations may be reduced, while concentrations of the active metabolite of clarithromycin may be increased.

Lower hormone levels and potential contraceptive failure.

Concentrations of these agents may be decreased by nevirapine.

Nevirapine concentrations may be increased.

Risk of severe myopathy or rhabdomyolysis may be increased.

Coadministration resulted in significant reduction in ketoconazole plasma concentrations. Do not coadminister ketoconazole and nevirapine.

Lower protease inhibitor plasma levels.

Rifabutin concentrations may be increased.

Lower nevirapine plasma levels.

May reduce nevirapine concentrations, resulting in loss of virologic response and possible resistance to nevirapine and the class of NNRTIs.

Plasma concentrations of warfarin may be altered, resulting in potential increases in coagulation time.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Fatigue (5%); headache (4%); malaise, paresthesia, somnolence (postmarketing).

Dermatologic

Rash (7% [21% in children]); Stevens-Johnson syndrome; toxic epidermal necrolysis (TEN); angioedema, blistering, bullous eruptions, facial edema, urticaria (postmarketing).

EENT

Conjunctivitis (postmarketing).

GI

Nausea (9%); abdominal pain, diarrhea (2%); oral lesions, ulcerative stomatitis, vomiting (postmarketing).

Hepatic

Symptomatic hepatic events (4%); cholestatic hepatitis, hepatic failure, hepatic necrosis, hepatitis including fatal fulminant hepatitis, jaundice (postmarketing).

Hematologic-Lymphatic

Neutropenia (9% in children); anemia (7% in children); anemia, eosinophilia, granulocytopenia, lymphadenopathy, neutropenia (postmarketing).

Hypersensitivity

Hypersensitivity, including anaphylaxis, severe rash, or rash accompanied by blisters; conjunctivitis; facial edema; fatigue; fever; general malaise; muscle or joint aches; oral lesions (postmarketing).

Lab Tests

Elevated ALT (14%); elevated AST (8%).

Metabolic-Nutritional

Redistribution and accumulation of body fat (postmarketing).

Musculoskeletal

Arthralgia, rhabdomyolysis associated with skin and/or liver reaction (postmarketing).

Renal

Impaired renal function (postmarketing).

Miscellaneous

Fever (postmarketing).

Precautions

Pregnancy

Category B .

Lactation

Excreted in breast milk. Ensure that HIV-infected mothers do not breast-feed their infants.

Children

For use in children 15 days of age and older.

Elderly

Select dose with caution, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant diseases or other drug therapy.

Renal Function

In patients receiving chronic hemodialysis, additional dosing is needed following each dialysis treatment.

Hepatic Function

Do not administer to patients with moderate or severe hepatic impairment.

Discontinuation

Do not restart treatment following severe hepatic, skin, or hypersensitivity reactions. Hepatic injury can progress after discontinuation of treatment.

Fat redistribution

Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement, peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance, may occur.

Hepatotoxicity

Consider the possibility of hepatotoxicity for the appearance of signs or symptoms of hepatitis, including fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness, or hepatomegaly.

Immune reconstitution syndrome

Has been reported.

Missed doses

Restart patients who interrupt maintenance dosing for more than 7 days on the recommended dosing (1 daily for 14 days followed by 1 twice daily).

Resistance

When used as monotherapy, resistant virus emerges rapidly and uniformly.

Skin reactions

Discontinue drug if skin rash accompanied by constitutional symptoms (eg, blistering, conjunctivitis, fever, general malaise, muscle or joint aches, oral lesions, swelling) occurs. If rash is mild to moderate in severity and not accompanied by constitutional symptoms, the drug can be continued with close monitoring. If rash develops during first 14 days of therapy, do not increase dosage beyond 200 mg daily until rash resolves.

Overdosage

Symptoms

Edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, vertigo, vomiting, weight decrease.

Patient Information

• Warn patient that this drug is not to be used by itself but is combined with other antiretroviral agents, and not to change the dose or stop taking any of the antiretroviral agents unless advised by health care provider.
• Advise patient to review patient information leaflet before starting therapy and with each refill of the medication.
• Advise patient to take prescribed dose without regard to meals, but to take with food if stomach upset occurs.
• Advise patient or caregiver using suspension to shake suspension before measuring dose and to administer prescribed dose using oral dosing syringe or dosing cup. If using dosing cup, advise patient or caregiver to thoroughly rinse the dosing cup with water and administer rinse water to patient.
• Advise patient that a 14-day lead-in period (lower dose) is used to reduce frequency of rash and not to exceed the prescribed dose during this period.
• Advise patient that if a dose is missed, to take the dose as soon as possible and then return to the normal schedule. However, if it is almost time for the next dose, advise patient to skip the dose and take the next dose at the regular time. Caution patient not to double the dose to catch up.
• Instruct patient that if therapy is stopped for longer than 7 days for any reason, not to restart therapy without discussing how to restart nevirapine with health care provider. Advise patient that therapy may have to be restarted using the 14-day lead-in dose again.
• Instruct patient to discontinue use and notify health care provider immediately if any of the following are noted: appetite loss, blisters, dark urine, decreased urination, facial swelling, fatigue, general body discomfort, mouth sores, muscle or joint aches, nausea, pale stools, red or inflamed eyelids, severe skin rash or rash accompanied by fever, swollen lymph nodes, tenderness on right side below ribs, or yellowing of skin or eyes.
• Advise patient that changes in body fat (increased fat in upper back and neck, breast, or around the trunk and loss of fat from legs, arms, or face) may occur but that the cause and long-term health effects of these changes are not known at this time. Advise patient to discuss with health care provider if noted and significant.
• Inform patient that drug does not completely eliminate HIV virus and, therefore, does not reduce risk of transmitting HIV. Inform patients that appropriate precautions must still be followed.
• Advise patient that drug is not a cure for HIV infection and that illnesses associated with HIV infection, including opportunistic infections, may still be acquired. Advise patient to remain under a health care provider's care.
• Advise women using combination oral contraceptives to use an additional nonhormonal form of contraception because nevirapine can reduce the effectiveness of combination oral contraceptives.
• Caution HIV-infected women that breast-feeding a baby could cause HIV infection in the baby.

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