Nevirapine

Pronunciation: ne-VIR-a-peen
Class: NNRTI

Trade Names

Viramune
- Tablets, oral 200 mg
- Suspension, oral 50 mg/mL

Viramune XR
- Tablets, ER, oral 400 mg

Pharmacology

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

Slideshow: Flashback: FDA Drug Approvals 2013

Pharmacokinetics

Absorption

Absorption is more than 90%; bioavailability is 93% (immediate release), 91% (oral solution), and 75% (ER). T max is 4 h (immediate release) and 24 h (ER). C max is approximately 2 mcg/mL (immediate release) and 2,060 ng/mL (ER).

Distribution

Nevirapine crosses the placenta and is found in breast milk. Protein binding is approximately 60%, 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 to several hydroxylated metabolites. In vitro studies indicated that metabolism is primarily by CYP2B6 and CYP3A.

Elimination

Nevirapine is eliminated in the urine (81.3%) and the feces (10.1%). Less than 3% of the parent compound is excreted in the 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

Renal Function Impairment

No change in pharmacokinetics in patients with mild, moderate, or severe renal impairment. Patients on dialysis showed a 44% reduction in AUC over a 1-week exposure. Nevirapine ER has not been studied in patients with renal dysfunction.

Hepatic Function Impairment

Patients with hepatic fibrosis had trough concentrations above 9,000 mcg/mL (2-fold the usual mean trough). Do not administer to patients with moderate or severe (Child-Pugh class B or C, respectively) hepatic impairment. Nevirapine ER has not been studied in patients with hepatic impairment.

Elderly

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

Children

Plasma concentrations were within the range observed in adults, but were more variable between patients, particularly in the second month of age.

Gender

Cl is 13.8% lower and trough concentrations are higher (approximately 20% to 30%) in women than men.

Race

Black patients showed approximately 30% higher trough concentrations than white patients.

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; for use as part of occupational and nonoccupational postexposure prophylaxis regimens.

Dosage and Administration

Adults ER

PO 400 mg once daily in combination with other antiretroviral agents, following a 14-day initial dosing period using the immediate-release formulation.

Immediate release

PO 200 mg daily initially for 14 days. Increase to 200 mg twice daily in combination with other antiretroviral agents.

Children 15 days and older (immediate release only)

PO 150 mg/m 2 once daily for 14 days, followed by 150 mg/m 2 twice daily thereafter in combination with other antiretroviral agents (max, 400 mg daily).

Dialysis
Adults and Children 15 days and older (immediate release only)

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.
  • ER tablets must be swallowed whole and not crushed, chewed, or divided.
  • Shake suspension before measuring dose. Administer dose using an oral dosing syringe or a dosing cup. If using a dosing cup, thoroughly rinse the dosing cup with water and administer the rinse water to the 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; after 28 days, seek an alternative regimen.
  • Permanently discontinue nevirapine if a symptomatic hepatic event occurs. Do not restart after recovery.
  • If dosing is interrupted for more than 7 days, restart the recommended 14-day (lead-in) dosing.
  • Patients already on a regimen of nevirapine immediate release twice daily in combination with other antiretroviral agents can be switched to nevirapine ER without the 14-day lead-in period.

Storage/Stability

Store between 59° and 86°F.

Drug Interactions

Amiodarone, carbamazepine, cisapride (available from the manufacturer on a limited-access protocol), clonazepam, cyclophosphamide, cyclosporine, diltiazem, disopyramide, ergotamine, ethosuximide, lidocaine systemic, nifedipine, sirolimus, tacrolimus, ulipristal, verapamil, zidovudine

Plasma levels may be decreased by nevirapine. Use with caution; dose adjustment of these drugs may be needed because of possible decrease in clinical effect.

Cabazitaxel, lurasidone, tyrosine kinase receptor inhibitors (eg, lapatinib, nilotinib, pazopanib)

Plasma concentrations of these agents may be decreased, reducing the pharmacologic effect. Avoid concurrent use with nevirapine.

Clarithromycin

Clarithromycin concentrations may be reduced, while concentrations of the active metabolite of clarithromycin may be increased. Consider an alternative to clarithromycin, such as azithromycin.

Contraceptives, hormonal (eg, ethinyl estradiol, norethindrone)

Lower hormone levels and potential contraceptive failure may occur. An alternative nonhormonal or an additional method of contraception is recommended.

Efavirenz

Efavirenz plasma concentrations may be decreased. In addition, coadministration has been associated with an increase in adverse reactions and no improvement in efficacy. Concurrent use is not recommended.

Exemestane

Exemestane plasma concentrations may be decreased, reducing the pharmacologic effect. Monitor the clinical response when nevirapine is started or stopped and adjust the exemestane dose as needed.

Fluconazole

Nevirapine concentrations may be increased. Use with caution and monitor for nevirapine-induced adverse reactions.

Itraconazole, ketoconazole

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

Maraviroc

Coadministration may increase maraviroc plasma concentrations. Monitor the clinical response and adjust the maraviroc dose as needed.

Opioid analgesics (eg, fentanyl, methadone)

Fentanyl and methadone levels may be decreased. Narcotic withdrawal syndrome has been reported. Monitor methadone maintenance patients for evidence of withdrawal when nevirapine is started, and adjust the methadone dose as needed.

Protease inhibitors (eg, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir)

Lower protease inhibitor plasma levels may occur. Do not coadminister nevirapine and atazanavir because atazanavir exposure is substantially decreased. Coadministration of nevirapine and fosamprenavir without ritonavir is not recommended. The appropriate dose of indinavir, nelfinavir, or saquinavir/ritonavir when used with nevirapine has not been established, but an increase in the dosage of indinavir and saquinavir may be required. Coadministration with darunavir/ritonavir may increase plasma concentrations of darunavir/ritonavir. In addition, atazanavir and fosamprenavir have been shown to increase nevirapine concentrations.

Rifabutin, rifampin

Lower nevirapine plasma levels may occur. Therefore, do not use with rifampin. When treating tuberculosis, use rifabutin instead of other rifamycins. Rifabutin and its metabolite concentrations are moderately increased when coadministered with nevirapine. Use with caution.

St. John's wort

May reduce nevirapine concentrations substantially, resulting in loss of virologic response and possible resistance to nevirapine and the class of NNRTIs. Coadministration is not recommended.

Warfarin

The anticoagulant effect of warfarin may be increased. Monitor coagulation parameters when starting or stopping nevirapine. Adjust the warfarin dose as needed.

Adverse Reactions

CNS

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

Dermatologic

Rash (13%); Stevens-Johnson syndrome; TEN.

GI

Nausea (9%); anorexia (3%); abdominal pain, diarrhea, vomiting (2%).

Hepatic

Hepatic events (9%); hepatitis (3%); jaundice (2%); fulminant and cholestatic hepatitis, hepatic failure, hepatic necrosis (postmarketing).

Hematologic-Lymphatic

Granulocytopenia (2%); anemia, eosinophilia, lymphadenopathy, neutropenia, thrombocytopenia (postmarketing).

Hypersensitivity

Allergic reactions, including anaphylaxis, angioedema, bullous eruptions, ulcerative stomatitis, and urticaria, hypersensitivity syndrome and hypersensitivity reactions with blistering, conjunctivitis, facial edema, general malaise, muscle or joint aches, and oral lesions, renal dysfunction (postmarketing).

Lab Tests

Increased cholesterol (16%); elevated ALT (14%); decreased neutrophils, increased LDL (13%); elevated AST (9%); increased alkaline phosphatase (4%); increased triglyceride, decreased Hgb (3%); increased bilirubin (2%); decreased platelets (1%); increased GGT.

Musculoskeletal

Myalgia (1%); arthralgia, rhabdomyolysis associated with skin and/or liver reaction (postmarketing).

Miscellaneous

Drug withdrawal, fever, redistribution and accumulation of body fat (postmarketing).

Precautions

Warnings

Skin reactions

Severe, life-threatening skin reactions (sometimes fatal) have occurred. Cases include Stevens-Johnson syndrome, TEN, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction. Check transaminase levels immediately for all patients who develop a rash in the first 18 weeks of treatment. The 14-day initiation period with immediate-release nevirapine must be strictly followed to decrease the incidence of rash. Discontinue nevirapine in patients developing signs or symptoms of severe skin or hypersensitivity reactions.

Hepatotoxicity

Severe, life-threatening, and, in some cases, fatal hepatotoxicity has been reported, especially in the first 18 weeks. These events are often associated with a rash. The risk of reactions is increased in women and in patients with higher CD4+ cell counts at the start of therapy. Women with CD4+ cell counts higher than 250 cells/mm 3 , including pregnant women, receiving nevirapine with other antiretroviral agents are at the greatest risk. If clinical hepatitis or transaminase elevations combined with rash or other systemic symptoms occur, permanently discontinue therapy.

Monitoring

Monitor patients intensively during the first 18 weeks to detect potentially life-threatening hepatotoxicity or skin reactions. Extra vigilance is warranted during the first 6 weeks of therapy, which is the period of greatest risk. Do not restart nevirapine following clinical hepatitis, or transaminase elevations combined with rash or other systemic symptoms, or following severe rash or hypersensitivity reactions.


Monitor

Monitor patients intensively during the first 18 weeks of therapy to detect potentially life-threatening hepatotoxicity or skin reactions. Extra vigilance is warranted during the first 6 weeks of therapy, which is the period of greatest risk. Check transaminases immediately if a patient experiences signs or symptoms suggestive of hepatitis and/or hypersensitivity reactions. Check transaminases immediately for all patients who develop a rash in the first 18 weeks of treatment. Carefully monitor patients with hepatic fibrosis or cirrhosis for evidence of drug-induced toxicity.


Pregnancy

Category B (manufacturer prescribing information).

Lactation

Excreted in breast milk with a median milk:maternal plasma ratio of 60.5% (range, 25.3% to 122.2%). Ensure that HIV-infected women do not breast-feed their infants.

Children

For use in children 15 days and older (immediate release); safety and efficacy not established in children (ER).

Elderly

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

Renal Function

In patients receiving long-term hemodialysis, additional dosing is needed for immediate-release nevirapine following each dialysis treatment. ER tablets have not been studied in patients with renal dysfunction.

Hepatic Function

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

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.

Immune reconstitution syndrome

Has been reported.

Resistance

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

Overdosage

Symptoms

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

Patient Information

  • Advise patients to read the Medication Guide before starting therapy and with each refill.
  • Warn patients 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 their health care provider.
  • Advise patient to take prescribed dose without regard to meals, but to take it with food if stomach upset occurs.
  • Advise patient or caregiver using suspension to shake the suspension before measuring the dose and to administer the prescribed dose using an oral dosing syringe or a dosing cup. If using a dosing cup, advise patient or caregiver to thoroughly rinse the dosing cup with water and administer the rinse water to the 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 patients that if a dose is missed, take the dose as soon as possible and then return to their normal schedule. However, if it is almost time for the next dose, advise patients to skip the dose and take the next dose at their regular time. Caution patients not to double the dose to catch up.
  • Instruct patients that if therapy is stopped for longer than 7 days for any reason, not to restart therapy without discussing how to restart nevirapine with their health care provider. Advise patients that therapy may have to be restarted again, using the 14-day lead-in dose with the immediate-release formulation.
  • Instruct patients to discontinue use and notify their 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 the skin or eyes.
  • Advise patients 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 patients to talk to their health care provider if changes in body fat are noted and significant.
  • Inform patients that nevirapine does not completely eliminate HIV virus and does not reduce the risk of transmitting HIV. Inform patient that appropriate precautions must still be followed.
  • Advise patients that nevirapine is not a cure for HIV infection and that illnesses associated with HIV infection, including opportunistic infections, may still be acquired. Advise patients to remain under care of their health care provider.
  • 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.
  • Instruct patient developing signs or symptoms of liver disease (eg, jaundice, anorexia, fatigue, liver tenderness) or severe skin reactions (eg, rash with blister, facial edema, muscle or joint aches) to discontinue nevirapine therapy and seek medical attention immediately.
  • Advise patient that intensive clinical and laboratory monitoring, including liver enzyme levels, is essential during the first 18 weeks of therapy to detect potentially life-threatening hepatotoxicity and skin reactions.
  • Advise patients to report the use of any other prescription or nonprescription medications or herbal products, particularly St. John's wort, to their health care provider.
  • Instruct patients to swallow the ER tablets whole and not to chew, crush, or divide them.
  • Inform patients that they may occasionally see soft remnants of the ER tablet in their stool.

Copyright © 2009 Wolters Kluwer Health.

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