Nevirapine Er (nevirapine)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Nevirapine, an antiretroviral agent, is a human immunodeficiency virus (HIV) nonnucleoside reverse transcriptase inhibitor (NNRTI).
Nevirapine is a human immunodeficiency virus (HIV) nonnucleoside reverse transcriptase inhibitor (NNRTI). While the complete mechanism of antiviral activity of nevirapine has not been fully elucidated, the drug inhibits replication of HIV-1 by interfering with viral RNA- and DNA-directed polymerase activities of reverse transcriptase. Nevirapine binds directly to HIV-1 reverse transcriptase and exerts a virustatic effect by acting as a specific, noncompetitive HIV-1 reverse transcriptase inhibitor.
The mechanism of action of nevirapine differs from that of HIV nucleoside reverse transcriptase inhibitors (NRTIs) (e.g., abacavir, didanosine, lamivudine, stavudine, zidovudine). NRTIs require intracellular conversion to triphosphate metabolites, which then compete with naturally occurring deoxynucleoside triphosphates for incorporation into viral DNA by reverse transcriptase and cause premature viral DNA chain termination by preventing further 5' to 3' phosphodiester linkages. Nevirapine, however, is noncompetitive with respect to primer-template or nucleoside triphosphate binding and is specific for HIV-1 reverse transcriptase.
The drug binds directly to heterodimeric HIV-1 reverse transcriptase and appears to inhibit viral RNA- and DNA-dependent DNA polymerase activities by disrupting the catalytic site of the enzyme.
The binding site for nevirapine on HIV-1 reverse transcriptase is near, but not at the proposed site of active polymerization, in a deep pocket lying between the beta sheets of the ''palm'' and at the base of the ''thumb'' subdomains of the enzyme's p66 subunit. In the absence of nevirapine, the binding of deoxynucleoside triphosphate to the reverse transcriptase-template complex results in a change in the conformation of reverse transcriptase. This conformational change is followed by a magnesium-dependent chemical reaction in which deoxynucleoside triphosphate is incorporated into the newly forming viral DNA; the conformational change appears to be the rate-limiting step of the reverse transcriptase catalysis of viral DNA formation.
Nevirapine appears to have no appreciable effect on the rate of or equilibrium constant for the conformational change but may slow the chemical reaction, which then becomes the rate-limiting step in the catalytic sequence. When nevirapine binds to the reverse transcriptase-template complex, changes may occur in the position of aspartic acid carboxyl groups in reverse transcriptase so that magnesium ions are not in proper alignment for the chemical reaction to occur efficiently, and the reaction is slowed. Therefore, although the nevirapine-reverse transcriptase-template complex may continue to bind deoxynucleoside triphosphate and to catalyze its incorporation into the newly forming viral DNA, it appears to do so at a slower rate.
Nevirapine is a highly specific inhibitor of HIV-1 reverse transcriptase, and results of in vitro studies indicate that nevirapine does not appear to inhibit cellular DNA polymerases, including human alpha-, beta-, gamma-, or delta-polymerases.
The pharmacokinetics of nevirapine have been studied in healthy adults, adults with HIV-1 infection, and pediatric patients 14 days of age and older with HIV-1 infection. Studies to date have not revealed clinically important race-related differences in the pharmacokinetics of nevirapine. Studies in adults 18-68 years of age have not revealed any age-related differences in the pharmacokinetics of nevirapine; however, pharmacokinetics of the drug have not been extensively studied to date in geriatric adults older than 55-65 years of age.
Immediate-release tablets containing nevirapine and the oral suspension containing nevirapine hemihydrate are bioequivalent and can be used interchangeably at doses up to 200 mg. Bioavailability of 400 mg of nevirapine administered as extended-release tablets relative to 400 mg administered as conventional (immediate-release) tablets is approximately 75%. Following oral administration of nevirapine immediate-release tablets or oral suspension in healthy or HIV-infected adults, the drug is readily (more than 90%) absorbed.
Absolute bioavailability of nevirapine in 12 healthy adults was 93% following administration of a single 50-mg immediate-release tablet or 91% following administration of an oral solution of the drug. Following multiple doses, peak plasma nevirapine concentrations appear to increase linearly in the dosage range of 200-400 mg daily. Following oral administration of a single 400-mg dose of nevirapine as an extended-release tablet in healthy adults, mean peak plasma concentrations were attained at a median of approximately 24 hours.
In HIV-infected pediatric patients 6 to less than 18 years of age who were switched to nevirapine extended-release tablets after at least 18 weeks of immediate-release nevirapine, overall mean systemic nevirapine exposure at steady-state after 10 days of therapy with the extended-release preparation was similar to that reported for the immediate-release preparation. At steady state, the observed geometric mean ratios of extended-release nevirapine to immediate-release nevirapine were approximately 97% for trough plasma concentrations and 94% for AUCs; the ratio for peak plasma concentrations was lower and consistent with the once-daily extended-release preparation.
Results of a study in 6 individuals indicate that nevirapine is distributed into CSF in concentrations that are 45% of concurrent plasma concentrations; this ratio is approximately equal to the fraction of the drug not bound to plasma proteins. At plasma concentrations of 1-10 mcg/mL, nevirapine is approximately 60% bound to plasma proteins. Nevirapine readily crosses the placenta in humans.
Nevirapine is distributed into human milk.
Nevirapine is extensively converted in vivo to several hydroxylated metabolites via cytochrome P-450 (CYP) oxidative metabolism. In vitro studies using human liver microsomes indicate that metabolism of nevirapine is mediated principally by CYP3A4, but other isoenzymes may also play a role in metabolism of the drug. There is evidence that nevirapine induces CYP3A4 and CYP2B6 enzymes resulting in autoinduction of its own metabolism.
The pharmacokinetics of autoinduction are characterized by an approximately 1.5- to 2-fold increase in the apparent oral clearance of nevirapine as treatment continues from a single dose to 2-4 weeks of dosing at a dosage of 200-400 mg daily. Autoinduction also results in a corresponding decrease in the terminal phase half-life of nevirapine in plasma from approximately 45 hours with a single dose to approximately 25-30 hours following multiple dosing using a dosage of 200-400 mg daily in adults. In a population substudy, women had a 13.8% lower clearance of nevirapine than men.
These results could not be explained by body weight or body mass index differences between men and women. Nevirapine is excreted in urine (81%), mainly as glucuronide conjugates of hydroxylated metabolites, and in feces (10%).
USES: Nevirapine is used with other HIV medications to help control HIV infection. It helps to decrease the amount of HIV in your body so your immune system can work better. This lowers your chance of getting HIV complications (such as new infections, cancer) and improves your quality of life.
Nevirapine belongs to a class of drugs known as non-nucleoside reverse transcriptase inhibitors (NNRTIs). Nevirapine is not a cure for HIV infection. To decrease your risk of spreading HIV disease to others, continue to take all HIV medications exactly as prescribed by your doctor.
Use an effective barrier method (latex or polyurethane condoms/dental dams) during sexual activity as directed by your doctor. Do not share personal items (such as needles/syringes, toothbrushes, and razors) that may have contacted blood or other body fluids. Consult your doctor or pharmacist for more details.
Nevirapine should not be used to prevent HIV infection after accidental exposure (such as needle sticks, blood/bodily fluid contact). Different HIV medications are used to prevent infection after exposure.
Generic name: nevirapine
Pronunciation: (ne-VIR-a-peen)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Nevirapine Er
Indications
The following indications are listed for Nevirapine Er:
- Hiv Infection
Also known as: Human Immunodeficiency Virus Disease, Human Immunodeficiency Virus Infection.
Dosing
Nevirapine therapy usually should be initiated using a low dosage of immediate-release nevirapine for the first 14 days since this appears to reduce the frequency of rash. Nevirapine extended-release tablets should not be used during the initial 14 days of nevirapine therapy. Patients not currently receiving nevirapine may receive the extended-release tablets after a lead-in period of 14 days of low dosage of immediate-release nevirapine. Patients already receiving usual dosage of immediate-release nevirapine may be switched to the extended-release tablets without the 14-day lead-in period.
If nevirapine therapy has been interrupted for more than 7 days for any reason and reinitiation of the drug is not contraindicated, the manufacturer states that the drug should be restarted using the recommended low initial dosage of immediate-release nevirapine for the first 14 days.
Dosage of nevirapine in pediatric patients is usually based on body surface area (BSA) calculated using the Mosteller formula.
If mild to moderate rash without constitutional symptoms occurs during the initial 14-day period of low dosage of immediate-release nevirapine, dosage should not be increased until the rash has resolved. The low dosage should not be continued for longer than 28 days; if the rash has not resolved by day 28, nevirapine should be discontinued and an alternative antiretroviral agent selected. If a severe rash or any rash with constitutional symptoms (e.g., fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction) occurs, discontinue nevirapine.
Nevirapine is administered orally without regard to food.
Nevirapine conventional (immediate-release) tablets and oral suspension are used in adults and pediatric patients 15 days of age or older.
Nevirapine extended-release tablets are used in adults and pediatric patients 6 years of age or older with a body surface area (BSA) of 1.17 m2or greater.
Store conventional (immediate-release) tablets at 20-25degreesC (excursions permitted to 15-30degreesC). Extended-release tablets should be stored at 20-25degreesC (excursions permitted to 15-30degreesC). Store nevirapine oral suspension at 20-25degreesC (excursions permitted to 15-30degreesC).
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No dosing information is available for this tab.
Drug interactions
Metabolism of nevirapine is mediated in part by the cytochrome P-450 (CYP) 3A4 and 2B6 isoenzymes, and plasma nevirapine concentrations may be decreased by concomitant use of drugs that induce these isoenzymes (e.g., rifabutin, rifampin) or may be increased by concomitant use of drugs that inhibit these isoenzymes (e.g., cimetidine, macrolides). In addition, nevirapine is an inducer of CYP3A4 and CYP2B6 and may attenuate the therapeutic effects of drugs metabolized by these isoenzymes. While principally an inducer of CYP3A4 and CYP2B6, nevirapine may also inhibit these enzymes; however, the drug may have only a minimal inhibitory effect on other substrates of CYP3A4 at therapeutic concentrations.
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).
The following drug interactions are based on studies using nevirapine conventional (immediate-release) tablets and are expected to also apply to nevirapine extended-release tablets.
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
There are no moderate interactions for this drug.
Contraindications
*Moderate or severe hepatic impairment (Child-Pugh class B or C).
*Do not use for postexposure prophylaxis following occupational exposure to HIV (PEP) or postexposure prophylaxis following nonoccupational exposure to HIV (nPEP).
There are no contraindication contraindications for this drug.
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
The most frequently reported adverse effect in patients receiving nevirapine is rash, developing in 15% of adult patients receiving nevirapine compared to 6% of those receiving placebo. In adults receiving nevirapine, 2% of rashes were reported as grade 3/4, compared to less than 1% in patients receiving placebo. During a lead-in period with immediate-release nevirapine, the development of grade 2 or higher rash in adults occurred in 3% of adult patients. After the lead-in period, the incidence of grade 2 or higher rash occurred in 3% of adults taking extended-release nevirapine.
In pediatric patients, the incidence of rash with immediate-release nevirapine was 21% (all causality). The incidence of grade 2 or higher rash was 1% in pediatric patients taking extended-release nevirapine.
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
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Safety and pharmacokinetics of nevirapine oral suspension have been evaluated in HIV-infected infants 15 days to less than 3 months of age. Safety, pharmacokinetics, and efficacy of nevirapine immediate-release tablets and oral suspension have been evaluated in pediatric patients 3 months to 18 years of age.
Nevirapine extended-release tablets can be used for treatment of HIV-1 infection in pediatric patients 6 years of age or older based on pharmacokinetic, safety, and antiretroviral activity data from an open-label trial evaluating the drug in pediatric patients 3 to less than 18 years of age and efficacy data from adults. The extended-release tablets are not recommended in pediatric patients 3 to less than 6 years of age because pharmacokinetic data are insufficient to support use in this age group; the tablets are not recommended in those less than 3 years of age because of inability to swallow tablets.
The most frequently reported adverse effects in children were similar to those observed in adults; however, granulocytopenia occurred more frequently in children than in adults. Stevens-Johnson syndrome or Stevens-Johnson/toxic epidermal necrolysis transition syndrome has occurred rarely in children receiving nevirapine. Rash and allergic reaction, including anaphylaxis, also have been reported. Anemia has been observed in children during postmarketing surveillance; whether anemia was due to nevirapine or concomitant drug therapy has not been determined.
To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral agents, including nevirapine, the Antiretroviral Pregnancy Registry was established through the collaboration of antiretroviral manufacturers and an advisory committee of practitioners. Clinicians are encouraged to contact the registry at 800-258-4263 or https://www.APRegistry.com to report cases of prenatal exposure to antiretroviral agents.
Data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects for nevirapine compared with the US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). Registry data include over 2600 reports of nevirapine exposures during pregnancy resulting in live births, including over 1100 first-trimester exposures to the drug. The prevalence of birth defects in live births was 3% following first-trimester exposures to nevirapine-containing regimens and 3.3% following second- or third-trimester exposures to nevirapine-containing regimens compared with the background rate of 2.7% in the reference population of the MACDP.
Literature reports indicate that minimum nevirapine plasma concentrations are decreased up to 29% in pregnancy with the use of immediate-release nevirapine; however, this reduction is not considered clinically meaningful and dosage adjustment is not considered necessary.
Severe hepatic events, including fatalities, have been reported in HIV-infected pregnant women receiving long-term nevirapine therapy as part of multiple-drug antiretroviral treatment. Because women (including pregnant women) with baseline CD4+ T-cell counts exceeding 250 cells/mm3 appear to be at higher risk of nevirapine-associated symptomatic and potentially fatal rash and hepatic toxicity, the drug should not be initiated in such women and only when potential benefits outweigh risks. It is not clear if pregnancy augments the risk of rash and hepatic toxicity observed in non-pregnant women.
Nevirapine is distributed into human milk. The effects of nevirapine on the breast-fed infant are unclear, and the effects on milk production are not known.
The HHS perinatal HIV transmission guideline provides updated recommendations on infant feeding. The guideline states that patients with HIV should receive evidence-based, patient-centered counseling to support shared decision making about infant feeding. During counseling, patients should be informed that feeding with appropriate formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant. Additionally, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum reduces the risk of breastfeeding HIV transmission to <1%, but does not completely eliminate the risk. Replacement feeding with formula or banked pasteurized donor milk is recommended when patients with HIV are not on antiretroviral therapy and/or do not have a suppressed viral load during pregnancy (at a minimum throughout the third trimester), as well as at delivery.
In general, dosage for geriatric patients should be selected carefully since these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.
Clinical studies of nevirapine to date have not included sufficient numbers of adults 65 years of age or older to determine whether geriatric individuals respond differently to the drug than younger adults. In general, dosage for geriatric patients should be selected carefully since these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.
ICD codes
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Last reviewed · Source: First Databank (FDB) drug data
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