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Nevirapine (Viramune)
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Class
Background
Manufacturer for U.S. Market
Approval
Generic Approvals
Formulation and Dosing
Clinical Use
Use in Initial vs Subsequent Therapy
Potential Adverse Effects
Interactions with Other Drugs
Resistance
Implications of nevirapine resistance for treatment with other antiretrovirals
Implications of resistance to other antiretrovirals for nevirapine treatment
Special Uses
References
Related Resources
DHHS Guidelines
Characteristics of NNRTIs
Drug Interactions with NNRTIs
Interactions between NNRTIs, Maraviroc, Raltegravir, and PIs
Drugs That Should Not Be Used with PIs, NNRTIs, or CCR5 Antagonists
Adverse Events of ARVs
Dosage Adjustments for ARV-ARV Drug Interactions (Adult Dosing)
Interactions Database
Stanford Resistance Figures/Notes
Drug Labeling (Package Insert)
Nevirapine (Viramune)
Class

Nonnucleoside reverse transcriptase inhibitor

Background
Manufacturer for U.S. Market

Boehringer Ingelheim

Approval

Nevirapine was approved by the FDA in 1996 for use in combination with nucleoside analogues in adults with HIV infection. Approval was based on studies showing that the combination of nevirapine with zidovudine + didanosine was more effective in increasing CD4 T-lymphocyte counts and decreasing HIV viral load than a regimen of zidovudine + didanosine alone.(1) Nevirapine was approved for pediatric use in 1998. Extended-release formulations for adults and for pediatric patients were approved in 2011 and 2012, respectively.

Generic Approvals

The FDA has approved several generic formulations of nevirapine for use in the United States. It has granted "tentative approved" status to a number of other generic formulations, making them eligible for purchase and use as part of the President's Emergency Plan for AIDS Relief (PEPFAR) in resource-limited countries.

Formulation and Dosing

Nevirapine is available in immediate-release tablets, extended-release tablets, and oral suspension.

Dosing of Nevirapine
Adult

Immediate-release (IR) tablet or oral suspension

200 mg QD for 14 days, then 200 mg BID

Extended-release (XR) tablet

400 mg QD

If initiating treatment with nevirapine: start with IR tablet, 200 mg QD for 14 days; then change to XR tablet, 400 mg QD

If switching from nevirapine IR formulation (200 mg BID) to XR formulation: start XR tablet, 400 mg QD (without lead-in dosage adjustment)

Nevirapine should not be initiated in women with CD4 counts of >250 cells/µL or men with CD4 counts of >400 cells/µL, unless the benefit clearly outweighs the risk*

PediatricImmediate-release (IR) tablet or oral suspension:
Age 15 days to <8 years
200 mg/m2 (BSA) QD for the first 14 days, then 200 mg/m2 BID; maximum total daily dosage: 400 mg
Age ≥8 years
120-150 mg/m2 (BSA) QD for the first 14 days, then 120-150 mg/m2 BID; maximum total daily dosage: 400 mg
Adolescent
200 mg QD for the first 14 days, then 200 mg BID

Extended-release (XR) tablet#:

Age ≥6 years to <18 years
BSA 0.58-0.83 mg/m2: 200 mg once daily (2 x 100 mg tablets)
BSA 0.84-1.16 mg/m2: 300 mg once daily (3 x 100 mg tablets)
BSA ≥1.17 mg/m2: 400 mg once daily

If initiating treatment with nevirapine: start with oral suspension or IR tablet: 150 mg/m2 QD for the first 14 days, then change to XR tablet at dosage appropriate to BSA (above)

If switching from nevirapine IR formulation to XR formulation: start XR tablet at dosage appropriate for BSA (above)

Nevirapine should not be initiated in postpubertal girls with CD4 counts of >250 cells/µL unless the benefit clearly outweighs the risk*

Prevention of Mother-to-Child TransmissionSee Mother-to-Child Transmission Guidelines

There are no food restrictions.
Nevirapine interacts with a number of antiretroviral medications; see nevirapine/other antiretroviral interaction table for information on recommended dosing adjustments.
No dosage adjustment is necessary in renal insufficiency.
Nevirapine should not be used in persons with moderate or more severe hepatic impairment, Child-Pugh Class B or C.
Please consult product labeling for detailed dosing information.
FDA Pregnancy Category B.
Clinical Use
Use in Initial vs Subsequent Therapy

Adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services designate regimens containing nevirapine in combination with specified 2-nucleoside analogue backbones as "other" regimens for use in initial treatment of HIV infection.

Nevirapine has been studied in several combination regimens for the treatment of HIV infection. Early trials comparing nevirapine-containing regimens with regimens of established potency were relatively small. In one small study, initial therapy with nevirapine + didanosine + stavudine compared favorably with the combination of efavirenz with the same 2 nucleoside analogues at 48 weeks of therapy.(2) A larger comparison of nevirapine with efavirenz, each combined with lamivudine + stavudine in initial therapy, found no significant difference between treatment arms in rates of virologic suppression or CD4 increase at 48 weeks.(3) This study also compared once-daily dosing of nevirapine with standard twice-daily dosing and found no significant differences in treatment outcomes between the two nevirapine arms. A large trial comparing once-daily extended release nevirapine with twice-daily immediate release formulation, each given in combination with emtricitabine + tenofovir in initial therapy, found comparable rates of HIV RNA suppression at 48 weeks.(4)

Small studies of initial treatment have found that the combination of nevirapine with several dual-nucleoside analogue backbones (emtricitabine + tenofovir, didanosine + stavudine, or lamivudine + zidovudine) compares favorably with atazanavir/ritonavir,(5) indinavir,(6) or nelfinavir (7) plus the same nucleoside analogues. In a small study, the combination of didanosine + tenofovir + nevirapine has demonstrated high rates of early virologic failure in treatment-naive individuals.(8) It is not yet known why this regimen resulted in high failure rates; pending further investigation, this combination should be avoided.

Data on the effectiveness of nevirapine in subsequent regimens are limited. Subsequent regimens using NNRTIs appear most effective in individuals who have not previously experienced virologic failure while using drugs of this class.

A number of studies (for example 9) have found that switching from a protease inhibitor to nevirapine in the setting of a fully suppressive regimen (with undetectable viral load at the time of switching) does not increase the risk of virologic failure. However, this risk may be increased in antiretroviral-experienced individuals.(10)

Potential Adverse Effects

The most common symptomatic side effect of nevirapine is rash, usually occurring in the first 6 weeks of treatment. Nevirapine-associated skin reactions usually are mild to moderate but in some cases are severe and life threatening. Rash may also accompany hepatotoxicity (see below). Patients with rash should be evaluated carefully for signs of severe skin reaction and for liver toxicity. Women tend to be at higher risk than men of developing nevirapine-associated rash. Likelihood of rash is reduced by the recommended initiation of nevirapine at half treatment dose, with increase to full dose if no rash is present after 2 weeks. When this dose escalation is used, prophylactic corticosteroids do not appear to reduce the risk of rash.(11)

Symptomatic liver toxicity occurs in approximately 4% of patients taking nevirapine for treatment of HIV infection; this may be accompanied by rash. Because life-threatening hepatoxicity has occurred, transaminases should be monitored closely, especially during the first 18 weeks of treatment. The risk of hepatotoxicity is higher in females than in males, and higher in patients with higher CD4 counts (>250 cells/µL in women, and >400 cells/µL in men) at initiation of nevirapine therapy. Women with CD4 counts of >250 cells/µL and men with CD4 counts of >400 cells/µL prior to initiation of nevirapine should start nevirapine only if the potential benefit outweighs the risk.(12) Patients with chronic hepatitis B or C infection also appear to be at higher risk of hepatic events. It does not appear that single doses of nevirapine cause symptomatic liver toxicity in mothers and children who are given this drug for prevention of perinatal HIV infection.

In case of severe skin, liver, or hypersensitivity reaction, nevirapine must be discontinued permanently.

Because virus resistant to all available NNRTIs can be selected rapidly during failure of a nevirapine-containing regimen, it is important to assess patient motivation and discuss possible side effects and strategies for their management before treatment with nevirapine is initiated.

Interactions with Other Drugs

Nevirapine induces metabolism by the cytochrome P450 3A (CYP3A) enzyme system, affecting the levels of many coadministered drugs, including other antiretrovirals. For example, coadministration with nevirapine significantly reduces levels of most protease inhibitors (darunavir is an exception), as well as numerous other medications including some hormonal contraceptives and statins, phenytoin, phenobarbital, and methadone. Drugs that induce the CYP3A system, such as rifampin and rifabutin, can decrease levels of nevirapine, whereas those that inhibit CYP3A activity, such as ketoconazole, cimetidine, and macrolide antibiotics, can increase nevirapine levels. Information on drug interactions should be consulted, as dosage adjustments are frequently required and some combinations are contraindicated.

Resistance

Resistance to nevirapine is associated with the selection of 1 or more of several resistance mutations.

Implications of nevirapine resistance for treatment with other antiretrovirals

Resistance mutations selected by nevirapine are typically associated with resistance to delavirdine and efavirenz, and also may result in resistance to etravirine and rilpivirine.

Implications of resistance to other antiretrovirals for nevirapine treatment

Resistance to other NNRTIs usually is associated with resistance to nevirapine.

Special Uses

Nevirapine has been used in various prophylaxis protocols to reduce risk of perinatal HIV transmission, for women who did not receive suppressive antiretroviral therapy during pregnancy, and their newborns. A regimen consisting of a single oral dose given to an HIV-infected mother at onset of labor, followed by a single oral dose to the newborn, showed a dramatic reduction in HIV transmission.(13) However, HIV resistant to NNRTIs was detected in the blood of participating mothers 6 weeks following the single dose of nevirapine, and nevirapine-resistant virus also was detected in infants for whom the regimen did not prevent HIV transmission.(14) The resulting drug resistance can contribute to failure of subsequent NNRTI-containing treatment regimens.(15) Other regimens that include nevirapine with nucleoside analogue tails have been used to further decrease the risk of HIV transmission while preventing the development of resistance to nevirapine. Nevirapine has also been given to breast feeding infants of HIV-infected mothers to prevent HIV transmission via breast milk.(16) These approaches may be indicated in resource-constrained settings, but combination maternal and infant antiretroviral prophylactic regimens are recommended, where available.

References
1.   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;124:1019-30.
2.  Nunez M, Soriano V, Martin-Carbonero L, et al. The SENC trial: a randomized, open-label study comparing efavirenz versus nevirapine. Results at 48 weeks. The XIV International AIDS Conference, Barcelona, July, 2002. Abstract TuPeB4441.
3.   van Leth F, Phanuphak P, Ruxrungtham K, et al; 2NN Study Team. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Lancet. 2004 Apr 17;363(9417):1253-63.
4.  Gathe J, Bogner J, Santiago S, et al. Comparison of 48 week efficacy and safety of 400mg QD nevirapine extended release formulation (Viramune XR) versus 200mg BID nevirapine immediate release formulation (Viramune IR) in combination with Truvada in antiretroviral (ARV) naive HIV-1 infected patients (VERxVE). In: Program and abstracts of the XVIII International AIDS Conference; July 18-23, 2010; Vienna. Abstract THLBB202.
5.  Soriano V, Koppe S, Migrone H, et al. Prospective randomised comparison of Nevirapine and Atazanavir/ritonavir both combined with Tenofovir DF/Emtricitabine in treatment-naive HIV-1 infected patients: ARTEN Study week 48 results. In: Program and abstracts of the 5th International AIDS Congress; July 19-22, 2009, Cape Town, South Africa. Poster LBPEB07.
6.   van Leeuwen R, Katlama C, Murphy RL, et al. A randomized trial to study first-line combination therapy with or without a protease inhibitor in HIV-1-infected patients. AIDS 2003; 17(7):987-999.
7.   Podzamczer D, Ferrer E, Consiglio E, et al. A randomized clinical trial comparing nelfinavir or nevirapine associated to zidovudine/lamivudine in HIV-infected naive patients (the Combine Study). Antivir Ther. 2002 Jun;7(2):81-90.
8.   Leon A, Martinez E, Mallolas J, et al. Early virological failure in treatment-naive HIV-infected adults receiving didanosine and tenofovir plus efavirenz or nevirapine. AIDS 2005;28;19(2):213-5.
9.   Negredo E, Cruz L, Paredes R, et al. Virological, immunological, and clinical impact of switching from protease inhibitors to nevirapine or to efavirenz in patients with human immunodeficiency virus infection and long-lasting viral suppression. in Infect Dis. 2002 Feb 15;34(4):504-10.
10.  Raffi F, Esnault JL, Reliquet V, et al. The Maintavir Study, Substitution of a Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) for a Protease Inhibitor (PI) in Patients with Undetectable Plasma HIV-1 RNA: 18 Months Follow-Up. Abstract 474. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. September 17-20, 2000; Toronto.
11.   Knobel H, Miro JM, Domingo P, et al; GESIDA 09/99 Study Group. Failure of a short-term prednisone regimen to prevent nevirapine-associated rash: a double-blind placebo-controlled trial: the GESIDA 09/99 study. J Acquir Immune Defic Syndr. 2001 Sep 1;28(1):14-8.
12.  Viramune (nevirapine) package insert, Boehringer Ingelheim Pharmaceuticals.
13.   Guay LA, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 1999;354:795-802.
14.   Eshleman SH, Becker-Pergola G, et al. Impact of human immunodeficiency virus type 1 (hiv-1) subtype on women receiving single-dose nevirapine prophylaxis to prevent hiv-1 vertical transmission (hiv network for prevention trials 012 study). J Infect Dis. 2001 Oct 1;184(7):914-7.
15.   Jourdain G, Ngo-Giang-Huong N, Le Coeur S, et al; Perinatal HIV Prevention Trial Group. Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy. N Engl J Med. 2004 Jul 15;351(3):229-40.
16.  Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. July 31, 2012. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf.
17.   Clarke SM, Mulcahy FM, Tjia J, et al. Pharmacokinetic interactions of nevirapine and methadone and guidelines for use of nevirapine to treat injection drug users. Clin Infect Dis. 2001 Nov 1;33(9):1595-7.