Granulocytopenia (occurring more frequently in children), skin rash, fever, hepatitis prodromal symptoms, hepatotoxicity, Stevens-Johnson syndrome, toxic epidermal necrolysis, gastrointestinal effects, and headache are the most common adverse effects seen with nevirapine use.[25]

Clinically symptomatic hepatotoxicity has been observed with initiation of and during continued use of nevirapine. Among the NNRTIs, nevirapine has the greatest potential for causing clinical hepatitis. Severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis, and hepatic failure, has been reported in patients treated with nevirapine. In some cases, patients presented with nonspecific prodromal signs or symptoms of hepatitis and progressed to hepatic failure.[26]

The greatest risk of severe and potentially fatal hepatic events, often associated with rash, occurs in the first 6 weeks of nevirapine treatment. Approximately two thirds of the cases of nevirapine-associated clinical hepatitis occur within the first 12 weeks of use.[27] However, the risk continues after this time and patients should be monitored closely for the first 18 weeks of treatment.

Clinical hepatitis and hepatic failure may be isolated or associated with signs of hypersensitivity, which may include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction. Patients with signs or symptoms of hepatitis must seek medical evaluation immediately and should be advised to discontinue nevirapine. In some cases, hepatic injury progresses despite discontinuation of treatment.[28]

Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled studies, nevirapine should not be initiated in adult females with CD4 counts greater than 250 cells/mm3 or in adult males with CD4 counts greater than 400 cells/mm3 unless the benefit outweighs the risk.[29]

Severe, life-threatening skin reactions, including fatal cases, have occurred in patients treated with nevirapine. These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction. Severe or life-threatening rash occurred in approximately 2% of clinically treated patients.[30] Fever, in the absence of any apparent cause, is a significant predictor for the development of rash in patients receiving nevirapine.[31] Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions must discontinue nevirapine as soon as possible.[32]

It is essential that patients be monitored intensively during the first 18 weeks of nevirapine therapy to detect potentially life-threatening hepatotoxicity or skin reactions. Because of the potential severity of clinical hepatitis, some clinicians advise close monitoring of liver enzymes and clinical symptoms after nevirapine initiation such as every 2 weeks for the first month, then monthly for the first 12 weeks, and every 1 to 3 months thereafter. Nevirapine should not be restarted following severe hepatic, skin, or hypersensitivity reactions. In some cases, hepatic injury has progressed despite discontinuation of treatment. In addition, the 14-day lead-in period with nevirapine 200 mg daily dosing must be strictly followed. Lead-in has been found to lessen the frequency of rash.[33]

Because most occupational HIV exposures do not result in transmission of HIV, health care providers considering prescribing postexposure prophylaxis for exposed persons must balance the risk for HIV transmission represented by the exposure and the exposure source against the potential toxicity of the specific agents used for postexposure prophylaxis. In many circumstances, the risks associated with nevirapine as part of a postexposure prophylaxis regimen outweigh the anticipated benefits. However, no serious toxicity has been reported in women or infants receiving two-dose nevirapine (the HIVNET 012 clinical trial regimen) for prevention of perinatal transmission of HIV.[34]

Contraindications
Nevirapine is contraindicated in patients with clinically significant hypersensitivity to any of the components contained in the tablet or the oral suspension.[42]

Except under special circumstances, nevirapine should not be used in patients with severe hepatic function impairment. Nevirapine is hepatotoxic and extensively metabolized by the liver. It is associated with a significant incidence of hepatotoxicity, usually occurring in the initial month of therapy. Risk-benefit should be considered in patients with renal function impairment, as nevirapine metabolites are extensively eliminated by the kidneys.[43]

Chemistry

CAS Name
6H-Dipyrido(3,2-b:2',3'-e)(1,4)diazepin-6-one, 11-cyclopropyl-5,11-dihydro-4-methyl-[44]

CAS Number
129618-40-2[45]

Molecular Formula
C15-H14-N4-O[46]

Elemental Composition
C67.65%, H5.30%, N21.04%, O6.01%[47]

Molecular Weight
266.30[48]

Melting Point
247 to 249 C[49]

Physical Description
White to off-white crystalline powder.[50]

Solubility
Solubility in water 0.1 mg/ml at neutral pH; highly soluble at pH less than 3.[51]

Other Names
BI-RG-587[52]
NVP[53]

Further Reading
Viramune Prescribing Information from the FDA web site [PDF]. A more current version may be available on the manufacturer's web site.

PMID/16425125 Eshleman SH, Hoover DR, Hudelson SE, Chen S, Fiscus SA, Piwowar-Manning E, Jackson JB, Kumwenda NI, Taha TE. Development of nevirapine resistance in infants is reduced by use of infant-only single-dose nevirapine plus zidovudine postexposure prophylaxis for the prevention of mother-to-child transmission of HIV-1. J Infect Dis. 2006 Feb 15;193(4):479-81. Epub 2006 Jan 11.

PMID/14562858 Harris M. Efficacy and durability of nevirapine in antiretroviral-experienced patients. J Acquir Immune Defic Syndr. 2003 Sep; 34 Suppl 1: S53-8. Review.

PMID/16511414 Jackson JB, Parsons T, Musoke P, Nakabiito C, Donnell D, Fleming T, Mirochnick M, Mofenson L, Fowler MG, Mmiro F, Guay L. Association of cord blood nevirapine concentration with reported timing of dose and HIV-1 transmission. AIDS. 2006 Jan 9;20(2):217-222.

PMID/16374215 McIntyre J. Strategies to prevent mother-to-child transmission of HIV. Curr Opin Infect Dis. 2006 Feb;19(1):33-8. Review.

PMID/12853746 Verweel G, Sharland M, Lyall H, Novelli V, Gibb DM, Dumont G, Ball C, Wilkins E, Walters S, Tudor-Williams G. Nevirapine use in HIV-1-infected children. AIDS. 2003 Jul 25; 17(11): 1639-47.

PMID/14562852 Wainberg MA. HIV resistance to nevirapine and other non-nucleoside reverse transcriptase inhibitors. J Acquir Immune Defic Syndr. 2003 Sep; 34 Suppl 1: S2-7. Review.

Manufacturer Information
Viramune
Boehringer Ingelheim Pharmaceuticals Inc
900 Ridgebury Rd / PO Box 368
Ridgefield, CT, 06877-0368
(800) 542-6257

Nevirapine
Boehringer Ingelheim Pharmaceuticals Inc
900 Ridgebury Rd / PO Box 368
Ridgefield, CT, 06877-0368
(800) 542-6257

References
[1] AHFS Drug Information - 2005; p. 692
[2] USP DI - 2005; p. 2125
[3] Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection - MMWR 2002;51 (No.RR-7) Updated as a Living Document on November 03, 2005 [23]. Available at: http://aidsinfo.nih.gov/.
[4] USP DI - 2005; p. 2125
[5] Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States - MMWR 2002;51 (No.RR-7) Updated as a Living Document on November 17, 2005 [23]. Available at: http://aidsinfo.nih.gov/.
[6] USP DI - 2005; p. 2131
[7] FDA - Viramune Prescribing Information, 01/11/05, p. 24. Available at: http://www.fda.gov/cder/foi/2005/20636s025,20933s014lbl.pdf. Accessed 03/15/06.
[8] FDA - Viramune Prescribing Information, 01/11/05, p. 24. Available at: http://www.fda.gov/cder/foi/2005/20636s025,20933s014lbl.pdf. Accessed 03/15/06.
[9] FDA - Viramune Prescribing Information, 01/11/05, p. 23. Available at: http://www.fda.gov/cder/foi/2005/20636s025,20933s014lbl.pdf. Accessed 03/15/06.
[10] FDA - Viramune Prescribing Information, 01/11/05, p. 24. Available at: http://www.fda.gov/cder/foi/2005/20636s025,20933s014lbl.pdf. Accessed 03/15/06.
[11] AHFS Drug Information - 2005; p. 691
[12] USP DI - 2005; p. 2125
[13] USP DI - 2005; p. 2125
[14] AHFS Drug Information - 2005; p. 689
[15] AHFS Drug Information - 2005; p. 689
[16] USP DI - 2005; p. 2125
[17] AHFS Drug Information - 2005; p. 692
[18] FDA - Viramune Prescribing Information, 01/11/05, pp. 6-7. Available at: http://www.fda.gov/cder/foi/2005/20636s025,20933s014lbl.pdf. Accessed 03/15/06.
[19] USP DI - 2005; p. 2126
[20] USP DI - 2005; p. 2125
[21] USP DI - 2005; p. 2125
[22] FDA - Viramune Prescribing Information, 01/11/05, p. 6. Available at: http://www.fda.gov/cder/foi/2005/20636s025,20933s014lbl.pdf. Accessed 03/15/06.
[23] FDA - Viramune Prescribing Information, 01/11/05, p. 5. Available at: http://www.fda.gov/cder/foi/2005/20636s025,20933s014lbl.pdf. Accessed 03/15/06.
[24] AHFS Drug Information - 2005; p. 691
[25] USP DI - 2005; p. 2129
[26] FDA - Viramune Prescribing Information, 01/11/05, p.13. Available at: http://www.fda.gov/cder/foi/2005/20636s025,20933s014lbl.pdf. Accessed 03/15/06.
[27] Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents - MMWR 2002;51 (No.RR-7) Updated as a Living Document on October 6, 2005 [23]. Available at: http://aidsinfo.nih.gov/.
[28] FDA - Viramune Prescribing Information, 01/11/05, p. 13. Available at: http://www.fda.gov/cder/foi/2005/20636s025,20933s014lbl.pdf. Accessed 03/15/06.
[29] FDA - Viramune Prescribing Information, 01/11/05, p. 14. Available at: http://www.fda.gov/cder/foi/2005/20636s025,20933s014lbl.pdf. Accessed 03/15/06.
[30] FDA - Viramune Prescribing Information, 01/11/05, p. 14. Available at: http://www.fda.gov/cder/foi/2005/20636s025,20933s014lbl.pdf. Accessed 03/15/06.
[31] USP DI - 2005; p. 2129
[32] FDA - Viramune Prescribing Information, 01/11/05, p. 4. Available at: http://www.fda.gov/cder/foi/2005/20636s025,20933s014lbl.pdf. Accessed 03/15/06.
[33] FDA - Viramune Prescribing Information, 01/11/05, p. 4. Available at: http://www.fda.gov/cder/foi/2005/20636s025,20933s014lbl.pdf. Accessed 03/15/06.
[34] USP DI - 2005; p. 2129
[35] USP DI - 2005; p. 2126
[36] USP DI - 2005; p. 2126
[37] USP DI - 2005; p. 2127
[38] USP DI - 2005; p. 2127
[39] USP DI - 2005; p. 2127
[40] USP DI - 2005; p. 2127
[41] BMS Virology - Important New Clinical Data, Potential Early Virologic Failure Associated With the Combination Antiretroviral Regimen of Tenofovir Disoproxil Fumarate, Didanosine, and Either Efavirenz or Nevirapine in HIV Treatment-Naive Patients with High Baseline Viral Loads. [Dear Healthcare Professional Letter]. New York: Bristol-Myers Squibb; Accessed Nov 12, 2004.
[42] USP DI - 2005; p. 2127
[43] USP DI - 2005; p. 2127
[44] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 03/15/06.
[45] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 03/15/06.
[46] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 03/15/06.
[47] Merck Index - 2001; p. 1163
[48] Merck Index - 2001; p. 1163
[49] Merck Index - 2001; p. 1163
[50] FDA - Viramune Prescribing Information, 01/11/05, p. 5. Available at: http://www.fda.gov/cder/foi/2005/20636s025,20933s014lbl.pdf. Accessed 03/15/06.
[51] Merck Index - 2001; p. 1163
[52] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 03/15/06.
[53] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 03/15/06.

Updated March 16, 2006

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