Food and Drug Administration - January 19, 2005
Richard Klein, Jeffrey Murray

The Food and Drug Administration (FDA) is issuing a public health advisory to inform health care providers and patients about recent safety-related changes to the nevirapine (Viramune) label (package insert) and about appropriate use of HIV triple combination therapy containing nevirapine, which is one treatment option in the United States and which is increasingly being used globally. The nevirapine label has been revised several times over the last two years to include more information on liver toxicity associated with long term nevirapine use. The Indications and Usage section of the Viramune label now recommends against starting nevirapine treatment in women with CD4+cell counts greater than 250 cells/mm³ unless benefits clearly outweigh risks. This recommendation is based on a higher observed risk of serious liver toxicity in patients with higher CD4 cell counts prior to initiation of therapy. In addition, the revised label now includes a Medication Guide to inform patients about risks associated with nevirapine when used for the treatment of HIV.

Both clinically symptomatic and asymptomatic liver toxicity are observed with long term use of nevirapine in combination with other HIV drugs. Asymptomatic liver toxicity is defined as increases in liver enzymes without any associated clinical signs or symptoms and is similar to that seen with other antiretroviral drugs. Symptomatic liver toxicity is more common with nevirapine compared to other antiretroviral drugs. Important information regarding symptomatic nevirapine liver toxicity is summarized below:

• Symptomatic nevirapine liver toxicity consists of elevated liver enzymes plus at least one symptom, which is typically rash but may include flu-like symptoms or fever. The severity of symptomatic liver toxicity ranges from mild symptoms with liver enzyme abnormalities to rapidly occurring liver failure and death.

• Symptomatic nevirapine liver toxicity typically occurs after only a few weeks of dosing and may progress to liver failure despite monitoring of laboratory tests, which is not characteristic of other antiretrovirals.

• Females and patients with higher CD4+ cell counts are at increased risk of liver toxicity. Females have a three fold higher risk of symptomatic nevirapine liver toxicity than males, and females with CD4+ cell counts > 250 cells/mm³ have a 12 fold higher risk of symptomatic liver toxicity than females with CD4+ cell counts < 250 (11% vs. 0.9%). Males with CD4+ cell counts > 400 cells/mm³ have a three fold higher risk of symptomatic liver toxicity than males with CD4+ cell counts < 400 (6.3% vs. 2.3%).

• Nevirapine-related deaths due to symptomatic liver toxicity, including some in HIV-infected pregnant women, have been reported to FDA's Medwatch program. Serious and fatal liver toxicity has not been reported after single doses of nevirapine.

In spite of the potential for serious and life-threatening liver toxicity and skin rashes with nevirapine, there are multiple reasons why nevirapine remains an important part of an HIV treatment regimen for many HIV-infected individuals world-wide. These reasons include:

• Triple antiretroviral regimens have been shown to have a large impact on the reduction of AIDS morbidity and mortality. Triple antiretroviral drug regimens containing a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI), such as nevirapine, are standard of care for HIV treatment and are needed to adequately and durably suppress virus.

• Many options are needed for HIV-infected patients since resistance to antiretroviral drugs or to an entire antiretroviral class can develop.

• Symptomatic liver toxicity has not been reported with the use of single doses of nevirapine to the mother and to the child for prevention of perinatal HIV infection.

• Alternatives to nevirapine are limited by other toxicities, potential drug interactions, and by the risk of drug related birth defects if given to a female in the first trimester of pregnancy.

• Nevirapine liver toxicity is less frequent (< 2% for both males and females with CD4+ cell counts < 250 cells/mm³) when started in patients with lower CD4 counts. Therefore, symptomatic liver toxicity in resource poor countries is likely to be much lower if World Health Organization standards are used for starting treatment. The WHO recommends the initiation of ART treatment in patients with advanced disease or with CD4 counts < 200 cells/mm³.

• Nevirapine is chemically stable in environmental conditions where other antiretrovirals are not.

• Symptomatic liver toxicity has not been reported in HIV-infected children, and nevirapine is available in a liquid formulation while many other antiretrovirals are not.

In conclusion, the seriousness of the underlying disease must be considered as part of the risk benefit analysis when treating HIV-infected patients. HIV infection will progress to AIDS and death if untreated. Treatment with combination antiretroviral drugs, including nevirapine, can slow clinical progression and may delay the development of AIDS or death for years. Health care providers should weigh the benefits and risks associated with nevirapine use before prescribing nevirapine for the treatment of their HIV-infected patients.

Richard Klein
Office of Special Health Issues, Food and Drug Administration

Jeffrey Murray
Division of Antiviral Drug Products, Food and Drug Administration
050119
FD050101

SOURCE: Food and Drug Administration (FDA).

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