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FDA Public Health Advisory for
Nevirapine (Viramune)
This public health advisory informs 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:
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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.
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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 five fold higher risk of symptomatic liver
toxicity than males with CD4+ cell counts < 400 (6.3% vs.
1.2%).
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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:
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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.
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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.
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Date created: January 19, 2005 |
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