Included as part of the PRECAUTIONS section.
Hepatotoxicity And Hepatic Impairment
Severe, life-threatening, and in some cases fatal
hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis
and hepatic failure, have been reported in patients treated with VIRAMUNE. In
controlled clinical trials, symptomatic hepatic events regardless of severity
occurred in 4% (range 0% to 11%) of subjects who received VIRAMUNE and 1% of
subjects in control groups.
The risk of symptomatic hepatic events regardless of
severity was greatest in the first 6 weeks of therapy. The risk continued to be
greater in the VIRAMUNE groups compared to controls through 18 weeks of
treatment. However, hepatic events may occur at any time during treatment. In
some cases, subjects presented with nonspecific, prodromal signs or symptoms of
fatigue, malaise, anorexia, nausea, jaundice, liver tenderness or hepatomegaly,
with or without initially abnormal serum transaminase levels. Rash was observed
in approximately half of the subjects with symptomatic hepatic adverse events.
Fever and flu-like symptoms accompanied some of these hepatic events. Some
events, particularly those with rash and other symptoms, have progressed to
hepatic failure with transaminase elevation, with or without
hyperbilirubinemia, hepatic encephalopathy, prolonged partial thromboplastin
time, or eosinophilia. Rhabdomyolysis has been observed in some patients experiencing
skin and/or liver reactions associated with VIRAMUNE use. Hepatitis/hepatic
failure may be associated with signs of hypersensitivity which can include severe
rash or rash accompanied by fever, general malaise, fatigue, muscle or joint
aches, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia,
lymphadenopathy, or renal dysfunction. Patients with signs or symptoms of
hepatitis must be advised to discontinue VIRAMUNE and immediately seek medical
evaluation, which should include liver enzyme tests.
The first 18 weeks of therapy with VIRAMUNE are a critical
period during which intensive clinical and laboratory monitoring of patients is
required to detect potentially life-threatening hepatic events. The optimal
frequency of monitoring during this time period has not been established. Some
experts recommend clinical and laboratory monitoring more often than once per
month, and in particular, include monitoring of liver enzyme tests at baseline,
prior to dose escalation and at two weeks post-dose escalation. After the
initial 18-week period, frequent clinical and laboratory monitoring should
continue throughout VIRAMUNE treatment.
Transaminases should be checked immediately if a patient
experiences signs or symptoms suggestive of hepatitis and/or hypersensitivity
reaction. Transaminases should also be checked immediately for all patients who
develop a rash in the first 18 weeks of treatment. Physicians and patients
should be vigilant for the appearance of signs or symptoms of hepatitis, such
as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools,
liver tenderness or hepatomegaly. The diagnosis of hepatotoxicity should be
considered in this setting, even if transaminases are initially normal or
alternative diagnoses are possible [see DOSAGE AND ADMINISTRATION].
If clinical hepatitis or transaminase elevations combined
with rash or other systemic symptoms occur, permanently discontinue VIRAMUNE.
Do not restart VIRAMUNE after recovery. In some cases, hepatic injury
progresses despite discontinuation of treatment.
The patients at greatest risk of hepatic events,
including potentially fatal events, are women with high CD4+ cell counts. In
general, during the first 6 weeks of treatment, women have a 3-fold higher risk
than men for symptomatic, often rash-associated, hepatic events (6% versus 2%),
and patients with higher CD4+ cell counts at initiation of VIRAMUNE therapy are
at higher risk for symptomatic hepatic events with VIRAMUNE. In a retrospective
review, women with CD4+ cell counts greater than 250 cells/mm³ had a 12-fold
higher risk of symptomatic hepatic adverse events compared to women with CD4+
cell counts less than 250 cells/mm³ (11% versus 1%). An increased risk was
observed in men with CD4+ cell counts greater than 400 cells/mm³ (6% versus 1%
for men with CD4+ cell counts less than 400 cells/mm³). However, all patients,
regardless of gender, CD4+ cell count, or antiretroviral treatment history,
should be monitored for hepatotoxicity since symptomatic hepatic adverse events
have been reported at all CD4+ cell counts. Co-infection with hepatitis B or C
and/or increased transaminase elevations at the start of therapy with VIRAMUNE
are associated with a greater risk of later symptomatic events (6 weeks or more
after starting VIRAMUNE) and asymptomatic increases in AST or ALT.
In addition, serious hepatotoxicity (including liver
failure requiring transplantation in one instance) has been reported in HIV-1
uninfected individuals receiving multiple doses of VIRAMUNE in the setting of
post-exposure prophylaxis (PEP), an unapproved use. Use of VIRAMUNE for
occupational and non-occupational PEP is contraindicated [see
Increased nevirapine trough concentrations have been
observed in some patients with hepatic fibrosis or cirrhosis. Therefore,
carefully monitor patients with either hepatic fibrosis or cirrhosis for
evidence of drug-induced toxicity. Do not administer nevirapine to patients
with moderate or severe (Child-Pugh Class B or C, respectively) hepatic
impairment [see CONTRAINDICATIONS, Use In Specific Populations,
and CLINICAL PHARMACOLOGY].
Severe and life-threatening skin reactions, including
fatal cases, have been reported, occurring most frequently during the first 6
weeks of therapy. These have included cases of Stevens-Johnson syndrome, toxic
epidermal necrolysis, and hypersensitivity reactions characterized by rash,
constitutional findings, and organ dysfunction including hepatic failure.
Rhabdomyolysis has been observed in some patients experiencing skin and/or
liver reactions associated with VIRAMUNE use. In controlled clinical trials,
Grade 3 and 4 rashes were reported during the first 6 weeks in 2% of VIRAMUNE
recipients compared to less than 1% of placebo subjects.
Patients developing signs or symptoms of severe skin reactions
or hypersensitivity reactions (including, but not limited to, severe rash or
rash accompanied by fever, general malaise, fatigue, muscle or joint aches,
blisters, oral lesions, conjunctivitis, facial edema, and/or hepatitis,
eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction) must
permanently discontinue VIRAMUNE and seek medical evaluation immediately. Do
not restart VIRAMUNE following severe skin rash, skin rash combined with
increased transaminases or other symptoms, or hypersensitivity reaction.
The first 18 weeks of therapy with VIRAMUNE are a
critical period during which intensive clinical and laboratory monitoring of
patients is required to detect potentially life-threatening skin reactions. The
optimal frequency of monitoring during this time period has not been
established. Some experts recommend clinical and laboratory monitoring more
often than once per month, and in particular, include monitoring of liver
enzyme tests at baseline, prior to dose escalation and at two weeks post-dose
escalation. After the initial 18-week period, frequent clinical and laboratory
monitoring should continue throughout VIRAMUNE treatment. In addition, the 14-day
lead-in period with VIRAMUNE 200 mg daily dosing has been demonstrated to
reduce the frequency of rash [see DOSAGE AND ADMINISTRATION].
If patients present with a suspected VIRAMUNE-associated
rash, measure transaminases immediately. Permanently discontinue VIRAMUNE in
patients with rashassociated transaminase elevations [see Hepatotoxicity and Hepatic Impairment].
Therapy with VIRAMUNE must be initiated with a 14-day
lead-in period of 200 mg per day (150 mg/m² per day in pediatric patients),
which has been shown to reduce the frequency of rash. Discontinue VIRAMUNE if a
patient experiences severe rash or any rash accompanied by constitutional
findings. Do not increase VIRAMUNE dose to a patient experiencing a mild to
moderate rash without constitutional symptoms during the 14-day lead-in period
of 200 mg per day (150 mg/m²/day in pediatric patients) until the rash has
resolved. The total duration of the once-daily lead-in dosing period must not
exceed 28 days at which point an alternative regimen should be sought [see DOSAGE
AND ADMINISTRATION]. Patients must be monitored closely if isolated rash of
any severity occurs. Delay in stopping VIRAMUNE treatment after the onset of
rash may result in a more serious reaction.
Women appear to be at higher risk than men of developing
rash with VIRAMUNE.
In a clinical trial, concomitant prednisone use (40 mg
per day for the first 14 days of VIRAMUNE administration) was associated with
an increase in incidence and severity of rash during the first 6 weeks of
VIRAMUNE therapy. Therefore, use of prednisone to prevent VIRAMUNE-associated
rash is not recommended.
VIRAMUNE must not be used as a single agent to treat
HIV-1 or added on as a sole agent to a failing regimen. Resistant virus emerges
rapidly when nevirapine is administered as monotherapy. The choice of new
antiretroviral agents to be used in combination with nevirapine should take
into consideration the potential for cross resistance. When discontinuing an
antiretroviral regimen containing VIRAMUNE, the long half-life of nevirapine
should be taken into account; if antiretrovirals with shorter half-lives than
VIRAMUNE are stopped concurrently, low plasma concentrations of nevirapine
alone may persist for a week or longer and virus resistance may subsequently
develop [see Microbiology].
See Table 4 for listings of established and potential
drug interactions [see DRUG INTERACTIONS].
Concomitant use of St. John's wort (Hypericum perforatum)
or St. John's wort-containing products and VIRAMUNE is not recommended.
Co-administration of St. John’s wort with non-nucleoside reverse transcriptase
inhibitors (NNRTIs), including VIRAMUNE, is expected to substantially decrease
NNRTI concentrations and may result in sub-optimal levels of VIRAMUNE and lead
to loss of virologic response and possible resistance to VIRAMUNE or to the
class of NNRTIs. Coadministration of VIRAMUNE and efavirenz is not recommended
as this combination has been associated with an increase in adverse reactions
and no improvement in efficacy.
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in
patients treated with combination antiretroviral therapy, including VIRAMUNE.
During the initial phase of combination antiretroviral treatment, patients
whose immune system responds may develop an inflammatory response to indolent
or residual opportunistic infections (such as Mycobacterium avium infection,
cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may
necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves’ disease, polymyositis,
and Guillain-Barré syndrome) have also been reported to occur in the setting of
immune reconstitution, however, the time to onset is more variable, and can
occur many months after initiation of treatment.
Redistribution/accumulation of body fat including central
obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting,
facial wasting, breast enlargement, and “cushingoid appearance” have been
observed in patients receiving antiretroviral therapy. The mechanism and long-term
consequences of these events are currently unknown. A causal relationship has
not been established.
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (Medication Guide).
Hepatotoxicity And Skin Reactions
Inform patients of the possibility of severe liver
disease or skin reactions associated with VIRAMUNE that may result in death.
Instruct patients developing signs or symptoms of liver disease or severe skin
reactions to discontinue VIRAMUNE and seek medical attention immediately,
including performance of laboratory monitoring. Symptoms of liver disease
include fatigue, malaise, anorexia, nausea, jaundice, acholic stools, liver
tenderness or hepatomegaly. Symptoms of severe skin or hypersensitivity
reactions include rash accompanied by fever, general malaise, fatigue, muscle
or joint aches, blisters, oral lesions, conjunctivitis, facial edema, and/or
Intensive clinical and laboratory monitoring, including
liver enzymes, is essential during the first 18 weeks of therapy with VIRAMUNE
to detect potentially lifethreatening hepatotoxicity and skin reactions.
However, liver disease can occur after this period; therefore, monitoring
should continue at frequent intervals throughout VIRAMUNE treatment. Extra
vigilance is warranted during the first 6 weeks of therapy, which is the period
of greatest risk of hepatic events. Advise patients with signs and symptoms of
hepatitis to discontinue VIRAMUNE and seek medical evaluation immediately. If
VIRAMUNE is discontinued due to hepatotoxicity, do not restart it. Patients,
particularly women, with increased CD4+ cell count at initiation of VIRAMUNE
therapy (greater than 250 cells/mm³ in women and greater than 400 cells/mm³ in
men) are at substantially higher risk for development of symptomatic hepatic
events, often associated with rash. Advise patients that co-infection with hepatitis
B or C and/or increased transaminases at the start of therapy with VIRAMUNE are
associated with a greater risk of later symptomatic events (6 weeks or more after
starting VIRAMUNE) and asymptomatic increases in AST or ALT [see WARNINGS
The majority of rashes associated with VIRAMUNE occur
within the first 6 weeks of initiation of therapy. Instruct patients that if
any rash occurs during the two-week lead-in period, do not escalate the
VIRAMUNE dose until the rash resolves. The total duration of the once-daily
lead-in dosing period should not exceed 28 days, at which point an alternative
regimen may need to be started. Any patient experiencing a rash should have
their liver enzymes (AST, ALT) evaluated immediately. Patients with severe rash
or hypersensitivity reactions should discontinue VIRAMUNE immediately and
consult a physician. VIRAMUNE should not be restarted following severe skin
rash or hypersensitivity reaction. Women tend to be at higher risk for
development of VIRAMUNE-associated rash [see WARNINGS AND PRECAUTIONS].
Administration And Missed Dosage
Inform patients to take VIRAMUNE every day as prescribed.
Advise patients not to alter the dose without consulting their doctor. If a
dose is missed, patients should take the next dose as soon as possible.
However, if a dose is skipped, the patient should not double the next dose.
To avoid overdose, inform patients that they should never
take immediate-release VIRAMUNE and extended-release VIRAMUNE XR concomitantly.
VIRAMUNE may interact with some drugs; therefore, advise
patients to report to their doctor the use of any other prescription,
non-prescription medication or herbal products, particularly St. John's wort [see
WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
Immune Reconstitution Syndrome
Advise patients to inform their healthcare provider
immediately of any signs or symptoms of infection, as inflammation from
previous infection may occur soon after combination antiretroviral therapy,
including when VIRAMUNE is started [see WARNINGS AND PRECAUTIONS].
Inform patients that redistribution or accumulation of
body fat may occur in patients receiving antiretroviral therapy and that the
cause and long-term health effects of these conditions are not known at this
time [see WARNINGS AND PRECAUTIONS].
Advise patients that there is a pregnancy registry that
monitors pregnancy outcomes in women exposed to VIRAMUNE during pregnancy [see Use
In Specific Populations].
Instruct women with HIV-1 infection not to breastfeed
because HIV-1 can be passed to the baby in the breast milk [see Use In Specific
Advise females of reproductive potential of the potential
for impaired fertility from VIRAMUNE [see Use In Specific Populations and
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term carcinogenicity studies in mice and rats were
carried out with nevirapine. Mice were dosed with 0, 50, 375 or 750 mg/kg/day
for two years. Hepatocellular adenomas and carcinomas were increased at all
doses in males and at the two high doses in females. In studies in which rats
were administered nevirapine at doses of 0, 3.5, 17.5 or 35 mg/kg/day for two
years, an increase in hepatocellular adenomas was seen in males at all doses
and in females at the high dose. The systemic exposure (based on AUCs) at all
doses in the two animal studies was lower than that measured in humans at the
200 mg twice daily dose. The mechanism of the carcinogenic potential is
However, in genetic toxicology assays, nevirapine showed
no evidence of mutagenic or clastogenic activity in a battery of in vitro and in
vivo studies. These included microbial assays for gene mutation (Ames:
Salmonella strains and E. coli), mammalian cell gene mutation assay
(CHO/HGPRT), cytogenetic assays using a Chinese hamster ovary cell line and a
mouse bone marrow micronucleus assay following oral administration. Given the
lack of genotoxic activity of nevirapine, the relevance to humans of
hepatocellular neoplasms in nevirapine-treated mice and rats is not known.
Impairment Of Fertility
In reproductive toxicology studies, evidence of impaired
fertility was seen in female rats at doses providing systemic exposure, based
on AUC, approximately equivalent to that provided with the recommended clinical
dose of VIRAMUNE.
Use In Specific Populations
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors
pregnancy outcomes in women exposed to nevirapine during pregnancy. Healthcare
providers are encouraged to register patients by calling the Antiretroviral
Pregnancy Registry (APR) at 1-800-258-4263.
Available data from the APR show no difference in the
risk of overall major birth defects for nevirapine compared with the background
rate for major birth defects of 2.7% in the U.S. reference population of the
Metropolitan Atlanta Congenital Defects Program (MACDP) [see Data]. The
rate of miscarriage is not reported in the APR. The estimated background rate
of miscarriage in clinically recognized pregnancies in the U.S. general
population is 15-20%. The background risk of birth defects and miscarriage for
the indicated population is unknown. Methodological limitations of the APR
include the use of MACDP as the external comparator group. The MACDP population
is not disease-specific, evaluates women and infants from a limited geographic
area, and does not include outcomes for births that occurred at <20 weeks
In literature reports, immediate-release nevirapine
exposure (Cmin) can be up to 29% lower during pregnancy. However, as this
reduction was not found to be clinically meaningful, dose adjustment is not
necessary [see Data].
There is a risk for severe hepatic events in pregnant
women exposed to VIRAMUNE [see Clinical Considerations]. In animal
reproduction studies, no evidence of adverse developmental outcomes were
observed following oral administration of nevirapine during organogenesis in
the rat and rabbit, at systemic exposures (AUC) to nevirapine approximately
equal (rats) and 50% higher (rabbits) than the exposure in humans at the
recommended 400 mg daily dose [see Data].
Maternal Adverse Reactions
Severe hepatic events, including fatalities, have been
reported in pregnant women receiving chronic VIRAMUNE therapy as part of
combination treatment of HIV-1 infection. Regardless of pregnancy status, women
with CD4+ cell counts greater than 250 cells/mm³ should not initiate VIRAMUNE
unless the benefit outweighs the risk. It is unclear if pregnancy augments the
risk observed in non-pregnant women [see WARNINGS AND PRECAUTIONS].
Based on prospective reports to the APR of over 2600
exposures to nevirapine during pregnancy resulting in live births (including
over 1100 exposed in the first trimester), there was no difference between
nevirapine and overall birth defects compared with the background birth defect
rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of
birth defects in live births was 2.8% (95% CI: 1.9 %, 4.0%) following first
trimester exposure to nevirapine-containing regimens and 3.2% (95% CI: 2.4%,
4.3%) for second/third trimester exposure to nevirapine-containing regimens.
There are several literature reports of chronic
administration of immediate-release nevirapine during pregnancy, in which
nevirapine pharmacokinetics were compared between pregnancy and postpartum. In
these studies, the mean difference in nevirapine Cmin during pregnancy as
compared to postpartum ranged from no difference to approximately 29% lower.
Nevirapine was administered orally to pregnant rats (at
0, 12.5, 25, and 50 mg per kg per day) and rabbits (at 0, 30, 100, and 300 mg
per kg per day) through organogenesis (on gestation days 7 through 16, and 6
through 18, respectively). No adverse developmental effects were observed at
doses producing systemic exposures (AUC) approximately equivalent to (rats) or
approximately 50% higher (rabbits) than human exposure at the recommended daily
dose. In rats, decreased fetal body weights were observed at a maternally toxic
dose at an exposure approximately 50% higher than the recommended daily dose.
The Centers for Disease Control and Prevention recommend
that HIV-1 infected mothers in the United States not breastfeed their infants
to avoid risking postnatal transmission of HIV-1 infection. Published data
report that nevirapine is present in human milk [see Data]. There are
limited data on the effects of nevirapine on the breastfed infant. There is no
information on the effects of nevirapine on milk production. Because of the
potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing
viral resistance (in HIV-positive infants), and (3) serious adverse reactions
in nursing infants, mothers should not breastfeed if they are receiving VIRAMUNE.
Based on five publications, immediate-release nevirapine
was excreted in breast-milk at median concentrations ranging from 4080 to 6795
ng/mL, and the median maternal breast-milk to maternal plasma concentration
ratio range was 59 to 88%. Reported infant nevirapine median plasma
concentrations were low, ranging from 734 to 1140 ng/mL. The estimated
nevirapine dose of 704 to 682 μg/kg/day for infants fed exclusively with
breast-milk was lower than the daily recommended nevirapine dose for infants.
Published literature indicates that rash and hyperbilirubinemia have been seen
in infants exposed to nevirapine through breastmilk.
Females And Males Of Reproductive Potential
Limited human data are insufficient to determine the risk
of infertility in humans. Based on results from animal fertility studies
conducted in rats, VIRAMUNE may reduce fertility in females of reproductive
potential. It is not known if these effects on fertility are reversible [see Nonclinical
The safety, pharmacokinetic profile, and virologic and
immunologic responses of VIRAMUNE have been evaluated in HIV-1 infected
pediatric subjects age 3 months to 18 years [see ADVERSE REACTIONS and Clinical
Studies]. The safety and pharmacokinetic profile of VIRAMUNE has been
evaluated in HIV-1 infected pediatric subjects age 15 days to less than 3
months [see ADVERSE REACTIONS and Clinical Studies].
The most frequently reported adverse events related to
VIRAMUNE in pediatric subjects were similar to those observed in adults, with
the exception of granulocytopenia, which was more commonly observed in children
receiving both zidovudine and VIRAMUNE [see ADVERSE REACTIONS and Clinical
Clinical trials of VIRAMUNE did not include sufficient
numbers of subjects aged 65 and older to determine whether elderly subjects
respond differently from younger subjects. In general, dose selection for an
elderly patient should be cautious, reflecting the greater frequency of
decreased hepatic, renal or cardiac function, and of concomitant disease or
other drug therapy.
In subjects with renal impairment (mild, moderate or
severe), there were no significant changes in the pharmacokinetics of
nevirapine. Nevirapine is extensively metabolized by the liver and nevirapine
metabolites are extensively eliminated by the kidney. Nevirapine metabolites
may accumulate in patients receiving dialysis; however, the clinical
significance of this accumulation is not known. No adjustment in nevirapine
dosing is required in patients with CrCl greater than or equal to 20 mL per
min. The pharmacokinetics of nevirapine have not been evaluated in patients
with CrCl less than 20 mL per min. In patients undergoing chronic hemodialysis,
an additional 200 mg dose following each dialysis treatment is indicated [see DOSAGE
AND ADMINISTRATION and CLINICAL PHARMACOLOGY].
Because increased nevirapine levels and nevirapine
accumulation may be observed in patients with serious liver disease, do not
administer VIRAMUNE to patients with moderate or severe (Child-Pugh Class B or
C, respectively) hepatic impairment [see CONTRAINDICATIONS, WARNINGS
AND PRECAUTIONS, and CLINICAL PHARMACOLOGY].