WARNINGS AND PRECAUTIONS
The most serious adverse reactions associated with VIRAMUNE
are hepatitis/hepatic failure, Stevens-Johnson syndrome, toxic epidermal
necrolysis, and hypersensitivity reactions. 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.
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 and 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 ].
Hepatotoxicityand 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 non-specific,
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. Patients
with signs or symptoms of hepatitis must be advised to discontinue
VIRAMUNE and immediately seek medical evaluation, which should include
liver enzyme tests.
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 Boxed Warning and Dosage and
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 Contraindications ].
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 [see Boxed Warning ]. Do not restart VIRAMUNE following
severe skin rash, skin rash combined with increased transaminases
or other symptoms, or hypersensitivity reaction.
If patients present with a suspected VIRAMUNE-associated
rash, measure transaminases immediately. Permanently discontinue VIRAMUNE
in patients with rash-associated transaminase elevations [see
Warnings and Precautions ].
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 (7) ].
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. Co-administration
of VIRAMUNE and efavirenz is not recommended as this combination has
been associated with an increase in adverse reactions and no improvement
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.
USE IN SPECIFIC POPULATIONS
Pregnancy Category B
There are no adequate and well-controlled
trials of VIRAMUNE in pregnant women. The Antiretroviral Pregnancy
Registry, which has been surveying pregnancy outcomes since January
1989, has not found an increased risk of birth defects following first
trimester exposures to nevirapine. The prevalence of birth defects
after any trimester exposure to nevirapine is comparable to the prevalence
observed in the general population.
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 Boxed Warning ].
VIRAMUNE should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
To monitor maternal-fetal outcomes of pregnant women
exposed to VIRAMUNE, an Antiretroviral Pregnancy Registry has been
established. Physicians are encouraged to register patients by calling 258-4263.
No observable teratogenicity was detected in reproductive studies
performed in pregnant rats and rabbits. The maternal and developmental
no-observable-effect level dosages produced systemic exposures approximately
equivalent to or approximately 50% higher in rats and rabbits, respectively,
than those seen at the recommended daily human dose (based on AUC).
In rats, decreased fetal body weights were observed due to administration
of a maternally toxic dose (exposures approximately 50% higher than
that seen at the recommended human clinical dose).
The Centers for Disease Control and Prevention recommend that
HIV-1 infected mothers not breastfeed their infants to avoid risking
postnatal transmission of HIV-1. Nevirapine is excreted in breast
milk. Because of both the potential for HIV-1 transmission and the
potential for serious adverse reactions in nursing infants, mothers
should be instructed not to breastfeed if they are receiving VIRAMUNE.
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 Studies ].
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