Approved Drug Label (PDF)
Boxed Warning
Additions
and/or revisions underlined:
MONITORING FOR HEPATOXICITY AND SKIN
REACTIONS:
5
Warnings and Precautions
Additions
and/or revisions underlined:
5.1 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 nevirapine.
The risk of symptomatic hepatic events
regardless of severity is greatest in the first 6 weeks of therapy. The risk
continued to be greater in the nevirapine groups in controlled clinical trials
through 18 weeks of treatment. However, hepatic events may occur at any time
during treatment. In some cases, patients 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 patients
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 nevirapine 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 nevirapine and immediately seek medical evaluation,
which should include liver enzyme tests.
The first 18 weeks of therapy with VIRAMUNE
XR 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 XR treatment.
Transaminases should be checked
immediately if a patient experiences signs or symptoms …
5.2 Skin Reactions
Severe and life-threatening skin
reactions, including fatal cases, have been reported … Do not restart
nevirapine following severe skin rash, skin rash combined with increased
transaminases or other symptoms, or hypersensitivity reaction...
The first 18 weeks of therapy with
VIRAMUNE XR 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
XR treatment...
7
Drug Interactions
Addition of the
following:
… 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 XR is started …
Pregnancy Registry
Advise patients that there is a
pregnancy registry that monitors pregnancy outcomes in women exposed to
VIRAMUNE XR during pregnancy.
Lactation
Instruct women with HIV-1 infection not
to breastfeed because HIV-1 can be passed to the baby in the breast milk.
Infertility
Advise females of reproductive potential
of the potential for impaired fertility from VIRAMUNE XR.
8
Use in Specific Populations
8.1 Pregnancy
PLLR conversion,
as below:
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.
Risk Summary
Available data for nevirapine in
pregnant women is from the use of VIRAMUNE immediate-release. 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
a U.S. reference population of the Metropolitan Atlanta
Congenital Defects Program (MACDP). 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 less than 20
weeks gestation.
There is a risk for severe hepatic
events in pregnant women exposed to VIRAMUNE XR. 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 400mg daily dose..
Clinical
Considerations
Maternal adverse reactions
Severe hepatic events, including
fatalities, have been reported in pregnant women receiving chronic nevirapine 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 nevirapine unless the benefit outweighs the risk. It is unclear if
pregnancy augments the risk observed in non-pregnant women.
Antiretroviral
Data
Human Data
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 a 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%) with second/third-trimester exposure to nevirapine-containing regimens.
8.2 Lactation
PLLR conversion, as below:
Risk
Summary
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 immediate-release is present
in human milk. 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 XR.
8.3 Females and Males of Reproductive Potential
PLLR conversion, as below:
Infertility
Limited human data are insufficient to
determine the risk of infertility in humans. Based on results from animal
fertility studies conducted in rats, VIRAMUME may reduce fertility in females
of reproductive potential. It is not known if these effects on fertility are
reversible.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Extensive
changes; please refer to label.
PATIENT COUNSELING INFORMATION
Addition of the
following:
Administration and
Missed Dosage
Inform patients to take VIRAMUNE XR
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.
To avoid overdose, inform patients that
they should never take immediate-release VIRAMUNE and extended-release VIRAMUNE
XR concomitantly.
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