Approved Drug Label (PDF)
Boxed Warning
Additions
and/or revisions underlined:
WARNING: LIFE-THREATENING (INCLUDING
FATAL) HEPATOTOXICITY and SKIN REACTIONS
… MONITORING FOR HEPATOTOXICITY AND
SKIN REACTIONS:
Patients must be monitored intensively
during the first 18 weeks of therapy …
5
Warnings and Precautions
Additions
and/or revisions underlined:
5.1 Hepatotoxicity and Hepatic
Impairment
... 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.
5.2
Skin Reactions
… 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 …
6
Adverse Reactions
6.1
Clinical Trial Experience
Clinical
Trial Experience in Adult Patients
The most serious adverse reactions
associated with VIRAMUNE are hepatitis …
Clinical
Trial Experience in Pediatric Patients …
6.2 Post-Marketing Experience …
7
Drug Interactions
Table 4 Established and Potential Drug
Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due
to Drug Interaction Established Drug Interactions: See Clinical Pharmacology
(12.3), Table 5 for Magnitude of Interaction.
Data
in table has changed somewhat; please refer to label.
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 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). 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.
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.
There is a risk for severe hepatic
events in pregnant women exposed to VIRAMUNE.. 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.
Clinical Considerations
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.
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 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.
Animal Data
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.
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 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.
Data
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.
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
Additions
and/or revisions underlined:
What is the most important information I
should know about VIRAMUNE?
VIRAMUNE can cause severe liver and skin
problems that may lead to death.
These problems …
VIRAMUNE can cause serious side
effects, including:
Severe liver problems. Some people
taking
VIRAMUNE may develop severe liver
problemsIn that can lead to liver failure and the need for a liver
transplant, or death. If you have liver problems you may get a rash.
Women have a higher risk of developing liver
problems during treatment with VIRAMUNE than men.
People who have abnormal liver test results before
starting VIRAMUNE and people with hepatitis B or C also have a greater risk of
getting liver problems.
Stop
taking VIRAMUNE and call your doctor right away if you have any of the
following symptoms of liver problems with or without a skin rash:
Severe skin reactions and rash. Some skin
reactions and rashes may be severe, life-threatening, and in some people, may
lead to death. Most severe skin reactions and rashes happen in the first 6
weeks of treatment with VIRAMUNE.
blisters
muscle or joint aches
red or inflamed eyes, like “pink eye”
(conjunctivitis)
mouth sores
swelling of your face
fever
feel unwell or like you have the flu
tiredness
Your doctor should do blood tests often
to check your liver function and check for severe skin reactions during
the first 18 weeks of treatment with VIRAMUNE. You should continue to see
your doctor and have your liver checked regularly during your treatment
with VIRAMUNE …
If your doctor tells you to stop treatment with
VIRAMUNE because you have had any of the
severe liver or skin symptoms
listed above, you should never take VIRAMUNE again.
What
is VIRAMUNE?
VIRAMUNE
tablets and VIRAMUNE oral solution are prescription HIV-1 medicines used with
other HIV-1 medicines to treat HIV-1 (Human Immunodeficiency Virus). HIV 1) in
adults and in children 15 days of age and older. HIV-1 is the virus that
causes AIDS (Acquired Immune Deficiency Syndrome).
If you are a woman with CD4+ counts higher than 250
cells/mm3 or a man with CD4+ counts higher than 400 cells/mm3, you and your doctor
will decide if starting VIRAMUNE is right for you.
Do
Not Take VIRAMUNE:
are breastfeeding
or plan to breastfeed.
VIRAMUNE can pass into
your breast milk and may harm your baby. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. Do not breastfeed
during treatment with VIRAMUNE.
Talk to your doctor about
the best way to feed your baby.
Tell
your doctor and pharmacist about all the medicines you take, including
prescription and over-the-counter medicines, vitamins and herbal supplements ….
Especially tell your doctor if you take St. John’s wort.
Some medicines interact with
VIRAMUNE. Keep a list of your
medicines to show your doctor or pharmacist.
You can ask your doctor or pharmacist for a list of medicines that interact with
VIRAMUNE.
Do not start taking a new medicine without
telling your doctor. Your doctor can tell you if it is safe
to take VIRAMUNE with other medicines.
How should I take VIRAMUNE?
Take VIRAMUNE exactly as your doctor
tells you to take it. Do not change your dose unless your doctor tells you to.
VIRAMUNE
is always taken in combination with other antiretroviral medicines.
VIRAMUNE
comes in three different forms. Your doctor will prescribe the form of VIRAMUNE
that is right for you.
VIRAMUNE may cause
serious side effects, including:
·
VIRAMUNE may cause
decreased fertility in females. Talk to your doctor if you have concerns about fertility.
PATIENT COUNSELING INFORMATION
Additions
and/or revisions underlined:
Administration
and Missed Dosage
Inform patients to take VIRAMUNE every
day as prescribed. Advise patients
not to alter the dose without consulting their doctor ...
To avoid overdose, inform patients
that they should never take immediate-release
VIRAMUNE and extended-release VIRAMUNE XR concomitantly.
Drug Interactions
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.
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 …
… Pregnancy Registry
Advise patients that there is a
pregnancy registry that monitors pregnancy outcomes in women exposed to
VIRAMUNE 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.
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