Approved Drug Label (PDF)
8
Use in Specific Populations
8.1 Pregnancy
Additions and/or revisions underlined:
Pregnancy
Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women
exposed to lamivudine
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 substantial difference in the risk of overall
major birth defects for lamivudine compared
with the background rate for major birth defects
of 2.7% reported in the U.S. reference population of the Metropolitan Atlanta
Congenital Defects Program
(MACDP). The APR uses the MACDP as a U.S. reference
population for birth defects
in the general population. The MACDP evaluates women and infants from a limited geographic
area and does not include
outcomes for births that occur at less than 20 weeks’ gestation. Of over 12,900 women exposed to lamivudine in the APR, less than 2% were HBV mono-infected. The majority of women exposed
to lamivudine in the APR were HIV-1–infected and were treated with higher doses of lamivudine compared with HBV mono-infected women. In addition
to lamivudine, HIV-1–infected women were also treated
with other concomitant medications for HIV-1 infection
(see Data). The estimated
rate of miscarriage for women exposed to lamivudine in the indicated population is unknown. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population
is 15% to 20%...
Data
Human Data: Based on prospective reports from the APR of over 12,900 exposures to
lamivudine
during pregnancy resulting in live births
(including over 5,400 exposed
in the first trimester and over 7,500 exposed
in the second/third trimester), there was no difference
between the overall
risk of birth defects with lamivudine
compared with the background birth defect rate of 2.7% observed in the U.S.
reference population of the MACDP. The prevalence of birthdefects in live births was 3.1% (95% CI: 2.7%
to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.9% (95% CI: 2.5% to 3.3%) following second/third trimester exposure to lamivudine-containing regimens.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATION
Extensive changes; please refer to
label
Approved Drug Label (PDF)
Boxed Warning
(additions
underlined)
WARNING: LACTIC ACIDOSIS AND
SEVERE HEPATOMEGALY WITH STEATOSIS, EXACERBATIONS OF HEPATITIS B, and RISK
OF HIV-1 RESISTANCE IF EPIVIR-HBV IS USED IN PATIENTS WITH UNRECOGNIZED OR
UNTREATED HIV-1 INFECTION
Lactic acidosis and severe
hepatomegaly with steatosis, including fatal cases, have been reported with the
use of nucleoside analogues and other antiretrovirals. Discontinue
EPIVIR-HBV if clinical or laboratory findings suggestive of lactic acidosis or
pronounced hepatotoxicity occur.
Severe acute exacerbations
of hepatitis B have been reported in patients who have discontinued
anti-hepatitis B therapy (including EPIVIR-HBV). Hepatic function should be
monitored closely with both clinical and laboratory follow-up for at least
several months in patients who discontinue anti-hepatitis B therapy. If
appropriate, initiation of anti-hepatitis
B therapy may be warranted.
EPIVIR-HBV is not approved
for the treatment of HIV-1 infection because the lamivudine dosage in
EPIVIR-HBV is subtherapeutic and monotherapy is inappropriate for the treatment
of HIV-1 infection. HIV-1 resistance may emerge in chronic hepatitis B-infected
patients with unrecognized or untreated HIV-1 infection. HIV counseling and
testing should be offered to all patients before beginning treatment with
EPIVIR-HBV and periodically during treatment.
7
Drug Interactions
7.2 Sorbitol
(new
subsection added)
Coadministration
of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent
reduction in lamivudine exposures. When possible, avoid use of
sorbitol-containing medicines with lamivudine. Consider more frequent
monitoring of HBV viral load when chronic coadministration cannot be avoided.
8
Use in Specific Populations
8.5 Geriatric Use
(additions
underlined)
Clinical
trials of EPIVIR-HBV did not include sufficient numbers of subjects aged 65 and
over to determine whether they respond differently from younger subjects. In
general, caution should be exercised in the administration of EPIVIR-HBV
in elderly patients reflecting the greater frequency of decreased hepatic,
renal, or cardiac function, and of concomitant disease or other drug therapy.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
(additions
underlined)
Advise the patient to read the FDA-approved patient
labeling (Patient Information).
Lactic
Acidosis and Severe Hepatomegaly with Steatosis
Advise
patients that lactic acidosis and severe hepatomegaly with steatosis, including
fatal cases, have been reported with use of EPIVIR-HBV. Advise patients to
contact their healthcare provider immediately and stop EPIVIR-HBV if they
develop clinical symptoms suggestive of lactic acidosis or pronounced
hepatotoxicity.
…
Drug
Interactions
Inform
patients that EPIVIR-HBV may interact with some drugs; therefore, patients
should be advised to report to their healthcare provider the use of any
prescription, non-prescription medication or herbal products. Advise patients
to avoid chronic use of sorbitol-containing prescription and over-the-counter medicines
when possible. Taking EPIVIR-HBV with chronically administered
sorbitol-containing medicines may decrease the concentrations of lamivudine.
…
PATIENT INFORMATION
(additions
underlined)
…
You may be more likely to
get lactic acidosis or severe liver problems if you are female, very overweight
(obese), or have been taking nucleoside analogue medicines for a long
time.
Worsening liver disease. Your hepatitis B infection may become worse after
stopping treatment with EPIVIR-HBV. Worsening liver disease can be serious and
may lead to death. If you stop treatment with EPIVIR-HBV, your healthcare
provider will need to check your health and do blood tests to check your liver
for at least several months after you stop taking EPIVIR-HBV.
Risk of HIV-1 resistance in people with
unknown HIV-1 infection or in people with untreated HIV-1 infection. If you have or get HIV-1 (Human Immunodeficiency
Virus type 1) that is not being treated with medicines while taking EPIVIR-HBV,
the HIV-1 virus may develop resistance to certain HIV-1 medicines and become
harder to treat.
Your healthcare provider should offer you counseling
and testing for HIV-1 infection before you start treatment for hepatitis B with
EPIVIR-HBV and during treatment.
EPIVIR-HBV tablets and EPIVIR-HBV oral solution
contain a lower dose of lamivudine than other medicines that contain lamivudine
and are used to treat HIV-1 infection.
…
Approved Drug Label (PDF)
5
Warnings and Precautions
5.3 Risk of HIV-1 Resistance if EPIVIR-HBV is Used in Patients with Unrecognized or Untreated HIV-1 Infection
(Additions and/or revisions are underlined)
EPIVIR-HBV tablets
and oral solution contain a lower lamivudine dose than the lamivudine dose used
to treat HIV-1 infection with EPIVIR tablets and oral solution or
with lamivudine-containing antiretroviral fixed-dose combination
products.
EPIVIR-HBV is
not appropriate for patients co-infected with HBV and HIV-1. If a
patient with unrecognized or untreated HIV-1 infection is prescribed
EPIVIR-HBV for the treatment of HBV, rapid emergence of HIV-1 resistance is
likely to result because of the subtherapeutic dose and the inappropriate use of monotherapy for HIV-1 treatment. HIV
counseling and testing should be offered to all patients before beginning treatment
with EPIVIR-HBV and periodically during treatment because of the risk of rapid
emergence of resistant HIV-1 and limitation of treatment options if EPIVIR-HBV
is prescribed to treat chronic hepatitis B in a patient who has unrecognized or
untreated HIV-1 infection or who acquires HIV-1 infection during
treatment.
6
Adverse Reactions
6.2 Postmarketing Experience
(Additions and/or revisions are underlined)
Blood and
Lymphatic System Disorders
Anemia
(including pure red cell aplasia and severe anemias progressing on therapy),
lymphadenopathy, splenomegaly, thrombocytopenia
8
Use in Specific Populations
8.1 Pregnancy
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion;
additions and/or revisions are
underlined)
Pregnancy
Exposure Registry
There is a pregnancy exposure registry that
monitors pregnancy outcomes in women exposed to lamivudine 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 substantial difference in the risk of overall major birth
defects for lamivudine compared with the background rate for major birth
defects of 2.7% reported in the U.S. reference population of the Metropolitan
Atlanta Congenital Defects Program (MACDP). The APR uses the MACDP as a U.S.
reference population for birth defects in the general population. The MACDP
evaluates women and infants from a limited geographic area and does not include
outcomes for births that occur at less than 20 weeks gestation. Of over 11,000
women exposed to lamivudine in the APR, less than 1% were treated for HBV. The
majority of women exposed to lamivudine in the APR were HIV-1-infected and were
treated with higher doses of lamivudine compared with HBV mono-infected women.
In addition to lamivudine, HIV-1-infected women were also treated with other
concomitant medications for HIV-1 infection. The estimated rate of miscarriage
for women exposed to lamivudine in the indicated population is unknown. The
estimated background rate of miscarriage in clinically recognized pregnancies
in the U.S. general population is 15% to 20%.
Oral
administration of lamivudine to pregnant rabbits during organogenesis resulted
in embryolethality at systemic exposure (AUC) similar to the recommended
clinical dose; however, no adverse developmental effects were observed with
oral administration of lamivudine to pregnant rats during organogenesis at
plasma concentrations (Cmax) 60 times the recommended clinical dose.
Data
Human Data: Based on prospective reports from the APR of over 11,000 exposures to
lamivudine (including over 4,600 exposed in the first trimester) during
pregnancy resulting in live births, less than 1% of which were patients with
HBV, there was no substantial difference in birth defects with lamivudine
compared with the birth defect rate of 2.7% observed in the comparator population of the MACDP. The prevalence of birth defects in
live births was 3.1% (95% CI: 2.6% to 3.6%) following first trimester exposure
to lamivudine-containing regimens and 2.8% (95% CI: 2.5% to 3.3%) following
second/third trimester exposure to lamivudine- containing regimens.
The
pharmacokinetics of lamivudine in patients with HBV or HIV-1 infection and in
healthy volunteers are similar at similar doses. Lamivudine pharmacokinetics
were studied in pregnant women with HIV-1 infection during 2 clinical trials
conducted in South Africa. The trials assessed pharmacokinetics in 16 women at
36 weeks gestation using 150 mg lamivudine twice daily (3 times the recommended
daily dosage for HBV) with zidovudine, 10 women at 38 weeks gestation using 150
mg lamivudine twice daily (3 times the recommended daily dosage for HBV) with
zidovudine, and 10 women at 38 weeks gestation using lamivudine 300 mg twice
daily (6 times the recommended daily dosage for HBV) without other antiretrovirals. Lamivudine
concentrations were generally similar in maternal, neonatal, and umbilical cord
serum samples.
In a subset of
subjects, amniotic fluid specimens were collected following natural rupture of
membranes and confirmed that lamivudine crosses the placenta in humans. Based
on limited data at delivery, median (range) amniotic fluid concentrations of
lamivudine were 3.9- (1.2- to 12.8-) fold greater compared with paired maternal
serum concentrations (n = 8).
Animal Data: Lamivudine was administered orally to pregnant rats (at 90, 600, and 4,000 mg per kg per day)
and rabbits (at 90, 300, and 1,000 mg per kg per day and at 15, 40, and 90 mg
per kg per day) during organogenesis (on gestation Days 7 through 16 [rat] and
8 through 20 [rabbit]). No evidence of fetal malformations due to lamivudine
was observed in rats and rabbits at doses producing plasma concentrations (Cmax) approximately 53 or
more times higher than human exposure at the recommended daily
dose. Evidence of early embryolethality in the absence of maternal toxicity
was seen in the rabbit at systemic exposures (AUC) similar to those
observed in humans, but there was no indication of this effect in the rat at plasma
concentrations (Cmax) 60 times
higher than human exposure
at the recommended daily dose.
Studies in pregnant rats showed that lamivudine is transferred to the fetus through
the placenta. In the fertility/pre- and postnatal development study in rats,
lamivudine was administered orally at doses of 180, 900, and
4,000 mg per kg per day (from prior to mating through postnatal Day 20). In the
study, development of the offspring, including fertility and reproductive performance,
was not affected by maternal administration of lamivudine at plasma
concentrations (Cmax) 104 times higher than human exposure.
8.2 Lactation
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion;
additions and/or revisions are
underlined)
Risk Summary
Lamivudine is
present in human milk. There is no information available regarding lamivudine
concentrations in milk from lactating women receiving lamivudine for treatment
of HBV infection. However, in lactating women with HIV-1 infection being treated
with lamivudine at 3 or 6 times the recommended daily dose for HBV, lamivudine
concentrations in milk were similar
to those observed in serum. The
lamivudine dose received by a breastfed infant of a mother being treated for
HIV-1 infection was estimated to be approximately 6% of the recommended daily
lamivudine dose for HBV in children over 2 years of age.
There is no
information available regarding the effects of the drug on the breastfed infant
or on milk production.
The
developmental and health benefits of breastfeeding should be considered along
with the mother’s clinical need for EPIVIR-HBV and any potential adverse
effects on the breastfed infant from lamivudine or from the underlying maternal
condition.
Data
In mothers with
HIV receiving lamivudine monotherapy (300 mg twice daily [6 times the
recommended daily dosage for HBV]) or combination therapy (150 mg
lamivudine twice daily [3 times the recommended daily dosage for HBV] with
300 mg zidovudine twice daily), the median breast milk to plasma lamivudine
concentration ratio was 0.6 to 3.3, and the estimated infant
daily dose was approximately 6% of the recommended 3-mg-per-kg daily lamivudine
dose for treatment of HBV in children over 2 years of age. In breastfed infants
of mothers with HIV-1 infection receiving lamivudine therapy, the blood
concentrations of lamivudine decreased after delivery and were undetectable at
6 months despite constant milk concentrations. This is consistent with
increased lamivudine renal clearance in the first 6 months of life.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions and/or revisions are underlined)
Lactic Acidosis
and Severe Hepatomegaly
Advise patients
that lactic acidosis and severe hepatomegaly with steatosis, including fatal
cases, have been reported with use of EPIVIR-HBV. Advise patients to contact
their healthcare provider
immediately and stop EPIVIR-HBV if they develop clinical symptoms suggestive of
lactic acidosis or pronounced hepatotoxicity.
Severe Acute
Exacerbation of Hepatitis after Discontinuation of Treatment
Inform patients
that discontinuation of anti-hepatitis B therapy, including EPIVIR-HBV, may
result in severe acute exacerbations of hepatitis B including decompensation of
liver disease. Advise patients not to discontinue EPIVIR-HBV without first
informing their healthcare provider.
Risk of
Development of HIV-1 Resistance in Patients with HIV-1 Co-infection
Counsel patients on
the importance of testing for HIV to avoid inappropriate therapy and
development of resistance to HIV. HIV counseling and testing should be offered
before starting EPIVIR-HBV and periodically during therapy. Inform patients
that if they have or develop HIV infection and are not receiving effective HIV
treatment, EPIVIR-HBV may increase the risk of development
of resistance to HIV medications. Advise patients that EPIVIR-HBV contains a lower dose of the same
active ingredient (lamivudine) as HIV drugs containing lamivudine.
Emergence of HBV
Resistance
Inform patients
that emergence of resistant hepatitis B virus and worsening of disease can
occur during treatment. Patients should promptly report any new or worsening
symptoms to their physician.
Hepatitis B
Transmission
Advise patients
that treatment with EPIVIR-HBV has not been shown to reduce the risk of
transmission of HBV to others through sexual contact or blood contamination.
Sucrose Content
of EPIVIR-HBV Oral Solution
Advise diabetic
patients that each 20-mL dose of EPIVIR-HBV oral solution contains 4 grams of
sucrose (1 mL = 200 mg of sucrose).
Pregnancy
Registry
Advise patients
that there is a pregnancy exposure registry that monitors pregnancy outcomes in
women exposed to EPIVIR-HBV during pregnancy.
Missed Dosage
Instruct
patients that if they miss a dose of EPIVIR-HBV, to take it as soon as they
remember. Advise patients not to double their next dose or take more than the
prescribed dose.
PATIENT INFORMATION
(Additions and/or revisions are underlined)
EPIVIR-HBV can cause serious side effects,
including:
- Severe liver problems…Call your healthcare provider right away if
you get any of the following signs or symptoms of liver problems:
- pain, aching, or tenderness on the
right side of your stomach area
- Risk of HIV-1 resistance in people with unknown HIV-1 infection or
in people with untreated HIV-1 infection. If you have or get HIV-1 (Human
Immunodeficiency Virus type 1) that is not being treated with
medicines while taking EPIVIR-HBV, the HIV-1 virus may develop
resistance to certain HIV-1 medicines and become harder to
treat.
How should I
take EPIVIR-HBV?
- If you miss a dose of EPIVIR-HBV, take it as soon as you remember.
Do not take 2 doses at the same time or take more than what your
healthcare provider tells you to take.
Get Email Alerts |
Guide
