WARNINGS
See
DESCRIPTION
Boxed Warnings.
Posttreatment Exacerbations of Hepatitis: In clinical
trials in non-HIV-infected patients treated with lamivudine
for chronic hepatitis B, clinical and laboratory evidence
of exacerbations of hepatitis have occurred after discontinuation
of lamivudine. These exacerbations have been detected
primarily by serum ALT elevations in addition to re-emergence
of hepatitis B viral DNA (HBV DNA). Although most events
appear to have been self-limited, fatalities have been
reported in some cases. Similar events have been reported
from post-marketing experience after changes from lamivudine-containing
HIV treatment regimens to non-lamivudine-containing regimens
in patients infected with both HIV and HBV. The causal
relationship to discontinuation of lamivudine treatment
is unknown. Patients should be closely monitored with
both clinical and laboratory follow-up for at least several
months after stopping treatment. There is insufficient
evidence to determine whether re-initiation of lamivudine
alters the course of posttreatment exacerbations of hepatitis.
COMBIVIR is a fixed-dose combination of lamivudine and
zidovudine. Ordinarily, COMBIVIR should not be administered
concomitantly with either lamivudine or zidovudine.
The complete prescribing information for all agents being
considered for use with COMBIVIR should be consulted before
combination therapy with COMBIVIR is initiated.
Bone Marrow Suppression
COMBIVIR should be used with caution in patients who
have bone marrow compromise evidenced by granulocyte count
<1,000 cells/mm3 or hemoglobin <9.5 g/dL (see ADVERSE
REACTIONS).
Frequent blood counts are strongly recommended in patients
with advanced HIV disease who are treated with COMBIVIR.
For HIV-infected individuals and patients with asymptomatic
or early HIV disease, periodic blood counts are recommended.
Lactic Acidosis/Severe Hepatomegaly with Steatosis: Lactic
acidosis and severe hepatomegaly with steatosis, including
fatal cases, have been reported with the use of antiretroviral
nucleoside analogues alone or in combination, including
zidovudine and lamivudine. A majority of these cases have
been in women. Caution should be exercised when administering
COMBIVIR to any patient, and particularly to those with
known risk factors for liver disease. Treatment with COMBIVIR
should be suspended in any patient who develops clinical
or laboratory findings suggestive of lactic acidosis or
hepatotoxicity.
Myopathy
Myopathy and myositis, with pathological changes similar
to that produced by HIV disease, have been associated
with prolonged use of zidovudine and therefore may occur
with therapy with COMBIVIR.
PRECAUTIONS
General
Reduction of doses of lamivudine is recommended for patients
with low body weight (less than 50 kg or 110 lb); therefore,
patients with low body weight should not receive COMBIVIR.
Patients with HIV and Hepatitis B Virus Coinfection
Safety and efficacy of lamivudine have not been established
for treatment of chronic hepatitis B in patients dually
infected with HIV and HBV. In non-HIV-infected patients
treated with lamivudine for chronic hepatitis B, emergence
of lamivudine-resistant HBV has been detected and has
been associated with diminished treatment response (see
EPIVIR-HBV package insert for additional information).
Emergence of hepatitis B virus variants associated with
resistance to lamivudine has also been reported in HIV-infected
patients who have received lamivudine-containing antiretroviral
regimens in the presence of concurrent infection with
hepatitis B virus. Posttreatment exacerbations of hepatitis
have also been reported (see
WARNINGS
).
Patients With Impaired Renal Function
Reduction of the dosages of lamivudine and zidovudine
is recommended for patients with impaired renal function.
Patients with creatinine clearance £50 mL/min should
not receive COMBIVIR.
Information for Patients
See PATIENT INFORMATION section.
Drug Interactions
See DRUG INTERACTIONS section.
Carcinogenesis, Mutagenesis, and Impairment of
Fertility
Carcinogenicity
Lamivudine: Lamivudine long-term
carcinogenicity studies in mice and rats showed no evidence
of carcinogenic potential at exposures up to 10 times
(mice) and 58 times (rats) those observed in humans at
the recommended therapeutic dose.
Zidovudine: Zidovudine was
administered orally at three dosage levels to separate
groups of mice and rats (60 females and 60 males in each
group). Initial single daily doses were 30, 60, and 120
mg/kg per day in mice and 80, 220, and 600 mg/kg per day
in rats. The doses in mice were reduced to 20, 30, and
40 mg/kg per day after day 90 because of treatment-related
anemia, whereas in rats only the high dose was reduced
to 450 mg/kg per day on day 91 and then to 300 mg/kg per
day on day 279.
In mice, seven late-appearing (after 19 months) vaginal
neoplasms (five non-metastasizing squamous cell carcinomas,
one squamous cell papilloma, and one squamous polyp) occurred
in animals given the highest dose. One late-appearing
squamous cell papilloma occurred in the vagina of a middle-dose
animal. No vaginal tumors were found at the lowest dose.
In rats, two late-appearing (after 20 months), non-metastasizing
vaginal squamous cell carcinomas occurred in animals given
the highest dose. No vaginal tumors occurred at the low
or middle dose in rats. No other drug-related tumors were
observed in either sex of either species.
At doses that produced tumors in mice and rats, the estimated
drug exposure (as measured by AUC) was approximately three
times (mouse) and 24 times (rat) the estimated human exposure
at the recommended therapeutic dose of 100 mg every 4
hours.
Two transplacental carcinogenicity studies were conducted
in mice. One study administered zidovudine at doses of
20 mg/kg per day or 40 mg/kg per day from gestation day
10 through parturition and lactation with dosing continuing
in offspring for 24 months postnatally. The doses of zidovudine
employed in this study produced zidovudine exposures approximately
three times the estimated human exposure at recommended
doses. After 24 months, at the highest dose, an increase
in incidence of vaginal tumors was noted with no increase
in tumors in the liver or lung or any other organ in either
gender. These findings are consistent with results of
the standard oral carcinogenicity study in mice, as described
earlier. A second study administered zidovudine at maximum
tolerated doses of 12.5 mg/day or 25 mg/day (~ 1,000 mg/kg
nonpregnant body weight or ~ 450 mg/kg of term body weight)
to pregnant mice from days 12 through 18 of gestation.
There was an increase in the number of tumors in the lung,
liver, and female reproductive tracts in the offspring
of mice receiving the higher dose level of zidovudine.
It is not known how predictive the results of rodent
carcinogenicity studies may be for humans.
Mutagenicity
Lamivudine: Lamivudine was
negative in a microbial mutagenicity screen, in an in
vitro cell transformation assay, in a rat micronucleus
test, in a rat bone marrow cytogenetic assay, and in an
assay for unscheduled DNA synthesis in rat liver. It was
mutagenic in a L5178Y/TK+/- mouse lymphoma assay and clastogenic
in acytogenetic assay using cultured human lymphocytes.
Zidovudine: Zidovudine was
mutagenic in a L5178Y/TK+/- mouse lymphoma assay, positive
in an in vitro cell transformation assay, clastogenic
in a cytogenetic assay using cultured human lymphocytes,
and positive in mouse and rat micronucleus tests after
repeated doses. It was negative in a cytogenetic study
in rats given a single dose.
Impairment of Fertility
Lamivudine: In a study of reproductive
performance, lamivudine, administered to male and female
rats at doses up to 130 times the usual adult dose based
on body surface area considerations, revealed no evidence
of impaired fertility (judged by conception rates) and
no effect on the survival, growth, and development to
weaning of the offspring.
Zidovudine: Zidovudine, administered
to male and female rats at doses up to 7 times the usual
adult dose based on body surface area considerations,
had no effect on fertility judged by conception rates.
Pregnancy
Pregnancy Category C.
COMBIVIR: There are no adequate
and well-controlled studies of COMBIVIR in pregnant women.
Reproduction studies with lamivudine and zidovudine have
been performed in animals (see Lamivudine and Zidovudine
below). COMBIVIR should be used during pregnancy only
if the potential benefits outweigh the risks.
Lamivudine: Reproduction studies
with orally administered lamivudine have been performed
in rats and rabbits at 130 and 60 times, respectively,
the usual adult dose (based on relative body surface area)
and have revealed no evidence of teratogenicity. Some
evidence of early embryolethality was seen in the rabbit
at doses similar to those produced by the usual adult
dose and higher, but there was no indication of this effect
in the rat at orally administered doses up to 130 times
the usual adult dose. Studies in pregnant rats and rabbits
showed that lamivudine is transferred to the fetus through
the placenta.
Zidovudine: Reproduction studies
with orally administered zidovudine in the rat and in
the rabbit at doses up to 500 mg/kg per day revealed no
evidence of teratogenicity with zidovudine. Zidovudine
treatment resulted in embryo/fetal toxicity as evidenced
by an increase in the incidence of fetal resorptions in
rats given 150 or 450 mg/kg per day and rabbits given
500 mg/kg per day. The doses used in the teratology studies
resulted in peak zidovudine plasma concentrations (after
one-half of the daily dose) in rats 66 to 226 times, and
in rabbits 12 to 87 times, mean steady-state peak human
plasma concentrations (after one-sixth of the daily dose)
achieved with the recommended daily dose (100 mg every
4 hours). In an additional teratology study in rats,.
a dose of 3,000 mg/kg per day (very near the oral median
lethal dose in rats of 3,683 mg/kg) caused marked maternal
toxicity and an increase in the incidence of fetal malformations.
This dose resulted in peak zidovudine plasma concentrations
350 times peak human plasma concentrations. No evidence
of teratogenicity was seen in this experiment at doses
of 600 mg/kg per day or less. Two rodent carcinogenicity
studies were conducted (see Carcinogenesis, Mutagenesis,
Impairment of Fertility).
Antiretroviral Pregnancy Registry:
To monitor maternal-fetal outcomes of pregnant women exposed
to COMBIVIR and other antiretroviral agents, an Antiretroviral
Pregnancy Registry has been established. Physicians are
encouraged to register patients by calling (800) 722-9292,
ext. 39437.
Nursing Mothers
The Centers for Disease Control and Prevention recommend
that HIV-infected mothers not breast-feed their infants
to avoid risking postnatal transmission of HIV infection.
COMBIVIR: Zidovudine is excreted
in breast milk (see CLINICAL PHARMACOLOGY: Special Populations:
Nursing Mothers); however, no data are available on COMBIVIR
or lamivudine. Therefore, there is a potential for adverse
effects in nursing infants. Mothers should be instructed
not to breast-feed if they are receiving COMBIVIR.
Pediatric Use
COMBIVIR should not be administered to pediatric patients
less than 12 years of age because it is a fixed-dose combination
that cannot be adjusted for this patient population.
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