CONTRAINDICATIONS
Lamivudine tablets and oral solution are contraindicated in patients with previously demonstrated
clinically significant hypersensitivity to any of the components of the products.
WARNINGS
PANCREATITIS IN PEDIATRIC PATIENTS: In pediatric patients with a history of
pancreatitis or other significant risk factors for the development of pancreatitis, the
combination of lamivudine and zidovudine should be used with extreme caution and only if
there is no satisfactory alternative therapy. Treatment with lamivudine should be stopped
immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of
pancreatitis occur (see ADVERSE REACTIONS.)
The complete prescribing information for zidovudine should be consulted before combination
therapy with lamivudine and zidovudine is initiated.
PRECAUTIONS
Patients With Impaired Renal Function: Reduction of the dosage of lamivudine is recommended
for patients with impaired renal function (see CLINICAL PHARMACOLOGY and DOSAGE
AND ADMINISTRATION.)
Patients With HIV and Hepatitis B Virus Coinfection: In clinical trials, some patients with HIV
infection who have chronic liver disease due to hepatitis B virus infection experienced clinical or
laboratory evidence of recurrent hepatitis upon discontinuation of lamivudine.
Information for the Patient:Lamivudine is not a cure for HIV infection and patients may continue to
experience illnesses associated with HIV infection, including opportunistic infections. Patients
should remain under the care of a physician when using lamivudine. Patients should be advised that
the use of lamivudine has not been shown to reduce the risk of transmission of HIV to others
through sexual contact or blood contamination.
Patients should be advised that the long-term effects of lamivudine are unknown at this time.
Lamivudine tablets and oral solution are for oral ingestion only.
Patients should be advised of the importance of taking lamivudine exactly as it is prescribed.
Parents or guardians should be advised to monitor pediatric patients for signs and symptoms of
pancreatitis.
Carcinogenesis, Mutagenesis, and Impairment of Fertility: Long-term carcinogenicity studies
of lamivudine in animals have not yet been completed. Lamivudine was not active in a microbial
mutagenicity screen or an in vitro cell transformation assay, but showed weak in vitro mutagenic
activity in a cytogenetic assay using cultured human lymphocytes and in the mouse lymphoma
assay. However, lamivudine showed no evidence of in vivo genotoxic activity in the rat at oral
doses of up to 2,000 mg/kg (approximately 65 times the recommended human dose based on body
surface area comparisons). In a study of reproductive performance, lamivudine, administered to rats
at doses up to 130 times the usual adult dose based on body surface area comparisons, revealed no
evidence of impaired fertility and no effect on the survival, growth, and development to weaning of
the offspring.
Pregnancy Category C: Reproduction studies have been performed in rats and rabbits at orally
administered doses up to approximately 130 and 60 times, respectively, the usual adult dose and
have revealed no evidence of harm to the fetus due to lamivudine. 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. There are no adequate and well-controlled studies in
pregnant women. Because animal reproductive toxicity studies are not always predictive of human
response, lamivudine should be used during pregnancy only if the potential benefits outweigh the
risks.
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women
exposed to lamivudine, an Antiretroviral Pregnancy Registry has been established. Physicians are
encouraged to register patients by calling (800) 722-9292, ext. 39437.
Nursing Mothers: A study in which lactating rats were administered 45 mg/kg of lamivudine
showed that lamivudine concentrations in milk were slightly greater than those in plasma. Although
it is not known if lamivudine is excreted in human milk, there is the potential for adverse effects
from lamivudine in nursing infants. Mothers should be instructed to discontinue nursing if they are
receiving lamivudine. This instruction is consistent with the Centers for Disease Control
recommendation that HIV-infected mothers not breast-feed their infants to avoid risking postnatal
transmission of HIV infection.
Pediatric Use: THERE ARE NO DATA ON THE USE OF LAMIVUDINE IN
COMBINATION WITH ZIDOVUDINE IN PEDIATRIC PATIENTS.
Lamivudine monotherapy was studied in one open-label, uncontrolled trial (study A2002) in 97
pediatric patients with the following demographics: male (56%), Caucasian (57%), median age of
7.7 years (range: 0.4 to 17.3 years), symptomatic HIV (84%), median duration of prior antiretroviral
therapy of 148 weeks, and median baseline CD4 of 132 cells/mm3. Pharmacokinetic properties of
lamivudine were assessed in a subset of 57 patients (age range: 4.8 months to 16 years, weight
range: 5 to 66 kg) after oral and IV administration of 1, 2, 4, 8, 12, and 20 mg/kg per day. In the 9
infants and children receiving 8 mg/kg per day (the usual recommended pediatric dose), absolute
bioavailability was 66% ± 26% (mean ± S.D.), which is less than the 86% ± 16% (mean ± S.D.)
observed in adolescents and adults. The mechanism for the diminished absolute bioavailability of
lamivudine in infants and children is unknown.
Systemic clearance decreased with increasing age in pediatric patients.
After oral administration of 8 mg/kg per day of lamivudine to 11 pediatric patients ranging from 4
months to 14 years of age, Cmax was 1.1 ± 0.6 mcg/ml and half-life was 2.0 ± 0.6 hours, (In adults
with similar blood sampling, the half-life was 3.7 ± 1 hours.) Total exposure to lamivudine, as
reflected by mean AUC values, was comparable between pediatric patients receiving an 8
mg/kg/day dose and adults receiving a 4 mg/kg/day dose.
Distribution of lamivudine into cerebrospinal fluid (CSF) was assessed in 38 pediatric patients after
multiple oral dosing with lamivudine. CSF samples were collected between 2 and 4 hours postdose.
At the dose of 8 mg/kg/day, CSF lamivudine concentrations in eight patients ranged from 5.6% to
30.9% (mean ± S.D. of 14.2% ± 7.9%) of the concentration in a simultaneous serum sample, with
CSF lamivudine concentrations ranging from 0.04 to 0.3 mcg/ml. (See INDICATIONS AND
USAGE, Description of Clinical Studies), WARNINGS, ADVERSE REACTIONS, and DOSAGE
AND ADMINISTRATION.