DRUG INTERACTIONS
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Long-term carcinogenicity studies with lamivudine 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 for HIV infection. 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, producing plasma levels of 35 to 45 times those in humans at the recommended dose for HIV infection. In a study of reproductive performance, lamivudine administered to rats at doses up to 4,000 mg/kg/day, producing plasma levels 47 to 70 times those in humans, revealed no evidence of impaired fertility and no effect on the survival, growth, and development to weaning of the offspring.
Pregnancy
Pregnancy Category C. Reproduction studies have been performed in rats and rabbits at orally administered doses up to 4,000 mg/kg/day and 1,000 mg/kg/day, respectively, producing plasma levels up to approximately 35 times that for the adult HIV dose. No evidence of teratogenicity due to lamivudine was observed. Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this effect in the rat at exposure levels up to 35 times those in humans. Studies in pregnant rats and rabbits showed that lamivudine is transferred to the fetus through the placenta.
In 2 clinical studies conducted in South Africa, pharmacokinetic measurements were performed on samples from pregnant women who received lamivudine beginning at Week 38 of gestation (10 women who received 150 mg twice daily in combination with zidovudine and 10 who received lamivudine 300 mg twice daily without other antiretrovirals) or beginning at Week 36 of gestation (16 women who received lamivudine 150 mg twice daily in combination with zidovudine). These studies were not designed or powered to provide efficacy information. Lamivudine pharmacokinetics in the pregnant women were similar to those obtained following birth and in non-pregnant adults. Lamivudine concentrations were generally similar in maternal, neonatal, and cord serum samples. In a subset of subjects from whom amniotic fluid specimens were obtained following natural rupture of membranes, amniotic fluid concentrations of lamivudine ranged from 1.2 to 2.5 mcg/mL (150 mg twice daily) and 2.1 to 5.2 mcg/mL (300 mg twice daily) and were typically greater than 2 times the maternal serum levels. See the ADVERSE REACTIONS section for the limited late-pregnancy safety information available from these studies. 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, a Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
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OVERDOSAGE
There is no known antidote for EPIVIR. One case of an adult ingesting 6 g of EPIVIR was reported; there were no clinical signs or symptoms noted and hematologic tests remained normal. Two cases of pediatric overdose were reported in ACTG300. One case was a single dose of 7 mg/kg of EPIVIR; the second case involved use of 5 mg/kg of EPIVIR twice daily for 30 days. There were no clinical signs or symptoms noted in either case. Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event. If overdose occurs, the patient should be monitored, and standard supportive treatment applied as required.
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