(Last updated: August 6, 2015; last reviewed: August 6, 2015)
Stavudine is classified as Food and Drug Administration (FDA) Pregnancy Category C.
Stavudine is clastogenic in in vitro and in vivo assays but not mutagenic in in vitro assays. In 2-year carcinogenicity studies in mice and rats, stavudine was non-carcinogenic in doses producing exposures 39 (mice) and 168 (rats) times human exposure at the recommended therapeutic dose. At higher levels of exposure (250 [mice] and 732 [rats] times human exposure at therapeutic doses), benign and malignant liver tumors occurred in mice and rats and urinary bladder tumors occurred in male rats.
Stavudine has not been shown to have an effect on reproduction or fertility in rodents. No evidence of impaired fertility was seen in rats with exposures (based on Cmax) up to 216 times that observed following a clinical dosage of 1 mg/kg/day.1 A dose-related cytotoxic effect has been observed on pre-implantation mouse embryos, with inhibition of blastocyst formation at a concentration of 100 µM and of post-blastocyst development at 10 µM.2
No evidence of teratogenicity was noted in rats or rabbits with exposures (based on Cmax) up to 399 and 183 times, respectively, that seen at a clinical dosage of 1 mg/kg/day. In rat fetuses, the incidence of a common skeletal variation—unossified or incomplete ossification of sternebra—was increased at 399 times human exposure, although no effect was observed at 216 times human exposure. A slight post-implantation loss was noted at 216 times human exposure, with no effect noted at approximately 135 times human exposure. An increase in early rat neonatal mortality (birth to day 4) occurred at 399 times human exposure, although survival of neonates was unaffected at approximately 135 times the human exposure.
Placental and Breast Milk Passage
A study in rats showed that stavudine is transferred to the fetus through the placenta. The concentration in fetal tissue was approximately one-half the concentration in maternal plasma.
In primates (pig-tailed macaques), fetal/maternal plasma concentrations were approximately 0.80.3 Stavudine is excreted into the breast milk of lactating rats.
Human Studies in Pregnancy
A Phase I/II safety and pharmacokinetic (PK) study has been conducted of combination stavudine and lamivudine in pregnant HIV-infected women and their infants (PACTG 332). Both drugs were well tolerated, with stavudine PKs similar to those in non-pregnant adults.4
Placental and Breast Milk Passage
Stavudine crosses the human placenta ex vivo, resulting in a fetal/maternal concentration of approximately 0.50. Stavudine also crosses into human breast milk, resulting in breast milk/maternal plasma concentrations of 1.0 to 1.76. Concentrations in nursing infants were negligible.5,6
No association was found between first-trimester exposure to stavudine and birth defects in a large French cohort study that had 70% power to detect an increased adjusted odds ratio of 1.5.7 In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures to stavudine in humans have been monitored to be able to detect at least a two-fold increased risk of overall birth defects. No such increase in birth defects has been observed with stavudine. Among cases of first-trimester stavudine exposure reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 2.6% (21 of 809 births; 95% CI, 1.6% to 4.0%) compared with a total prevalence in the US population of 2.7%, based on Centers for Disease Control and Prevention surveillance.8
Other Safety Data
Lactic acidosis, in some cases fatal, has been described in pregnant women receiving the combination of didanosine and stavudine along with other antiretroviral (ARV) agents.9-11 The FDA and Bristol-Myers Squibb have issued a warning to health care professionals that pregnant women may be at increased risk of fatal lactic acidosis when prescribed didanosine and stavudine in combination (see Recommendations for Use of Antiretroviral Drugs During Pregnancy and Long-Term Follow-Up of Antiretroviral Drug-Exposed Infants). These drugs should be prescribed together for pregnant women only when the potential benefit clearly outweighs the potential risk. Clinicians should prescribe this ARV combination in pregnancy with caution and generally only when other nucleoside analog drug combinations have failed or have caused unacceptable toxicity or side effects.