Antineoplastic
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
No reports describing the use of azacitidine in human pregnancy have been located. The animal reproduction data at a small fraction of the human dose suggest risk, but the absence of human pregnancy experience prevents a more complete assessment. Pregnant women should not be given this drug, especially in the 1st trimester. If an inadvertent pregnancy occurs, the woman should be advised of the potential risk for severe adverse effects in the embryo and fetus. In addition, because of the animal fertility studies, men should be advised not to father a child while receiving azacitidine (1), and for several months after treatment.
FETAL RISK SUMMARY
Azacitidine, a pyrimidine nucleoside analog of cytidine, inhibits methylation of DNA. It is the same antineoplastic subclass as decitabine and nelarabine. Azacitidine is given by injection. It is indicated for the treatment of patients with the following myelodysplastic syndrome (MDS) subtypes: refractory anemia or ringed refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia (1). The metabolites are apparently inactive. The mean elimination half-lives of azacitidine and its metabolites are about 4 hours (1).
Reproduction studies have been conducted in mice and rats. In pregnant mice, a single intraperitoneal (IP) dose, which was about 8% of the recommended human daily dose based on BSA (RHDD), on gestation day 10 caused a 44% frequency of embryo death (resorption). IP doses that were about 4%–16% of the RHDD given on or before gestation day 15 were associated with developmental abnormalities in the brain. In pregnant rats, embryotoxicity was evident when an IP dose (about 8% of the RHDD) was given on gestation days 4–8 (post-implantation). No embryotoxicity was observed when the drug was given on gestation days 1–3 (pre-implantation). Fetal deaths were observed when a single IP dose was given on gestation days 9 or 10; on day 9, the average number of live animals per liter was reduced to 9% of controls. In addition, single IP doses on gestation days 9, 10, 11, or 12 were associated with CNS anomalies (exencephaly/encephalocele), limb defects (micromelia, club foot, and syndactyly), micrognathia, gastroschisis, edema, and rib abnormalities (1).
Azacitidine was carcinogenic in long-term studies in mice and rats. Tumors of the hematopoietic system were seen in female mice given IP doses that were about 8% of the RHDD 3 times weekly for 52 weeks. A similar dose given once per week in mice for 50 weeks caused an increased incidence of tumors in the lymphoreticular system, lung, mammary gland, and skin. A study in male rats dosed twice weekly with about 20%–80% of the RHDD revealed an increased incidence of testicular tumors. Azacitidine was mutagenic and clastogenic in multiple tests (1).
In fertility studies, daily doses that were about 9% of the RHDD given to male mice for 3 days before mating with untreated females were associated with reduced fertility and loss of offspring during subsequent embryonic and postnatal development. When male rats were dosed 3 times weekly for 11 or 16 weeks at about 20%–40% of the RHDD, decreased weight of the testes and epididymides and decreased sperm counts accompanied by decreased pregnancy rates and increased loss of embryos in mated females were observed (1).
It is not known if azacitidine crosses the human placenta. The molecular weight (244) and elimination half-life suggest that the drug will cross to the embryo and/or fetus.
BREASTFEEDING SUMMARY
No reports describing the use of azacitidine during human lactation have been located. The molecular weight (244) and the elimination half-life (about 4 hours) suggest that the drug will be excreted into breast milk. The potential effects of this exposure on a nursing infant are unknown, but the effects may be severe. In adults, the most common adverse effects are nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, fatigue, constipation, neutropenia, and ecchymosis (1).
Reference
1.Product information. Vidaza. Pharmion, 2007.