Antineoplastic
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
No reports describing the use of decitabine 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 of embryo–fetal risk. 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 decitabine and for 2 months after treatment (1).
FETAL RISK SUMMARY
Decitabine is an analog of the natural nucleoside 2′-deoxycytidine that is administered by IV infusion every 8 hours for 3 days, and then repeated 6 weeks for at least four cycles. It is in the same antineoplastic subclass as azacitidine and nelarabine. Decitabine is indicated for the treatment of patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and Intermediate-1, Intermediate-2, and High-Risk International Prognostic Scoring System groups (1). The metabolic fate of decitabine is not known, but the terminal-phase half-life is about 0.5 hours. Plasma protein binding is <1% (1).
Reproduction studies have been conducted in mice and rats. In pregnant mice, a single intraperitoneal (IP) dose, given on gestational days 8, 9, 10, or 11, that was 2% of the daily recommended clinical dose based on BSA (DRCD) was associated with reduced fetal weight and supernumerary ribs. A dose that was about 7% of the DRCD caused reduced fetal weight, fetal death, and defects (supernumerary ribs, fused vertebrae and ribs, cleft palate, vertebral defects, hindlimb defects, and digital defects of fore- and hindlimbs). Moreover, when the 7% dose was given on gestational day 10, body weights of offspring were significantly reduced at all postnatal time points. Neither the 2% nor 7% doses caused maternal toxicity (1).
In pregnant rats, single IP doses, given on gestational days 9–12, that were about 5%, 8%, or 13% of the DRCD, respectively, were not maternal toxic but did cause developmental toxicity. There were no surviving fetuses with any dose given on day 9. A dose that was ≥8% of the DRCD given on day 10 caused a significant decrease in fetal survival and reduced fetal weight. Dose-related malformations also were observed: Increased incidences of vertebral and rib anomalies (all dose levels); fore-digit defects (doses ≥8% of the DRCD); and exophthalmia, exencephaly, and cleft palate (13% of the DRCD). The highest dose also was associated with reduced size and ossification of the long bones in the limbs (1).
Studies for carcinogenicity have not been conducted with decitabine, but the drug was mutagenic and caused chromosomal rearrangements in larvae of fruit flies. Fertility tests have been conducted in mice. Untreated female mice, when mated with males exposed in utero had decreased fertility. No adverse effects on survival, body weight gain, or hematological measurements were observed in male mice given IP doses that were about 0.3% to 1% of the DRCD 3 times a week for 7 weeks. However, a dose about 0.7% of the DRCD was associated with reduced testes weight, abnormal histology, and significant decreases in sperm count. In female mice mated with these males, pregnancy rates were reduced and postimplantation loss was significantly increased (1).
It is not known if decitabine crosses the human placenta. The molecular weight (about 228) and lack of plasma protein binding suggest that the drug will cross, but the very short terminal phase half-life will limit the amount of drug at the maternal: fetal interface.
BREASTFEEDING SUMMARY
No reports describing the use of decitabine during human lactation have been located.
The molecular weight (about 228) and lack of plasma protein binding suggest that the drug will be excreted into breast milk, but the very short terminal-phase half-life will limit the amount excreted. The effect of this exposure on a nursing infant is unknown, but the potential toxicity may be severe. In adults, the most common adverse effects are neutropenia, thrombocytopenia, anemia, fatigue, pyrexia, nausea, cough, petechiae, constipation, diarrhea, and hyperglycemia (1).
Reference
1.Product information. Dacogen. MGI Pharma, 2007.