Antineoplastic
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
No reports describing the use of temozolomide in human pregnancy have been located. The animal reproduction data suggest risk, but the absence of human pregnancy experience prevents a more complete assessment of embryo–fetal risk. The recommended first cycle of temozolomide is 42 days of consecutive therapy, followed by an increased dose for six cycles (5 consecutive days of therapy in each 4-week cycle). Thus, exposure could potentially occur throughout most of gestation. Women of childbearing age should employ adequate contraceptive methods to prevent pregnancy. However, if a woman requires temozolomide and informed consent is obtained, therapy should not be withheld because of pregnancy. If an inadvertent pregnancy occurs during therapy, the woman should be advised of the unknown, but potentially severe, risk for her embryo and/or fetus.
FETAL RISK SUMMARY
Temozolomide, an imidazotetrazine derivative, is an oral prodrug that undergoes rapid nonenzymatic conversion at physiologic pH to the reactive compound MTIC. The cytotoxic effect of MTIC is thought to be mainly due to alkylation of DNA. There are no other agents in this antineoplastic subclass. Temozolomide is indicated for the treatment of adult patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment. It also is indicated for the treatment of adult patients with refractory anaplastic astrocytoma. Plasma protein binding of temozolomide is minimal (about 15%) and its elimination half-life is short (1.8 hours) (1).
Reproduction studies have been conducted in rats and rabbits. During organogenesis, rats and rabbits were given daily oral doses that were 0.375 and 0.75 times, respectively, the maximum recommended human dose based on BSA (MRHD) for 5 consecutive days. Numerous malformations were observed in both species, including defects of the external organs, soft tissues, and skeletons. Daily doses that were 0.75 times the MRHD also caused embryolethality (resorptions) (1).
Short-term studies for carcinogenicity have been conducted in rats. When rats were given a dose of temozolomide that was equal to the MRHD for 5 consecutive days every 28 days for three cycles, mammary carcinomas were found in males and females. When six cycles were given with doses that were 0.125, 0.25, or 0.625 times the MRHD, mammary carcinomas were observed at all doses. In addition, the highest dose was associated with multiple other tumors (1).
It is not known if temozolomide crosses the human placenta. The molecular weight of the parent compound (about 194) and the minimal plasma protein binding suggest that the drug will cross to the embryo and fetus. However, after absorption, temozolomide undergoes rapid hydrolysis to MTIC, and this compound also may cross the placenta.
BREASTFEEDING SUMMARY
No reports describing the use of temozolomide during human lactation have been located.
The molecular weight of the parent compound (about 194) and the minimal plasma protein binding (about 15%) suggest that the drug will be excreted into breast milk. Moreover, after absorption, temozolomide undergoes rapid hydrolysis to the active agent MTIC, so this compound also may be excreted into milk. The effect of these exposures on a nursing infant is unknown. In adults, the drug is rapidly and completely absorbed and may also be absorbed by a nursing infant. Thus, it is best that a woman receiving this agent does not breastfeed. If she chooses to do so, the infant should be closely monitored for the most common or serious adverse effects observed in adults. These effects include alopecia, nausea, vomiting, anorexia, headache, constipation, fatigue, thrombocytopenia, and convulsions (1).
Reference
1.Product information. Temodar. Schering, 2007.