DBL Fluorouracil Use In Pregnancy & Lactation

Effects on fertility: Fluorouracil has not been adequately studied in animals to permit an evaluation of its effects on fertility and general reproductive performance. No specific studies to evaluate the effects of fluorouracil on male fertility have been conducted; however, fluorouracil was toxic to male reproductive organs, indicating that fluorouracil has the potential to impact reproductive function and fertility. Adverse effects of fluorouracil were evident in testes in male rats following repeat oral dosing at 30 mg/kg/day for 1month. Doses of 125 or 250 mg/kg, administered intraperitoneally, have been shown to induce chromosomal aberrations and changes in chromosomal organisation of spermatogonia in rats.
Spermatogonial differentiation was also inhibited by fluorouracil, resulting in transient infertility. However, in studies with a strain of mouse which is sensitive to the induction of sperm head abnormalities after exposure to a range of chemical mutagens and carcinogens, fluorouracil did not produce any abnormalities at oral doses of up to 80 mg/kg/day. In female rats, fluorouracil, administered intraperitoneally at weekly doses of 25 or 50 mg/kg for three weeks during the pre-ovulatory phase of oogenesis, significantly reduced the incidence of fertile matings, delayed the development of pre- and post-implantation embryos, increased the incidence of pre-implantation lethality and induced chromosomal anomalies in these embryos. In a limited study in rabbits, a single 25 mg/kg dose of fluorouracil or 5 daily doses of 5 mg/kg had no effect on ovulation, appeared not to affect implantation and had only a limited effect in producing zygote destruction.
Effects of fluorouracil on the gonads and reproduction capacity of humans are not fully known. However, based on animal studies, male and female fertility may be compromised. Also, compounds such as fluorouracil, which interfere with DNA, RNA and protein synthesis, might be expected to have adverse effects on gametogenesis. In general, use of a contraceptive is recommended during cytotoxic drug therapy.
Use in pregnancy - Category D: Fluorouracil may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women, however, fetal defects and miscarriages have been reported. Fluorouracil administered parenterally has been shown to be teratogenic in mice, rats and hamsters, and embryo lethal in monkeys. Fetal malformations included cleft palate, skeletal defects, and deformed appendages and tails. Potential effects of fluorouracil on peri and postnatal development have not been studied in animals. However, in rats fluorouracil has been found to cross the placental barrier and to cause fetal mortality. Fluorouracil is strictly contraindicated in pregnancy (see Contraindications).
Safety for use in pregnancy has not been established. Women of childbearing age should be advised to avoid pregnancy and to use a highly effective method of contraception during fluorouracil therapy and for at least 6 months after last dose. Fluorouracil should only be used in women of childbearing potential if the expected benefits outweigh the risks of therapy, and adequate contraception is used. If the patient becomes pregnant whilst receiving the drug she should be advised of the potential hazards on the fetus. It is also recommended to advise the patient to seek genetic counselling prior to treatment with fluorouracil, if appropriate and available.
Men treated with fluorouracil should be advised not to father a child during and for at least 3 months following cessation of treatment. Advise on fertility preservation should be sought prior to treatment by both male and female patients because of the possibility of irreversible infertility due to therapy with fluorouracil. Men undergoing fluorouracil treatment should also ensure they use effective contraceptive measures.
Use in lactation: It is not known whether fluorouracil is excreted in breast milk. To avoid possible harmful effects in the infant, breast-feeding is not advised during fluorouracil therapy.