Cytoprotective Agent (Antineoplastic)
PREGNANCY RECOMMENDATION: Compatible—Maternal Benefit >> Embryo–Fetal Risk
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
The limited animal and human data and the pharmacokinetic properties of mesna suggest that the drug poses little, if any, risk to a human fetus. There is no experience, however, in the 1st trimester. Moreover, mesna is probably not protective against ifosfamide- or cyclophosphamide-induced birth defects if these chemotherapy agents are used in the 1st trimester. However, the maternal benefits from use of the agent with ifosfamide or cyclophosphamide to lessen or prevent hemorrhagic cystitis appear to outweigh the unknown fetal risks.
FETAL RISK SUMMARY
Mesna (sodium 2-mercaptoethane sulfonate) is a cytoprotective agent that is used to prevent hemorrhagic cystitis caused by ifosfamide (approved indication) and cyclophosphamide (off label indication). Upon administration, the agent is rapidly oxidized to its only metabolite, mesna disulfide (dimesna). Dimesna remains in the intravascular compartment and is rapidly eliminated by the kidneys where it is changed back to mesna. The elimination half-lives of mesna and dimesna in the blood are 0.36 and 1.17 hours, respectively (1).
Reproduction studies have been conducted in rats and rabbits. Both species were given doses up to 1000 mg/kg during pregnancy without evidence of fetal harm (1). Two studies investigated the reproductive effects of mesna in pregnant rats and rabbits (2,3). In rats, IV doses up to 800 mg/kg on days 7–17 were associated with lumbar ribs at 400 mg/kg and decreased fetal weight at 800 mg/kg (2). Increased open field activity was observed in rat pups exposed in utero to doses of 400 mg/kg or higher. In pregnant rabbits treated similarly, decreased fetal weights and lumbar ribs were observed with doses of 600 mg/kg or higher (3).
In a 1986 study with rats, two doses of mesna were evaluated to determine if they were protective against cyclophosphamide-induced teratogenicity (4). The low dose (5 mg/kg) offered no protection, but the high dose (30 mg/kg) significantly decreased the number of fetuses with external and skeletal malformations. However, the protection was not extensive enough to be considered effective in protecting pregnant women exposed to cyclophosphamide (4).
In a 2003 study, mesna was combined with ifosfamide to determine if the cytoprotective agent could decrease the toxic effects of ifosfamide on the testes and semen characteristics of rabbits (5). Three groups of male rabbits were given different doses of the combination (ifosfamide 30, 45, or 60 mg/kg plus mesna 6, 9, or 12 mg/kg, followed by a second equal dose of mesna 4 hours later, respectively). Each group received 10 weekly treatments. Controls were given either mesna alone (three groups) or saline (one group). Dose-related ifosfamide-mesna suppression of spermatogenesis and epididymal sperm maturation was observed. In addition, the investigators noted incomplete recovery of the germinal epithelium (5).
It is not known if mesna crosses the human placenta. The molecular weight (about 164) is low enough to cross the placenta, but the short elimination half-life of the parent compound and its rapid metabolism to a metabolite that is restricted to the intravascular compartment suggest that little, if any, exposure of embryo or fetus occurs.
Two reports have described the use of mesna in human pregnancy. In both cases, mesna was combined with ifosfamide in the 2nd and/or 3rd trimesters (see Ifosfamide).
BREASTFEEDING SUMMARY
No reports describing the use of mesna during lactation have been located. The molecular weight (about 164) is low enough for excretion into breast milk, but the short elimination half-life of the parent compound (0.36 hours) and its rapid metabolism to a metabolite that is restricted to the intravascular compartment suggest that little, if any, of the drug will appear in milk. However, mesna is always combined with ifosfamide or cyclophosphamide and women receiving these antineoplastic agents should not breastfeed.
References
1.Product information. Mesna. Gensia Sicor Pharmaceuticals, 2000.
2.Komai Y, Itoh I, Iriyam K, Ishimura K, Fuchigami K, Kobayashi F. Reproduction study of mesna—teratogenicity study in rats by intravenous administration. Kiso to Rinsho 1990;24:6553–94. As cited by Shepard TH. Catalog of Teratogenic Agents. 10th ed. Baltimore, MD: The Johns Hopkins University Press, 2001:323.
3.Komai Y, Itoh I, Ishimura K, Fuchigami K, Kobayashi F. Reproduction study of mesna—teratogenicity study in rabbits by intravenous administration. Kiso to Rinsho 1990;24:6596–602. As cited in Shepard TH. Catalog of Teratogenic Agents. 10th ed. Baltimore, MD: The Johns Hopkins University Press, 2001:323.
4.Slott VL, Hales BF. Sodium 2-mercaptoethane sulfonate protection against cyclophosphamide-induced teratogenicity in rats. Toxicol Appl Pharmacol 1986;82:80–6.
5.Ypsilantis P, Papaioannou N, Psalla D, Politou M, Pitiakoudis M, Simopoulos C. Effects of subchronic ifosfamide-mesna treatment on testes and semen characteristics in the rabbit. Reprod Toxicol 2003;17:699–708.