Antimigraine
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Moderate Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
Although no adverse outcomes were observed in liveborn offspring in the Merck Prospective Registry or clinical trials, the limited number of exposures studied is not sufficient to detect a risk of rare disorders such as individual birth defects (1). However, a 2008 review of triptans in pregnancy found no evidence for teratogenicity, but the data did suggest a possible increase in the rate of preterm birth (2).
FETAL RISK SUMMARY
Rizatriptan, an oral, selective 5-hydroxytryptamine1B/1D receptor agonist, is indicated for the treatment of acute migraine attacks with or without aura in adults. The drug is metabolized to inactive metabolites. Plasma protein binding is low (14%) and the average plasma half-life is 2–3 hours (3).
Reproduction studies have been conducted in rats and rabbits. Female rats were treated before and during mating, and throughout gestation and lactation with doses that produced maternal exposures (AUC) 15 and 225 times, respectively, the exposure in humans from the maximum recommended human dose of 30 mg (MRHD). These doses were not maternal toxic, but did cause decreased birth weight and reduced preweaning and postweaning weight gain in offspring. In a prenatal and postnatal development toxicity study in rats, doses producing maternal exposures 225 to more than 500 times the MRHD caused toxicity in the offspring as shown by increased mortality at birth and for the first 3 days after birth, reduced preweaning and postweaning weight gain, and decreased learning capacity. The no-effect dose for all of these effects was approximately 7.5 times the MRHD. In embryo and fetal development studies, no teratogenic effects were observed in rats and rabbits given doses during organogenesis producing maternal exposures 225 and 115 times, respectively, the MRHD. Fetal weights were decreased at these doses, but maternal weight gain was also reduced. The developmental no-effect doses, in both species, were approximately 15 times the MRHD. Rizatriptan crosses the placentas of rats and rabbits (3).
It is not known if rizatriptan crosses the human placenta. The molecular weight of the free base (about 269), low plasma protein binding, and moderate plasma half-life suggest that exposure of the embryo–fetus should be expected.
In the Merck Pregnancy Registry program, 81 women were prospectively enrolled after exposure to rizatriptan (1). The outcomes of these pregnancies were 26 lost to follow-up, 3 spontaneous abortions (SABs), 1 elective abortion (EAB) (chromosomal anomaly—partial replication of chromosome 3 in a 39-year-old woman), 2 fetal deaths (1 cord accident; twin B), 1 neonatal death (due to prematurity), and 50 live births. The 3 SABs occurred in the 1st trimester. In addition to the chromosomal anomaly noted above, three outcomes involved congenital defects: juxtaposition of the arteries (exposure timing unknown), bladder outlet obstruction in twin B (mother with gestational diabetes and hypertension; twin A live birth, twin B died at 23 weeks), and hypospadias of the glans (surgical correction required). Of nine retrospective reports, three involved outcomes with congenital anomalies: two cases of chromosomal abnormalities (one a de novo duplication of chromosome 2 and one with Turner syndrome) and one case of anencephaly (EAB at 16 weeks).
In international prospective reports, three cases of congenital anomalies were described (trimester of exposure): (a) premature infant with growth restriction, subependymal cyst, interatrial communication, and mild persistent ductus arteriosus (1st trimester); (b) hemangioma of unreported size of the head and neck (1st trimester); and (c) trisomy 21, died in utero at 20 weeks. International retrospective reports involved two cases of defects: a baby born with cataracts and the other with an unspecified fetal anomaly. In clinical trials, there were no known adverse effects among live births (1).
The manufacturer maintains a pregnancy registry for women exposed to rizatriptan. Health care professionals are encouraged to report pregnancy exposures to the registry by calling the toll-free number 800-986-8999.
BREASTFEEDING SUMMARY
No reports describing the use of rizatriptan in human lactation have been located. The molecular weight of the free base (about 269), low plasma protein binding (14%), and moderate plasma half-life (2–3 hours) suggest that the drug will be excreted into breast milk. The effect of this exposure on a nursing infant is unknown.
References
1.Eleventh annual report from the Merck Pregnancy Registry for Maxalt (rizatriptan benzoate) covering the period from approval (June 1998) through July 31, 2009.
2.Soldin OP, Dahlin J, O’Mara DM. Triptans in pregnancy. Ther Drug Monit 2008;30:5–9.
3.Product information. Maxalt. Merck, 2008.