Risk Factor: CM
Class: Central nervous system drugs/ Antimigraine agents
Fetal Risk Summary
Naratriptan is an oral selective serotonin (5-hydroxytryptamine; 5-HT) receptor subtype agonist used for the acute treatment of migraine headaches. The safety and effectiveness of naratriptan have not been established for cluster headaches (1).
Developmental toxicity was observed in pregnant rats and rabbits at oral doses producing maternal plasma drug levels as low as 11 and 2.5 times, respectively, the plasma levels in humans receiving the maximum recommended daily dose (MRDD) of 5 mg (1). Toxicity consisted of embryo lethality, minor fetal structural variations, pup mortality, and offspring growth retardation. In pregnant rats during the period of organogenesis, daily oral doses of 10, 60, and 340 mg/kg/day that resulted in maternal plasma levels 11, 70, and 470 times the human plasma levels obtained with the MRDD, respectively, were associated with dose-related increases in embryonic death and in the incidence of fetal structural variations: incomplete, irregular ossification of skull bones, sternebrae, and ribs (1). A no-effect dose for these toxicities was not established. The highest dose was associated with maternal toxicity as evidenced by decreased body weight gain. When naratriptan was administered before and throughout the mating period at 60 mg/kg/day or greater, there was an increase in preimplantation loss. Impairment of fertility in both male (testicular effects) and female (anestrus) rats occurred at higher doses. Exposure to the two highest doses60 and 340 mg/kg/daylate in gestation and during lactation resulted in offspring behavioral impairment (tremors) and decreased viability and growth (1).
Pregnant rabbits received daily oral doses during organogenesis that produced maternal plasma levels ranging from 2.5 to 140 times the human levels produced by the MRDD on a body surface area basis (1). Developmental toxicity, observed at all doses, consisted of embryonic death and fetal variations (major blood vessel variations, supernumerary ribs, and incomplete skeletal ossification). Fetal skeletal malformation (fused sternebrae) was observed in one rabbit subspecies at the highest dose. A no-effect dose for these toxicities was not established (1).
No reports describing the placental transfer of naratriptan in humans have been located. However, the relatively low molecular weight of the compound, about 372 for the hydrochloride salt, suggests that the drug will cross to the fetus.
A manufacturer’s pregnancy registry, covering November 1997 through October 2000, has prospectively (reported before the pregnancy outcome was known) enrolled 37 pregnancies exposed to naratriptan (2). Of these, 10 outcomes are pending and 12 cases have been lost to follow-up. Naratriptan exposure occurred in the 1st trimester in 14 and in the 2nd trimester in one. One spontaneous abortion occurred before 20 weeks’ gestation in a woman who received naratriptan in the 1st trimester. The remaining 14 cases all ended with live births, none of which had congenital defects. Retrospective reports (reported after the outcome was known) are often biased (only adverse outcomes are reported). There was one retrospective report of an adverse outcome in a pregnancy exposed in the 1st trimester. In that case, the defects and outcome were pentalogy of Cantrellabdominal wall defect, pericardial defect, agenesis of the diaphragm, absence of sternum, and congenital heart diseaseand fetal death. Although no birth defects were observed in prospective reports, the registry considers the data to represent a sample of insufficient size for reaching definitive conclusions regarding the possible teratogenic risk of naratriptan (2).
In summary, naratriptan is not an animal teratogen but does produce dose-related embryo and fetal developmental toxicity. Human pregnancy experience, however, is too limited to assess the safety of the drug or its teratogenic potential. A 1998 review on the safety of migraine treatment in pregnancy recommended that naratriptan and other similar agents (see also Sumatriptan) be avoided during pregnancy (3).
Breast Feeding Summary
Naratriptan is excreted in the milk of nursing rats (1), but no reports describing the use of naratriptan during human lactation have been located. The molecular weight of the hydrochloride salt (about 372) is low enough, however, that passage into the milk should be expected. The effects of this exposure, if any, on a nursing infant are unknown.
- Product information. Amerge. Glaxo Wellcome, 1999.
- Sumatriptan and Naratriptan Pregnancy Registries. Interim Report. 1 January 1996 through 31 October 2000. Glaxo Wellcome, January 2001.
- Pfaffenrath V, Rehm M. Migraine in pregnancy. What are the safest treatment options? Drug Saf 1998;19:3838.