Antimigraine
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Moderate Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
Sumatriptan has caused toxicity and malformations in one animal species, but the drug does not appear to present a major teratogenic risk in humans. There was no consistent pattern among the reported birth defects to suggest a common cause. The studies, however, lack the sensitivity to identify minor anomalies because of the absence of standardized examinations. In one study, late-appearing major defects may also have been missed due to the timing of the questionnaires. Thus, although the data are generally reassuring, the number and follow-up of exposed pregnancies are still too limited to assess, with confidence, the safety of the agent or its teratogenic potential. 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 (1).
FETAL RISK SUMMARY
Sumatriptan (GR 43175) is a selective serotonin (5-hydroxytryptamine 1 [5-HT]) receptor subtype agonist used for the acute treatment of migraine headaches. It is available in oral tablets and as an SC injection. Sumatriptan has also been used for the treatment of cluster headaches. The drug is closely related to almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, and zolmitriptan.
It is metabolized to inactive metabolites. Plasma protein binding is low (14%–21%) and the elimination half-life is about 2.5 hours (2).
Sumatriptan was embryolethal in rabbits when given in daily IV doses approximately equivalent to the maximum recommended single human SC dose of 6 mg based on BSA (MRHD). The doses were at or close to those producing maternal toxicity. Fetuses of rabbits administered oral sumatriptan (at doses >50 times the MRHD) during organogenesis had an increased incidence of cervicothoracic vascular and skeletal anomalies. In contrast, embryo or fetal lethality was not observed in pregnant rats treated throughout organogenesis with IV doses approximately 20 times the MRHD. Moreover, no rat embryo–fetal lethality or teratogenicity was observed with daily SC doses before and throughout gestation (2). Shepard (3) described a study in which no fetal adverse effects were observed in rats given up to 1000 mg/kg orally during organogenesis.
No studies examining the placental transfer of sumatriptan in animals or humans have been located. The molecular weight (about 414), low plasma protein binding, and the elimination half-life suggest that exposure of the embryo and fetus should be expected.
Individual reports and data from Medicaid studies totaled 14 spontaneous abortions (SABs) with the use of sumatriptan during early pregnancy (F. Rosa, personal communication, FDA, 1996). Seven birth defect case reports received by the FDA included two chromosomal anomalies (both of which could have been exposed before conception), one infant with an ear tag, one case of a phocomelia, a reduction defect of the lower limbs (tibial aplasia), a case of developmental retardation, and one unspecified defect (some of these defects appear to be also included in data from the pregnancy registry cited below).
An interim report of the Sumatriptan/Naratriptan/Treximet Pregnancy Registry, covering the period January 1, 1996 through April 30, 2009, described the outcomes of 761 prospectively enrolled pregnancies exposed to sumatriptan: 578 outcomes (including 6 sets of twins and 1 set of triplets), 170 lost to follow-up, and 21 pending (4). Some of the data were also reported in a 1997 abstract (5). There were 494 outcomes with earliest exposure in the 1st trimester, 66 with earliest exposure in the 2nd trimester, 14 in the 3rd trimester, and 4 exposed at an unspecified time. In the 1st trimester group, there were 20 birth defects (16 live births, 1 fetal death, and 3 elective abortions [EABs]), whereas in the group with no birth defects reported, there were 427 live births, 4 fetal deaths, and 11 EABs. In the combined 1st trimester group, there were 32 SABs (<20 weeks’ gestation). In the 66 outcomes with earliest exposure in the 2nd trimester, there were 3 live births with birth defects and 63 live births without defects. The 3rd trimester group had 14 live births without defects, and the unspecified group had 1 EAB with a birth defect and 3 live births without defects. Excluding fetal deaths and EABs without reported birth defects and all SABs, the observed proportion of birth defects in the 1st trimester group was 4.5% (95% confidence interval [CI] 2.8%–6.9%). For any trimester exposure, the proportion (with the same exclusions) was 4.5% (95% CI 3.0%–6.7%). The prevalence of birth defects in women with migraine has been estimated at 3.4%. The Registry noted the occurrence of ventricular septal defects in 4 of the 447 (0.89%) prospective 1st trimester exposures, 2 of which were clinically insignificant. There were three pregnancies exposed to Treximet (sumatriptan plus naproxen) prospectively enrolled and all are pending outcome (4).
Although retrospective reports (reported after the pregnancy outcome was known) are often biased (only adverse outcomes are reported), there were 26 birth defects reported to the Registry, 23 with earliest exposure in the 1st trimester, 1 with earliest exposure in the 2nd trimester, and 2 with unspecified trimester. Review of all birth defects from prospective and retrospective reports revealed no signal or consistent pattern to suggest a common etiology (4).
A 1998 report (first published in 1997 as an abstract [6]) described the prospectively determined pregnancy outcomes of 96 women exposed to sumatriptan (95 exposed during 1st trimester) (7). No difference in the rate of major birth defects was found between the study patients and nonteratogen-exposed controls or disease-matched controls. One major birth defect was reported in a sumatriptan-exposed infant: vesicoureteral reflux requiring bilateral reimplant (7).
A 1998 noninterventional observational cohort study described the outcomes of pregnancies in women who had been prescribed ≥1 of 34 newly marketed drugs by general practitioners in England (8). Data were obtained by questionnaires sent to the prescribing physicians one month after the expected or possible date of delivery. In 831 (78%) of the pregnancies, a newly marketed drug was thought to have been taken during the 1st trimester with birth defects noted in 14 (2.5%) singleton births of the 557 newborns (10 sets of twins). In addition, two birth defects were observed in aborted fetuses. However, few of the aborted fetuses were examined. Sumatriptan was taken during the 1st trimester in 35 pregnancies. The outcomes of these pregnancies included 4 SABs, 3 EABs, 5 pregnancies lost to follow-up, and 23 normal infants (2 premature) (8).
A 2004 case report described a 24-year-old woman who took sumatriptan (100 mg about once a week), naproxen (550 mg about twice a week), and bisoprolol (5 mg/day) for migraine headaches during the first 5 weeks of pregnancy (9). An elective cesarean section was performed at 37 weeks’ for breech presentation to deliver a 3125-g male infant. The infant had a wide bilateral cleft lip/palate, marked hypertelorism, a broad nose, and bilateral but asymmetric toe abnormalities (missing and hypoplastic phalanges) (9).
In an in vitro study, only high concentrations of sumatriptan were capable of increasing uterine contractions (10). The findings suggested that therapeutic concentrations of the drug would not induce preterm labor.
A second 2008 review of triptans in pregnancy concluded that sumatriptan appeared to be safe for use in the 1st trimester for the treatment of new-onset or worsened migraines (11). However, the data were insufficient to similarly classify other triptans.
Required statement (4): Sumatriptan: The number of exposed pregnancy outcomes accumulated to date represents a sample of insufficient size for reaching definitive conclusions regarding the possible teratogenic risk of sumatriptan. Specifically, the sample size to date remains too small for formal comparisons of the frequency of specific birth defects. If the baseline frequency of total birth defects is 3 in 100 live births, a sample size of 324 for 1st trimester exposure has an 80 percent chance (80% power) of correctly detecting at least a 1.9-fold increase from baseline in the frequency of birth defects. If the baseline frequency of specific birth defects is 1 in 1000 live births, a sample size of 324 for 1st trimester exposure has an 80 percent (80% power) of correctly detecting at least an 8.1-fold increase from baseline in the frequency of a specific birth defect.
Naratriptan: The data represent a sample of insufficient size for reaching definitive conclusions regarding the possible teratogenic risk of naratriptan. If the baseline frequency of total birth defects is 3 in 100 live births, a sample size of 31 for the 1st trimester exposure has an 80 percent chance (80% power) of correctly detecting at least a 4.6-fold increase from baseline in the frequency of total birth defects. If the baseline frequency for a specific birth defect is 1 in 1000 live births, a sample size of 31 for 1st trimester exposure has an 80 percent chance (80% power) of correctly detecting at least a 40.9-fold increase from baseline in the frequency of a specific birth defect.
The number of exposed pregnancy outcomes accumulated to date represents a sample of insufficient size for reaching definitive conclusions regarding the possible teratogenic risk of sumatriptan or naratriptan. It is expected that a teratogenic exposure in the 1st trimester would result in an increased frequency of one or a combination of individual defects or types of defects, but not necessarily in all defects.
As reporting of pregnancies to the Sumatriptan and Naratriptan Registry is voluntary, it is possible that even in prospectively reported pregnancies there could be bias in type of pregnancies reported. For example, differential reporting of low-risk or high-risk pregnancies may be a potential limitation to this type of registry. In addition, reporting of defects from maternal health care providers may limit detection of detects not immediately apparent at birth. Despite this, the Registry is intended both to supplement animal toxicology studies and other structured epidemiologic studies and clinical trial data, and to assist clinicians in weighing the risks and benefits of treatment for individual patients and circumstances.
BREASTFEEDING SUMMARY
Sumatriptan is excreted into human milk. Five women with a mean duration of lactation of 22.2 weeks (range 10.8–28.4 weeks) were administered a 6-mg SC dose of sumatriptan (12). Milk samples were obtained hourly for 8 hours by emptying both breasts of each subject with a breast pump. Frequent blood samples were also obtained from the women. The mean milk:plasma ratio was 4.9. The mean cumulative excretion of drug in milk during the 8-hour sampling period was 12.6 mcg and, by extrapolation, a total recovery of only 14.4 mcg after a 6-mg dose. Using this latter value, the authors estimated that the mean weight-adjusted dose (mcg sumatriptan/kg of infant body weight as a percentage of the mother’s dose in mcg/kg) for the infants would have been 3.5%. The investigators considered the risk to a nursing infant from this exposure to be not significant (12).
In adults, the mean oral bioavailability of sumatriptan is 14%–15% (range 10%–26%) (2,13), suggesting that absorption from the gastrointestinal tract is inhibited. Thus, although the oral absorption in infants may be markedly different from adults, the amount of sumatriptan reaching the systemic circulation of a breastfeeding infant is probably negligible. Discarding the milk for 8 hours after a dose, an interval during which about 88% of the amount excreted into milk can be recovered, would reduce even more the small amounts present in milk. The American Academy of Pediatrics classifies sumatriptan as compatible with breastfeeding (14).
References
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2.Product information. Imitrex. GlaxoSmithKline, 2007.
3.Shepard TH. Catalog of Teratogenic Agents. 8th ed. Baltimore, MD: The Johns Hopkins University Press, 1995:397.
4.The Sumatriptan/Naratriptan/Treximet Pregnancy Registry. Interim Report. 1 January 1996 through 30 April 2009. GlaxoSmithKline, August 2009.
5.Eldridge RE, Ephross SA. Monitoring birth outcomes in the sumatriptan pregnancy registry (abstract). Teratology 1997;55:48.
6.Shuhaiber S, Pastuszak A, Schick B, Koren G. Pregnancy outcome following gestational exposure to sumatriptan (Imitrex) (abstract). Teratology 1997;55:103.
7.Shuhaiber S, Pastuszak A, Schick B, Matsui D, Spivey G, Brochu J, Koren G. Pregnancy outcome following first trimester exposure to sumatriptan. Neurology 1998;51:581–3.
8.Wilton LV, Pearce GL, Martin RM, Mackay FJ, Mann RD. The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England. Br J Obstet Gynaecol 1998;105:882–9.
9.Kajantie E, Somer M. Bilateral cleft lip and palate, hypertelorism and hypoplastic toes. Clin Dysmorphol 2004;13:195–6.
10.Gei A, Longo M, Vedernikov Y, Saade G, Garfield R. The effect of sumatriptan on the uterine contractility of human myometrium (abstract). Am J Obstet Gynecol 2001;184:S193.
11.Evans EW, Lorber KC. Use of 5-HT1 agonists in pregnancy. Ann Pharmacother 2008;42:543–9.
12.Wojnar-Horton RE, Hackett LP, Yapp P, Dusci LJ, Paech M, Ilett KF. Distribution and excretion of sumatriptan in human milk. Br J Clin Pharmacol 1996;41:217–21.
13.Fullerton T, Gengo FM. Sumatriptan: a selective 5-hydroxytryptamine receptor agonist for the acute treatment of migraine. Ann Pharmacother 1992;26:800–8.
14.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.