Exposure to Rizatriptan During Pregnancy: Post-Marketing Experience up to 30 June 2004

Abstract

Merck & Co., Inc. evaluates outcomes of the use of rizatriptan during pregnancy through a Pregnancy Registry in the United States (US) and spontaneous reports for pregnancies reported from sources outside the US. Review of the outcomes of 25 prospective pregnancy reports in the Pregnancy Registry and reports from other sources does not suggest that treatment with rizatriptan predisposes patients to spontaneous abortions or congenital anomalies. However, the number of reports is small. Healthcare providers in the United States are encouraged to report any prenatal exposure to rizatriptan by calling the Pregnancy Registry at [phone] or visiting the Registry's website at http://www.merckpregnancyregistries.com

Introduction

Migraine is a primary headache disorder that affects over 28 million Americans. Epidemiological studies have indicated that approximately 18% of women suffer from the disorder and that the prevalence is highest during the reproductive years (1). Migraine attacks may occur for the first time during pregnancy and may show a variable course during gestation (2), improving or exacerbating during the course of the pregnancy.

Studies suggest that women suffering from migraines and who use medications to treat their migraines do not differ from pregnant migraineurs not taking medication (3–5), or from women without migraine (4–5), in the reported incidence of miscarriages, toxemia, congenital anomalies, or still births. The pharmacological treatment of migraines during pregnancy includes acetaminophen as the drug of choice, as well as nonsteroidal anti-inflammatory agents, such as aspirin and ibuprofen (both of which should be avoided during the last trimester of pregnancy (6)). While mild attacks may be managed effectively with these analgesics, more disabling headaches often respond better to specific antimigraine drugs (7), including the more recently developed ‘triptans’ (i.e. serotonin 5-HT_1B/1D receptor agonists such as sumatriptan, zolmitriptan, rizatriptan, etc.). Thus, there may be a population of pregnant women who feel compelled to seek more effective relief but some medications, like ergot alkaloids, are contraindicated in pregnant women (7), limiting the choices available for treatment. Other antimigraine medications, such as the triptans are used during pregnancy, but there is limited information about their effects on the developing fetus (2, 7).

Each triptan has been assigned FDA Pregnancy Category C; ‘either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no controlled studies in women; or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus.’. While the results of preclinical studies in pregnant animals are summarized in the respective US package circulars for the triptans, studies evaluating the safety of triptans in pregnant women are not available. However, Fox et al. (8), and Loder (9) examined clinical trial and postmarketing data for sumatriptan and found no evidence of increased spontaneous abortions or teratogenic effects in overlapping populations of more than 400 patients, including more than 300 in a Registry.

Rizatriptan benzoate (MAXALT^®, Merck & Co., Inc.) is a selective 5-HT_1B/1D receptor agonist which has been marketed for the treatment of migraine since 1998. Developmental effects were not observed in preclinical (animal) studies of rizatriptan. Since rizatriptan may be used by women of child-bearing potential, it was considered appropriate, in the interest of public health, and in order to help inform physicians and patients, to formally collect data on the use of rizatriptan during pregnancy through postmarketing surveillance. Merck & Co. Inc. therefore established a Pregnancy Registry for rizatriptan for the purpose of standardizing the collection of data concerning treatment of pregnant patients in the United States. In this communication, we summarize the data from the US pregnancy registry and from worldwide sources concerning treatment with rizatriptan during pregnancy that has been reported to Merck and Co., Inc. up to 30 June 2004.

Methods

Merck established a Pregnancy Registry Program for US reports of pregnancy involving exposure to several products that may be used by women of childbearing age, including rizatriptan. The goal of the Registries is to acquire information about use during pregnancy and the outcomes of the pregnancies in women who receive the products (10).

The Pregnancy Registry Program, initiated in 1995 with the varicella vaccine, is operated by the Clinical Risk Management and Safety Surveillance Department of Merck Research Laboratories. Rizatriptan was added to the program upon licensure in 1998. Patients with exposure to the drugs included in the Registry are enrolled if the following criteria are met:

• exposure to the drug anytime from first day of last menstrual period throughout pregnancy;

• residency in the United States or Puerto Rico;

• identification of a healthcare provider;

• some form of patient identification to allow for follow-up.

Health care providers are encouraged to enroll patients through inclusion of information about the Registry in the prescribing information for the product, and on a dedicated website (http://www.merckpregnancyregistries.com). At enrolment or upon request, the patient's health care provider is sent an annual report from the Pregnancy Registry describing the information collected to date for the Merck drug of interest, a patient consent form, an initial pregnancy questionnaire which collects information on the pregnancy and the drug exposure, and an outcome questionnaire, to be returned at the time of delivery or when the pregnancy outcome is otherwise determined. Patients also call to report pregnancies and request information and these reports are also enrolled provided they meet the enrolment criteria described above.

Spontaneous reports of drug use during pregnancy are classified as prospective (report received before the outcome of the pregnancy is known) or retrospective (report is received after the outcome of the pregnancy is known). Because of the bias toward reporting abnormal outcomes, retrospective reports are analysed separately from prospective reports. Reports of adverse pregnancy outcomes (spontaneous or induced abortions, fetal deaths, birth defects, and serious maternal or fetal complications) are sent to the FDA and other regulatory agencies as required by law. Birth defects are classified according to the Center for Disease Control and Prevention (CDC) guidelines (11) and may be reviewed singly or in aggregate by a consultant dysmorphologist.

Data collected in the Pregnancy Registry are analysed on an ongoing basis to detect possible signals of birth defects and other negative pregnancy outcomes. The data are summarized in an annual report which is sent to health care providers upon request or upon enrolment of a patient and to Merck subsidiaries worldwide. An aggregate summary of data for each registry product is included in safety reports that are periodically sent to regulatory agencies worldwide.

The data included in the Pregnancy Registry for rizatriptan from introduction of the drug into the market in 1998 up to 30 June 2004 are summarized below. Although not enrolled in the Pregnancy Registry, reports containing patient data from sources outside the United States for this period are also reviewed.

Results

As of 30 June 2004, 55 women have been enrolled in the Pregnancy Registry for rizatriptan, 51 prospectively and 4 retrospectively. Exposures to Maxalt occurred in all trimesters and in some cases throughout pregnancy (42 first trimester exposures, 4 second trimester exposures, 1 third trimester exposure and 8 with unknown timing of exposure).

Prospective reports

Of the 51 prospective reports, outcomes of 14 pregnancies are pending and outcomes for 12 pregnancies are unknown because the patients have been lost to follow-up. The outcomes of 25 prospective pregnancy reports have been reported to the Registry for MAXALT (Table 1). Of these, 20 were live births: 19 normal healthy term infants; and 1 infant death within 24 h of birth due to prematurity (24 weeks gestation) attributed to an incompetent cervix. One late fetal death at approximately 36 weeks gestation was reported and was attributed by the health care provider to a cord accident. Three spontaneous abortions have been reported, at approximately 6, 8 and 12 weeks gestation, with no further information on the products of conception. There was one elective abortion at 21 weeks gestation following prenatal diagnosis of multiple anomalies (renal, ophthalmic, cerebellar, and cardiac) due to a partial replication of chromosome 3, which was attributed by the health care provider to advanced maternal age (39 years).

Table 1

Pregnancy outcomes in prospective reports of prenatal e re to rizatriptan

Total women	Live births	Spontaneous abortions	Fetal deaths	Elective abortions	Outcome pending	Lost to follow-up
51	20∗	3	1†	1‡	14	12

∗

Includes 1 neonatal death due to prematurity,

†

Cord accident,

‡

Chromosomal anomaly.

Retrospective reports

Four retrospective reports have been received by the Registry, two of which described abnormal outcomes. One reported on an infant with an abnormal karyotype diagnosed by amniocentesis (de novo duplication of chromosome 2). The mother was 38 years old and had taken rizatriptan during the first four months of gestation. The infant was delivered at term with syndactyly of the middle digits, a large fontanelle, a two-vessel umbilical cord, and an MRI showing multiple brain abnormalities. Geneticists consulted by the obstetrician and the paediatrician considered the chromosomal duplication to be spontaneous, possibly related to advanced maternal age. Another retrospective report described an elective abortion performed at 16 weeks gestation following the prenatal diagnosis of anencephaly. Exposure was reported to have been two doses taken around the time of conception.

Spontaneous reports from sources outside the USA

While the Pregnancy Registry collects information concerning pregnancies in the United States, Merck and Co. Inc. collects information on all pregnancies reported to its subsidiaries outside the United States. For rizatriptan, there were 28 prospective reports and 7 retrospective reports from outside the United States. Of the 28 prospective reports, there were 4 reports of live births of healthy infants and 3 reports of spontaneous abortions. In the remaining 21 reports, the pregnancy outcomes are either pending or follow-up information was unable to be obtained. Of 7 retrospective reports, there were 2 reports of live births of normal infants and 5 reports of spontaneous abortions (two of which occurred in one patient over the course of 2 years). There were no reports of congenital anomalies among these reports.

In addition to reports of pregnancy received directly by the Company, a report of exposures to rizatriptan during pregnancy have been obtained from the Swedish Medical Birth Registry (SMBR) (12). The SMBR records prenatal exposures reported by the woman during her first prenatal visit, thereby usually collecting information on first trimester exposures. Over 95% of all births in Sweden are included in this prospective registry. The SMBR recently published a summary of findings regarding migraine treatment during pregnancy (3). Up to February 2004, 41 reports of liveborn infants of mothers who had taken rizatriptan during pregnancy were identified; one infant had a congenital anomaly – a report of glandular hypospadias (12).

Discussion

In the Pregnancy Registry for MAXALT,^® one congenital anomaly has been prospectively reported – a chromosomal anomaly attributed to advanced maternal age. Anomalies identified in the retrospective cohort (chromosomal duplication defect, anencephaly) are unlikely to be related to drug exposure. One report of glandular hypospadias, a relatively common congenital anomaly, was reported out of 41 live born infants in the Swedish Medical Birth Registry (12).

In total, out of 65 prospective reports of live births that have been received (20 in the Merck Pregnancy Registry, 4 in non-US spontaneous reports, 41 from the SMBR), two congenital anomalies were reported, for a rate of 2/65 (3.1%, 95% CI 0.4, 11.1). The US population background rate for congenital anomalies is 3.1% (13).

Conclusion

Review of reports in the Pregnancy Registry for MAXALT and from other sources does not suggest that treatment with rizatriptan increases the risk of congenital anomalies. However, the currently available data do not have sufficient power to reliably detect an increase in overall rate of anomalies or an increase in risk of common or rare individual birth defects. This data does add to available information about triptan use during pregnancy but due to the small number of pregnancies reported does not allow accurate risk estimates to be generated. Therefore, the current prescribing information, which states that rizatriptan should be used in pregnant women only if the potential benefit justifies the potential risk to the fetus remains appropriate.

The Clinical Risk Management and Safety Surveillance Department and the Pregnancy Registry for MAXALT will continue to monitor reports of exposure to the drug during pregnancy as part of the Company's ongoing evaluation of the safety of rizatriptan. Healthcare providers in the United States are encouraged to report any prenatal exposure to rizatriptan by calling the Pregnancy Registry at [phone] or visiting the Registry's website at http://www.merckpregnancyregistries.com Outside of the US, reports should be made to the local Merck subsidiary.