Topiramate (Topamax®) and risk of birth defects

There has been new evidence suggesting an increase in the risk of cleft lip and cleft palate in infants born to women treated with topiramate monotherapy during pregnancy.

Topiramate (Topamax®, Johnson & Johnson Pte Ltd) is an anti-epileptic drug licensed locally since 1998 for the treatment of certain types of seizures in patients with epilepsy and for the prevention of migraine headache in adults.

US Food and Drug Administration (FDA)

In March 2011, FDA announced new evidence indicating that prenatal exposure to topiramate increases the risk of the development of oral defects such as cleft lip and cleft palate in the foetus.¹

The new data is derived from the North American Anti-epileptic Drug (NAAED) Pregnancy Registry, showing an increased risk of oral clefts in infants exposed to topiramate monotherapy during the first trimester of pregnancy. The prevalence of oral clefts was found to be 1.2% in infants exposed to topiramate in utero as compared to a prevalence of 0.39% to 0.46% in infants exposed to other anti-epileptic drugs (AEDs). This is contrated with the prevalence of 0.12% observed in infants born to mothers without epilepsy or treatment with AEDs. The relative risk of oral clefts in topiramate-exposed pregnancies was found to be 9.6 (95% CI 3.6 - 25.7)21.3 (95% CI=7.9 - 57.1) in the NAAED Pregnancy Register as compared to the background risk in the population.

Data from the United Kingdom Epilepsy and Pregnancy Register also reported a similar increased prevalence of oral clefts (3.2%) among infants exposed to topiramate monotherapy in utero. This translates to a 16-fold increase in the risk of oral clefts in topiramate-exposed pregnancies when compared to the background incidence (0.2%).

Topiramate was previously classified by the FDA as a Pregnancy Category C drug due to inadequate human data on foetal risk. With new human data indicating evidence of human foetal risk in acquiring oral clefts, topiramate has been reclassified to Pregnancy Category D.

Local regulatory actions

To date, HSA has not received any local reports of birth defects associated with the use of topiramate. The existing “Pregnancy and Lactation” section of the local package insert for Topamax® will be strengthened to reflect this new safety information. A Dear Healthcare Professional Letter (DHCPL)^3,4 has been issued in August 2011 to inform healthcare professionals of this new safety information, as well as the information that has been included in the package insert.

HSA's advisory

Healthcare professionals are advised to weigh the benefits and risks of prescribing topiramate to women of childbearing potential. Should topiramate be considered the treatment of choice , healthcare professionals are encouraged to inform patients about the increased risk of oral clefts when topiramate is used during the first trimester of pregnancy and to emphasise the importance of using an effective birth control method.

Healthcare professionals are also encouraged to report all adverse reactions suspected to be associated with the use of topiramate to the Vigilance Branch of HSA.

References

1. FDA Drug Safety Communication: Risk of oral clefts in children born to mothers taking Topamax (topiramate).
   http://www.fda.gov/Drugs/DrugSafety/ucm245085.htm ↗ (opens in new tab)

2. FDA Package insert for Topamax®
   http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020505s042.020844s0361b1.pdf ↗ (opens in new tab)

3. HSA website. Dear Healthcare Professional Letters (DHCPL).
   https://www.hsa.gov.sg/announcements/Dear-Healthcare-Professional-Letters

4. MOH-Health Professional Portal (HPP).
   http://www.hpp.moh.gov.sg ↗ (opens in new tab)