Key Points
- The FDA decision was based upon newly available data in humans suggesting a link between the drug's use in the first trimester
of pregnancy and oral cleft formation in newborns.
- Previously, data suggesting fetal harm with topiramate was available only from animal sources.
FDA announced that it was reclassifying topiramate (Topamax, Ortho-McNeil-Janssen Pharmaceuticals) from a Pregnancy Category
C to a Pregnancy Category D drug. This decision was based upon newly available data in humans suggesting a link between the
drug's use in the first trimester of pregnancy and oral cleft (a small notch in the lip or a groove that runs into the roof
of the mouth and nose) formation in newborns.
Pregnancy Category D drugs are those with positive evidence of human fetal risk based on human data, but still may be used
in pregnant women in certain situations when its benefits are thought to outweigh potential risks. Previously, data suggesting
fetal harm with topiramate was available only from animal studies.
Topiramate first gained FDA marketing approval in 1996 and is currently indicated for the treatment of certain types of seizure
disorders and prevention of migraine. Topiramate also is frequently used for various off-label purposes (eg, treatment of
psychiatric disorders, neuropathic pain, and substance abuse).
This recent FDA action stemmed from inspection of data provided by the North American Antiepileptic Drug (NAAED) Pregnancy
Registry. Upon review of this data, the agency found that newborns exposed to topiramate monotherapy during the first trimester
of pregnancy were more likely to develop an oral cleft compared to those who were not (RR=21.3; 95% CI, 7.9–57.1). Similar
conclusions were drawn from a review of the United Kingdom Epilepsy and Pregnancy Register (incidence of oral cleft: 3.2%
vs 0.2%, RR increase of ~16 fold). In their published safety communication, FDA agency officials stressed, "The benefits and the risks of topiramate should
be carefully weighed when prescribing this drug for women of childbearing age, particularly when topiramate is considered
for a condition not usually associated with permanent injury or death." They continued, "Appropriate alternative treatment
should be considered."
Because evidence suggested oral clefts form during the first trimester of pregnancy—before many women know they are pregnant—the
agency is also recommending prescribers encourage the use of effective forms of contraception in women of childbearing age
prescribed topiramate.
It is estimated that about 4.3 million Americans filled at least 1 topiramate prescription at a retail pharmacy between 2007
and 2010.
SOURCES
FDA. FDA Drug Safety Communication: Risk of oral clefts in children born to mothers taking topiramate (Topamax). Available
at: http://www.fda.gov/Drugs/DrugSafety/ucm245085.htm. Accessed March 5, 2011.
Topamax [package insert]. Titusville, NJ: Ortho-McNeil-Janssen Pharmaceuticals, Inc.; 2009.
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