Discussion Questions

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  Why is this study question important?

  
  
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  When and how were exposures identified?

  
  
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  How was the analysis carried out?

  
  
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  What were the results?

  
  
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  What were the study’s strengths and weaknesses?

  
  
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  How can we put this study in context?

Introduction

Topiramate was approved in the United States in 1996 for the treatment of generalized tonic-clonic and partial seizures. An indication for migraine prophylaxis was added in 2004. The drug has been used on an off-label basis for eating, sleep, and psychiatric disorders. Recently, a combination of phentermine and topiramate was approved for chronic weight management in overweight or obese adults with a weight-related disorder. Researchers, noting that some of these conditions are particularly prevalent among women of child-bearing age, looked for a link between topiramate use in pregnancy and cleft lip with or without cleft palate in offspring.

George A. Macones, MD, MSCE, Associate Editor

Introduction

Topiramate was approved in the United States in 1996 for the treatment of generalized tonic-clonic and partial seizures. An indication for migraine prophylaxis was added in 2004. The drug has been used on an off-label basis for eating, sleep, and psychiatric disorders. Recently, a combination of phentermine and topiramate was approved for chronic weight management in overweight or obese adults with a weight-related disorder. Researchers, noting that some of these conditions are particularly prevalent among women of child-bearing age, looked for a link between topiramate use in pregnancy and cleft lip with or without cleft palate in offspring.

George A. Macones, MD, MSCE, Associate Editor

Background

Macones: Thank you for coming today to discuss this interesting paper on a newer antiseizure medication, topiramate, and birth defects. What do you think of this study question?

Cahill: I think it is very important for a number of reasons. First, use of antiseizure drugs is common in women of reproductive age. This population includes the estimated 0.5% of pregnant women in the United States who have epilepsy. Thus, the question of medication safety for this indication comes up very often. Second, some of the older antiseizure meds, such as valproate and phenytoin, have a well-characterized risk for a constellation of congenital abnormalities. Sometimes I think we all look at new drugs as “safe,” when, in fact, data to support this idea have yet to be generated. Third, postmarketing studies suggested that this drug might be associated with clefting, although in truth, the data are conflicting and based on small numbers. So yes, this is a good question.

Macones: You mentioned postmarketing studies—what exactly does that mean?

Cahill: Essentially, drug approval requires 3 steps or phases. Phase I and II studies are focused on dose-finding and toxicity. Phase III studies are generally large clinical trials that focus on safety and efficacy. A postmarketing study is oftentimes termed a phase IV study; it occurs after drug approval, generally enrolls larger numbers of patients, and is more focused on identification of rare adverse events, which might not have been detected in Phase III studies.