Topiramate

At Motherisk, we receive increasing numbers of queries from women and clinicians about the use of topiramate during pregnancy, mostly related to its use for migraine or seizures.Topiramate is approved for treatment of seizures and for migraine prevention, and in 2012, the Food and Drug Administration approved the combination of extended-release topiramate with the stimulant phentermine (Qsymia) as a chronic treatment for weight management.

When topiramate was initially approved in 1996, human reproductive data were scarce, but animal data suggested that a high dose of topiramate in rats and rabbits may induce some congenital malformations. Since that time, quite a few studies – but not all – have suggested that topiramate may be associated with an increased risk of oral clefts (cleft lip and cleft palate). Studies that have found an increased risk associated with first trimester exposure to topiramate include the North American AED Pregnancy Registry, which found a rate of 14 cases per 1,000 – more than tenfold greater than the rate in the general population.

For seizures and migraines, the FDA has labeled topiramate a pregnancy category D drug (there is evidence of human fetal risk, but “the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks.” ) For Qsymia, however, topiramate is contraindicated in pregnancy and is a pregnancy category X, because its use “can cause fetal harm and weight loss offers no potential benefit to a pregnant woman,” the labeling states.

Based on arecent analysis of six controlled studies in the literature of more than 3,000 pregnancies exposed during the first trimester, we determinedthat the risk of oral clefts associated with first trimester exposure was increased by sixfold over controls. To put this into context, in the general population, oral clefts occur in less than 1% (0.07%), whereas in the studies, the rate was 0.36%, about a fivefold increase.

Until the approval of the weight loss indication, women of reproductive age with epilepsy or migraines prescribed topiramate were a relatively small group. But because obesity is so common, we are now in a situation where a drug that is likely a human teratogen, based on strong evidence, will be used by far more women of childbearing age, and an increase in unintended pregnancies exposed to the drug probably will occur. In phase III clinical trials of Qsymia, quite a few women got pregnant, which is not surprising since women who are obese may have more difficulty knowing they are pregnant, for hormonal and other reasons.

Clinicians and women who take the drug for weight loss need to be aware of this risk. It is important to counsel women of childbearing age who are on this medication about the need for contraception during treatment, and to have a pregnancy test before treatment, and every month during treatment. An important factor to keep in mind is that the maximum topiramate dose for weight loss is 92 mg a day, while the typical epilepsy dose is 200-400 mg a day, and for migraines, is 100 mg a day. It may turn out that the same risk may not be evident with the lower dose.

As the labeling states, women who become pregnant while on this drug should stop taking it immediately, and clinicians should counsel them about the possible risks to the fetus. Health care providers and patients should report pregnancies exposed to Qsymia to the Qsymia Pregnancy Surveillance Program, which is monitoring maternal-fetal outcomes of exposed pregnancies, at 888-998-4887, or the FDA’s MedWatch program at 800-332-1088.

Dr. Koren is professor of pediatrics, pharmacology, pharmacy, medicine, and medical genetics at the University of Toronto. He heads the Research Leadership for Better Pharmacotherapy During Pregnancy and Lactation at the Hospital for Sick Children, Toronto, where he is director of the Motherisk Program. He was a consultant to Vivus, the manufacturer of Qsymia. E-mail him at obnews@frontlinemedcom.com.

At Motherisk, we receive increasing numbers of queries from women and clinicians about the use of topiramate during pregnancy, mostly related to its use for migraine or seizures.Topiramate is approved for treatment of seizures and for migraine prevention, and in 2012, the Food and Drug Administration approved the combination of extended-release topiramate with the stimulant phentermine (Qsymia) as a chronic treatment for weight management.

When topiramate was initially approved in 1996, human reproductive data were scarce, but animal data suggested that a high dose of topiramate in rats and rabbits may induce some congenital malformations. Since that time, quite a few studies – but not all – have suggested that topiramate may be associated with an increased risk of oral clefts (cleft lip and cleft palate). Studies that have found an increased risk associated with first trimester exposure to topiramate include the North American AED Pregnancy Registry, which found a rate of 14 cases per 1,000 – more than tenfold greater than the rate in the general population.

For seizures and migraines, the FDA has labeled topiramate a pregnancy category D drug (there is evidence of human fetal risk, but “the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks.” ) For Qsymia, however, topiramate is contraindicated in pregnancy and is a pregnancy category X, because its use “can cause fetal harm and weight loss offers no potential benefit to a pregnant woman,” the labeling states.

Based on arecent analysis of six controlled studies in the literature of more than 3,000 pregnancies exposed during the first trimester, we determinedthat the risk of oral clefts associated with first trimester exposure was increased by sixfold over controls. To put this into context, in the general population, oral clefts occur in less than 1% (0.07%), whereas in the studies, the rate was 0.36%, about a fivefold increase.

Until the approval of the weight loss indication, women of reproductive age with epilepsy or migraines prescribed topiramate were a relatively small group. But because obesity is so common, we are now in a situation where a drug that is likely a human teratogen, based on strong evidence, will be used by far more women of childbearing age, and an increase in unintended pregnancies exposed to the drug probably will occur. In phase III clinical trials of Qsymia, quite a few women got pregnant, which is not surprising since women who are obese may have more difficulty knowing they are pregnant, for hormonal and other reasons.

Clinicians and women who take the drug for weight loss need to be aware of this risk. It is important to counsel women of childbearing age who are on this medication about the need for contraception during treatment, and to have a pregnancy test before treatment, and every month during treatment. An important factor to keep in mind is that the maximum topiramate dose for weight loss is 92 mg a day, while the typical epilepsy dose is 200-400 mg a day, and for migraines, is 100 mg a day. It may turn out that the same risk may not be evident with the lower dose.

As the labeling states, women who become pregnant while on this drug should stop taking it immediately, and clinicians should counsel them about the possible risks to the fetus. Health care providers and patients should report pregnancies exposed to Qsymia to the Qsymia Pregnancy Surveillance Program, which is monitoring maternal-fetal outcomes of exposed pregnancies, at 888-998-4887, or the FDA’s MedWatch program at 800-332-1088.

Dr. Koren is professor of pediatrics, pharmacology, pharmacy, medicine, and medical genetics at the University of Toronto. He heads the Research Leadership for Better Pharmacotherapy During Pregnancy and Lactation at the Hospital for Sick Children, Toronto, where he is director of the Motherisk Program. He was a consultant to Vivus, the manufacturer of Qsymia. E-mail him at obnews@frontlinemedcom.com.

At Motherisk, we receive increasing numbers of queries from women and clinicians about the use of topiramate during pregnancy, mostly related to its use for migraine or seizures.Topiramate is approved for treatment of seizures and for migraine prevention, and in 2012, the Food and Drug Administration approved the combination of extended-release topiramate with the stimulant phentermine (Qsymia) as a chronic treatment for weight management.

When topiramate was initially approved in 1996, human reproductive data were scarce, but animal data suggested that a high dose of topiramate in rats and rabbits may induce some congenital malformations. Since that time, quite a few studies – but not all – have suggested that topiramate may be associated with an increased risk of oral clefts (cleft lip and cleft palate). Studies that have found an increased risk associated with first trimester exposure to topiramate include the North American AED Pregnancy Registry, which found a rate of 14 cases per 1,000 – more than tenfold greater than the rate in the general population.

For seizures and migraines, the FDA has labeled topiramate a pregnancy category D drug (there is evidence of human fetal risk, but “the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks.” ) For Qsymia, however, topiramate is contraindicated in pregnancy and is a pregnancy category X, because its use “can cause fetal harm and weight loss offers no potential benefit to a pregnant woman,” the labeling states.

Based on arecent analysis of six controlled studies in the literature of more than 3,000 pregnancies exposed during the first trimester, we determinedthat the risk of oral clefts associated with first trimester exposure was increased by sixfold over controls. To put this into context, in the general population, oral clefts occur in less than 1% (0.07%), whereas in the studies, the rate was 0.36%, about a fivefold increase.

Until the approval of the weight loss indication, women of reproductive age with epilepsy or migraines prescribed topiramate were a relatively small group. But because obesity is so common, we are now in a situation where a drug that is likely a human teratogen, based on strong evidence, will be used by far more women of childbearing age, and an increase in unintended pregnancies exposed to the drug probably will occur. In phase III clinical trials of Qsymia, quite a few women got pregnant, which is not surprising since women who are obese may have more difficulty knowing they are pregnant, for hormonal and other reasons.

Clinicians and women who take the drug for weight loss need to be aware of this risk. It is important to counsel women of childbearing age who are on this medication about the need for contraception during treatment, and to have a pregnancy test before treatment, and every month during treatment. An important factor to keep in mind is that the maximum topiramate dose for weight loss is 92 mg a day, while the typical epilepsy dose is 200-400 mg a day, and for migraines, is 100 mg a day. It may turn out that the same risk may not be evident with the lower dose.

As the labeling states, women who become pregnant while on this drug should stop taking it immediately, and clinicians should counsel them about the possible risks to the fetus. Health care providers and patients should report pregnancies exposed to Qsymia to the Qsymia Pregnancy Surveillance Program, which is monitoring maternal-fetal outcomes of exposed pregnancies, at 888-998-4887, or the FDA’s MedWatch program at 800-332-1088.

Dr. Koren is professor of pediatrics, pharmacology, pharmacy, medicine, and medical genetics at the University of Toronto. He heads the Research Leadership for Better Pharmacotherapy During Pregnancy and Lactation at the Hospital for Sick Children, Toronto, where he is director of the Motherisk Program. He was a consultant to Vivus, the manufacturer of Qsymia. E-mail him at obnews@frontlinemedcom.com.