Drugs, Pregnancy, and Lactation: New Weight Loss Drugs

The need for effective weight management medications as an adjunct to diet and exercise has escalated in the United States as obesity has reached epidemic proportions.

However, in recent years, several Food and Drug Administration–approved medications for weight loss have been plagued with safety concerns and many have been removed from the market, leaving clinicians with limited choices for treatment of overweight or obese patients.

In 2012, two new weight loss medications were approved by the FDA – the first new medications approved for this indication in over a decade (N. Engl. J. Med. 2012;367:1577-9).

As of February 2013, one of the two products, a combination product containing the anorexant phentermine and the anticonvulsant topiramate in an extended-release form, is currently available by prescription in the United States. Marketed as Qysmia, the product is intended to be used together with a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index of 30 kg/m² or greater (obese).

The medication is also indicated for adults with a BMI of 27 or greater (overweight) who also have at least one weight-related medical condition such as high blood pressure, type 2 diabetes, or high cholesterol. The recommended starting daily dose contains 3.75 mg of phentermine and 23 mg of topiramate; the maximum dose contains 15 mg of phentermine and 92 mg of topiramate.

In part, due to concerns about the teratogenicity of topiramate, Qysmia has been designated a category X drug, and specific pregnancy prevention measures in the form of a Risk Evaluation and Mitigation Strategy (REMS) have been put in place. The medication can be obtained only by prescription obtained directly from a health care provider, and providers receive training on the risks of birth defects. A prescription for Qysmia can only be filled by specially certified mail order pharmacies in the United States.

Educational materials indicate that the drug should not be prescribed to women who are pregnant or who are planning on becoming pregnant. Women who are not planning pregnancy but have the potential to become pregnant should have a negative pregnancy test before starting the drug and again every month while taking the drug, and they should use an effective method or combination of methods of contraception. The manufacturer has also initiated a pregnancy surveillance system.

Given the likelihood that many women of reproductive age will use this medication, even with a REMS in place, the potential for unintentional exposure in pregnancy exists. In the inevitable event of an exposed pregnancy, what are the specific risks and their magnitude? The concern about birth defects with this medication stems from previously published data suggesting that topiramate used in monotherapy for other indications, most commonly epilepsy, is associated with an increased risk for oral clefts (cleft lip with or without cleft palate). Although numbers are still small, a few studies have suggested the risk for oral clefts, with the most recent a large pooled case-control analysis from two data sources in the United States (Am. J. Obstet. Gynecol. 2012;207:405e1-7). The pooled estimate of the risk of oral clefts was 5.36 with very wide confidence intervals (1.49-20.07), based on seven exposed children with cleft lip with or without cleft palate. To the extent that this estimate is correct, this translates to an absolute risk of about 5 in 1,000 first-trimester topiramate-exposed pregnancies, compared with a baseline risk of about 1 in 1,000 in unexposed pregnancies.

Published studies of topiramate and oral clefts have not involved sufficient numbers of exposed and affected children to allow examination of a dose threshold; however, the range of recommended doses for seizure prevention in adults treated with topiramate monotherapy (50-400 mg/day) overlaps with the dosing range of topiramate contained in Qysmia. It is important to note that based on the published reports suggesting an increased risk for oral clefts, the pregnancy category for topiramate alone was recently changed from a C to a D, while the pregnancy category for Qysmia is an X. The rationale behind the category D is likely that the benefits of topiramate might outweigh the risks in a pregnant woman with a seizure disorder for whom topiramate is the only effective medication. However, topiramate use for weight loss would typically never be indicated in pregnancy.

The second drug, lorcaserin (Belviq), is a single-ingredient serotonergic medication – a selective agonist of the 5-HT_2C receptor. Lorcaserin was approved by the FDA in 2012, but as of February 2013, it is not yet available in the United States. This medication also received a pregnancy category X designation; however, in this situation, it was presumably for the sole reason that intentional weight loss in pregnancy is not recommended. Preclinical data for lorcaserin did not suggest teratogenicity, but maternal exposure in rats late in gestation resulted in lower pup body weight that persisted into adulthood.

To the extent that these new medications are effective in reducing and maintaining BMI within a healthier range in women who are currently overweight or obese, they may lead to improvement in subsequent pregnancy outcomes. However, avoiding exposure to these medications during early pregnancy will be a challenge, even with pregnancy prevention guidance and restricted distribution programs. Postmarketing surveillance for outcomes of inadvertently exposed pregnancies will be essential.

Dr. Chambers is associate professor of pediatrics and family and preventive medicine at the University of California, San Diego. She is director of the California Teratogen Information Service and Clinical Research Program. Dr. Chambers is a past president of the Organization of Teratology Information Specialists and past president of the Teratology Society. She said she had no relevant financial disclosures. To comment, e-mail her at [email protected].

The need for effective weight management medications as an adjunct to diet and exercise has escalated in the United States as obesity has reached epidemic proportions.

However, in recent years, several Food and Drug Administration–approved medications for weight loss have been plagued with safety concerns and many have been removed from the market, leaving clinicians with limited choices for treatment of overweight or obese patients.

In 2012, two new weight loss medications were approved by the FDA – the first new medications approved for this indication in over a decade (N. Engl. J. Med. 2012;367:1577-9).

As of February 2013, one of the two products, a combination product containing the anorexant phentermine and the anticonvulsant topiramate in an extended-release form, is currently available by prescription in the United States. Marketed as Qysmia, the product is intended to be used together with a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index of 30 kg/m² or greater (obese).

The medication is also indicated for adults with a BMI of 27 or greater (overweight) who also have at least one weight-related medical condition such as high blood pressure, type 2 diabetes, or high cholesterol. The recommended starting daily dose contains 3.75 mg of phentermine and 23 mg of topiramate; the maximum dose contains 15 mg of phentermine and 92 mg of topiramate.

In part, due to concerns about the teratogenicity of topiramate, Qysmia has been designated a category X drug, and specific pregnancy prevention measures in the form of a Risk Evaluation and Mitigation Strategy (REMS) have been put in place. The medication can be obtained only by prescription obtained directly from a health care provider, and providers receive training on the risks of birth defects. A prescription for Qysmia can only be filled by specially certified mail order pharmacies in the United States.

Educational materials indicate that the drug should not be prescribed to women who are pregnant or who are planning on becoming pregnant. Women who are not planning pregnancy but have the potential to become pregnant should have a negative pregnancy test before starting the drug and again every month while taking the drug, and they should use an effective method or combination of methods of contraception. The manufacturer has also initiated a pregnancy surveillance system.

Given the likelihood that many women of reproductive age will use this medication, even with a REMS in place, the potential for unintentional exposure in pregnancy exists. In the inevitable event of an exposed pregnancy, what are the specific risks and their magnitude? The concern about birth defects with this medication stems from previously published data suggesting that topiramate used in monotherapy for other indications, most commonly epilepsy, is associated with an increased risk for oral clefts (cleft lip with or without cleft palate). Although numbers are still small, a few studies have suggested the risk for oral clefts, with the most recent a large pooled case-control analysis from two data sources in the United States (Am. J. Obstet. Gynecol. 2012;207:405e1-7). The pooled estimate of the risk of oral clefts was 5.36 with very wide confidence intervals (1.49-20.07), based on seven exposed children with cleft lip with or without cleft palate. To the extent that this estimate is correct, this translates to an absolute risk of about 5 in 1,000 first-trimester topiramate-exposed pregnancies, compared with a baseline risk of about 1 in 1,000 in unexposed pregnancies.

Published studies of topiramate and oral clefts have not involved sufficient numbers of exposed and affected children to allow examination of a dose threshold; however, the range of recommended doses for seizure prevention in adults treated with topiramate monotherapy (50-400 mg/day) overlaps with the dosing range of topiramate contained in Qysmia. It is important to note that based on the published reports suggesting an increased risk for oral clefts, the pregnancy category for topiramate alone was recently changed from a C to a D, while the pregnancy category for Qysmia is an X. The rationale behind the category D is likely that the benefits of topiramate might outweigh the risks in a pregnant woman with a seizure disorder for whom topiramate is the only effective medication. However, topiramate use for weight loss would typically never be indicated in pregnancy.

The second drug, lorcaserin (Belviq), is a single-ingredient serotonergic medication – a selective agonist of the 5-HT_2C receptor. Lorcaserin was approved by the FDA in 2012, but as of February 2013, it is not yet available in the United States. This medication also received a pregnancy category X designation; however, in this situation, it was presumably for the sole reason that intentional weight loss in pregnancy is not recommended. Preclinical data for lorcaserin did not suggest teratogenicity, but maternal exposure in rats late in gestation resulted in lower pup body weight that persisted into adulthood.

To the extent that these new medications are effective in reducing and maintaining BMI within a healthier range in women who are currently overweight or obese, they may lead to improvement in subsequent pregnancy outcomes. However, avoiding exposure to these medications during early pregnancy will be a challenge, even with pregnancy prevention guidance and restricted distribution programs. Postmarketing surveillance for outcomes of inadvertently exposed pregnancies will be essential.

Dr. Chambers is associate professor of pediatrics and family and preventive medicine at the University of California, San Diego. She is director of the California Teratogen Information Service and Clinical Research Program. Dr. Chambers is a past president of the Organization of Teratology Information Specialists and past president of the Teratology Society. She said she had no relevant financial disclosures. To comment, e-mail her at [email protected].

The need for effective weight management medications as an adjunct to diet and exercise has escalated in the United States as obesity has reached epidemic proportions.

However, in recent years, several Food and Drug Administration–approved medications for weight loss have been plagued with safety concerns and many have been removed from the market, leaving clinicians with limited choices for treatment of overweight or obese patients.

In 2012, two new weight loss medications were approved by the FDA – the first new medications approved for this indication in over a decade (N. Engl. J. Med. 2012;367:1577-9).

As of February 2013, one of the two products, a combination product containing the anorexant phentermine and the anticonvulsant topiramate in an extended-release form, is currently available by prescription in the United States. Marketed as Qysmia, the product is intended to be used together with a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index of 30 kg/m² or greater (obese).

The medication is also indicated for adults with a BMI of 27 or greater (overweight) who also have at least one weight-related medical condition such as high blood pressure, type 2 diabetes, or high cholesterol. The recommended starting daily dose contains 3.75 mg of phentermine and 23 mg of topiramate; the maximum dose contains 15 mg of phentermine and 92 mg of topiramate.

In part, due to concerns about the teratogenicity of topiramate, Qysmia has been designated a category X drug, and specific pregnancy prevention measures in the form of a Risk Evaluation and Mitigation Strategy (REMS) have been put in place. The medication can be obtained only by prescription obtained directly from a health care provider, and providers receive training on the risks of birth defects. A prescription for Qysmia can only be filled by specially certified mail order pharmacies in the United States.

Educational materials indicate that the drug should not be prescribed to women who are pregnant or who are planning on becoming pregnant. Women who are not planning pregnancy but have the potential to become pregnant should have a negative pregnancy test before starting the drug and again every month while taking the drug, and they should use an effective method or combination of methods of contraception. The manufacturer has also initiated a pregnancy surveillance system.

Given the likelihood that many women of reproductive age will use this medication, even with a REMS in place, the potential for unintentional exposure in pregnancy exists. In the inevitable event of an exposed pregnancy, what are the specific risks and their magnitude? The concern about birth defects with this medication stems from previously published data suggesting that topiramate used in monotherapy for other indications, most commonly epilepsy, is associated with an increased risk for oral clefts (cleft lip with or without cleft palate). Although numbers are still small, a few studies have suggested the risk for oral clefts, with the most recent a large pooled case-control analysis from two data sources in the United States (Am. J. Obstet. Gynecol. 2012;207:405e1-7). The pooled estimate of the risk of oral clefts was 5.36 with very wide confidence intervals (1.49-20.07), based on seven exposed children with cleft lip with or without cleft palate. To the extent that this estimate is correct, this translates to an absolute risk of about 5 in 1,000 first-trimester topiramate-exposed pregnancies, compared with a baseline risk of about 1 in 1,000 in unexposed pregnancies.

Published studies of topiramate and oral clefts have not involved sufficient numbers of exposed and affected children to allow examination of a dose threshold; however, the range of recommended doses for seizure prevention in adults treated with topiramate monotherapy (50-400 mg/day) overlaps with the dosing range of topiramate contained in Qysmia. It is important to note that based on the published reports suggesting an increased risk for oral clefts, the pregnancy category for topiramate alone was recently changed from a C to a D, while the pregnancy category for Qysmia is an X. The rationale behind the category D is likely that the benefits of topiramate might outweigh the risks in a pregnant woman with a seizure disorder for whom topiramate is the only effective medication. However, topiramate use for weight loss would typically never be indicated in pregnancy.

The second drug, lorcaserin (Belviq), is a single-ingredient serotonergic medication – a selective agonist of the 5-HT_2C receptor. Lorcaserin was approved by the FDA in 2012, but as of February 2013, it is not yet available in the United States. This medication also received a pregnancy category X designation; however, in this situation, it was presumably for the sole reason that intentional weight loss in pregnancy is not recommended. Preclinical data for lorcaserin did not suggest teratogenicity, but maternal exposure in rats late in gestation resulted in lower pup body weight that persisted into adulthood.

To the extent that these new medications are effective in reducing and maintaining BMI within a healthier range in women who are currently overweight or obese, they may lead to improvement in subsequent pregnancy outcomes. However, avoiding exposure to these medications during early pregnancy will be a challenge, even with pregnancy prevention guidance and restricted distribution programs. Postmarketing surveillance for outcomes of inadvertently exposed pregnancies will be essential.

Dr. Chambers is associate professor of pediatrics and family and preventive medicine at the University of California, San Diego. She is director of the California Teratogen Information Service and Clinical Research Program. Dr. Chambers is a past president of the Organization of Teratology Information Specialists and past president of the Teratology Society. She said she had no relevant financial disclosures. To comment, e-mail her at [email protected].