FDA Approves Weight-Loss Drug Qsymia, Despite Cardiac Qualms

The combination of phentermine and topiramate has been approved for the treatment of weight loss with stipulations: a risk evaluation and mitigation strategy that addresses the potential teratogenic and adverse cardiac effects of the product, according to the Food and Drug Administration.

In the widely anticipated FDA announcement on July 17, Dr. Janet Woodcock, director of the agency’s Center for Drug Evaluation and Research, said in a statement that the phentermine-topiramate combination "used responsibly in combination with a healthy lifestyle that includes a reduced-calorie diet and exercise, provides another treatment option for chronic weight management in Americans who are obese or are overweight and have at least one weight-related comorbid condition."

The combination has been approved for treatment of adults with a body mass index of at least 30 kg/m², or those with a BMI of at least 27 who also have weight-related comorbidities.

The product contains an immediate-release formulation of phentermine, a sympathomimetic amine approved for short-term weight loss that has been marketed in the United States since 1959; and a controlled-release formulation of topiramate, approved for treating adult epilepsy in 1996, migraine prophylaxis in 2004, and pediatric epilepsy in 2011.

The combination has been approved for treatment of adults with a body mass index of at least 30 kg/m², or those with a BMI of at least 27 who also have weight-related comorbidities, in combination with diet and exercise.

The risk evaluation and mitigation strategy (REMS) addresses the teratogenicity of topiramate, which is known to increase the risk of oral clefts at the higher doses used for treating epilepsy, and the possible adverse cardiac effects of phentermine, which increases the pulse rate. The REMS includes a patient medication guide that is provided with each filled prescription, health care provider training, and distribution of the product through certified pharmacies.

It will be marketed as Qsymia by Vivus, not Qnexa, the original proposed trade name. After a starting dose of 3.75 mg/23 mg of phentermine/topiramate daily for 2 weeks, the recommended dose is 7.5 mg of phentermine with 46 mg of extended-release topiramate. A higher dose (15 mg/92 mg) is available for select patients who do not reach their weight-loss goal. These phentermine and topiramate doses are lower than the doses available for the two products available separately.

"Females of reproductive potential must not be pregnant when starting Qsymia therapy or become pregnant while taking Qsymia," should have a negative pregnancy test before starting treatment and monthly during treatment, and should consistently use effective contraception while on the weight-loss drug, according to the FDA statement. If a patient on treatment does not lose at least 5% of body weight after 12 weeks on the higher dose, treatment should be stopped, "as these patients are unlikely to achieve clinically meaningful weight loss with continued treatment," the statement added.

Approval was based on the results of two, 1-year studies involving nearly 4,000 obese and overweight people, mostly white females, with and without significant comorbidities, comparing phentermine-topiramate to placebo. Patients on the recommended and the higher doses of phentermine-topiramate lost an average of 6.7% and 8.9% of their weight, respectively, over those on placebo. About 62% of those on the recommended dose and 69% of those on the highest dose lost at least 5% of their baseline body weight, compared with about 20% of those on placebo. The most common side effects associated with treatment are paresthesias, dizziness, altered taste sensation, insomnia, constipation, and dry mouth.

In the studies, those who had not lost at least 3% of their body weight by week 12 of treatment were unlikely to achieve and sustain weight loss with continued treatment. As a result, it’s recommended that patients be evaluated by 12 weeks to determine whether they should stop treatment or start the higher dose, according to the FDA.

At a meeting in February, the majority of an FDA advisory panel voted that the benefit-risk profile of the medication supported its approval, with panelists in favor of approval citing evidence in clinical trials that treatment was associated with substantial weight loss and a favorable impact on obesity-related comorbidities in some patients, and the small number of effective nonsurgical weight loss treatments currently available. However, they stressed that the drug should be used only in appropriate patients, and they remained concerned about increases in pulse rate associated with treatment; the potential for cardiac adverse events; and the potential for an increased risk of oral clefts, although that risk may be lower than with the higher doses used for epilepsy and migraine prophylaxis, they said.

When the advisory panel first reviewed the phentermine-topiramate combination in July 2010, the majority voted against approval because of concerns about associated teratogenicity and increases in heart rate (by a mean of 1.6 beats/min at the highest dose). At the FDA’s request, the company studied the cardiovascular risks and teratogenic potential further and developed the REMS.

Vivus is required to conduct 10 postmarketing studies, including long-term cardiovascular outcomes studies in overweight and obese people with cardiovascular disease, studies in obese children and adolescents, and studies to evaluate drug utilization and pregnancy exposures. The company expects to make the drug available in the fourth quarter of 2012.

This is the second drug product approved for weight loss in 13 years. In June, the FDA approved lorcaserin hydrochloride (Belviq), a selective serotonin 2C receptor agonist at a dosage of 10 mg twice a day for the same indication.

Click here for prescribing information.

The combination of phentermine and topiramate has been approved for the treatment of weight loss with stipulations: a risk evaluation and mitigation strategy that addresses the potential teratogenic and adverse cardiac effects of the product, according to the Food and Drug Administration.

In the widely anticipated FDA announcement on July 17, Dr. Janet Woodcock, director of the agency’s Center for Drug Evaluation and Research, said in a statement that the phentermine-topiramate combination "used responsibly in combination with a healthy lifestyle that includes a reduced-calorie diet and exercise, provides another treatment option for chronic weight management in Americans who are obese or are overweight and have at least one weight-related comorbid condition."

The combination has been approved for treatment of adults with a body mass index of at least 30 kg/m², or those with a BMI of at least 27 who also have weight-related comorbidities.

The product contains an immediate-release formulation of phentermine, a sympathomimetic amine approved for short-term weight loss that has been marketed in the United States since 1959; and a controlled-release formulation of topiramate, approved for treating adult epilepsy in 1996, migraine prophylaxis in 2004, and pediatric epilepsy in 2011.

The combination has been approved for treatment of adults with a body mass index of at least 30 kg/m², or those with a BMI of at least 27 who also have weight-related comorbidities, in combination with diet and exercise.

The risk evaluation and mitigation strategy (REMS) addresses the teratogenicity of topiramate, which is known to increase the risk of oral clefts at the higher doses used for treating epilepsy, and the possible adverse cardiac effects of phentermine, which increases the pulse rate. The REMS includes a patient medication guide that is provided with each filled prescription, health care provider training, and distribution of the product through certified pharmacies.

It will be marketed as Qsymia by Vivus, not Qnexa, the original proposed trade name. After a starting dose of 3.75 mg/23 mg of phentermine/topiramate daily for 2 weeks, the recommended dose is 7.5 mg of phentermine with 46 mg of extended-release topiramate. A higher dose (15 mg/92 mg) is available for select patients who do not reach their weight-loss goal. These phentermine and topiramate doses are lower than the doses available for the two products available separately.

"Females of reproductive potential must not be pregnant when starting Qsymia therapy or become pregnant while taking Qsymia," should have a negative pregnancy test before starting treatment and monthly during treatment, and should consistently use effective contraception while on the weight-loss drug, according to the FDA statement. If a patient on treatment does not lose at least 5% of body weight after 12 weeks on the higher dose, treatment should be stopped, "as these patients are unlikely to achieve clinically meaningful weight loss with continued treatment," the statement added.

Approval was based on the results of two, 1-year studies involving nearly 4,000 obese and overweight people, mostly white females, with and without significant comorbidities, comparing phentermine-topiramate to placebo. Patients on the recommended and the higher doses of phentermine-topiramate lost an average of 6.7% and 8.9% of their weight, respectively, over those on placebo. About 62% of those on the recommended dose and 69% of those on the highest dose lost at least 5% of their baseline body weight, compared with about 20% of those on placebo. The most common side effects associated with treatment are paresthesias, dizziness, altered taste sensation, insomnia, constipation, and dry mouth.

In the studies, those who had not lost at least 3% of their body weight by week 12 of treatment were unlikely to achieve and sustain weight loss with continued treatment. As a result, it’s recommended that patients be evaluated by 12 weeks to determine whether they should stop treatment or start the higher dose, according to the FDA.

At a meeting in February, the majority of an FDA advisory panel voted that the benefit-risk profile of the medication supported its approval, with panelists in favor of approval citing evidence in clinical trials that treatment was associated with substantial weight loss and a favorable impact on obesity-related comorbidities in some patients, and the small number of effective nonsurgical weight loss treatments currently available. However, they stressed that the drug should be used only in appropriate patients, and they remained concerned about increases in pulse rate associated with treatment; the potential for cardiac adverse events; and the potential for an increased risk of oral clefts, although that risk may be lower than with the higher doses used for epilepsy and migraine prophylaxis, they said.

When the advisory panel first reviewed the phentermine-topiramate combination in July 2010, the majority voted against approval because of concerns about associated teratogenicity and increases in heart rate (by a mean of 1.6 beats/min at the highest dose). At the FDA’s request, the company studied the cardiovascular risks and teratogenic potential further and developed the REMS.

Vivus is required to conduct 10 postmarketing studies, including long-term cardiovascular outcomes studies in overweight and obese people with cardiovascular disease, studies in obese children and adolescents, and studies to evaluate drug utilization and pregnancy exposures. The company expects to make the drug available in the fourth quarter of 2012.

This is the second drug product approved for weight loss in 13 years. In June, the FDA approved lorcaserin hydrochloride (Belviq), a selective serotonin 2C receptor agonist at a dosage of 10 mg twice a day for the same indication.

Click here for prescribing information.

The combination of phentermine and topiramate has been approved for the treatment of weight loss with stipulations: a risk evaluation and mitigation strategy that addresses the potential teratogenic and adverse cardiac effects of the product, according to the Food and Drug Administration.

In the widely anticipated FDA announcement on July 17, Dr. Janet Woodcock, director of the agency’s Center for Drug Evaluation and Research, said in a statement that the phentermine-topiramate combination "used responsibly in combination with a healthy lifestyle that includes a reduced-calorie diet and exercise, provides another treatment option for chronic weight management in Americans who are obese or are overweight and have at least one weight-related comorbid condition."

The combination has been approved for treatment of adults with a body mass index of at least 30 kg/m², or those with a BMI of at least 27 who also have weight-related comorbidities.

The product contains an immediate-release formulation of phentermine, a sympathomimetic amine approved for short-term weight loss that has been marketed in the United States since 1959; and a controlled-release formulation of topiramate, approved for treating adult epilepsy in 1996, migraine prophylaxis in 2004, and pediatric epilepsy in 2011.

The combination has been approved for treatment of adults with a body mass index of at least 30 kg/m², or those with a BMI of at least 27 who also have weight-related comorbidities, in combination with diet and exercise.

The risk evaluation and mitigation strategy (REMS) addresses the teratogenicity of topiramate, which is known to increase the risk of oral clefts at the higher doses used for treating epilepsy, and the possible adverse cardiac effects of phentermine, which increases the pulse rate. The REMS includes a patient medication guide that is provided with each filled prescription, health care provider training, and distribution of the product through certified pharmacies.

It will be marketed as Qsymia by Vivus, not Qnexa, the original proposed trade name. After a starting dose of 3.75 mg/23 mg of phentermine/topiramate daily for 2 weeks, the recommended dose is 7.5 mg of phentermine with 46 mg of extended-release topiramate. A higher dose (15 mg/92 mg) is available for select patients who do not reach their weight-loss goal. These phentermine and topiramate doses are lower than the doses available for the two products available separately.

"Females of reproductive potential must not be pregnant when starting Qsymia therapy or become pregnant while taking Qsymia," should have a negative pregnancy test before starting treatment and monthly during treatment, and should consistently use effective contraception while on the weight-loss drug, according to the FDA statement. If a patient on treatment does not lose at least 5% of body weight after 12 weeks on the higher dose, treatment should be stopped, "as these patients are unlikely to achieve clinically meaningful weight loss with continued treatment," the statement added.

Approval was based on the results of two, 1-year studies involving nearly 4,000 obese and overweight people, mostly white females, with and without significant comorbidities, comparing phentermine-topiramate to placebo. Patients on the recommended and the higher doses of phentermine-topiramate lost an average of 6.7% and 8.9% of their weight, respectively, over those on placebo. About 62% of those on the recommended dose and 69% of those on the highest dose lost at least 5% of their baseline body weight, compared with about 20% of those on placebo. The most common side effects associated with treatment are paresthesias, dizziness, altered taste sensation, insomnia, constipation, and dry mouth.

In the studies, those who had not lost at least 3% of their body weight by week 12 of treatment were unlikely to achieve and sustain weight loss with continued treatment. As a result, it’s recommended that patients be evaluated by 12 weeks to determine whether they should stop treatment or start the higher dose, according to the FDA.

At a meeting in February, the majority of an FDA advisory panel voted that the benefit-risk profile of the medication supported its approval, with panelists in favor of approval citing evidence in clinical trials that treatment was associated with substantial weight loss and a favorable impact on obesity-related comorbidities in some patients, and the small number of effective nonsurgical weight loss treatments currently available. However, they stressed that the drug should be used only in appropriate patients, and they remained concerned about increases in pulse rate associated with treatment; the potential for cardiac adverse events; and the potential for an increased risk of oral clefts, although that risk may be lower than with the higher doses used for epilepsy and migraine prophylaxis, they said.

When the advisory panel first reviewed the phentermine-topiramate combination in July 2010, the majority voted against approval because of concerns about associated teratogenicity and increases in heart rate (by a mean of 1.6 beats/min at the highest dose). At the FDA’s request, the company studied the cardiovascular risks and teratogenic potential further and developed the REMS.

Vivus is required to conduct 10 postmarketing studies, including long-term cardiovascular outcomes studies in overweight and obese people with cardiovascular disease, studies in obese children and adolescents, and studies to evaluate drug utilization and pregnancy exposures. The company expects to make the drug available in the fourth quarter of 2012.

This is the second drug product approved for weight loss in 13 years. In June, the FDA approved lorcaserin hydrochloride (Belviq), a selective serotonin 2C receptor agonist at a dosage of 10 mg twice a day for the same indication.

Click here for prescribing information.