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After a delay of more than 3 years, the Food and Drug Administration has approved the nation’s third weight-loss drug, a combination of naltrexone and bupropion.
The extended release tablets (Contrave; Orexigen and Takeda) are approved for use in adults who have a body mass index of at least 30 kg/m2, or those with a BMI of at least 27 kg/m2 and at least one additional weight-related condition such as hypertension, type 2 diabetes, or dyslipidemia. The agency recommended that Contrave be used in addition to caloric restriction and increased physical activity.
Dr. Timothy Garvey, chair of the American Association of Clinical Endocrinologists’ scientific committee, lauded the approval.
"We have a new tool now to treat obesity – and that is very good news," he said in an interview.
He said Contrave will be a valuable addition to the existing weight-loss medications: the phentermine/topiramate combo (Qsymia; Vivus) and lorcaserin (Belviq; Arena).
"There are no head-to-head trials with the other drugs, so we really can’t say much about relative efficacy," said Dr. Garvey. "But when you look at the placebo-subtracted weight loss in all the phase III data, it looks like Contrave is in the middle, with about a 6% loss over lifestyle interventions alone. So it’s not as effective as the topiramate combination, but more effective than lorcaserin."
In the pivotal, 56-week phase III trials, those taking Contrave lost 5%-8% of their baseline body weight, compared with a loss of 1%-2% in those on placebo. The proportion of those who lost at least 5% of their baseline body weight ranged from 45%-56% of those on the proposed dose, compared with 16%-43% of those on placebo.
The FDA guidance on weight-loss drugs suggests a 12-week efficacy evaluation – if the patient has not lost at least 5% of total body weight by then, the drug should be discontinued and another started.
It’s not possible to predict who will respond best to which drug, although there are some things to consider when choosing, said Dr. Garvey, who is chair of the department of nutrition at the University of Alabama at Birmingham.
"For example, women of childbearing age need to take precautions against becoming pregnant if they take the topiramate combination, and should stop it right away if they do become pregnant. And since lorcaserin is a serotonergic drug, it has to be used very cautiously in patients who are on other serotonergic medications. We definitely need more safety data there."
Additionally, none of the weight-loss drugs should be used in children or teens until more studies confirm their safety for those patients, "All of the companies are planning these trials, and we hope they will complete them expeditiously," Dr. Garvey said. "Childhood and adolescent obesity is a huge problem, and we really need some good treatment options there."
Because it contains bupropion, an antidepressant that has been associated with an increased risk of suicidal thoughts and actions, the drug carries a black box warning. Bupropion is also known to lower seizure threshold, so the drug should not be used in patients with seizure disorders. If a seizure occurs while taking on the medication, it should be permanently discontinued. Nor should it be used in patients with uncontrolled hypertension.
Orexigen and Takeda originally brought the drug forward in December 2011. It was not approved at that time because of concerns about its effect on blood pressure – an unexpected move, and one that Orexigen management called "a big setback."
About a quarter of those in the 56-week pivotal phase III trial experienced significant blood pressure increases of at least 10% above their baseline, compared with about 20% of those in the control arm. Increases of diastolic blood pressure of at least 5 mm Hg over baseline occurred in 37% of those on the combination, compared with 29% of those on placebo. About a quarter in the active arm also had heart rate increases of at least 10 beats per minute, compared with 19% of those taking placebo.
Because of these concerns, the FDA required the drug companies to conduct a large, double-blinded, randomized, placebo-controlled trial to investigate the risk of major cardiovascular events. Takeda and Orexigen then launched the 4-year, 8,900 patient Light study, which is still ongoing. Endpoints are major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) in overweight and obese subjects who have concomitant diabetes and/or other cardiovascular risk factors.
In June, citing encouraging preliminary results, Takeda and Orexigen brought Contrave to the FDA once more – only to be shot down again, at least temporarily. The agency required a review extension in order to come to agreement on the final form of postmarketing surveillance, said Denise Powell, a spokeswoman for Orexigen.
"At that time, FDA said the data looked good," she said in an interview. "We just needed more time to work out the postmarketing requirements."
Those will include:
• A cardiovascular outcomes trial to assess the cardiovascular risk associated with Contrave use.
• Two efficacy, safety, and clinical pharmacology studies in pediatric patients (one in patients 12-17 years old, and one in patients 7-11 years old).
• A juvenile animal toxicity study with a particular focus on growth and development as well as behavior, learning, and memory.
• A cardiac conduction study.
• Clinical trials to evaluate dosing in patients with hepatic or renal impairment.
• A clinical trial to evaluate the potential for interactions between the medication and other drugs.
Contrave contains an extended-release formulation of 8 mg naltrexone and 90 mg bupropion. It is to be administered in an in a 4-week upward titration schedule, with a single morning tablet during week 1; a single tablet at morning and evening during week 2; two tablets in the morning and one in the evening during week 3; and two tablets both morning and evening from week 4 and onward.
Dr. Garvey is a consultant for Daiichi Sankyo, LipoScience, Takeda, Vivus, Boehringer Ingelheim, Janssen, Eisai, and Novo Nordisk. He has received research funding from Merck, AstraZeneca, Weight Watchers, Eisai, and Sanofi.
On Twitter @alz_gal
After a delay of more than 3 years, the Food and Drug Administration has approved the nation’s third weight-loss drug, a combination of naltrexone and bupropion.
The extended release tablets (Contrave; Orexigen and Takeda) are approved for use in adults who have a body mass index of at least 30 kg/m2, or those with a BMI of at least 27 kg/m2 and at least one additional weight-related condition such as hypertension, type 2 diabetes, or dyslipidemia. The agency recommended that Contrave be used in addition to caloric restriction and increased physical activity.
Dr. Timothy Garvey, chair of the American Association of Clinical Endocrinologists’ scientific committee, lauded the approval.
"We have a new tool now to treat obesity – and that is very good news," he said in an interview.
He said Contrave will be a valuable addition to the existing weight-loss medications: the phentermine/topiramate combo (Qsymia; Vivus) and lorcaserin (Belviq; Arena).
"There are no head-to-head trials with the other drugs, so we really can’t say much about relative efficacy," said Dr. Garvey. "But when you look at the placebo-subtracted weight loss in all the phase III data, it looks like Contrave is in the middle, with about a 6% loss over lifestyle interventions alone. So it’s not as effective as the topiramate combination, but more effective than lorcaserin."
In the pivotal, 56-week phase III trials, those taking Contrave lost 5%-8% of their baseline body weight, compared with a loss of 1%-2% in those on placebo. The proportion of those who lost at least 5% of their baseline body weight ranged from 45%-56% of those on the proposed dose, compared with 16%-43% of those on placebo.
The FDA guidance on weight-loss drugs suggests a 12-week efficacy evaluation – if the patient has not lost at least 5% of total body weight by then, the drug should be discontinued and another started.
It’s not possible to predict who will respond best to which drug, although there are some things to consider when choosing, said Dr. Garvey, who is chair of the department of nutrition at the University of Alabama at Birmingham.
"For example, women of childbearing age need to take precautions against becoming pregnant if they take the topiramate combination, and should stop it right away if they do become pregnant. And since lorcaserin is a serotonergic drug, it has to be used very cautiously in patients who are on other serotonergic medications. We definitely need more safety data there."
Additionally, none of the weight-loss drugs should be used in children or teens until more studies confirm their safety for those patients, "All of the companies are planning these trials, and we hope they will complete them expeditiously," Dr. Garvey said. "Childhood and adolescent obesity is a huge problem, and we really need some good treatment options there."
Because it contains bupropion, an antidepressant that has been associated with an increased risk of suicidal thoughts and actions, the drug carries a black box warning. Bupropion is also known to lower seizure threshold, so the drug should not be used in patients with seizure disorders. If a seizure occurs while taking on the medication, it should be permanently discontinued. Nor should it be used in patients with uncontrolled hypertension.
Orexigen and Takeda originally brought the drug forward in December 2011. It was not approved at that time because of concerns about its effect on blood pressure – an unexpected move, and one that Orexigen management called "a big setback."
About a quarter of those in the 56-week pivotal phase III trial experienced significant blood pressure increases of at least 10% above their baseline, compared with about 20% of those in the control arm. Increases of diastolic blood pressure of at least 5 mm Hg over baseline occurred in 37% of those on the combination, compared with 29% of those on placebo. About a quarter in the active arm also had heart rate increases of at least 10 beats per minute, compared with 19% of those taking placebo.
Because of these concerns, the FDA required the drug companies to conduct a large, double-blinded, randomized, placebo-controlled trial to investigate the risk of major cardiovascular events. Takeda and Orexigen then launched the 4-year, 8,900 patient Light study, which is still ongoing. Endpoints are major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) in overweight and obese subjects who have concomitant diabetes and/or other cardiovascular risk factors.
In June, citing encouraging preliminary results, Takeda and Orexigen brought Contrave to the FDA once more – only to be shot down again, at least temporarily. The agency required a review extension in order to come to agreement on the final form of postmarketing surveillance, said Denise Powell, a spokeswoman for Orexigen.
"At that time, FDA said the data looked good," she said in an interview. "We just needed more time to work out the postmarketing requirements."
Those will include:
• A cardiovascular outcomes trial to assess the cardiovascular risk associated with Contrave use.
• Two efficacy, safety, and clinical pharmacology studies in pediatric patients (one in patients 12-17 years old, and one in patients 7-11 years old).
• A juvenile animal toxicity study with a particular focus on growth and development as well as behavior, learning, and memory.
• A cardiac conduction study.
• Clinical trials to evaluate dosing in patients with hepatic or renal impairment.
• A clinical trial to evaluate the potential for interactions between the medication and other drugs.
Contrave contains an extended-release formulation of 8 mg naltrexone and 90 mg bupropion. It is to be administered in an in a 4-week upward titration schedule, with a single morning tablet during week 1; a single tablet at morning and evening during week 2; two tablets in the morning and one in the evening during week 3; and two tablets both morning and evening from week 4 and onward.
Dr. Garvey is a consultant for Daiichi Sankyo, LipoScience, Takeda, Vivus, Boehringer Ingelheim, Janssen, Eisai, and Novo Nordisk. He has received research funding from Merck, AstraZeneca, Weight Watchers, Eisai, and Sanofi.
On Twitter @alz_gal
After a delay of more than 3 years, the Food and Drug Administration has approved the nation’s third weight-loss drug, a combination of naltrexone and bupropion.
The extended release tablets (Contrave; Orexigen and Takeda) are approved for use in adults who have a body mass index of at least 30 kg/m2, or those with a BMI of at least 27 kg/m2 and at least one additional weight-related condition such as hypertension, type 2 diabetes, or dyslipidemia. The agency recommended that Contrave be used in addition to caloric restriction and increased physical activity.
Dr. Timothy Garvey, chair of the American Association of Clinical Endocrinologists’ scientific committee, lauded the approval.
"We have a new tool now to treat obesity – and that is very good news," he said in an interview.
He said Contrave will be a valuable addition to the existing weight-loss medications: the phentermine/topiramate combo (Qsymia; Vivus) and lorcaserin (Belviq; Arena).
"There are no head-to-head trials with the other drugs, so we really can’t say much about relative efficacy," said Dr. Garvey. "But when you look at the placebo-subtracted weight loss in all the phase III data, it looks like Contrave is in the middle, with about a 6% loss over lifestyle interventions alone. So it’s not as effective as the topiramate combination, but more effective than lorcaserin."
In the pivotal, 56-week phase III trials, those taking Contrave lost 5%-8% of their baseline body weight, compared with a loss of 1%-2% in those on placebo. The proportion of those who lost at least 5% of their baseline body weight ranged from 45%-56% of those on the proposed dose, compared with 16%-43% of those on placebo.
The FDA guidance on weight-loss drugs suggests a 12-week efficacy evaluation – if the patient has not lost at least 5% of total body weight by then, the drug should be discontinued and another started.
It’s not possible to predict who will respond best to which drug, although there are some things to consider when choosing, said Dr. Garvey, who is chair of the department of nutrition at the University of Alabama at Birmingham.
"For example, women of childbearing age need to take precautions against becoming pregnant if they take the topiramate combination, and should stop it right away if they do become pregnant. And since lorcaserin is a serotonergic drug, it has to be used very cautiously in patients who are on other serotonergic medications. We definitely need more safety data there."
Additionally, none of the weight-loss drugs should be used in children or teens until more studies confirm their safety for those patients, "All of the companies are planning these trials, and we hope they will complete them expeditiously," Dr. Garvey said. "Childhood and adolescent obesity is a huge problem, and we really need some good treatment options there."
Because it contains bupropion, an antidepressant that has been associated with an increased risk of suicidal thoughts and actions, the drug carries a black box warning. Bupropion is also known to lower seizure threshold, so the drug should not be used in patients with seizure disorders. If a seizure occurs while taking on the medication, it should be permanently discontinued. Nor should it be used in patients with uncontrolled hypertension.
Orexigen and Takeda originally brought the drug forward in December 2011. It was not approved at that time because of concerns about its effect on blood pressure – an unexpected move, and one that Orexigen management called "a big setback."
About a quarter of those in the 56-week pivotal phase III trial experienced significant blood pressure increases of at least 10% above their baseline, compared with about 20% of those in the control arm. Increases of diastolic blood pressure of at least 5 mm Hg over baseline occurred in 37% of those on the combination, compared with 29% of those on placebo. About a quarter in the active arm also had heart rate increases of at least 10 beats per minute, compared with 19% of those taking placebo.
Because of these concerns, the FDA required the drug companies to conduct a large, double-blinded, randomized, placebo-controlled trial to investigate the risk of major cardiovascular events. Takeda and Orexigen then launched the 4-year, 8,900 patient Light study, which is still ongoing. Endpoints are major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) in overweight and obese subjects who have concomitant diabetes and/or other cardiovascular risk factors.
In June, citing encouraging preliminary results, Takeda and Orexigen brought Contrave to the FDA once more – only to be shot down again, at least temporarily. The agency required a review extension in order to come to agreement on the final form of postmarketing surveillance, said Denise Powell, a spokeswoman for Orexigen.
"At that time, FDA said the data looked good," she said in an interview. "We just needed more time to work out the postmarketing requirements."
Those will include:
• A cardiovascular outcomes trial to assess the cardiovascular risk associated with Contrave use.
• Two efficacy, safety, and clinical pharmacology studies in pediatric patients (one in patients 12-17 years old, and one in patients 7-11 years old).
• A juvenile animal toxicity study with a particular focus on growth and development as well as behavior, learning, and memory.
• A cardiac conduction study.
• Clinical trials to evaluate dosing in patients with hepatic or renal impairment.
• A clinical trial to evaluate the potential for interactions between the medication and other drugs.
Contrave contains an extended-release formulation of 8 mg naltrexone and 90 mg bupropion. It is to be administered in an in a 4-week upward titration schedule, with a single morning tablet during week 1; a single tablet at morning and evening during week 2; two tablets in the morning and one in the evening during week 3; and two tablets both morning and evening from week 4 and onward.
Dr. Garvey is a consultant for Daiichi Sankyo, LipoScience, Takeda, Vivus, Boehringer Ingelheim, Janssen, Eisai, and Novo Nordisk. He has received research funding from Merck, AstraZeneca, Weight Watchers, Eisai, and Sanofi.
On Twitter @alz_gal
