Phentermine/topiramate - Free Weight Loss Clinical Trials

The combination of the drugs phentermine and topiramate extended-release (ER) (trade name Qsymia kyoo-sim-EE-uh) is a medication used for weight loss. In clinical trials, phentermine/topiramate ER was associated with modest but statistically significant weight loss when compared with placebo. This weight loss was associated with improvements in weight-related comorbidities such as improved glycemia, decreased blood pressure, and improved cholesterol.

Phentermine/topiramate ER was developed by Vivus, Inc., a California pharmaceutical company. Phentermine is a sympathomimetic amine which acts as an appetite suppressant and stimulant. Topiramate is an anticonvulsant that has weight loss side effects. The exact mechanism of action for both drugs is unknown.

In 2012 the U.S. Food and Drug Administration approved phentermine/topiramate ER as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of at least 30 kg/m², or at least 27 kg/m² (overweight) in the presence of at least one weight-related comorbidity such as hypertension, type 2 diabetes mellitus, or dyslipidemia. Phentermine/topiramate ER is available in certified retail pharmacies nationwide and also available through a certified mail-order pharmacy network. Approval was denied by European regulatory authorities, who cited potential risk to the heart and blood vessels, psychiatric side effects, and cognitive side effects in explaining their decision.

Medical uses

In clinical trials, people treated with the highest dose of phentermine/topiramate ER in combination with a program of diet and exercise lost 10% to 11% of their body weight compared to 1% to 2% for those who received placebo. In addition, 62% to 70% of subjects receiving the recommended dose or top dose of phentermine/topiramate ER achieved >=5% weight by week 56 (ITT-LOCF) compared to 17% to 21% of those receiving a sugar pill.

Adverse effects

In clinical trials, the most common adverse events which occurred at a rate >=5% and >=1.5 times placebo included paraesthesia (tingling in fingers/toes), dizziness, dysgeusia (altered taste), insomnia, constipation, and dry mouth.

In the U.S., the drug label contains warnings for increased heart rate, suicidal behavior and ideation, glaucoma, mood and sleep disorders, creatine elevation, and metabolic acidosis. Some of these warnings are based on historical observations in epilepsy patients taking topiramate. The FDA is requiring the company to perform a post-approval cardiovascular outcomes trial, due in part to the observation of increased heart rate in some people taking the drug in clinical trials.

Pregnancy

Phentermine/topiramate ER can cause fetal harm. Data from pregnancy registries and epidemiology studies indicate that a fetus exposed to topiramate in the first trimester of pregnancy has an increased risk of oral clefts (cleft lip with or without cleft palate). If a patient becomes pregnant while taking phentermine/topiramate ER, treatment should be discontinued immediately, and the patient should be apprised of the potential hazard to a fetus. Females of reproductive potential should have a negative pregnancy test before starting phentermine/topiramate ER and monthly thereafter during phentermine/topiramate ER therapy. Females of reproductive potential should use effective contraception during phentermine/topiramate ER therapy.

Contraindications

Phentermine/topiramate ER is contraindicated in pregnancy, glaucoma, hyperthyroidism, during or within 14 days of taking monoamine oxidase inhibitors, and in patients with hypersensitivity or idiosyncrasy to sympathomimetic amines. Phentermine/topiramate ER can cause an increase in resting heart rate.

Risk Evaluation and Mitigation Strategy (REMS)

Phentermine/topiramate ER was approved with a REMS program to ensure that benefits of treatment outweigh the risks. Because of the teratogenic risk associated with phentermine/topiramate ER therapy, phentermine/topiramate ER is distributed via certified pharmacies.

Approval history

In December 2009 VIVUS, Inc. submitted a new drug application (NDA) to the FDA and on March 1, 2010, VIVUS, Inc. announced that the FDA accepted the NDA for review.

In October 2010, the FDA announced its decision to not approve phentermine/topiramate ER in its current form and issued a Complete Response Letter (CRL) to VIVUS due to lack of long-term data and concerns about side effects including elevated heart rate, major adverse cardiovascular events, and birth defects.

The FDA expressed concerns about the potential for phentermine/topiramate ER to cause birth defects and requested that Vivus assess the feasibility of analyzing existing healthcare databases to determine the historical incidence of oral cleft in offspring of women treated with topiramate for migraine prophylaxis (100 mg).

In October 2011, VIVUS resubmitted the NDA to the FDA with responses to the issues addressed in the CRL. The FDA accepted the NDA in November 2011.

On September 18, 2012, Qsymia became available on the US market.

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