Oral Therapy for Chronic Weight Management - Qsymia® (phentermine and topiramate extended-release) capsules

The FDA approved Qsymia^® (phentermine and topiramate extended-release) capsules in July 2012 as an adjunct to a reduced calorie diet and increased physical activity for chronic weight management in people with a body mass index ≥30 kg/m² (obese) or ≥27 kg/m² (overweight) and ≥1 weight-related comorbidity such as hypertension, type 2 diabetes, or high cholesterol. The drug, marketed by VIVUS Inc., is an oral medication that combines phentermine (a sympathomimetic amine anorectic) and topiramate extended-release (an antiepileptic drug).

Patients are advised to take a capsule once daily in the morning and should avoid taking it at night to prevent insomnia. The recommended dosage is 3.75-mg phentermine/23-mg topiramate extended-release for 14 days and then 7.5-mg phentermine/46-mg topiramate extended-release afterward.

The drug is not to be used by pregnant women, patients with glaucoma, patients with an overactive thyroid, patients taking monoamine oxidase inhibitors, and patients with allergies to any of the drug’s ingredients.

Phentermine and topiramate extended-release was approved with a Risk Evaluation and Mitigation Strategy to advise patients of safety information and educate patients and providers of the risk of birth defects associated with the first exposure to the drug.

VIVUS Inc. is required to conduct 10 postmarketing requirements, including a long-term cardiovascular outcomes trial to evaluate the risk for major adverse cardiac events such as heart attack and stroke, according to an FDA news release.

The FDA approved phentermine and topiramate extended-release based on the results of 2 phase 3 trials: CONQUER and EQUIP. Both were randomized, double-blind, placebo-controlled studies that tested the drug in obese and/or overweight individuals. VIVUS Inc. funded both studies.

This First Report Managed Care Product Spotlight provides a summary of the pivotal trials that evaluated the safety and efficacy of phentermine and topiramate extended-release.

CONQUER TRIAL

Below is a summary of a randomized, double-blind, placebo-controlled, phase 3 study that evaluated 2 doses of phentermine plus topiramate extended-release as an adjunct to diet and lifestyle modifications in overweight and obese patients.

Reference

Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet [doi:10.1016/S0140-6736(11)60205-5].

Study Objective

The trial was designed to assess the efficacy of the phentermine plus topiramate combination for weight loss as assessed with change in body weight and the proportion of patients who achieved a weight loss of at least 5%.

Method

The authors randomized patients at 93 centers in the United States in a 2:1:2 ratio to receive once-daily treatment with 7.5-mg phentermine/46-mg topiramate,
15-mg phentermine/92-mg topiramate, or placebo for 56 weeks. All patients also received standardized counseling for diet and lifestyle modifications. Each capsule was identical in size and appearance.

During the first 4 weeks of treatment, patients had dose titration that started with
3.75-mg phentermine/23-mg topiramate or placebo with weekly increases in phentermine and topiramate until achieving the assigned doses. Patients who discontinued taking the drug were encouraged to remain in the study and continue with lifestyle counseling and complete assessments.

At baseline, patients received a manual advising them of lifestyle changes and to reduce their caloric intake by 500 kcal per day. They had study visits during screening and at baseline, weeks 2 and 4 during the drug titration period, and every 4 weeks afterward. They were assessed for body weight, blood pressure, heart rate, waist circumference, clinical and laboratory variables, concomitant drugs, adverse events, and treatment compliance. They were also administered the 9-item Patient Health Questionnaire to assess depressive symptoms and functional impairment. When warranted, patients were referred to a mental health professional.

VIVUS Inc. helped the authors with protocol design, data analyses, and preparation and interpretation of the journal article. However, the authors were responsible for the data and analyses and could freely express their views.

Population

The study included 2487 patients who were enrolled between November 1, 2007, and June 30, 2009. The baseline characteristics were similar among the 3 groups. The mean age was 51.1 years, mean body weight was 103.1 kg, mean BMI was 36.6 kg/m², 70% of patients were women, and 86% were white.

Patients were eligible if they were from 18 to 70 years of age, had a BMI from 27 kg/m² to 45 kg/m², and had ≥2 comorbidities at baseline, including systolic blood pressure from 140 mm Hg to 160 mm Hg, diastolic blood pressure from 90 mm Hg to 100 mm Hg, taking ≥2 antihyperintensive drugs, using ≥2 lipid-lowering therapies, and type 2 diabetes managed with lifestyle changes or metformin monotherapy.

Patients were excluded if they had systolic blood pressure >160 mm Hg and diastolic blood pressure >100 mm Hg, had type 1 diabetes, used antidiabetic drugs other than metformin, had a history of nephrolithiasis or recurrent major depression, the presence or history of suicidal behavior, and current substantial depressive symptoms. Patients were allowed to use antidepressants if they were stable for 3 months, although they could not use tricyclic antidepressant drugs or monoamine oxidase inhibitors.

Of the patients included, 52% had hypertension, 36% had hypertriglyceridemia, 68% had impaired glucose intolerance or impaired fasting glucose, and 16% had type 2 diabetes.

Primary end point

• Percentage weight loss at week 56

 Secondary end points

• Change from baseline to week 56 in waist circumference
• Change from baseline to week 56 in systolic blood pressure
• Change from baseline to week 56 in total cholesterol
• Change from baseline to week 56 in triglycerides
• Change from baseline to week 56 in fasting glucose

 Results

The authors concluded that after 56 weeks of treatment, the combination of phentermine and topiramate extended-release in combination with lifestyle interventions led to greater weight loss compared with placebo.

Patients who took placebo had a mean reduction in body weight of 1.4 kg compared with 8.1 kg in the 7.5-mg phentermine/46-mg topiramate group (P<.0001), and 10.2 kg in the 15-mg phentermine/92-mg topiramate group (P<.0001).

In addition, 21% of patients in the placebo group achieved at least a 5% reduction in body weight compared with 62% of patients in the 7.5-mg phentermine/46-mg topiramate group (P<.0001), and 70% of patients in the 15-mg phentermine/92-mg topiramate group (P<.0001).

Further, 7% of patients in the placebo group achieved at least a 10% reduction in body weight compared with 37% of patients in the 7.5-mg phentermine/46-mg topiramate group (P<.0001), and 48% of patients in the 15-mg phentermine/92-mg topiramate group (P<.0001).

There were also significant improvements in blood pressure, waist circumference, concentrations of lipids, glycemia, and inflammatory biomarkers in patients who took the combination of phentermine plus topiramate compared with those in the placebo group.

The most common adverse events were dry mouth, paraesthesia, constipation, insomnia, dizziness, and dysgeusia. Meanwhile, 4% of patients in the placebo group had depression-related adverse events compared with 4% of patients in the 7.5-mg phentermine/46-mg topiramate group, and 7% of patients in the 15-mg phentermine/92-mg topiramate group. Further, 3% of patients in the placebo group had anxiety-related adverse events compared with 5% of patients in the 7.5-mg phentermine/46-mg topiramate group, and 8% of patients in the 15-mg phentermine/92-mg topiramate group.

The authors noted a few limitations, including that end-point assessments were only available for 31% of patients, which they said was consistent with other weight loss trials. Other limitations were that the study had no patients with BMI >45 kg/m², 86% of patients were white, and only 30% were men, making it difficult to generalize the findings to a larger population.

EQUIP TRIAL

Below is a summary of a randomized, double-blind, placebo-controlled trial that evaluated the safety and efficacy of a controlled-release combination of phentermine and topiramate for weight loss and metabolic improvements.

Reference

Allison DB, Gadde KM, Garvey WT, et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity [doi:10.1038/oby.2011.330].

Study Objective

The trial was designed to assess 2 doses of phentermine plus topiramate in men and women with class 2 and 3 obesity.

Method

Patients were randomized in a 2:1:2 ratio to receive once-daily placebo, 3.75-mg phentermine/23-mg topiramate, or 15-mg phentermine/92-mg topiramate for 56 weeks. After they were screened, patients entered a blinded, 4-week titration period starting with placebo or 3.75-mg phentermine/23-mg topiramate and then had 52 weeks of treatment with the assigned drug dosage.

Study participants, physicians, site staff, and sponsor representatives were blinded to the patient assignments until the end of the trial. The study drug and placebo pill were indistinguishable, according to the authors.

Each patient received a manual instructing them about lifestyle counseling and were advised to have a 500 kcal daily reduction in dietary intake, increased water consumption, and increased physical activity.

The patients had fasting blood samples drawn at baseline and at weeks 4, 8, 16, 28, and 56. At each visit, the authors also monitored adverse events, including occurrence date, severity, relationship to the study drug, action taken, and outcome.

VIVUS Inc. assisted the authors with initial study design, data analyses, and reporting.

Population

The 1267 patients were enrolled at 91 sites in the United States beginning in November 2007, with the last study visit occurring in May 2009. At baseline, the 3 groups were well balanced. The mean age was 42.7 years, and the mean BMI was 42.0 kg/m². In addition, 83% of patients were females, and 17% were black. The authors noted that the patients were not at an increased risk of cardiometabolic disease based on blood pressure, fasting glucose, triglycerides, and cholesterol levels.

Patients were included if they were from 18 to 70 years of age, had BMI ≥35 kg/m² with no upper limit, had triglycerides ≤200 mg/dl with treatment of 0 or 1 lipid-lowering medications, had blood pressure ≤140/90 mm Hg with treatment of 0 or 2 anti-hyperintensive medications, and fasting serum glucose level ≤110 mg/dl.

Primary end points

• Percent weight loss
• Proportions of patients achieving at least a 5% weight loss

Secondary end points

• Waist circumference
• Systolic blood pressure
• Diastolic blood pressure
• Fasting glucoseLipid measures

Results

The authors concluded that the combination of phentermine plus topiramate in conjunction with lifestyle modification led to weight loss in obese patients and improved many cardiovascular and metabolic risk factors, including waist circumference, systolic blood pressure, and total cholesterol.

After 56 weeks of treatment, patients who took placebo had a mean reduction in body weight of 1.6% compared with 5.1% in the 3.75-mg phentermine/23-mg topiramate group (P<.0001), and 10.9% in the 15-mg phentermine/92-mg topiramate group (P<.0001).

Further, 17.3% of patients in the placebo group had lost at least 5% of their body weight from baseline to 56 weeks compared with 44.9% in the 3.75-mg phentermine/23-mg topiramate group (P<.0001), and 66.7% in the 15-mg phentermine/92-mg topiramate group (P<.0001).

The most common adverse events were paresthesia, dry mouth, constipation, dysgeusia, and insomnia.

The authors noted a few limitations of the study, among them was that 40% of patients dropped out, although they said the rate was consistent with obesity trials lasting 56 weeks. Also, the study included mostly white people, and many of them did not have significant obesity-associated comorbid diseases, according to the authors.

SAFETY NOTES

The product’s Prescribing Information notes that the combination of phentermine and topiramate extended-release can cause fetal harm, cognitive dysfunction, mood disorders, and an increase in resting heart rate and serum creatinine. Pregnant women should not use the drug, and women who become pregnant while taking the drug should discontinue treatment immediately.

Patients treated with phentermine and topiramate extended-release should be monitored for the emergence of or worsening of depression, suicidal thoughts or behavior, and/or unusual changes in mood or behavior. In addition, there have been reports of patients having secondary angle closure glaucoma.

According to the product’s Medication Guide, patients are advised to tell their healthcare providers if they have thoughts about suicide or dying, attempts to commit suicide, new or worsening depression, new or worsening anxiety, feeling agitated or restless, panic attacks, insomnia, new or worsening irritability, active aggressive, or other unusual changes in behavior or mood. They should also tell them about any sudden decrease in vision or if they have secondary angle closure glaucoma, which could lead to permanent vision loss if not treated.

Qsymia Facts

• Qsymia was approved by the FDA on July 17, 2012, as an addition to a reduced-calorie diet and exercise for chronic weight management
• Qsymia is marketed by VIVUS Inc.

Additional Resource

Prescribing Information for Qsymia: www.qsymia.com/pdf/prescribing-information.pdf