Pharmacology Update

Phentermine/Topiramate Extended-Release Capsules (Qsymia™ CIV)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA.

Drs. Elliott and Chan report no financial relationships relevant to this field of study.

THE FDA HAS APPROVED A SECOND WEIGHT-LOSS DRUG WITHIN the last month. This product is a combination of phentermine, an anorectic, and the antiepileptic topiramate. Phentermine/topiramate (PHEN/TPM) is manufactured by Catalent Pharma Solutions and marketed by Vivus Inc. as Qsymia.

Indications

PHEN/TPM is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults.1 PHEN/TPM is for adults who are obese (≥ 30 kg/m2) or overweight (≥ 27 kg/m2) with at least one comorbidity such as diabetes, hypertension, or dyslipidemia.

Dosage

The recommended starting dose is 3.75 mg of PHEN and 23 mg of TPM daily for 14 days, after which it may be increased to 7.5 mg/46 mg daily. If a 3% weight loss has not been achieved after 12 weeks, treatment may be discontinued or the dose may be increased further to 15 mg/92 mg after 12 weeks. If a 5% weight loss is not achieved after 12 weeks of treatment with 15 mg/92 mg, treatment should be discontinued. In patients with severe renal dysfunction or moderate hepatic dysfunction, the dose should not exceed 7.5 mg/46 mg. Discontinuation of treatment should be done gradually to avoid possible seizures.1

PHEN/TPM is available as 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg capsules.

Potential Advantages

PHEN/TPM provides another alternative with a different mechanism of action for weight loss in obese and overweight patients.

Potential Disadvantages

Topiramate may increase the risk of suicidal thoughts and behavior, mood disorders, cognitive impairment, kidney stones, oligohidrosis, and hyperthermia.1

Comments

The efficacy of PHEN/TPM was evaluated in two randomized, double-blind, placebo-controlled studies of 56 weeks duration.1-3 Study 1 (EQUIP) enrolled obese subjects and study 2 (CONQUER) enrolled obese and overweight subjects with two or more significant comorbidities. Both studies had a 4-week titration period and a 56-week treatment period. Subjects in EQUIP were randomized at a ratio of 2:1:2 to placebo (n = 514), PHEN/TPM 3.75 mg/23 mg (low dose; n = 241), and 15 mg/92 mg (n = 512). Subjects in CONQUER were randomized at the same ratio to placebo (n = 994), PHEN/TPM 7.5 mg/46 mg (mid-dose; n = 498), and 15 mg/92 mg (top dose; n = 995). Efficacy endpoints were percent of weight loss from baseline to week 56 and percent achieving at least 5% loss of body weight. The secondary endpoint was percent of subjects achieving at least 10% loss of body weight. Analysis was based on intent-to-treat and last observation carried forward. In EQUIP, the percent mean difference in placebo-adjusted weight loss (95% CI) was 3.5% 92.4-4.7) for 3.75 mg/23 mg and 9.4% (8.4-10.3) for the 15 mg/92 mg. The percentage of patients (placebo subtracted [95% CI]) losing ≥ 5% body weight was 27.6% (20.4-34.8) and 49.4% (44.1-54.7), respectively. For a 10% weight loss, the values were 11.4% and 39.8%. For CONQUER, placebo-subtracted mean changes from baseline were 6.6% for 7.5 mg/46 mg and 8.6% for 15 mg/92 mg. Values for the 5% and 10% weight loss were 41.3% and 49.2%, and 29.9% and 40.3%, respectively. PHEN/TPM modestly improved cardiovascular, metabolic, and anthropometric risk factors (e.g., blood pressure, lipid profile, and waist circumference) in a dose-dependent manner with waist circumference being the most significantly affected. The placebo subtracted differences for the three strengths were -2.5, -5.2, and -6.8/-7.8.1

In a small similarly designed study (n = 130), obese type 2 diabetic subjects were randomized to placebo or top dose of PHEN/TPM.4 Mean weight loss was 9.4% for PHEN/TPM and 2.7% for placebo. Percent with 5% or greater weight loss was 49% and 13%, respectively. Change in HbA1c was 1.6% and 1.1% (P = 0.38). The most common adverse events mid-dose vs placebo were dry mouth (13.5% vs 2.8%), paresthesia (13.7% vs 1.9%), constipation (15.1% vs 6.1%), elevation of serum creatinine ≥ 0.3 mg/dL (7.2% vs 2.0%), and dysgeusia (7.4% vs 1%).

Clinical Implications

PHEN/TPM is the second recent addition for the pharmacologic management of obesity after lorcaserin. The magnitude of benefit appears similar between the lowest dose of PHEN/TPM and lorcaserin. The FDA Guidance for Industry: Developing Products for Weight Management indicates that the primary efficacy endpoint should show a statistical difference of 5%, or at least 35%, and approximately double the proportion of subjects in the drug group should achieve a loss of 5% or greater in baseline body weight compared to the control group.5 Both lorcaserin and low-dose PHEN/TPM did not reach the efficacy benchmark of a statistical difference of 5% in mean weight loss between drug and placebo. The mid and top doses of PHEN/TPM did meet this benchmark as provided in the FDA guidance.

References

1. Qsymia™ Prescribing Information. Mountain View, CA: Vivus Inc.; July 2012.

2. Gadde KM, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): A randomised, placebo-controlled, phase 3 trial. Lancet 2011;377:1341-1352.

3. Allison DB, et al. Controlled-release phentermine/topiramate in severely obese adults: A randomized controlled trial (EQUIP). Obesity 2012;20:330-342.

4. www.fda.gov/downloads/advisorycommittees/.../drugs/.../ucm218821.pdf. Accessed July 30, 2012.

5. http://www.fda.gov/downloads/Drugs/.../Guidances/ucm071612.pdf. Accessed July 30, 2012.