Because the regulation of food intake is controlled by several pathways, it has been hypothesized that combining two drugs with different mechanisms of action could improve efficacy (and tolerability if used in lower doses) compared with single-drug therapy.

Phentermine-topiramate — In 2012, the US Food and Drug Administration (FDA) approved a preparation of  phentermine and extended-release topiramate (in one capsule) for adults with a body mass index (BMI) ≥30 kg/m² or with a BMI ≥27 kg/m² with at least one weight-related comorbidity (eg, hypertension, diabetes, dyslipidemia). We do not recommend phentermine-topiramate  for patients with cardiovascular disease (hypertension or coronary heart disease). Phentermine-topiramate may be considered for obese, postmenopausal women and men without cardiovascular disease, particularly those who do not tolerate orlistat, lorcaseri or liraglutide. The efficacy and safety of combining generic phentermine with generic topiramate for weight loss (each taken individually) has not yet been established.

Efficacy — This combination has been shown to enhance weight loss in the first year of use, as illustrated by the following trials:

●A combination of controlled-release phentermine-topiramate (7.5/46 mg or 15/92 mg) was compared with placebo in 2487 adults with BMI of 27 to 45 kg/m² and two or more comorbidities [57]. After one year, mean weight loss was greater in those assigned to active treatment (8 to 10 versus 1.4 kg with placebo [8 to 10 percent versus 1.2 percent of baseline body weight]). Only 61 percent of participants completed one year of treatment.

In a 52-week extension of the above trial (78 percent of eligible subjects participating), mean total weight loss (from baseline to 108 weeks) was significantly better than placebo (9.6, 10.9, and 2.1 kg [9.3, 10.5, and 1.8 percent of baseline body weight] for low dose, high dose, and placebo, respectively) [11]. Of note, phentermine-topiramate was less effective for weight loss in the second year of use, although most individuals were able to maintain the weight they lost in year 1. In those subjects who were able to participate in the second year of the trial, the therapy was well tolerated.

●In another trial, men and women with BMI ≥35 kg/m²were randomly assigned to controlled-release phentermine-topiramate (3.75/23 mg or 15/92 mg) or placebo [58]. After 56 weeks, mean weight loss was greater in the active treatment groups (mean reduction 6, 12.6, and 1.9 kg [5.1, 10.9, and 1.6 percent of baseline body weight]). Among those assigned to active treatment, 45 to 67 percent lost at least 5 percent of baseline weight compared with 17 percent of placebo patients.

Adverse effects — The most common adverse events in these trials were dry mouth (13 to 21 versus 2 percent), constipation (15 to 17 versus 6 percent), and paresthesia (14 to 21 versus 2 percent) [57,58]. There was a dose-related increase in the incidence of psychiatric (eg, depression, anxiety) and cognitive (eg, disturbance in attention) adverse events in the active treatment group. Although blood pressure improved slightly with active therapy, there was an increase in heart rate (0.6 to 1.6 beats/min) compared with placebo.

Dosing and contraindications — The initial dose of phentermine-topiramate is 3.75/23 mg for 14 days, followed by 7.5/46 mg thereafter. If after 12 weeks a 3 percent loss in baseline body weight is not achieved, the dose can be increased to 11.25/69 mg for 14 days and then to 15/92 mg daily [59]. If an individual does not lose 5 percent of body weight after 12 weeks on the highest dose, phentermine-topiramate should be discontinued gradually as abrupt withdrawal of topiramate can cause seizures.

Combination phentermine-topiramate is contraindicated during pregnancy because of an increased risk of orofacial clefts in infants exposed to the combination drug during the first trimester of pregnancy. Women of childbearing age should have a pregnancy test before starting this drug and monthly thereafter. It is also contraindicated in patients with hyperthyroidism, glaucoma, and in patients who have taken monoamine oxidase inhibitors within 14 days. Because topiramate can produce renal stones, this combination preparation should be used cautiously in patients with a history of renal stones.

Clinicians who prescribe phentermine-topiramate are encouraged to enroll in a Risk Evaluation and Mitigation Strategy (REMS), which includes an online or print formal training module detailing safety information .Pharmacies that dispense the drug require certification, which involves identifying a representative to oversee the REMS program, and providing patients with a medication guide and brochure each time the drug is dispensed, detailing the risks of birth defects.