By Professor Juan Tamargo, Madrid, Spain
Qsymia is a formulation of two off-patent drugs already on the market: immediate-release phentermine and controlled-release topiramate. Phentermine is an amphetamine-like compound, currently licensed as a short-term weight loss agent due to its central appetite-inhibiting effects. Topiramate is an anticonvulsant with weight-loss effects probably due to increased taste aversion.
Qsymia is recommended alongside lifestyle intervention for obese persons (BMI > 30 kg/m2) and for overweight persons (BMI > 27 kg/m2) with associated comorbidities, such as type 2 diabetes and hypertension. It will be commercialized in three strengths: phentermine-IR/topiramate-CR 3.75/23 mg, 7.5/46 mg, and 15/92 mg. These doses are 2- to 4-fold lower than those approved for either drug when used as monotherapies.
During phase II-III development, Qsymia was studied in more than 2000 obese and overweight patients. Most of this weight loss occurred within the first six months of treatment and was followed by subsequent weight stabilization. After the first year, significant and dose-related improvements in blood pressure, glycemic indices, and lipid parameters, including HDL cholesterol, were shown.
The most common adverse events reported with Qsymia treatment were paresthesia, dry mouth, and constipation. During phase III studies, depressive symptoms, increased risk for sleep disorders and cognitive impairment were observed at the highest doses tested. Thus, Qsymia’s labeling will mention the possibility of an increased risk for suicidal ideation and behavior. Another potential area of concern is the increase in the incidence of major malformations (cleft lip and palate) in babies born to mothers taking topiramate. Women of childbearing potential should be advised to use adequate contraception while taking Qsymia and should be warned that topiramate may lessen contraceptives’ effectiveness. Furthermore, monthly pregnancy testing is advocated, as obesity is frequently associated with oligomenorrhea, and drug-induced weight loss may improve fertility. It is very important and adequate birth control in women taking Qnexa and it is strongly recommended pregnancy testing before and during drug treatment and stopping the drug immediately if a pregnancy occurs.
It is important to remember that the effect of Qsymia on long-term CV morbidity remains unknown until a well-powered CV and all-mortality outcome study is performed. There is a concern about CV risks and the increased risk of cleft lip with or without cleft palate. Indeed, a small mean increase in heart rate was observed in Qsymia treated patients (1.6 beats/min for the top dose) compared with placebo. Thus, the long-term effects on CV risk are unknown.
References
1. Allison DB, Gadde KM, Garvey WT, et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring). 2012;20:330-342.
2. 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 placebo-controlled, phase 3 trial. Lancet. 2011;377:1341-1352.
3. Garvey WT, Ryan DH, Look M, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr. 2012;95:297-308.