Vivus, which makes an experimental weight-loss pill, received bad news this week after an ingredient in the medicine was claimed to be associated with oral clefts in babies whose mothers took it in pregnancy. Vivus’s diet pill, Qnexa, combines topiramate with the appetite suppressant phentermine.
Earlier in 2011, the FDA asked Vivus earlier this year to use existing databases to determine the risk of oral cleft in children whose mothers took topiramate. The drug is used to prevent migraines and seizures, and is marketed as Topamax.
The analysis, dubbed Fortress, found the risk of cleft palates or cleft lips was 5.44 times higher for the group in which mothers had taken topiramate alone or in combination with other anti-seizure drugs in the first trimester of pregnancy, Vivus said yesterday in a statement.
From the Vivus briefing documents submitted to the FDA:
QNEXA, or VI-0521, is an investigational weight-loss therapy that is a novel combination of low-dose immediate-release phentermine (1/8 to 1/2 of marketed dose) and controlled-release topiramate (1/16 to 1/4 of marketed dose); both drugs are approved and marketed in the United States. The prescription use of these drugs spans more than 50 years for phentermine and more than 13 years for topiramate. Phentermine hydrochloride, at a labeled dose up to 37.5 mg/day (Adipex-P package insert 2005; Appendix 1), is the most prescribed weight-loss drug with approximately 6.1 million prescriptions written in 2009 (Information Management System [IMS] data). The phentermine label, restricted to short-term management of obesity, limits its clinicalpplication for the chronic treatment of obesity and weight-related co-morbidities. The primary mechanism of action of phentermine for weight loss is an anorectic effect occurring through the release of norepinephrine in the hypothalamus.
Topiramate is approved for treatment of seizure disorders at recommended doses up to 400 mg/day and for migraine headache prophylaxis at recommended doses up to 100 mg/day (Topamax package insert 2009; Appendix 1). More than 9 million prescriptions were written in 2009 for topiramate (IMS data). Available pharmacological evidence suggests that topiramateinduced weight loss may result from increased satiety due to decreased gastrointestinal motility (Topiramate Summary Basis for Approval 1995), increased taste aversion (Supuran 2008), increased energy expenditure, and decreased caloric intake (Bray 2003; Richard 2000; Richard 2002; Picard 2000). Moreover, published clinical studies have shown that topiramate monotherapy produces significant and dose-related weight loss in conjunction with clinically meaningful improvements in lipids, glycemic control, and blood pressure (Ben-Menachem 2003; Wilding 2004; Bray 2003). While the positive effects of topiramate on co-morbidities are primarily driven by weight loss, data from nonclinical and clinical studies provide evidence for additional positive effects of topiramate on glycemic parameters, blood pressure, and lipids (Stenlöf 2007; Astrup 2004) that are independent of weight reduction. Topiramate, however, is not approved for weight loss and is also associated with dose-limiting side effects, which prevent or limit its use as a single agent at the doses necessary to produce significant weight loss or cardiometabolic benefits.
Source here: //www.bloomberg.com/news/2011-12-21/vivus-drops-as-diet-drug-ingredient-affiliated-with-defects.html
and here: //www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm218821.pdf