The trusted source for
healthcare information and
Weight-loss Drug Effective Without Cardiac Side Effects?
In this issue: Lorcaserin submitted for FDA review, FDA advisory panel votes against phentermine/topiramate, mixed vote on rosiglitazone, advisory panel votes to remove breast cancer indication from bevacizumab labeling, no increase in seizures found with DTaP vaccine, new REMS for quinine.
Weight loss without cardiac side effects
A new weight-loss medication may soon be available in the United States. Arena pharmaceuticals has filed a new drug application with the FDA for lorcaserin, a selective serotonin 2C-receptor agonist, and will likely get a formal review this fall. Unlike previous nonselective serotonergic agonists such as fenfluramine and dexfenfluramine, which were effective at causing weight loss, but also inhibited serotonin 2B receptors in the heart and were associated with valvulopathy, lorcaserin is specific for the serotonin 2C receptor in the brain.
Results from a company-sponsored study were published in the in New England Journal of Medicine and validate the effectiveness of the drug. The phase III trial was conducted at 98 academic and private trial sites, where 3180 patients were randomly assigned to receive lorcaserin 10 mg or placebo twice daily. After 1 year, patients receiving the active drug were randomly reassigned in a 2:1 ratio to continue to receive lorcaserin or change to placebo. All patients were age 18-65 years with a BMI of 30-45 or 27-45 kg/m2 with one coexisting condition, including hypertension, dyslipidemia, cardiovascular disease, impaired glucose tolerance, or sleep apnea. Patients were also counseled on lifestyle modification. Echocardiography was done at baseline and every 6 months thereafter.
At the end of 1 year, 47.5% of patients receiving lorcaserin lost 5% or more of their baseline body weight as compared with 20.3% of patients receiving placebo (P < 0.001). The average patient in the lorcaserin group lost 5.8% of their body weight compared with 2.2% in the placebo group (P < 0.001), and more patients in the active treatment group lost 10% or more of their baseline body weight than in the placebo group (22.6% vs 7.7%; P < 0.001). In those who lost weight with the active drug, the loss was maintained in a greater proportion of patients who continued to receive lorcaserin in year 2 compared to those who were reassigned to placebo (67.9% vs 50.3%; P < 0.001). Markers of cardiovascular risk were improved in the active treatment group including C-reactive protein, fibrinogen levels, lipid levels, and insulin resistance. Systolic and diastolic blood pressures also decreased slightly in the lorcaserin group. Significantly, there was no evidence of cardiac valvulopathy found with use of lorcaserin and the rate of serious side effects was similar in the two groups.
The authors conclude that lorcaserin was associated with significant weight loss and improved maintenance of weight loss as compared to placebo (N Engl J Med 2010;363:245-256). Already being tagged the new, safe "diet drug," it is a sure bet that approval of lorcaserin will be associated with tremendous interest from our patients.
Advisory panel votes against Qnexa
An FDA advisory panel recommended against approving (10-7 vote) the combination weight-loss drug Qnexa® (phentermine/topiramate) because of concerns about safety. The drug appears to be effective at inducing weight loss, but is associated with significant side effects including depression, anxiety, sleep disorders, attention, memory, and language and other cognitive disorders, as well as metabolic acidosis, increased heart rate, and teratogenicity. Qnexa is a combination of two available drugs and both remain on the market individually. Phentermine was approved in 1959 and is currently indicated as short-term treatment for weight reduction. It was part of the infamous Fen/Phen combination along with fenfluramine (later dexfenfluramine; both fenfluramine and dexfenfluramine were eventually removed from the market when they were found to cause pulmonary hypertension and cardiac valvulopathy). Topiramate is approved for the treatment of seizures and migraine prophylaxis. The FDA generally follows the recommendations of its expert panels.
Mixed vote on rosiglitazone
The same FDA committee also recently ruled on the embattled diabetes drug rosiglitazone (Avandia®), and the vote was decidedly mixed. GlaxoSmithKline's rosiglitazone has been under intense scrutiny since 2007 when a study from the Cleveland Clinic linked the drug to an increased rate of heart attacks (N Engl J Med 2007;356:2457-2471). Recently, the FDA has evaluated reports from the New York Times and others that the company suppressed crucial safety information about the drug for years. At the July meeting of the Endocrinologic and Metabolic Advisory Committee, 12 members voted to withdraw rosiglitazone from the market, 10 voted to keep the drug on the market with additional warnings and restrictions, 7 wanted additional warnings only, and 3 members voted for no label changes. The FDA is not required to follow the advice of its advisory panels, and it is unclear what course they will take when they finally make a decision later this year.
Breast cancer indication for bevacizumab
The Oncologic Drugs Advisory committee of the FDA has recommended removing the indication for breast cancer treatment for bevacizumab (Avastin®). The 12-1 vote was made after data were presented that the drug provided no survival benefit when used in combination with docetaxel, while contributing significant adverse effects. Bevacizumab, a humanized monoclonal antibody, which blocks new blood vessel formation (angiogenesis inhibitor), also carries indications for treatment of colon, lung, kidney, and brain cancers.
No increase in seizures with DTaP vaccine
The diphtheria-tetanus-acellular pertussis vaccine (DTaP) does not increase the risk of seizures in children, according to a recent article published on-line in Pediatrics. The previously used diphtheria-tetanus-whole-cell pertussis vaccine (DTP) is associated with seizures, but there were limited data on DTaP. Using data from the CDC's Vaccine Safety Data linked project, a retrospective study from 1997 through 2006 at 7 managed-care organizations was performed. Eligible children were age 6 weeks to 23 months and had not previously received DTP. Of the more than 433,000 children who were vaccinated, there were 7191 seizure events. The adjusted incident rate for seizures across all doses was 0.87 in the cohort analysis and 0.91 in the comparison group with the same patients during unexposed periods. The authors conclude that they did not observe an increased risk for seizures after DTaP among children age 6 weeks to 23 months.
New REMS for quinine
The FDA banned the OTC use of quinine sulfate for the treatment of nocturnal leg cramps in 1994 after receiving more than 150 reports of adverse reactions, including 23 deaths. Quinine sulfate (brand name Qualaquin®) remains the only quinine product on the market, but is approved only for the treatment of uncomplicated malaria caused by Plasmodium falciparum. Qualaquin, however, is much more commonly used off-label for nighttime leg cramps. The FDA continues to get reports of life-threatening hematologic reactions associated with quinine sulfate including thrombocytopenia, hemolytic-uremic syndrome/TTP, hearing loss, and cardiovascular problems. Between 2005 and 2008 there were 38 cases of serious side effects including 2 deaths. The FDA has announced a new Risk Evaluation and Medication Strategy (REMS) for Qualaquin that will include a Medication Guide explaining what the medication is and is not approved for, as well as the potential side effects of the drug. The medication guide specifically states that "Qualaquin should not be used for nighttime leg cramps," and those using it for this indication are at risk of serious side effects (FDA Drug Safety Communication, July 8, 2010).
This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5468. E-mail: email@example.com.