FDA Heightens Warnings on Chantix

Pharmacology Watch

In this issue: Stop smoking drug Chantix rates stronger warning from FDA; Type 2 diabetes surgery on the way?; Vytorin study inconclusive; Influenza A virus found resistant to Tamiflu; FDA actions.

The FDA has strengthened its warning on the stop smoking drug varenicline (Chantix). Last November the agency issued an Early Communication regarding reports of changes in behavior, agitation, depressed mood, suicidal ideation, and suicidal behavior in patients taking the drug. After review of recent reports, the agency now says that it appears increasingly likely that there may be an association between varenicline and neuropsychiatric symptoms. The FDA has asked Pfizer, the manufacturer of the drug, to elevate the prominence of these warnings on the package label, and the company along with the FDA is working on a Medication Guide for patients. The FDA is recommending that patients should tell their health-care providers about any history of psychiatric illness prior to starting varenicline. There is evidence that the drug may cause worsening of current psychiatric illness, and cause old psychiatric illness to reoccur. Moreover health-care professionals, patients, patients' families, and caregivers should be alert to monitor for changes in mood and behavior in patients treated with varenicline. The FDA warning also states that vivid, unusual, or strange dreams may occur while taking the drug and that patients may experience impairment of the ability to drive or operate heavy machinery. Varenicline was approved in May 2006 under the trade name Chantix by Pfizer Pharmaceuticals to ease withdrawal symptoms associated with smoking cessation.

Weight-loss Surgery Answer for Type 2 Diabetics?

Could surgery be the answer for type 2 diabetes? In a new study from Australia, 60 patients with type 2 diabetes and a BMI of 30-40 were randomized to adjustable gastric banding surgery or conventional therapy. Conventional therapy focused on weight loss by lifestyle changes. The main outcome measure was remission of type 2 diabetes and secondary measures included weight and components of the metabolic syndrome. Remission of type 2 diabetes was achieved by 22 patients in the surgical group (73%) vs 4 patients in the conventional therapy group (13%). Relative risk for remission in the surgical group was 5.5 (95% CI, 2.2-14.0). Surgical patients lost more weight, mean (SD) 20.7% (8.6%) vs 1.7% (5.2%) for the nonsurgical group at two years (P <.001 there were no serious complications in either group. the average weight loss to achieve remission of type diabetes was which achieved surgical patients and only medical therapy patients. authors conclude that for with more likely through greater loss. these results should be confirmed larger diverse population have long-term efficacy assessed>JAMA 2008;299:316-323). An accompanying editorial suggests that gastrointestinal tract surgery may offer a new goal in diabetes management—remission rather than just treatment. The editorialists also suggest that the cost and risks of such surgery must be balanced with the costs and risks of long-term diabetes management (JAMA 2008; 299:341-343).

Vytorin Needs More Study

Vytorin has been in the news recently after Merck/Schering-Plough released the preliminary results of the Effect of Combined Ezetimibe and High-Dose Simvastatin vs Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia (ENHANCE) study. Vytorin is a combination of the statin simvastatin (Zocor) and ezetimibe (Zetia), a medication that blocks cholesterol absorption through the gut. The combination drug is better at lowering LDL than either drug alone, and it was hoped that this would translate to improved cardiovascular outcomes. ENHANCE randomized 720 patients with heterozygous familial hypercholesterolemia to treatment with either simvastatin 80 mg daily or Vytorin (simvastatin 80 mg plus ezetimibe 10 mg). Mean LDL cholesterol levels at baseline were 320 mg/dl. Simvastatin alone lowered LDL by 41% while Vytorin lowered LDL by 58%. The primary endpoint was change in mean carotid intima media thickness after two years of treatment. There was no difference in this primary endpoint or in the incidence of any adverse effects between the two treatment arms. ENHANCE was widely reported as a failure for Vytorin, and there were even reports that Vytorin increased the rate of plaque production, which was not the case. The study has been criticized because of its small size, atypical patient population, and primary outcome (carotid intimal media thickness) which is not a clinical outcome. The American College of Cardiology issued a statement on January 15 suggesting that "major clinical decisions not be made on the basis of the ENHANCE study alone." The FDA issued a statement on January 25 stating that it will conduct a review of Merck and Schering-Plough's trial once the final results of the study are available. Data from the ENHANCE study is due to be presented at the American College of Cardiology meeting in March.

Virus Resistant to Tamiflu Causing Concern

A small percentage of the influenza A virus causing illness worldwide this winter is resistant to oseltamivir (Tamiflu), according to the World Health Organization. Tamiflu-resistant forms have been found in European countries, Canada, and the US. Generally mutations of this sort attenuate the virus, making it less infectious; however this is not found be the case with the resistant strain of A/N1H1 known as A(H1N1 H274Y). The highest rate of resistance was found in Norway with 75% of isolated viruses showing resistance. The rate of resistance in the US was 3.8%. There are currently no plans to change recommendations for use of Tamiflu; however, WHO officials are "troubled by the discovery" according to the New York Times.

Choice of Antivirals for Flu

In other flu-related news, the CDC reports that primary care physicians frequently used inappropriate flu drugs during last year's flu season. A survey published in MMWR found that of 730 respondents, 54% prescribed anti-viral agents and of those, one quarter prescribed amantadine or rimantadine. These drugs are no longer recommended because of a high rate of viral resistance (MMWR 1/25/08:57(03); 61-65). Finally, the FDA has approved a real-time test for influenza A and B and RSV. The test, called ProFlu+ Assay produces results within about three hours, and has a 98% sensitivity, and 83% specificity. The assay is marketed by Prodesse Inc.

FDA Actions:

The FDA has strengthened its warning on the contraceptive patch Ortho Evra regarding the risk of venous thromboembolism. The warning is based on a study conducted by the Boston Collaborative Drug Surveillance Program that showed that the patch was associated with a higher risk of venous thromboembolism than oral contraceptive pills.

The FDA has taken the strongest stance yet against the use of over-the-counter cough and cold products for children younger than two years of age. On January 17 the agency issued a Public Health Advisory for parents and caregivers recommending that the products should not be used to treat infants and children because of reports of serious adverse events including death, convulsions, rapid heart rates, and decreased levels of consciousness. The agency continues to review use of these medications on children aged two to 11.

The FDA has warned seven pharmacy operations that produce "bio-identical hormone replacement therapy" that claims of their products' effectiveness may be false and misleading because they are not supported by medical evidence. These products are frequently compounded by large pharmacy operations and contain estrogen, progesterone, and estriol. Claims range from reduced risk of stroke, cancer, and lower rates of Alzheimer's disease associated with products. Compounded drugs are not reviewed by the FDA for safety and effectiveness however misleading claims violate federal laws. The FDA considers the term "bio-identical" a marketing term which implies benefit for which there's no medical or scientific basis. Compounding pharmacy that do not address these violations are subject to further enforcement according to the FDA press release.

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) 262-5431. E-mail: iris.young@ahcmedia.com.