Pharmacology Watch

FDA issues Multiple Drug Warnings

In this issue: FDA issues multiple drug safety alerts; ARBs and cancer risk; and FDA actions.

Avoid high-dose simvastatin

The FDA is advising physicians to avoid high-dose simvastatin (Zocor) because of the risk of myopathy and rhabdomyolysis. The agency is advising that patients should not be started on the 80 mg dose and patients who already are on 80 mg should be continued only if they have been on that dose for 1 year or longer. The recommendations are based on results of the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocystine (SEARCH) trial — a 7-year randomized, controlled trial comparing the efficacy and safety of simvastatin 80 mg vs simvastatin 20 mg with or without vitamin B12 and folate in survivors of myocardial infarction. There was no significant difference in the incidence of major vascular events between the two doses; however, 52 patients (0.9%) in the 80-mg group developed myopathy vs one patient (0.02%) in the 20-mg group. Of the high-dose group, 22 patients (0.4%) developed rhabdomyolysis vs no patients in the 20-mg group. The risk for myopathy and rhabdomyolysis with simvastatin 80 mg was highest in the first 12 months of treatment. Of concern, the risk of myopathy was approximately doubled in patients taking a calcium channel blocker, particularly diltiazem. The majority of patients who developed myopathy also had a genetic variant that affects coding of the transporter responsible for simvastatin uptake in the liver, resulting in higher serum simvastatin levels. The FDA not only recommends against using simvastatin 80 mg, but also suggests that the drug is contraindicated for use in patients taking itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, and danazol. The maximum dose of simvastatin should be only 10 mg in patients taking amiodarone, verapamil, and diltiazem while the maximum dose is 20 mg in patients taking amlodipine and ranolazine. The new guidance recommends using a different statin if the patient's LDL targets aren't met with the 40-mg simvastatin dose. The loss of high-dose simvastatin comes as a blow to cost-concious consumers who now likely will be prescribed brand name atorvastatin (Lipitor) or rosuvastatin (Crestor). Generic atorvastatin is likely to be available in late 2011.

Increased risk of prostate cancer

The FDA has issued a somewhat controversial warning regarding an increased risk for high-grade prostate cancer associated with the 5-alfa reductase inhibitors finasteride (Proscar, Propecia) and dutasteride (Avodart, Jalyn). Ironically, the new warning stems from studies designed to evaluate whether the drugs offer protection against prostate cancer. Both drugs are marketed to treat benign prostate hypertrophy and both are known to significantly decrease the prostate-specific antigen levels. In separate studies, both drugs were investigated to see if they reduce the incidence of prostate cancer. FDA experts reviewed the results of the Prostate Cancer Prevention Trial (PCPT), which evaluated finasteride vs placebo for 7 years, and the Reduction by Dutasteride of Prostate Cancer Events trial (REDUCE), which compared dutasteride to placebo for 4 years. Prostate cancers were significantly reduced in both trials; however, the reduction was limited to low-grade prostate cancers with a Gleason score of 6 or lower. The rate of cancers with a Gleason score of 8-10 was increased in both studies. Previous analyses of these data have suggested that finasteride did not increase the risk of high-grade prostate cancers, but rather made them easier to diagnose by decreasing the volume of the prostate (Clin Cancer Res 2009;15:4694-4699; J Natl Cancer Inst 2007;99:1366-1374). The FDA panel, however, disagrees and feels it prudent to add a warning to labeling of both medications regarding increased risk of high-grade prostate cancer associated with use of the drugs. The guidance further recommends that prior to initiating therapy patients should be evaluated to rule out other urologic conditions, including prostate cancer, that might mimic benign prostatic hypertrophy.

Actos and bladder cancer risk

The diabetes drug pioglitazone (Actos) is the subject of a new warning from the FDA regarding possible bladder cancer risk associated with use of the drug. The FDA ongoing safety review suggests that use of pioglitazone for more than 1 year may be associated with increased risk of bladder cancer based on review of a 5-year interim analysis of an ongoing 10-year epidemiologic study. Patients who had been on pioglitazone the longest and who had the highest cumulative dose of the drug had a slightly increased risk of bladder cancer. This warning falls on the heels of a French study that also showed increased risk of bladder cancer. Based on these findings, France's drug regulatory agency has suspended use of the drug. While the FDA is not recommending withdrawing the drug from the market, it does recommend avoiding pioglitazone in patients with active bladder cancer and using it with caution in patients with prior history of bladder cancer. Thiazolidinediones — including pioglitazone — have also come under scrutiny in recent years because of increased risk of congestive heart failure and bone fractures in females.

Chantix and cardiovascular events

The FDA has issued an alert regarding varenicline (Chantix) regarding a small increased risk of certain cardiovascular adverse events in patients who have cardiovascular disease. The warning regarding the smoking cessation drug was the result of review of a randomized, double-blind, placebo-controlled trial of 700 smokers with cardiovascular disease who were treated with varenicline or placebo. The overall rate of adverse effects was low but cardiovascular events, including heart attack, were reported more frequently in the treatment group. The warning will result in a change in labeling for the drug and the FDA is also requiring Pfizer, the drug manufacturer, to conduct an analysis of other trials to further assess the risk. Varenicline already carries a box warning regarding neuropsychiatric symptoms including suicidality.

ARBs and cancer risk

Finally some good news from the FDA. After a 2010 meta-analysis showed a possible link between angiotensin receptor blockers (ARBs) and cancer, the agency has completed its own review and has found no evidence of increased risk of "cancer events" including new cancers, cancer-related deaths, breast cancer, lung cancer, or prostate cancer associated with the drugs. The agency conducted a much larger meta-analysis than the original study, including more than 150,000 patients in 31 long-term, randomized, controlled clinical trials. The rate of cancer events in the ARB group was 1.82 per 100 patient years while the rate in the non-ARB group was 1.84 per 100 patient years (relative risk of incident cancer in patients taking ARBs 0.99, 95% confidence interval, 0.92 to 1.06) There was no statistically significant difference in cancer death rates or incidence of individual cancer types. The agency continues to monitor this issue but currently states that the benefits of ARBs continue to outweigh the potential risks (summary available at

FDA actions

The FDA has approved the first generic version of levofloxacin (Levaquin). The popular fluoroquinolone is commonly used for treatment of respiratory infections, sinusitis, prostatitis, pyelonephritis and skin infections. Generic forms will include tablets, oral solutions, and injectable solutions.

The FDA has approved an abuse-resistant short-acting oxycodone tablet. Pfizer Pharmaceuticals has licensed the "AVERSION Technology" from Acura Pharmaceuticals. The technology prevents dissolving and injecting tablets by creating a gel when mixed with water or other solvents that prevents snorting crushed tablets by burning nasal passages, and also prevents intentional swallowing of excess quantities by adding niacin which causes intense flushing, itching, and sweating. Long-acting oxycodone (OxyContin) was similarly reformulated in 2010 to prevent misuse and abuse.

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) 262-5404. E-mail: