Statins and the Incidence of Rhabdomyolysis
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The most commonly prescribed statins have a low incidence of rhabdomyolysis, according to the results a new study of more than 250,000 patients. Atorvastatin, pravastatin, and simvastatin were found have very low and virtually indistinguishable rates of rhabdomyolysis of 0.44 per 10,000 person-years (95% CI, 0.20-0.84). The data were obtained from 11 managed care health plans across United States from January 1, 1998, through June 30, 2001. Cerivastatin (Baycol-Bayer), which was withdrawn from the market in 2001, was found have a much of a higher rate of rhabdomyolysis, 5.34 cases per 10,000 person-years (95% CI, 1.46-13.68). The concomitant use of a fibrate with atorvastatin, pravastatin, or simvastatin was found to have increased the rate to 5.98 (95% CI, 0.72-216.0), while use of a fibrate with cerivastatin dramatically increased the rate to 1035 cases per 10,000 person-years of treatment (95% CI, 389-2117), or nearly 1 in 10. Older patients, especially those with diabetes, were found to have higher rates of rhabdomyolysis. The authors conclude that the most commonly prescribed statins have a low incidence of rhabdomyolysis, which is increased with the addition of a fibrate (JAMA. 2004;292:2585-2590).
The study confirms the safety of the most commonly used statins, but raises issues regarding the post marketing surveillance of cerivastatin. These concerns were addressed in a review in the same issue of JAMA regarding the potential conflict of interest once initial reports of rhabdomyolysis were reported to the company, and the delay in the availability of this information to consumers. The critique is accompanied by Bayer’s rebuttal (JAMA. 2004;292:2622-2631, 2643-2646, 2655-2657, 2658-2659), which makes fascinating reading given the recent criticisms of the FDA and post marketing surveillance regarding coxibs.
A Crackdown on Importation of Drugs
Officials in both the United States and Canada are taking steps to crack down on the importation of prescription medications across the border. A New York District Court issued an injunction in December against Canada Care Drugs Inc., which gave the FDA authority to inspect the company to assure that they no longer import drugs to American consumers. The FDA had petitioned the court to take this action based on a sting operation run by the agency. FDA investigators purchased Neurontin and Sporanox through Canada Care. Instead of Neurontin, investigators received APO-gabapentin and NOVO-gabapentin, formulations of the drug that are not subject to FDA scrutiny in this country. The Sporanox shipment included 84 tablets of the correct drug, but investigators felt that the amount was excessive, determining that patients should not take Sporanox continuously without checking with their physician. The court is scheduling a trial date for Canada Care, an action that is sure to put other Canadian importation companies on alert. Meanwhile, the Canadian government is also cracking down on Internet pharmacies that export drugs to the United States without evaluation by Canadian doctors. The government is considering making it illegal for Canadian doctors to countersign prescriptions from other countries. This move in Canada is prompted by concern over shortages of drugs for Canadian citizens, especially given threats by American drug companies to withhold additional shipments of drugs to Cananda, where they have strict price controls, knowing that many of these drugs may come back to the US market were there are no price controls. These moves are strongly supported by PhRMA, the powerful pharmaceutical advocacy group.
FDA Actions
The FDA has approved a new non-benzodiazepine hypnotic for the treatment of insomnia. Sepracor, a company that specializes in marketing active isomers of currently approved drugs, has received approval to market eszopiclone, the active (S)-isomer of zoplicone, which is available outside the United States. The drug is similar to zopidem (Ambien) and zaleplon (Sonata) in that it has a lower incidence of tolerance, dependence, and withdrawal symptoms than benzodiazepines. Based on a 6-month, double-blind, placebo-controlled safety and efficacy trial, the FDA decided not to limit eszoplicone’s indication to short-term use. Eszoplicone will be available in 1mg, 2mg, and 3mg tablets, and will be marketed in United States under the trade name Lunesta. Sepracor is also studying the drug for treatment of insomnia in patients with depression or pain, and in peri-menopausal women.
Novartis has received approval to market darifenacin extended release tablets for the treatment of overactive bladder with symptoms of urging incontinence, urgency, and frequency. The drug is an M3 (muscarinic) receptor blocker that increases urinary capacity and decreases urinary episodes and frequency of incontinence, along with feelings of urgency. Darifenacin, which is already available in Europe, will be marketed in the United States as Enablex.
Drugs approved under the FDAs accelerated approval program are often approved on the basis of surrogate end points, such as tumor markers that would indicate the likelihood of clinical benefit. The FDA, however, requires that cancer drugs in particular, must document clinical benefit in subsequent studies to remain marketable. A recent case-in-point is AstraZeneca’s gefitnib (Iressa), which was approved for treatment of non small cell lung cancer in patients who failed other courses of cancer therapy. A recent study of gefitnib involving nearly 1700 patients failed to show a survival benefit better than placebo. The drug, which was initially approved in 2003, now faces a FDA review to determine whether the drug will be removed from the market. In a letter to physicians, AstraZeneca "urges you to consider other treatment options in recurrent non small cell lung cancer patient population." In the meantime, Genentech and Roche’s erlotinib (Tarceva), which has shown survival benefit for the same patient population, remains a viable option.
The FDA has issued a Public Health Advisory regarding the use of anti-inflammatories including COX-2 inhibitors because of recent indications that the drugs may increase the risk of cardiovascular disease and stroke. The agency is requiring evaluation of all prevention studies that involve the COX-2 inhibitors celecoxib (Celebrex) and valdecoxib (Bextra) to ensure that adequate precautions are in place. Several prevention studies regarding potential benefit of these drugs on colon polyps and Alzheimer’s disease are either in progress or planned in the near future. Meanwhile, the agency is recommending that physicians should prescribed Celebrex or Bextra with caution, particularly in patients at risk for cardiovascular disease, and should weigh the risk vs benefits.
The FDA is also recommending that consumers should use over-the-counter anti-inflammatories in strict accordance with the label directions, taking them for no longer than 10 days without consulting a physician.
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) 262-5416. E-mail: [email protected].
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