FDA
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Food and Drug Administration
U.S. Department of Health and Human Services
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T99-04                          Print Media:         301-827-6242
January 15, 1999                
                                Consumer Inquiries:  888-INFO-FDA

FDA APPROVES NEW TREATMENT FOR PAINFUL LEG DISORDER

FDA has approved Pletal (cilostazol) a new drug for treating stable intermittent claudication, a severe pain, aching or cramping in the legs that occurs with walking. Intermittent claudication results from "peripheral arteriosclerotic vascular disease" -- a condition more commonly known as atherosclerosis or hardening of the arteries. Atherosclerosis occurs when deposits of fatty substances build up, in this case in the legs, leading to an inadequate blood supply to the leg muscles.

This drug is the first to be approved for this indication in more than 15 years. Pletal has not been evaluated either for safety or effectiveness among patients with more severe peripheral vascular disease who have claudication pain at rest, leg ulcer or gangrene.

Intermittent claudication affects several million, predominantly elderly, Americans. It can greatly impair their ability to walk without considerable discomfort and can seriously affect their ability to exercise or even engage in ordinary activities of daily life. Standard effective treatments have included intensive exercise regimens, and drug treatments, i.e., pentoxifylline (Trental), and under certain circumstances, re-vascularization procedures (operations to open the leg arteries or provide a replacement artery).

Pletal was studied in eight clinical trials (most of three to six months duration) that enrolled patients with intermittent claudication whose ability to walk even short distances was severely compromised. In six of the eight studies, patients treated with Pletal (at either 50 or 100 mg taken twice daily) compared to those treated with a placebo, were able to walk further before claudication began and also before the pain became intolerable and forced them to stop walking.

Additionally, patients treated with Pletal reported a greater increase in both walking distance and walking speed during daily routines.

Clinical studies in several thousand patients did not identify serious toxicity, but there are two important concerns with the use of Pletal that are identified in physician labeling for the drug and in a patient-directed brochure.

The first concern is that Pletal is pharmacologically related to a group of drugs studied for heart failure, the phosphodiestrase III inhibitors, several which have shown increased deaths rates in patients with severe heart failure. It is not known what effect these drugs have on people with less severe heart failure or no heart failure.

Pletal was studied in about 2100 patients with claudication, many of whom had other conditions such as a history of heart attacks or diabetes, but the patients did not have severe heart failure. In the patients studied there was a low mortality rate, 0.8% in patients treated with Pletal, 0.7% in placebo patients. There was insufficient evidence to determine whether Pletal has an adverse survival effect in patients without heart failure. The manufacturer plans to further study the mortality effect in sicker patients with claudication. Ordinarily Pletal would not be used by severe heart failure patients because their ability to exercise is limited by heart failure, not claudication. Labeling will remind both physicians and patients that Pletal should never be used (is contraindicated) in patients with heart failure. The labeling will also point out that there is insufficient information to determine whether Pletal has an adverse survival effect in patients without heart failure.

The second concern is that Pletal has not been studied in combination with Clopidogril, a drug recently approved for use in patients with peripheral vascular disease to reduce the rate of serious events (heart attacks, stroke, and death). Clopidogril was not available while Pletal was being developed, but is potentially important for patients with peripheral vascular disease. Concern arises because both Pletal and clopidogril inhibit platelet function, and it is possible that combined use could lead to excessive bleeding. Pletal was, however, used with aspirin, which also inhibits platelet function, without an apparent adverse interaction (increase in bleeding). Studies of Pletal and clopidogril will be conducted after marketing of Pletal. Meanwhile, labeling will remind physicians of the lack of information on this concomitant use.

The drug will be marketed by Otsuka American Pharmaceutical, Inc. of Rockville, Md.

For more information on this topic, see Cilostazol Drug Information on this Website.

(posted 1-15-99 by LJC/IISSG)