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| |  FDA Approves Pletal For Intermittent Claudication ROCKVILLE, MD -- Jan. 18, 1999 -- The United States Food and Drug Administration has approved Otsuka America Pharmaceutical, Inc.’s Pletal(R) (cilostazol) for the reduction of symptoms for patients with intermittent claudication. Intermittent claudication is a symptom of peripheral arterial disease and often causes debilitating pain in the legs, which can greatly reduce a person's ability to walk. Symptoms include pain, aches, cramps, or severe fatigue involving one or both lower extremities, which is provoked by walking and can greatly reduce mobility. Pletal is the first new compound in over 15 years indicated for the reduction of the symptoms of intermittent claudication as measured by increased walking distance. Pletal targets multiple processes related to peripheral circulation, including inhibition of platelet aggregation, increasing vasodilation and, in vitro inhibiting smooth-muscle cell proliferation. It also has an effect on plasma lipids (raising HDL-cholesterol and lowering triglycerides). "Patients with intermittent claudication find that all activities that involve walking or ambulation are severely impaired," said William Hiatt, M.D., University of Colorado Health Sciences Center, one of the investigators involved in the clinical trials. "Medical therapies that improve walking tolerance of even two to three blocks, allow patients to return to activities that they couldn't pursue before." Pletal improved the maximum distance walked (ACD-absolute claudication distance) on a treadmill, in all seven trials conducted in the United States. Additionally, time to initial pain, also known as pain-free walking distance or ICD (initial claudication distance), improved as well. While the exercise treadmill test result was the primary endpoint to assess improvement, other efficacy endpoints supported the benefit of Pletal, including the walking impairment questionnaire. In seven phase III clinical trials conducted in the United States, patients treated with Pletal experienced statistically and clinically greater improvement in maximum walking distance and other measures compared to those treated with placebo. In one of the largest clinical trials conducted, treatment with Pletal for 24 weeks increased walking distance 106 meters or 345 feet more than treatment with placebo. This improvement was seen while patients were tested on a treadmill set at an incline (12.5 percent) at two mph. Superiority over placebo was seen as early as the first observation point of two or four weeks after starting therapy. In the key clinical trials, the magnitude of improvement in the groups treated with Pletal was greater at each successive time point. The most common side effects associated with Pletal in these studies were headache, diarrhea, abnormal stools, dizziness, palpitation and tachycardia. In most cases, the side effects were mild to moderate in severity and, overall, side effects uncommonly led to discontinuation. Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV congestive heart failure. Pletal is contraindicated in patients with congestive heart failure of any severity. Pletal is contraindicated in patients with known or suspected hypersensitivity to any of its components. Current pharmacological approaches for intermittent claudication are limited and variable outcomes have been reported. Medical therapy has routinely included unsupervised exercise programs and cessation of smoking, but patient participation and compliance have been disappointing. Surgery and angioplasty are appropriate and effective for some patients; however, these procedures are not indicated for the many patients who have multisegmental involvement or whose disease state does not warrant the risks of invasive procedures.
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