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Pletal for the Treatment of Intermittent Claudication

Brand Name: Pletal
Active Ingredient: cilostazol
Approved uses: the reduction of symptoms of intermittent claudication, as indicated by an increase in walking distance
Dosage Form(s): Tablets (50 mg and 100 mg)
Company Name: Otsuka America Pharmaceutical, Inc.
Availability: Prescription only

Pletal for the Treatment of Intermittent ClaudicationIntroduction

Treatment options for intermittent claudication – a severe pain, aching or cramping in the legs that occurs with walking – include exercise regimens, surgery, and pharmacological therapy. Until recently the only medication available for the treatment of intermittent claudication has been Trental® (pentoxifylline). Pletal (cilostazol) provides a new option for improving the symptoms of this condition. This drug is the first to be approved for this indication in more than 15 years.

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.

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).

How It Works

The mechanism of the effects of Pletal (cilostazol) on the symptoms of intermittent claudication is not fully understood. Pletal and several of its metabolites are cyclic AMP (cAMP) phosphodiesterase III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in cAMP in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation.

Pletal (cilostazol): Clinical Study Results

The clinical efficacy of Pletal (50 mg or 100 mg twice daily) was evaluated in eight large, randomized, placebo-controlled, double-blind studies of 12 to 24 weeks’ duration. The ability of Pletal (cilostazol) to improve walking distance in patients with stable intermittent claudication was the main outcome measure. When compared to placebo, patients receiving Pletal experienced statistically significant improvements in walking distance. In some patients the beneficial effect was seen in two to four weeks.

In these trails, the range of improvement in maximal walking distance in patients receiving Pletal 100 mg twice a day ranged from 28% to 100%. The range is expressed as the mean change from baseline walking distance. Conversely, the placebo group experienced a change of -10% to 30%. In six of the trials, patients were asked to complete a questionnaire to assess the impact of the drug on walking distances. A pooled analysis of the results of the questionnaire showed that patients taking Pletal (cilostazol) reported improvements in both walking distance and speed when compared to placebo. These improvements were seen in subgroups defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age, and concomitant use of beta blockers or calcium channel blockers.

Pletal (cilostazol) is metabolized extensively by cytochrome P-450 isoenzymes, primarily CYP3A4 with CYP2C19 involved to a lesser extent. Coadministration of Pletal with drugs that alter the activity of these P-450 enzymes should be done cautiously. It is recommended that drinking grapefruit juice, which inhibits CYP3A4, be avoided.

At this time, there is no information with respect to the efficacy and safety of the concurrent use of Pletal and clopidogrel (Plavix®). Clopidogrel is a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Studies of concomitant use of Pletal and clopidogrel are planned.

Pletal for the Treatment of Intermittent ClaudicationWhat The Patient Should Know

Pletal (cilostazol) should not be used in patients who have, or develop, congestive heart failure. Pletal and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs that exert this pharmacologic effect have caused decreased survival in patients with congestive heart failure.

The long-term effects of phosphodiesterase III inhibitors in patients without congestive heart failure are unknown. Among patients who were participating in the 3-6 month placebo-controlled studies, the death rate was similar in both groups and less than 1%. These patients were relatively stable and had not had a recent heart attack or stoke and had no rest pain or other signs of rapidly progressing disease. However, there is no data on long-term risk or risk in patients with more severe underlying heart disease.

Pletal (cilostazol) should be taken at least one half-hour before or two hours after breakfast or dinner.

Certain foods and medications can affect plasma levels of Pletal in the body. The latter include erythromycin (Erythrocin ®), ketoconazole (Nizoral ®), itraconazole (Sporanox ®), diltiazem (Cardizem ®), and omeprazole (Prilosec ®). This list is not complete and the patient should discuss any current or new medications with their doctor or pharmacist.

Pletal (cilostazol) should not be taken with grapefruit juice.

Side effects of Pletal that have been reported include headache, diarrhea, abnormal stools, increased heart rate, and palpitations.

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