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Pletaal is contraindicated in patients with congestive heart failure. In patients without congestive heart failure, the long-term effects of PDE III inhibitors (including Pletaal) are unknown. Patients in the 3-6 month placebo-controlled trials of Pletaal were relatively stable (no recent myocardial infarction or strokes, no rest pain or other signs of 0.8% in the group on Pletaal). The calculated relative risk of death of 1.2 has a wide 95% confidence limit (0.5-3.1). There are no data as to longer-term risk or risk in patients with more severe underlying heart disease.
Use in patients at risk of bleeding or with other antiplatelet agents: Pletaal inhibits platelet aggregation but in a reversible manner. Caution is advised in patients at risk of bleeding from surgery or pathologic processes. Platelet aggregability returns to normal within 96 hours of stopping Pletaal.
Caution is advised in patients with thrombocytopenia.
Cautions should also be exercised for patients treated concomitantly with two or more additional antiplatelet or anticoagulant agents (e.g acetylsalicylic acid, clopidogrel, heparin, warfarin, acenocoumarol, dabigatran, rivaroxaban or apixaban) for increased potential risk of bleeding.
Hematologic adverse reactions: Caution is advised in patients with thrombocytopenia. Rare cases have been reported of thrombocytopenia or leukopenia progressing to agranulocytosis when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol. Patients under long-term use of Pletaal should be monitored periodically for any signs or symptoms of decreased white blood cell count and / or platelet count.
Use with Clopidogrel: There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and clopidogrel, a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and clopidgrel, caution should be advised for checking bleeding times during coadministration.
Information for Patients: Patients should be advised: to read the patient package insert for Pletaal carefully before starting therapy and to reread it each time therapy is renewed in case the information has changed.
to take Pletaal at least one-half hour before or two hours after food.
that the beneficial effects of Pletaal on the symptoms of intermittent claudication may not be immediate. Although the patient may experience benefit in 2 to 4 weeks after initiation of therapy, treatment for up to 12 weeks may be required before a beneficial effect is experienced.
about the uncertainty concerning cardiovascular risk in long-term use or in patients with severe underlying heart disease, as described under PRECAUTIONS.
Cardiovascular: Events of left ventricular outflow tract obstruction have been reported in patients with sigmoid shaped interventricular septum. Pletal/Pletaal should be used with caution in patients at risk, especially in elderly patients. Additional tests or an echocardiogram can be performed if the patient develops a de novo cardiac murmur after starting cilostazol.
Based on its mechanism of action, cilostazol may induce tachycardia, palpitation, tachyarrhythmia and/or hypotension. The increase in heart rate associated with cilostazol is approximately 5 to 7 bpm; in patients at risk this consequently may induce angina pectori.
Special caution should be used for patients with a history of tachyarrhythmia who are being treated for intermittent claudication. Cilostazol should be initiated by physicians experienced in the management of intermittent claudication.
The physician should reassess the patient after 3 months of treatment with a view to discontinuing cilostazol where an inadequate effect is observed or symptoms have not been improved.
Also precautions must be used for patients with unstable angina pectoris, myocardial infarction within the last 6 months, or a coronary intervention in the last 6 months who are being treated for intermittent claudication. Patients receiving treatment with cilostazol should continue with their life-style modifications (smoking cessation and exercise), and pharmacological interventions (such as lipid lowering and antiplatelet treatment) to reduce the risk of cardiovascular events.
A significant increase in PRP (pressure rate product) was observed during long-term administration of Pletaal in a study conducted in Japan to evaluate the drug's efficacy in the prevention of recurrence of cerebral infarction. Increased pulse rate possibly resulting from the treatment with cilostazol could induce angina pectoris in patients with coronary artery stenosis.
Effects on Ability to Drive Vehicles and Operate Machinery: There are no controlled studies of the effects Pletaal on driving performance. Some patients have reported dizziness or vertigo while on Pletaal, and such patients should be cautioned against driving or operating machinery.
Severe Hepatic Impairment: Patients with moderate or severe hepatic impairment have not been studied in clinical trials.
Special caution should be advised when Pletaal is used in patients with severe hepatic impairment.
Severe Renal Impairment: Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95-98%).
Special caution should be advised when Pletaal is used in patients with severe renal impairment: creatinine clearance ≤ 25 ml/min.
Use in Pregnancy: Pregnancy Category C: In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights, and increased incidences of cardiovascular, renal, and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib, and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD, and exposure to 3,4-dehydro-cilostazol was barely detectable.
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).
There are no adequate and well-controlled studies in pregnant women.
Use in Lactation: Transfer of cilostazol into milk has been reported in experimental animals (rats).
Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue Pletaal.
Use in Children: The safety and effectiveness of Pletaal in pediatric patients have not been established.
Use in Elderly: Of the total number of subjects (n = 2274) in clinical studies of Pletaal, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism, and elimination of cilostazol and its metabolites.
