Cilostazol

Pronunciation

(sil OH sta zol)

U.S. Brand Names

Pletal®

Synonyms

OPC-13013

Generic Available

Yes

Canadian Brand Names

Pletal®

Use

Symptomatic management of peripheral vascular disease, primarily intermittent claudication; currently being investigated for the treatment of acute coronary syndromes and for graft patency improvement in percutaneous coronary interventions with or without stenting

Use - Unlabeled/Investigational

Investigational: Treatment of acute coronary syndromes and for graft patency improvement in percutaneous coronary interventions with or without stenting

Pregnancy Risk Factor

Pregnancy Implications

In animal studies, abnormalities of the skeletal, renal and cardiovascular system were increased. In addition, the incidence of stillbirth and decreased birth weights were increased.

Lactation

Excretion in breast milk unknown/not recommended

Contraindications

Hypersensitivity to cilostazol or any component of the formulation; heart failure (of any severity)

Warnings/Precautions

Use with caution in patients receiving platelet aggregation inhibitors (effects are unknown), hepatic impairment (not studied). Use with caution in patients receiving inhibitors of CYP3A4 (such as ketoconazole or erythromycin) or inhibitors of CYP2C19 (such as omeprazole); use with caution in severe underlying heart disease; use is not recommended in nursing mothers

Adverse Reactions

>10%:

Central nervous system: Headache (27% to 34%)

Gastrointestinal: Abnormal stools (12% to 15%), diarrhea (12% to 19%)

Miscellaneous: Infection (10% to 14%)

2% to 10%:

Cardiovascular: Peripheral edema (7% to 9%), palpitation (5% to 10%), tachycardia (4%)

Central nervous system: Dizziness (9% to 10%)

Gastrointestinal: Dyspepsia (6%), nausea (6% to 7%), abdominal pain (4% to 5%), flatulence (2% to 3%)

Neuromuscular & skeletal: Back pain (6% to 7%), myalgia (2% to 3%)

Respiratory: Rhinitis (7% to 12%), pharyngitis (7% to 10%), cough (3% to 4%)

<2%: Chills, facial edema, fever, edema, malaise, nuchal rigidity, pelvic pain, retroperitoneal hemorrhage, cerebral infarction/ischemia, CHF, cardiac arrest, hemorrhage, hypotension, MI/ischemia, postural hypotension, ventricular arrhythmia, supraventricular arrhythmia, syncope, anorexia, cholelithiasis, colitis, duodenitis, peptic ulcer, duodenal ulcer, esophagitis, esophageal hemorrhage, gastritis, hematemesis, melena, tongue edema, diabetes mellitus, anemia, ecchymosis, polycythemia, purpura, increased creatinine, gout, hyperlipidemia, hyperuricemia, arthralgia, bone pain, bursitis, anxiety, insomnia, neuralgia, dry skin, urticaria, amblyopia, blindness, conjunctivitis, diplopia, retinal hemorrhage, cystitis, albuminuria, vaginitis, vaginal hemorrhage, urinary frequency

Overdosage/Toxicology

Experience with overdosage in humans is limited. Headache, diarrhea, hypotension, tachycardia, and/or cardiac arrhythmias may occur. Treatment is symptomatic and supportive. Hemodialysis is unlikely to be of value. In some animal models, high-dose or long-term administration was associated with a variety of cardiovascular lesions, including endocardial hemorrhage, hemosiderin deposition and left ventricular fibrosis, coronary arteritis, and periarteritis.

Drug Interactions

Substrate of CYP1A2 (minor), 2C19 (minor), 2D6 (minor), 3A4 (major)

Increased effect/toxicity: Increased concentrations of cilostazol have been observed during concurrent therapy with omeprazole, an inhibitor of CYP2C19 and during concurrent therapy with inhibitors of CYP3A4 such as clarithromycin, erythromycin, itraconazole, fluconazole, miconazole, fluvoxamine, fluoxetine, nefazodone, sertraline, and diltiazem. Platelet aggregation with aspirin is further inhibited when coadministered with cilostazol, it remains unclear whether concurrent oral anticoagulants or other antiplatelet drugs can increase cilostazol toxicity.

Ethanol/Nutrition/Herb Interactions

Food: Taking cilostazol with a high-fat meal may increase peak concentration by 90%. Avoid concurrent ingestion of grapefruit juice due to the potential to inhibit CYP3A4.

Mechanism of Action

Cilostazol and its metabolites are inhibitors of phosphodiesterase III. As a result cyclic AMP is increased leading to inhibition of platelet aggregation and vasodilation. Other effects of phosphodiesterase III inhibition include increased cardiac contractility, accelerated AV nodal conduction, increased ventricular automaticity, heart rate, and coronary blood flow.

Pharmacodynamics/Kinetics

Onset of action: 2-4 weeks; may require up to 12 weeks

Protein binding: 97% to 98%

Metabolism: Hepatic via CYP3A4 (primarily), 1A2, 2C19, and 2D6; at least one metabolite has significant activity

Half-life elimination: 11-13 hours

Excretion: Urine (74%) and feces (20%) as metabolites

Dosage

Adults: Oral: 100 mg twice daily taken at least one-half hour before or 2 hours after breakfast and dinner; dosage should be reduced to 50 mg twice daily during concurrent therapy with inhibitors of CYP3A4 or CYP2C19 (see Drug Interactions)

Dietary Considerations

It is best to take cilostazol 30 minutes before or 2 hours after meals.

Patient Education

Use exactly as directed; do not discontinue without consulting prescriber. Beneficial effect may take between 2-12 weeks. Take on empty stomach (30 minutes before or 2 hours after meals). Do not take with grapefruit juice. You may experience nervousness, dizziness, or fatigue (use caution when driving or engaging in tasks requiring alertness until response to treatment is known); nausea, vomiting, or flatulence (small, frequent meals, frequent mouth care, chewing gum or sucking hard candy may help); or postural hypotension (change position slowly when rising from sitting or lying position or climbing stairs). Report chest pain, palpitations, unusual heartbeat, or swelling of extremities; unusual bleeding; unresolved GI upset or pain; dizziness, nervousness, sleeplessness, or fatigue; muscle cramping or tremor; unusual cough; or other adverse effects. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.

Anesthesia and Critical Care Concerns/Other Considerations

In some animal models, high-dose or long-term administration was associated with a variety of cardiovascular lesions, including endocardial hemorrhage, hemosiderin deposition and left ventricular fibrosis, coronary arteritis, and periarteritis.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Postural hypotension and tongue edema (per manufacturer). If a patient is to undergo elective surgery and an antiplatelet effect is not desired, a medical consult is suggested to consider reduction or discontinuation of cilostazol dose prior to surgery.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

Headache and dizziness are common; may rarely cause anxiety or insomnia

Mental Health: Effects on Psychiatric Treatment

CYP3A4 inhibitors (fluvoxamine, fluoxetine, nefazodone, sertraline) may increase the concentrations of cilostazol

Dosage Forms

Tablet: 50 mg, 100 mg

International Brand Names

Aggravan® (ID); Cebralat® (BR); Pletaal® (AR, ID, JP, TH); Pletal® (CA, GB)

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