Cilostazol

Cilostazol
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi

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Black Box Warning

CONTRAINDICATION See full prescribing information for complete Boxed Warning. * 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. Cilostazol is contraindicated in patients with congestive heart failure of any severity.

Overview

Cilostazol is a phosphodiesterase 3 (PDE3) inhibitor and platelet aggregation inhibitor that is FDA approved for the {{{indicationType}}} of intermittent claudication, as indicated by an increased walking distance. There is a Black Box Warning for this drug as shown here. Common adverse reactions include palpitations, peripheral edema, tachyarrhythmia, abdominal pain, diarrhea, indigestion, decreased platelet aggregation, backache, myalgia, dizziness, headache, cough, pharyngitis, and rhinitis.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Intermittent Claudication

• Dosing Information

• 100 mg PO bid, taken at least half an hour before or two hours after breakfast and dinner.
• A dose of 50 mg PO bid should be considered during coadministration of such inhibitors of CYP3A4 as ketoconazole, itraconazole, erythromycin and diltiazem, and during coadministration of such inhibitors of CYP2C19 as omeprazole.
• Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.
• Discontinuation of Therapy

• The available data suggest that the dosage of Cilostazol can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

Secondary Prophylaxis of Noncardioembolic Ischemic Stroke or TIA

• Developed by: American College of Chest Physicians (ACCP)

• Dosing Information

• In patients with a history of noncardioembolic ischemic stroke or TIA, ACCP recommends long-term treatment with aspirin (75-100 mg once daily), clopidogrel (75 mg once daily), aspirin/extended-release dipyridamole (25 mg/200 mg bid), or Cilostazol (100 mg bid) over no antiplatelet therapy (Grade 1A), oral anticoagulants (Grade 1B), the combination of clopidogrel plus aspirin (Grade 1B), or triflusal (Grade 2B).

• Of the recommended antiplatelet regimens, ACCP suggests clopidogrel or aspirin/extended-release dipyridamole over aspirin (Grade 2B) or Cilostazol (Grade 2C).

Elective Percutaneous Coronary Intervention with Bare-Metal or Drug-Eluting Stent

• Developed by: American College of Chest Physicians (ACCP)

• Dosing Information

• Use of low-dose aspirin 75 to 100 mg daily and clopidogrel 75 mg daily alone is recommended, rather than Cilostazol in addition to these drugs (Grade 1B).
• Aspirin 75 to 100 mg daily and clopidogrel 75 mg daily as part of dual antiplatelet therapy is suggested, rather than the use of either drug with Cilostazol (Grade 1B).
• Cilostazol 100 mg twice daily as substitute for either low-dose aspirin 75 to 100 mg daily or clopidogrel 75 mg daily as part of a dual antiplatelet regimen is suggested in patients with an allergy or intolerance of either drug class (Grade 2C).

Non–Guideline-Supported Use

Primary Prophylaxis of Cerebrovascular Accident

• Dosing Information

• 100–200 mg PO qd

Prophylaxis of Femoral Artery Occlusion After Percutaneous Coronary Intervention

• Dosing Information

• Cilostazol 200 mg/day plus aspirin 100 mg/day significantly reduced the rate of restenosis of femoropopliteal lesions, and significantly improved event-free survival at 12 months after percutaneous transluminal angioplasty with provisional nitinol stenting when compared with use of aspirin alone.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

• The safety and effectiveness of Cilostazole in pediatric patients have not been established.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Cilostazol in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Cilostazol in pediatric patients.

Contraindications

• Congestive heart failure of any severity
• Hemostatic disorders or active pathologic bleeding, such as bleeding peptic ulcer and intracranial bleeding
• Hypersensitivity to any of its components

Warnings

CONTRAINDICATION See full prescribing information for complete Boxed Warning. * 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. Cilostazol is contraindicated in patients with congestive heart failure of any severity.

Precautions

• Hematologic Adverse Reactions

• 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.

• 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 clopidogrel, caution is advised for checking bleeding times during coadministration.

• Hepatic Impairment

• Patients with moderate or severe hepatic impairment have not been studied in clinical trials. Special caution is advised when Cilostazol is used in such patients.

• 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 is advised when Cilostazol is used in patients with severe renal impairment: estimated creatinine clearance < 25 mL/min.

• Use with other antiplatelet agents

• Cilostazol 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 Cilostazol. Caution is advised in patients receiving both Cilostazol and any other antiplatelet agent, or in patients with thrombocytopenia.

• Cardiovascular Toxicity

• Repeated oral administration of Cilostazol to dogs (30 or more mg/kg/day for 52 weeks, 150 or more mg/kg/day for 13 weeks, and 450 mg/kg/day for 2 weeks), produced cardiovascular lesions that included endocardial hemorrhage, hemosiderin deposition and fibrosis in the left ventricle, hemorrhage in the right atrial wall, hemorrhage and necrosis of the smooth muscle in the wall of the coronary artery, intimal thickening of the coronary artery], and coronary arteritis and periarteritis. At the lowest dose associated with cardiovascular lesions in the 52-week study, systemic exposure (AUC) to unbound Cilostazol was less than that seen in humans at the maximum recommended human dose (MRHD) of 100 mg b.i.d. Similar lesions have been reported in dogs following the administration of other positive inotropic agents (including PDE III inhibitors) and/or vasodilating agents. No cardiovascular lesions were seen in rats following 5 or 13 weeks of administration of Cilostazol at doses up to 1500 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound Cilostazol were only about 1.5 and 5 times (male and female rats, respectively) the exposure seen in humans at the MRHD. Cardiovascular lesions were also not seen in rats following 52 weeks of administration of Cilostazol at doses up to 150 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound Cilostazol were about 0.5 and 5 times (male and female rats, respectively) the exposure in humans at the MRHD. In female rats, Cilostazol AUCs were similar at 150 and 1500 mg/kg/day. Cardiovascular lesions were also not observed in monkeys after oral administration of Cilostazol for 13 weeks at doses up to 1800 mg/kg/day. While this dose of Cilostazol produced pharmacologic effects in monkeys, plasma Cilostazol levels were less than those seen in humans given the MRHD, and those seen in dogs given doses associated with cardiovascular lesions.

Adverse Reactions

Clinical Trials Experience

• Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. Cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on Cilostazol and 134 days for patients on placebo.
• The only adverse event resulting in discontinuation of therapy in ≥ 3% of patients treated with Cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with Cilostazol 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included palpitation and diarrhea, both 1.1% for Cilostazol (all doses) versus 0.1% for placebo.
• The most commonly reported adverse events, occurring in ≥ 2% of patients treated with Cilostazol 50 or 100 mg b.i.d., are shown in the table (below).

This image of the FDA label is provided by the National Library of Medicine.

• Other events seen with an incidence of ≥ 2%, but occurring in the placebo group at least as frequently as in the 100 mg b.i.d. group were: asthenia, hypertension, vomiting, leg cramps, hypesthesia, paresthesia, dyspnea, rash, hematuria, urinary tract infection, flu syndrome, angina pectoris, arthritis, and bronchitis.
• Less frequent adverse events (<2%) that were experienced by patients exposed to Cilostazol 50 mg b.i.d. or 100 mg b.i.d. in the eight controlled clinical trials and that occurred at a frequency in the 100 mg b.i.d. group greater than in the placebo group, regardless of suspected drug relationship, are listed below.

Body as a Whole

Chills, face edema, fever, generalized edema, malaise, neck rigidity, pelvic pain, retroperitoneal hemorrhage.

Cardiovascular

Atrial fibrillation, atrial flutter, cerebral infarct, cerebral ischemia, congestive heart failure, cardiac arrest, hemorrhage, hypotension, myocardial infarction, myocardial ischemia, nodal arrhythmia, postural hypotension, supraventricular tachycardia, syncope, varicose vein, vasodilation, ventricular extrasystoles, ventricular tachycardia.

Digestive

Anorexia, cholelithiasis, colitis, duodenal ulcer, duodenitis, esophageal hemorrhage, esophagitis, increased GGT, gastritis, gastroenteritis, gum hemorrhage, hematemesis, melena, peptic ulcer, periodontal abscess, rectal hemorrhage, peptic ulcer, tongue edema.

Endocrine

Diabetes mellitus.

Hematologic and Lymphatic

Anemia, ecchymosis, iron deficiency anemia, polycythemia, purpura.

Metabolic and Nutritional

Increased creatinine, gout, hyperlipemia, hyperuricemia.

Musculoskeletal

Arthralgia, bone pain, bursitis.

Nervous

Anxiety, insomnia, neuralgia.

Respiratory

Asthma, epistaxis, hemoptysis, pneumonia, sinusitis.

Skin and Appendages

Dry skin, furunculosis, skin hypertrophy, urticaria.

Special Senses

Amblyopia, blindness, conjunctivitis, diplopia, ear pain, eye hemorrhage, retinal hemorrhage, tinnitus.

Urogenital

Albuminuria, cystitis, urinary frequency, vaginal hemorrhage, vaginitis.

Postmarketing Experience

The following events have been reported spontaneously from worldwide postmarketing experience since the launch of cilostazol in the U.S.

Blood and Lymphatic System Disorders

Agranulocytosis, aplastic anemia, granulocytopenia, thrombocytopenia, leukopenia, bleeding tendency

Cardiac Disorders

Torsades de pointes, QTc prolongation (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. complete atrioventricular block, heart failure and bradyarrhythmia, when treated with cilostazol. Cilostazol was used "off label" due to its positive chronotropic action.)

Gastrointestinal Disorders

Gastrointestinal hemorrhage

General Disorders and Administration Site Conditions

Pain, chest pain, hot flushes

Hepatobiliary disorders

Hepatic dysfunction/Abnormal liver function tests, jaundice

Injury, Poisoning and Procedural Complications

Extradural hematoma and subdural hematoma

Investigations

Blood glucose increased, blood uric acid increased, platelet count decreased, white blood cell count decreased, increase in BUN (blood urea increased), blood pressure increase

Nervous System Disorders

Intracranial hemorrhage, cerebral hemorrhage, cerebrovascular accident

Respiratory, Thoracic and Mediastinal Disorders

Pulmonary hemorrhage, interstitial pneumonia

Skin and Subcutaneous Tissue Disorders

Subcutaneous hemorrhage, pruritus, skin eruptions including Stevens-Johnson syndrome, skin drug eruption (dermatitis medicamentosa)

Vascular Disorders

Subacute thrombosis (These cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting.)

Drug Interactions

• Drug

• Description

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• Pregnancy Category

Pregnancy Category (AUS):

• Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cilostazol in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Cilostazol during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Cilostazol with respect to nursing mothers.

Pediatric Use

There is no FDA guidance on the use of Cilostazol with respect to pediatric patients.

Geriatic Use

There is no FDA guidance on the use of Cilostazol with respect to geriatric patients.

Gender

There is no FDA guidance on the use of Cilostazol with respect to specific gender populations.

Race

There is no FDA guidance on the use of Cilostazol with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Cilostazol in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Cilostazol in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Cilostazol in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Cilostazol in patients who are immunocompromised.

Administration and Monitoring

Administration

• Oral

• Intravenous

Monitoring

There is limited information regarding Monitoring of Cilostazol in the drug label.

Condition1

• Description

IV Compatibility

There is limited information regarding IV Compatibility of Cilostazol in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

• Description

Management

• Description

Chronic Overdose

There is limited information regarding Chronic Overdose of Cilostazol in the drug label.

Pharmacology

Mechanism of Action

There is limited information regarding Cilostazol Mechanism of Action in the drug label.

Structure

This image is provided by the National Library of Medicine.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Cilostazol in the drug label.

Pharmacokinetics

There is limited information regarding Pharmacokinetics of Cilostazol in the drug label.

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Cilostazol in the drug label.

Clinical Studies

There is limited information regarding Clinical Studies of Cilostazol in the drug label.

Condition1

• Description

How Supplied

There is limited information regarding Cilostazol How Supplied in the drug label.

Storage

There is limited information regarding Cilostazol Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Patient Counseling Information of Cilostazol in the drug label.

Precautions with Alcohol

• Alcohol-Cilostazol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• Pletal®

Look-Alike Drug Names

• N/A

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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