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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(sil OH sta zol)
Generic Available (U.S.)
Yes
Index Terms
U.S. Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Symptomatic management of peripheral vascular disease, primarily intermittent claudication
Use: Unlabeled/Investigational
Adjunct with aspirin and clopidogrel for prevention of stent thrombosis and restenosis after coronary stent placement
Pregnancy Risk Factor
C
Pregnancy Considerations
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
Breast-Feeding Considerations
It is not known whether cilostazol is excreted in human milk. Because of the potential risk to nursing infants, a decision to discontinue the drug or discontinue nursing should be made.
Contraindications
Hypersensitivity to cilostazol or any component of the formulation; heart failure (HF) of any severity; hemostatic disorders or active bleeding
Warnings/Precautions
Boxed warnings:
• Cardiovascular disease: See “Disease-related concerns” below.
Concerns related to adverse effects:
• Leukopenia: Discontinue therapy if leukopenia occurs; progression to agranulocytosis (reversible) has been reported when cilostazol was not immediately stopped.
Disease-related concerns:
• Cardiovascular disease: [U.S. Boxed Warning]: The use of this drug is contraindicated in patients with heart failure of any severity. Phosphodiesterase inhibitors have decreased survival rates in patients with class III-IV heart failure. Use with caution in patients with underlying heart disease.
• Hepatic impairment: Use with caution in patients with moderate-to-severe hepatic impairment.
• Renal impairment: Use with caution in patients with severe renal impairment (Clcr <25 mL/minute).
• Thrombocytopenia: Discontinue therapy if thrombocytopenia occurs; progression to agranulocytosis (reversible) has been reported when cilostazol was not immediately stopped.
Concurrent drug therapy issues:
• Clopidogrel: When cilostazol and clopidogrel are used concurrently, manufacturer recommends checking bleeding times.
• High potential for interactions: Use with caution in patients taking strong CYP3A4 inhibitors, moderate or strong CYP3A4 inducers and major CYP3A4 substrates (see Drug Interactions); consider alternative agents that avoid or lessen the potential for CYP-mediated interactions.
• Platelet aggregation inhibitors: Use with caution in patients receiving other platelet aggregation inhibitors.
Other warnings/precautions:
• Elective surgery: Withhold for at least 4-6 half-lives prior to elective surgical procedures.
Adverse Reactions
>10%:
Central nervous system: Headache (27% to 34%)
Gastrointestinal: Abnormal stools (12% to 15%), diarrhea (12% to 19%)
Respiratory: Rhinitis (7% to 12%)
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%), vertigo (up to 3%)
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: Pharyngitis (7% to 10%), cough (3% to 4%)
<2%: Albuminuria, amblyopia, anemia, anorexia, anxiety, arthralgia, asthma, atrial fibrillation, atrial flutter, blindness, bone pain, bursitis, cardiac arrest, cerebral infarction/ischemia, chills, cholelithiasis, colitis, conjunctivitis, CHF, creatinine increased, cystitis, diabetes mellitus, diplopia, dry skin, duodenal ulcer, duodenitis, ear pain, ecchymosis, edema, epistaxis, esophageal hemorrhage, esophagitis, facial edema, fever, gastritis, GGT increased, gout, gum hemorrhage, hematemesis, hemorrhage, hemoptysis, hyperlipidemia, hyperuricemia, hypotension, insomnia, malaise, melena, myocardial infarction/ischemia, neuralgia, nodal arrhythmia, nuchal rigidity, pelvic pain, periodontal abscess, peptic ulcer, pneumonia, polycythemia, postural hypotension, purpura, rectal hemorrhage, retinal hemorrhage, retroperitoneal hemorrhage, sinusitis, supraventricular tachycardia, syncope, tinnitus, tongue edema, urinary frequency, varicose vein, ventricular extrasystole, ventricular tachycardia
Postmarketing and/or case reports: Agranulocytosis, aplastic anemia, blood pressure increased, blood urea increased, cerebrovascular accident, chest pain, coronary stent thrombosis, extradural hematoma, gastrointestinal hemorrhage, granulocytopenia, hepatic dysfunction, hot flashes, hyperglycemia, interstitial pneumonia, intracranial hemorrhage, jaundice, leukopenia, pain, pulmonary hemorrhage, pruritus, QTc prolongation, subcutaneous hemorrhage, Stevens-Johnson syndrome, subdural hematoma, thrombocytopenia, thrombosis, torsade de pointes, uric acid increased
Metabolism/Transport Effects
Substrate of CYP1A2 (minor), 2C19 (minor), 2D6 (minor), 3A4 (major)
Drug Interactions
Anticoagulants: Antiplatelet Agents may enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of Cilostazol. Risk D: Consider therapy modification
Antiplatelet Agents: May enhance the anticoagulant effect of other Antiplatelet Agents. Risk C: Monitor therapy
Collagenase (Systemic): Antiplatelet Agents may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Risk C: Monitor therapy
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Management: Upon completion/discontinuation of conivaptan, allow at least 7 days before initiating therapy with drugs that are CYP3A4 substrates. Risk D: Consider therapy modification
CYP2C19 Inhibitors (Moderate): May decrease the metabolism of CYP2C19 Substrates. Risk C: Monitor therapy
CYP2C19 Inhibitors (Strong): May decrease the metabolism of CYP2C19 Substrates. Risk D: Consider therapy modification
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Dasatinib: May enhance the anticoagulant effect of Antiplatelet Agents. Risk C: Monitor therapy
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Drotrecogin Alfa: Antiplatelet Agents may enhance the adverse/toxic effect of Drotrecogin Alfa. Bleeding may occur. Management: When possible, avoid use of drotrecogin within 7 days of use of any IIb/IIIa antagonists, higher dose aspirin (more than 650 mg/day), or use of other antiplatelet agents. Risk D: Consider therapy modification
Esomeprazole: May enhance the adverse/toxic effect of Cilostazol. Esomeprazole may increase the serum concentration of Cilostazol. Esomeprazole may increase the serum concentration of OPC-13015, an active metabolite of Cilostazol. Management: Monitor for increased cilostazol effects when coadministered with esomeprazole. The manufacturer recommends considering a 50% dose reduction of cilostazol (eg, 100 mg twice daily to 50 mg twice daily) with concomitant use of these agents. Risk D: Consider therapy modification
Glucosamine: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy
Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Antiplatelet Agents. Bleeding may occur. Risk D: Consider therapy modification
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Ibritumomab: Antiplatelet Agents may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Risk C: Monitor therapy
Macrolide Antibiotics: May decrease the metabolism of Cilostazol. Exceptions: Azithromycin; Azithromycin (Systemic); Spiramycin. Risk D: Consider therapy modification
Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Antiplatelet Agents. An increased risk of bleeding may occur. Nonsteroidal Anti-Inflammatory Agents may diminish the cardioprotective effect of Antiplatelet Agents. This interaction is likely specific to aspirin, and not to other antiplatelet agents. Risk C: Monitor therapy
Omega-3-Acid Ethyl Esters: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy
Omeprazole: May enhance the adverse/toxic effect of Cilostazol. Omeprazole may increase the serum concentration of Cilostazol. Omeprazole may increase the serum concentration of OPC-13015, an active metabolite of Cilostazol. Management: Monitor for increased effects of cilostazol when coadministered with omeprazole. Consider a 50% dose reduction of cilostazol (eg, 100 mg twice daily to 50 mg twice daily) with concomitant use of these agents. Risk D: Consider therapy modification
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Antiplatelet Agents. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Risk C: Monitor therapy
Pentoxifylline: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy
Salicylates: Antiplatelet Agents may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Risk C: Monitor therapy
Thrombolytic Agents: Antiplatelet Agents may enhance the anticoagulant effect of Thrombolytic Agents. Risk C: Monitor therapy
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Tositumomab and Iodine I 131 Tositumomab: Antiplatelet Agents may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse events may be increased. Risk C: Monitor therapy
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.
Herb/Nutraceutical: St John's wort may decrease the levels/effects of cilostazol. Avoid alfalfa, anise, bilberry, bladderwrack, bromelain, cat's claw, chamomile, coleus, cordyceps, dong quai, evening primrose oil, fenugreek, feverfew, garlic, ginger, ginkgo biloba, ginseng (American), ginseng (Panax), ginseng (Siberian), grape seed, green tea, guggul, horse chestnut seed, horseradish, licorice, prickly ash, red clover, reishi, SAMe (S-adenosylmethionine), sweet clover, turmeric, white willow (all have additional antiplatelet activity).
Storage
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
Mechanism of Action
Cilostazol and its metabolites are inhibitors of phosphodiesterase III. As a result, cyclic AMP is increased leading to reversible inhibition of platelet aggregation, vasodilation, and inhibition of vascular smooth muscle cell proliferation.
Pharmacodynamics/Kinetics
Onset of action: 2-4 weeks; may require up to 12 weeks
Protein binding: Cilostazol 95% to 98%; active metabolites 66% to 97%
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
Dosage adjustment for cilostazol with concomitant medications:
CYP2C19 inhibitors (see Drug Interactions): Dosage of cilostazol should be reduced to 50 mg twice daily
CYP3A4 inhibitors (see Drug Interactions): Dosage of cilostazol should be reduced to 50 mg twice daily
Administration: Oral
Administer cilostazol 30 minutes before or 2 hours after meals.
Dietary Considerations
It is best to take cilostazol 30 minutes before or 2 hours after meals.
Patient Education
Take on empty stomach (30 minutes before or 2 hours after meals). Inform prescribers and dentists that you are taking this medication prior to scheduling any surgery or dental procedure. You may experience nervousness, dizziness, fatigue, nausea, vomiting, flatulence, or postural hypotension. Report chest pain, palpitations, unusual heartbeat, swelling of extremities, unusual bleeding, unresolved GI upset or pain, dizziness, nervousness, sleeplessness, fatigue, muscle cramping or tremor, or unusual cough.
Geriatric Considerations
Elderly must be evaluated for cardiac status. Since CHF is common, this disease cannot be overlooked.
Anesthesia and Critical Care Concerns/Other Considerations
Evidence-Based Information: Considered effective treatment in patients with lower extremity peripheral arterial disease (PAD) and is recommended for patients with moderate-to-severe disabling intermittent claudication (in the absence of heart failure) unresponsive to exercise therapy, and who are not candidates for surgical or catheter-based intervention (Sobel, 2008). A therapeutic trial should be considered in all patients with lifestyle-limiting claudication.
Cardiovascular Considerations
Because of its chronotropic effects, arrhythmogenic effects, and similarity to other phosphodiesterase III inhibitors, cilostazol is contraindicated in patients with HF of any severity.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
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
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral: 50 mg, 100 mg
Pletal®: 50 mg, 100 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Cilostazol)
50 mg (60): $107.99
Tablets (Pletal)
50 mg (60): $132.99
100 mg (60): $114.98
References
Douglas JS Jr, Holmes DR Jr, Kereiakes DJ, et al, “Coronary Stent Restenosis in Patients Treated With Cilostazol,” Circulation, 2005, 112(18 ):2826-32.
Hirsch AT, Haskal ZJ, Hertzer NR, et al, “ACC/AHA Guidelines for the Management of Patients With Peripheral Arterial Disease (Lower Extremity, Renal, Mesenteric, and Abdominal Aortic): Executive Summary. A Collaborative Report of the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease),” Circulation , 2006, 113(11):e463-654. Available at http://www.acc.org/clinical/guidelines/pad/index.pdf
Lee SW, Park SW, Hong MK, et al, “Comparison of Cilostazol and Clopidogrel After Successful Coronary Stenting,” Am J Cardiol, 2005, 95(7):859-62.
Lee SW, Park SW, Kim YH, et al, “Comparison of Triple Versus Dual Antiplatelet Therapy After Drug-Eluting Stent Implantation (From the DECLARE-Long Trial),” Am J Cardiol, 2007, 100(7):1103-8.
Sobel M and Verhaeghe R, “Antithrombotic Therapy for Peripheral Artery Occlusive Disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition),” Chest, 2008, 133(6 Suppl):815-43.
International Brand Names
Lexi-Comp.com
Last full review/revision May 2011
Content last modified May 2011
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