Generic Name: Cilostazol
Class: Platelet-Aggregation Inhibitors
Chemical Name: 6-[4-(1-Cyclohexyl-1H-tetrazol-5-yl)-butoxy]-3,4-dihydro-2(1H)-quinolinone
Molecular Formula: C20H27N5O2
CAS Number: 73963-72-1

Warning(s)

  • Contraindicated in patients with CHF of any severity.1 2 Decreased survival observed in patients with NYHA class III or IV CHF who received other drugs that inhibit phosphodiesterase (PDE) type 3.1 2

Introduction

Platelet-aggregation inhibitor and arterial vasodilator.1 7 8

Uses for Pletal

Intermittent Claudication

Symptomatic management of intermittent claudication (improvement in walking distance and speed).1 2 3 4 9 10

The American College of Chest Physicians (ACCP) suggests addition of cilostazol to aspirin or clopidogrel therapy in patients with refractory intermittent claudication who do not respond to conservative measures (e.g., smoking cessation, exercise).1011

Improves walking distance and speed in patients with stable intermittent claudication.1 2 3 9

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Efficacy not established in patients with rapidly progressing claudication, leg pain at rest, ischemic leg ulcers, or gangrene.1

Long-term effects on limb preservation and hospitalization not fully elucidated.1

Thrombotic Complications of Coronary Angioplasty

Has been used alone or in combination with other antiplatelet agents (e.g., aspirin, clopidogrel) to prevent thrombosis and restenosis following coronary angioplasty/stenting.2 5 6 7 8 13 14 15 21 22 1010 However, use of cilostazol in patients with coronary artery stents generally not recommended by experts,994 1010 except possibly in those with allergy or intolerance to aspirin or clopidogrel; in such cases, ACCP suggests possible use as a substitute for either aspirin or clopidogrel in a dual antiplatelet regimen.1010

Ischemic Stroke

Has been used for secondary prevention of noncardioembolic stroke or TIAs in patients with a history of TIAs or ischemic stroke.1009

ACCP, the American Stroke Association (ASA), and AHA consider cilostazol an acceptable antiplatelet therapy for secondary prevention of noncardioembolic ischemic stroke or TIAs; other options include aspirin monotherapy, clopidogrel, or the combination of aspirin and extended-release dipyridamole.990 1009 When selecting an appropriate antiplatelet regimen, consider factors such as the patient's individual risk for recurrent stroke, tolerance, and cost of the different agents.990

Pletal Dosage and Administration

Administration

Oral Administration

Administer orally at least one-half hour before or 2 hours after breakfast and dinner.1 2

Dosage

Adults

Intermittent Claudication
Oral

100 mg twice daily.1 2

Patients receiving concomitant therapy with CYP3A4 (e.g., diltiazem, erythromycin, itraconazole, ketoconazole) or CYP2C19 (e.g., omeprazole) inhibitors: Initially, 50 mg twice daily.1 2 13 (See Specific Drugs and Foods under Interactions.)

Thrombotic Complications of Coronary Angioplasty
Oral

100 mg twice daily has been used as a substitute for either aspirin or clopidogrel as part of a dual antiplatelet regimen in patients with coronary artery stents who have an allergy or intolerance to aspirin or clopidogrel.1010

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.1 13 (See Hepatic Impairment under Cautions.)

Renal Impairment

No specific dosage recommendations at this time.1 (See Renal Impairment under Cautions.)

Cautions for Pletal

Contraindications

  • CHF of any severity.1 2 (See Boxed Warning.)

  • Hemostatic disorders or active pathologic bleeding, such as bleeding peptic ulcer or intracranial bleeding.1

  • Known hypersensitivity to cilostazol or any ingredient in the formulation.1 17

Warnings/Precautions

General Precautions

Cardiovascular Effects

Consider possible adverse cardiovascular effects (e.g., increased heart rate) when used in patients with heart disease (e.g., CAD).1 13 Long-term effects not known in patients with underlying heart disease more severe than that studied in clinical trials (i.e., no recent MI or stroke, no arrhythmias, no unstable angina or other signs of rapidly progressing cardiovascular disease).1 2 13 19 Do not use in patients with CHF.1 (See Boxed Warning.)

Use with Clopidogrel

Limited information regarding safety and efficacy of concurrent use with clopidogrel.1 Unknown whether concurrent clopidogrel therapy has additive effect on bleeding time.1 Use caution and monitor bleeding times during concomitant therapy.1

Hematologic Effects

Possible thrombocytopenia or leukopenia progressing to agranulocytosis if cilostazol is not immediately discontinued; agranulocytosis reversible with discontinuance of cilostazol.1

Specific Populations

Pregnancy

Category C.1

Lactation

Distributed into milk in rats;1 discontinue nursing or drug because of potential risk in nursing infants.1

Pediatric Use

Safety and efficacy not established in children <18 years of age.1 2 13

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1 2

Hepatic Impairment

Not studied in patients with moderate to severe hepatic impairment;1 2 19 use with caution.1 13

Renal Impairment

Use with particular caution in patients with severe renal impairment (Clcr <25 mL/minute).1 Safety and efficacy not established in patients undergoing hemodialysis.1 2 (See Elimination Route under Pharmacokinetics.)

Common Adverse Effects

Headache, diarrhea, abnormal (e.g., loose) stools, dizziness, infection, palpitation, pharyngitis, back pain, nausea, peripheral edema, rhinitis, dyspepsia, increased cough, tachycardia.1 3 4 9 10 17

Interactions for Pletal

Metabolized by CYP3A4, and to a lesser extent, CYP2C19.1

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4 and CYP2C19: potential pharmacokinetic interaction (increased plasma cilostazol concentrations, decreased clearance).1 2 13 19

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Antifungals, azoles

Possible increased plasma cilostazol concentrations1 2 13 19

If used concomitantly, consider reduced cilostazol dosage (i.e., 50 mg twice daily)1 2

Anti-infectives, macrolides

Possible increases in plasma cilostazol concentrations with certain macrolide antibiotics (e.g., erythromycin, clarithromycin)1 2 19

Pharmacokinetic interaction unlikely with azithromycin19

If used concomitantly with certain macrolide antibiotics (e.g., erythromycin, clarithromycin), consider reduced cilostazol dosage (i.e., 50 mg twice daily)1 2

Aspirin

Potential additive effects on aPTT, PT, and/or bleeding time 1 19

Increased risk of hemorrhage not observed with low-dose aspirin;1 2 6 effect of concurrent analgesic doses of aspirin not known1 13

Clopidogrel

Potential additive antiplatelet effects 1 13

Pharmacokinetic interaction unlikely19

Caution advised; monitor bleeding times during concurrent administration1

Danazol

Possible increases in plasma cilostazol concentrations2 13

If used concomitantly, consider reduced cilostazol dosage (i.e., 50 mg twice daily)2 13

Diltiazem

Increased plasma cilostazol concentrations and decreased clearance1 2 19

If used concomitantly, consider reduced cilostazol dosage (i.e., 50 mg twice daily)1 2

Fluoxetine

Possible increases in plasma cilostazol concentrations1 2

If used concomitantly, consider reduced cilostazol dosage (i.e., 50 mg twice daily)1 2

Fluvoxamine

Possible increases in plasma cilostazol concentrations1 2

If used concomitantly, consider reduced cilostazol dosage (i.e., 50 mg twice daily)1 2

Grapefruit juice

Peak plasma cilostazol concentrations increased by about 50% but no effect on AUC1 2 13 19

Indinavir

Possible increased plasma cilostazol concentrations2

Lovastatin

Possible pharmacokinetic interaction; increased plasma lovastatin concentration and decreased plasma cilostazol concentration1 15 19

Not considered clinically important1 15 19

Nefazodone

Possible increased plasma cilostazol concentrations1 13

If used concomitantly, consider reduced cilostazol dosage (i.e., 50 mg twice daily)1 2

Omeprazole

Increased plasma concentrations of active cilostazol metabolite (3,4-dehydro-cilostazol)1 2 19

Use with caution; if used concomitantly, consider reduced cilostazol dosage (i.e., 50 mg twice daily)1 2

Quinidine

Pharmacokinetic interaction unlikely1

Sertraline

Possible increases in plasma cilostazol concentrations1 2 19

If used concomitantly, consider reduced cilostazol dosage (i.e., 50 mg twice daily)1 2

Warfarin

Potential additive effects on aPTT, PT, and/or platelet aggregation1

Pharmacokinetic and pharmacodynamic effects of multiple-dose concurrent therapy not known1 2 19

Pletal Pharmacokinetics

Absorption

Bioavailability

Absorbed following oral administration; bioavailability not determined.1

Onset

Peak pharmacodynamic effects (antiplatelet activity, heart-rate increase, decrease in DBP) within approximately 6 hours.25 In intermittent claudication, symptomatic relief may occur within 2–4 weeks of initial therapy; ≤12 weeks may be required to obtain optimum therapeutic effect.1 2 3 4

Food

Food increases absorption; approximately 90% increase in peak plasma concentration and 25% increase in AUC when administered with a high-fat meal.1 13 18

Increased plasma concentrations may be associated with a higher incidence of adverse effects;13 drug should be taken on an empty stomach.1 13 (See Oral Administration under Dosage and Administration.)

Concomitant ingestion of grapefruit juice increased peak plasma cilostazol concentrations by approximately 50% but had no effect on AUC.1 13

Distribution

Extent

Distributed into milk in rats; not known whether crosses placenta or distributes into milk in humans.1

Plasma Protein Binding

95–98% (mainly albumin).1

Special Populations

In patients with severe renal impairment, metabolite levels increase, and protein binding of drug and metabolites altered; overall drug activity appears unchanged.1

In patients who smoke, drug exposure decreases by approximately 20%.1

Elimination

Metabolism

Metabolized to active metabolites in the liver by CYP isoenzymes, principally CYP3A4, and to lesser extent, by CYP2C19.1 2 17 Two metabolites are active; one metabolite accounts for ≥50% of pharmacologic activity (PDE inhibition).1

Elimination Route

Excreted principally in urine (74%) and also in feces (20%) as active and inactive metabolites.1

Unlikely to be removed by hemodialysis because of high (95–98%) protein binding.1

Half-life

Approximately 11–13 hours (drug and active metabolites).1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

Actions

  • Quinolinone-derivative selective phosphodiesterase (PDE) type 3 inhibitor; platelet-aggregation inhibitor and arterial vasodilator.1 7 8

  • Appears to inhibit activation of cellular PDE type 3, resulting in suppressed degradation and increased concentrations of cyclic adenosine-3′,5′-monophosphate (cAMP) in platelets and blood vessels.1 7 8 17 Increased cAMP concentrations appear to mediate arterial vasodilation and inhibition of platelet aggregation.1 2 7 8 17

  • Favorably alters concentrations of certain lipoproteins; reduces plasma triglycerides and increases HDL-cholesterol concentrations.1 2 3 9 12 13 No effect on plasma concentrations of total cholesterol, LDL-cholesterol, or lipoprotein(a) (Lp[a]).12 13

Advice to Patients

  • Importance of providing patient a copy of manufacturer’s patient information each time therapy is prescribed.1

  • Importance of adherence to prescribed directions for use.1

  • Importance of not taking cilostazol if CHF (e.g., shortness of breath, swelling of the legs) is present.1 19

  • Importance of taking cilostazol at least one-half hour before or 2 hours after food.1 19

  • Importance of informing patient that up to 12 weeks of cilostazol therapy may be required before symptomatic relief of intermittent claudication occurs.1 19

  • Importance of informing patient that cardiovascular risk during long-term use or in patients with severe underlying heart disease currently is not known.1 19

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1 19

  • Importance of informing patients of other important precautionary information. (See Cautions.)1

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Cilostazol

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

50 mg*

Pletal

Otsuka

100 mg*

Pletal

Otsuka

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Cilostazol 100MG Tablets (ROXANE): 60/$27.99 or 180/$73.96

Cilostazol 50MG Tablets (TEVA PHARMACEUTICALS USA): 60/$107.99 or 180/$309.99

Pletal 100MG Tablets (OTSUKA AMERICA): 60/$114.98 or 180/$330.96

Pletal 50MG Tablets (OTSUKA AMERICA): 60/$132.99 or 180/$366.00

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 15, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Otsuka America Pharmaceutical, Inc. Pletal (cilostazol) tablets prescribing information. Rockville, MD; 2007 May.

2. Reilly MP, Mohler ER. Cilostazol: treatment of intermittent claudication. Ann Pharmacother. 2001; 35:48-56. [IDIS 457647] [PubMed 11197586]

3. Beebe HG, Dawson DL, Cutler BS et al. A new pharmacological treatment for intermittent claudication: results of a randomized, multicenter trial. Arch Intern Med. 1999; 159:2041-50. [IDIS 436111] [PubMed 10510990]

4. Dawson DL, Cutler BS, Hiatt WR et al. A comparison of cilostazol and pentoxifylline for treating intermittent claudication. Am J Med. 2000; 109:523-30. [IDIS 455734] [PubMed 11063952]

5. Kunishima T, Musha H, Eto F et al. A randomized trial of aspirin versus cilostazol therapy after successful coronary stent implantation. Clin Ther. 1997; 19:1058-66. [IDIS 397239] [PubMed 9385493]

6. Park SW, Lee CW, Kim HS et al. Comparison of cilostazol versus ticlopidine therapy after stent implantation. Am J Cardiol. 1999; 84:511-4. [PubMed 10482146]

7. Take S, Matsutani M, Ueda H et al. Effect of cilostazol in preventing restenosis after percutaneous transluminal coronary angioplasty. Am J Cardiol. 1997; 79:1097-9. [IDIS 385361] [PubMed 9114771]

8. Tsuchikane E, Fukihara A, Kobayashi T et al. Impact of cilostazol on restenosis after percutaneous coronary balloon angioplasty. Circulation. 1999; 100:21-6. [IDIS 433954] [PubMed 10393676]

9. Money SR, Herd A, Isaacsohn JL et al. Effect of cilostazol on walking distances in patients with intermittent claudication caused by peripheral vascular disease. J Vasc Surg. 1998; 27:267-75. [PubMed 9510281]

10. Dawson DL, Cutler BS, Meissner MH et al. Cilostazol has beneficial effects in treatment of intermittent claudication. Circulation. 1998; 98:678-86. [IDIS 412599] [PubMed 9715861]

11. Mallikaarjun S, Forbes WP, Bramer SL et al. Interaction potential and tolerability of the coadministration of cilostazol and aspirin. Clin Pharmacokinet. 1999; 37(suppl 2):87-93. [PubMed 10702891]

12. Elam MB, Heckman J, Crouse JR et al. Effect of the novel antiplatelet agent cilostazol on plasma lipoproteins in patients with intermittent claudication. Arterioscler Thromb Vasc Biol. 1998; 18:1942-7. [PubMed 9848888]

13. Otsuka, Rockville, MD: Personal communication.

14. Yoon YS, Shim WH, Lee DH et al. Usefulness of cilostazol versus ticlopidine in coronary artery stenting. Am J Cardiol. 1999; 84:1375-80. [IDIS 440880] [PubMed 10606107]

15. Park SW, Lee CW, Kim HS et al. Effects of cilostazol on angiographic restenosis after coronary stent placement. Am J Cardiol. 2000; 86:499- 503. [IDIS 451914] [PubMed 11009265]

16. Bramer SL, Brisson J, Corey AE et al. Effect of multiple cilostazol doses on single dose lovastatin pharmacokinetics in healthy volunteers. Clin Pharmacokinet. 1999; 37(Suppl 2):69-77.

17. Hiatt WR. Medical treatment of peripheral arterial disease and claudication. N Engl J Med. 2001; 344:1608-21. [IDIS 463925] [PubMed 11372014]

18. Bramer SL, Forbes WP. Relative bioavailability and effects of a high fat meal on single dose cilostazol pharmacokinetics. Clin Pharmacokinet. 1999; 37(Suppl 2):13-23. [PubMed 10702883]

19. IVAX Pharmaceuticals. Cilostazol tablets prescribing information. Miami, FL; 2005 Feb.

21. Douglas JS Jr, Holmes DR Jr, Kereiakes DJ et al. Coronary stent restenosis in patients treated with cilostazol. Circulation. 2005; 112:2826-32. [PubMed 16246948]

22. Schömig A, Kastrati A, Wessely R. Prevention of restenosis by systemic drug therapy: back to the future? Circulation. 2005;112; 2759-2761. Editorial.

24. Hiatt WR, Money SR, Brass EP. Long-term safety of cilostazol in patients with peripheral artery disease: the CASTLE study (Cilostazol: A STudy in Long-term Effects). J Vasc Surg. 2008; 47:330-6. [PubMed 18155871]

25. Woo SK, Kang WK, Kwon KI. Pharmacokinetic and pharmacodynamic modeling of the antiplatelet and cardiovascular effects of cilostazol in healthy humans. Clin Pharmacol Ther. 2002; 71:246-52. [PubMed 11956507]

990. Furie KL, Kasner SE, Adams RJ et al. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011; 42:227-76. [PubMed 20966421]

994. Levine GN, Bates ER, Blankenship JC et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol. 2011; 58:e44-122. [PubMed 22070834]

1009. Lansberg MG, O'Donnell MJ, Khatri P et al. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 Suppl):e601S-36S. [PubMed 22315273]

1010. Vandvik PO, Lincoff AM, Gore JM et al. Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 Suppl):e637S-68S.

1011. Alonso-Coello P, Bellmunt S, McGorrian C et al. Antithrombotic therapy in peripheral artery disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 Suppl):e669S-90S. [PubMed 22315275]

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