Pletal

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

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  Contraindicated in patients with CHF of any severity.^{1 2} Decreased survival observed in patients with New York Heart Association (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 20}

The American College of Chest Physicians (ACCP) suggests use in patients with disabling intermittent claudication who do not respond to conservative measures (risk factor modification, exercise) and who are not candidates for surgical or catheter-based interventions.²⁰ Use not suggested in patients with less disabling intermittent claudication because of its high cost and modest effect on walking distance.²⁰

Not evaluated in patients with rapidly progressing claudication, leg pain at rest, ischemic leg ulcers, or gangrene.¹

Long-term effects of cilostazol 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 23}

ACCP recommends dual antiplatelet therapy with clopidogrel and aspirin in preference to combination therapy with aspirin and either ticlopidine or cilostazol in patients undergoing stent implantation.²³

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 alone or in combination with aspirin (e.g., 81 mg daily) has been used in a limited number of patients.^{5 6 13 14 15}

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

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  CHF of any severity.^{1 2} (See Boxed Warning.)

  
  


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

  
  


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  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 (Cl_cr <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

ActionsActions

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

  
  


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  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}

  
  


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  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

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

  
  


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  Importance of adherence to prescribed directions for use.¹

  
  


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

  
  


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

  
  


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

  
  


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  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}

  
  


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

  
  


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

  
  


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  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 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Cilostazol 50MG Tablets (COREPHARMA LLC): 60/$81.99 or 180/$229.99

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

Pletal 50MG Tablets (OTSUKA AMERICA): 60/$132.99 or 180/$366

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions January 2011. 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.

20. Sobel M, Verhaeghe R. Antithrombotic therapy for peripheral artery occlusive disease. American College of Chest Physicians evidence-based clinical practice guidelines (8th ed). Chest. 2008; 133(Suppl):815S-43S. [PubMed 18574279]

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.

23. Becker RC, Meade TW, Berger PB et al. The primary and secondary prevention of coronary artery disease: American College of Chest Physicians evidenced-based clinical practice guidelines (8th ed). Chest. 2008; 133 (Suppl): 776S-814S. [PubMed 18574278]

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]

More Pletal resources

• Pletal Side Effects (in more detail)
• Pletal Dosage
• Pletal Use in Pregnancy & Breastfeeding
• Drug Images
• Pletal Drug Interactions
• Pletal Support Group
• 1 Review for Pletal - Add your own review/rating

• Pletal Prescribing Information (FDA)


• Pletal MedFacts Consumer Leaflet (Wolters Kluwer)


• Pletal Concise Consumer Information (Cerner Multum)


• Pletal Advanced Consumer (Micromedex) - Includes Dosage Information


• Cilostazol Prescribing Information (FDA)


• Cilostazol Professional Patient Advice (Wolters Kluwer)

Compare Pletal with other medications

• Intermittent Claudication