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Cilostazol

Pronunciation

Pronunciation

(sil OH sta zol)

Index Terms

  • OPC-13013

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

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Tablet, Oral:

Pletal: 50 mg, 100 mg

Generic: 50 mg, 100 mg

Brand Names: U.S.

  • Pletal

Pharmacologic Category

  • Antiplatelet Agent
  • Phosphodiesterase-3 Enzyme Inhibitor
  • Vasodilator

Pharmacology

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.

Metabolism

Hepatic; CYP1A2 (minor), CYP2C19 (major), CYP2D6 (minor), CYP3A4 (major)

Excretion

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

Onset of Action

Effect on walking distance: 2 to 4 weeks; may require up to 12 weeks

Half-Life Elimination

~11 to 13 hours

Protein Binding

Cilostazol 95% to 98%; active metabolites 66% to 97%

Special Populations: Renal Function Impairment

Severe renal impairment increases metabolite concentrations and alters protein binding of the parent drug.

Dialysis: It is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (has not been studied).

Special Populations Note

Smoking decreases exposure by ~20%.

Use: Labeled Indications

Intermittent claudication: Reduction of symptoms of intermittent claudication, as indicated by an increased walking distance.

Use: Unlabeled

Adjunct with aspirin and clopidogrel for prevention of stent thrombosis and restenosis after coronary stent placement; as an alternative agent to either aspirin or clopidogrel in a dual antiplatelet regimen when allergy or drug intolerance to either agent occurs in patients who have undergone elective PCI with bare metal or drug-eluting stent placement; secondary prevention of noncardioembolic ischemic stroke or transient ischemic attack (TIA)

Contraindications

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

Dosage

Adults: Oral:

Intermittent claudication: 100 mg twice daily. The American College of Chest Physicians recommends use when refractory to exercise therapy and smoking cessation; use in combination with either aspirin or clopidogrel (ACCP [Guyatt, 2012])

Note: Discontinue treatment if symptoms are not improved after 3 months of therapy

PCI (following elective stent placement) (off-label use): 100 mg twice daily in combination with aspirin or clopidogrel. Note: Only recommended in patients with an allergy or intolerance to either aspirin or clopidogrel (ACCP [Guyatt, 2012]).

Secondary prevention of noncardioembolic stroke or TIA (off-label use): 100 mg twice daily. Note: Clopidogrel or aspirin/extended release dipyridamole recommended over the use of cilostazol (ACCP [Guyatt, 2012]).

Dosage adjustment with concomitant medications:

CYP2C19 inhibitors (eg, fluconazole, omeprazole, ticlopidine): Reduce cilostazol to 50 mg twice daily

Strong or moderate CYP3A4 inhibitors (eg, diltiazem, erythromycin, itraconazole, ketoconazole): Reduce cilostazol to 50 mg twice daily

Dosage adjustment in renal impairment:

CrCl ≥25 mL/minute: No dosage adjustment necessary (Mallikaarjun, 1999).

CrCl <25 mL/minute: No dosage adjustment necessary (Mallikaarjun, 1999). Severe renal impairment increases metabolite concentrations; use with caution.

End-stage renal disease (ESRD) on dialysis: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); however, high protein binding makes removal by dialysis unlikely.

Dosage adjustment in hepatic impairment:

Mild impairment: No dosage adjustment necessary (Bramer, 1999).

Moderate to severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); use with caution.

Administration

Oral: Administer 30 minutes before or 2 hours after meals (breakfast and dinner).

Storage

Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Drug Interactions

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the antiplatelet effect of other Agents with Antiplatelet Properties. Monitor therapy

Anagrelide: May enhance the adverse/toxic effect of Cilostazol. Monitor therapy

Anticoagulants: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Apixaban: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Apixaban. Specifically, the risk for bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely. Monitor therapy

ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Collagenase (Systemic): Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP2C19 Inhibitors: May increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in patients who are also receiving inhibitors of CYP2C19. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in adult patients who are also receiving moderate inhibitors of CYP3A4. Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in adult patients who are also receiving strong inhibitors of CYP3A4. Consider therapy modification

Dabigatran Etexilate: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Dabigatran Etexilate. Agents with Antiplatelet Properties may increase the serum concentration of Dabigatran Etexilate. This mechanism applies specifically to clopidogrel. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May enhance the anticoagulant effect of Agents with Antiplatelet Properties. Monitor therapy

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Deoxycholic Acid: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Monitor therapy

Dofetilide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. Monitor therapy

Edoxaban: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Glucosamine: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Consider therapy modification

Hydrocodone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Hydrocodone. Monitor therapy

Ibritumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Limaprost: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Limit the maximum adult dose of lomitapide to 30 mg daily when used in combination with any weak CYP3A4 inhibitor. Consider therapy modification

Luliconazole: May increase the serum concentration of CYP2C19 Substrates. Monitor therapy

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Mifepristone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Multivitamins/Fluoride (with ADE): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with AE, No Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Monitor therapy

Obinutuzumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Monitor therapy

Omega-3 Fatty Acids: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Monitor therapy

Pentoxifylline: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Avoid combination

Prostacyclin Analogues: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Riociguat: Cilostazol may enhance the hypotensive effect of Riociguat. Management: Riociguat is contraindicated with nonselective phosphodiesterase (PDE) inhibitors and PDE type 5 inhibitors. Other types of PDE inhibitors are not contraindicated, but caution is advised and patients should be monitored for hypotension. Monitor therapy

Rivaroxaban: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Rivaroxaban. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Monitor therapy

Salicylates: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

St Johns Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Thrombolytic Agents: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents. Monitor therapy

Tipranavir: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tositumomab and Iodine I 131 Tositumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse events may be increased. Monitor therapy

Urokinase: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Urokinase. Avoid combination

Vitamin E: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Vitamin E (Oral): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Adverse Reactions

>10%:

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

Gastrointestinal: Diarrhea (12% to 19%), abnormal stools (12% to 15%)

Infection: Infection (10% to 14%)

Respiratory: Rhinitis (7% to 12%)

1% to 10%:

Cardiovascular: Palpitations (5% to 10%), peripheral edema (7% to 9%), tachycardia (4%), atrial fibrillation (<2%), atrial flutter (<2%), cardiac arrest (<2%), cardiac failure (<2%), cerebral infarction (<2%), edema (<2%), hypotension (<2%), myocardial infarction (<2%), nodal arrhythmia (<2%), orthostatic hypotension (<2%), supraventricular tachycardia (<2%), syncope (<2%), varicose veins (<2%), ventricular premature contractions (<2%), ventricular tachycardia (<2%)

Central nervous system: Dizziness (9% to 10%), vertigo (3%) , chills (<2%), insomnia (<2%), malaise (<2%), neuralgia (<2%)

Dermatologic: Ecchymoses (<2%), skin hypertrophy (<2%), urticarial (<2%), xeroderma (<2%)

Endocrine & metabolic: Albuminuria (<2%), gout (<2%), hyperlipidemia (<2%), hyperuricemia (<2%), increased gamma-glutamyl transferase (<2%)

Gastrointestinal: Nausea (7%), dyspepsia (6%), abdominal pain (4% to 5%), flatulence (3%), anorexia (<2%), cholelithiasis (<2%), colitis (<2%), duodenal ulcer (<2%), duodenitis (<2%), esophageal hemorrhage (<2%), esophagitis (<2%), gastritis (<2%), gastroenteritis (<2%), gingival hemorrhage (<2%), hematemesis (<2%), melena (<2%), peptic ulcer (<2%), periodontal abscess (<2%)

Genitourinary: Cystitis (<2%), urinary frequency (<2%), vaginal hemorrhage (<2%), vaginitis (<2%)

Hematologic & oncologic: Anemia (<2%), hemorrhage (<2%), hemorrhage (eye, <2%), iron deficiency anemia (<2%), polycythemia (<2%), purpura (<2%), rectal hemorrhage (<2%), retroperitoneal hemorrhage (<2%)

Hypersensitivity: Tongue edema (<2%)

Neuromuscular & skeletal: Back pain (7%), myalgia (3%), arthralgia (<2%), bursitis (<2%), neck stiffness (<2%), ostealgia (<2%)

Ophthalmic: Blindness (<2%), conjunctivitis (<2%), diplopia (<2%), retinal hemorrhage (<2%)

Otic: Otalgia (<2%), tinnitus (<2%)

Renal: Increased serum creatinine (<2%)

Respiratory: Pharyngitis (10%), cough (3% to 4%), asthma (<2%), epistaxis (<2%), hemoptysis (<2%), pneumonia (<2%), sinusitis (<2%)

Miscellaneous: Fever (<2%)

<2% (Limited to important or life-threatening): Agranulocytosis, anaphylaxis, aplastic anemia, cerebral hemorrhage, cerebrovascular accident, coronary thrombosis (stent), gastrointestinal hemorrhage, granulocytopenia, hematoma (extradural), hepatic insufficiency, hyperglycemia, hypersensitivity, hypertension, interstitial pneumonitis, intracranial hemorrhage, jaundice, leukopenia, prolonged Q-T interval on ECG, pancytopenia, pulmonary hemorrhage, Stevens-Johnson syndrome, subcutaneous hemorrhage, subdural hematoma, thrombocytopenia, thrombosis, torsades de pointes

ALERT: U.S. Boxed Warning

Contraindication:

Cilostazol is contraindicated with patients with heart failure of any severity. Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared with placebo in patients with class III to IV heart failure.

Warnings/Precautions

Concerns related to adverse effects:

• Cardiovascular effects: May induce tachycardia, palpitation, tachyarrhythmia, and/or hypotension.

• Hematologic effects: Cases of thrombocytopenia or leukopenia progressing to agranulocytosis, reversible upon discontinuation, have been reported when not immediately discontinued; monitor platelets and white blood cell counts periodically.

Disease-related concerns:

• Hemostatic disorders: Cilostazol has not been studied in patients with active pathological bleeding or hemostatic disorders; avoid use in these patients.

• Cardiovascular disease: [US 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. Patients with history of ischemic heart disease may be at increased risk for exacerbation of angina pectoris or myocardial infarction.

• Hepatic impairment: Use with caution in patients with moderate to severe hepatic impairment (has not been studied).

• Renal impairment: Use with caution in patients with severe renal impairment (CrCl <25 mL/minute).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Elective surgery: Time required to recover adequate platelet function is ~2 days (Hill, 2011). Of note, bleeding times were not significantly altered by cilostazol after 3 to 14 days of treatment (Kim, 2004; Wilhite, 2003).

Monitoring Parameters

Platelets and WBC counts periodically

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dizziness, headache, diarrhea, abnormal stools, nausea, abdominal pain, pharyngitis, or rhinorrhea. Have patient report immediately to prescriber signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), signs of infection, angina, severe dizziness, passing out, tachycardia, arrhythmia, or swelling of arm or leg (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating, and advising patients.

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