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  • CLASSES

    Platelet Camp Enhancing Platelet Aggregation Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Platelet aggregation inhibitor with vasodilating activity; for the reduction of the symptoms of intermittent claudication.

    COMMON BRAND NAMES

    Pletal

    HOW SUPPLIED

    Cilostazol/Pletal Oral Tab: 50mg, 100mg

    DOSAGE & INDICATIONS

    For the treatment of claudication associated with peripheral vascular disease (PVD); including the treatment of peripheral arterial disease in patients with diabetic neuropathy†, and for the treatment of chronic arterial occlusion due to arteriosclerosis obliterans† or thromboangiitis obliterans† (Buerger's disease†).
    Oral dosage
    Adults

    The recommended dose is 100 mg PO twice daily. A dosage of 50 mg PO twice daily should be considered for patients concomitantly receiving inhibitors of CYP3A4 or CYP2C19.

    For thromboembolism prophylaxis in recipients of a coronary artery stent† following percutaneous coronary intervention (PCI)†, to prevent acute coronary thrombosis (i.e., abrupt closure) and the need for revascularization.
    Oral dosage
    Adults

    A dosage of 100 mg PO twice daily has been suggested. A dosage of 50 mg PO twice daily should be considered for patients concomitantly receiving inhibitors of CYP3A4 or CYP2C19. One trial in 70 patients demonstrated that cilostazol treatment resulted in lower restenosis rates (8.6%) versus those who received aspirin (26.8%); the difference was statistically significant.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    200 mg/day PO.

    Elderly

    200 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Dose adjustments do not appear necessary in patients with mild, stable hepatic impairment. Cilostazol has not been studied in patients with moderate to severe hepatic disease.

    Renal Impairment

    Dose adjustments do not appear to be necessary for patients with mild to moderate renal impairment (i.e., SCr <= 2.5 mg/dL). Plasma concentrations of cilostazol and its metabolites are expected to be higher in patients with severe renal impairment (SCr > 2.5 mg/dL), but specific guidelines for dosage adjustments in this patient population are not available.
     
    Intermittent hemodialysis
    No in vivo data are available. Since cilostazol is highly-protein bound, it is unlikely that it can be cleared by hemodialysis.
     
    Peritoneal dialysis
    No in vivo data are available. Since cilostazol is highly-protein bound, it is unlikely that it can be cleared by peritoneal dialysis (CAPD).

    ADMINISTRATION

    Oral Administration

    Administer tablets on an empty stomach at least 30 minutes before or 2 hours after breakfast and dinner with a full glass of water.
    Do not administer with grapefruit juice.

    STORAGE

    Pletal:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Bleeding, GI bleeding, intracranial bleeding, peptic ulcer disease, retinal bleeding, retroperitoneal bleeding, surgery, thrombocytopenia, trauma

    Cilostazol is contraindicated in patients with hemostatic disorders or active pathologic bleeding, such as GI bleeding, retinal bleeding, retroperitoneal bleeding, or intracranial bleeding. Cilostazol should be used with caution in individuals who have lesions with a propensity to bleed, such as patients with peptic ulcer disease. Furthermore, caution is advised in using cilostazol in patients at risk of bleeding from surgery, trauma, or other pathologic processes and in patients with thrombocytopenia. If a patient is to undergo elective surgery and platelet aggregation inhibition is not desired, cilostazol should be discontinued at least 4 days prior to the surgery. Cilostazol inhibits platelet aggregation in a reversible manner; platelet aggregability returns to normal within 96 hours of drug discontinuation.

    Driving or operating machinery, hypertension, hypotension

    In clinical trials within the approved prescribing limits, significant changes in blood pressure were not noted in study subjects with normal blood pressure or controlled hypertension who were receiving cilostazol. However, because cilostazol pharmacologically produces arterial vasodilation in vascular beds it should be used with caution in patients with clinical hypotension because the drug could potentially exacerbate this condition. Orthostatic hypotension has been reported. Because cilostazol may cause dizziness, patients should not perform tasks that require mental alertness, such as driving or operating machinery, until they have determined how cilostazol affects them.

    Acute myocardial infarction, angina, cardiac arrhythmias, cardiac disease, coronary artery disease, heart failure, myocardial infarction, tachycardia, valvular heart disease, ventricular tachycardia

    Cilostazol and its metabolites are contraindicated in patients with heart failure of any severity. Other medications that are phosphodiesterase III inhibitors (i.e., inamrinone, milrinone) have caused decreased survival compared to placebo with outpatient use in persons with class III or IV heart failure. Based on its mechanism of action, cilostazol may induce tachycardia, palpitation, tachyarrhythmia, and/or hypotension. The increase in heart rate associated with cilostazol is approximately 5 to 7 bpm. Cilostazol should be used with caution in patients with a history of any cardiac disease, including angina, ventricular tachycardia, uncontrolled hypertension, cardiac arrhythmias, and valvular heart disease. Patients with a history of ischemic heart disease (coronary artery disease) may be at risk for exacerbations of angina pectoris or myocardial infarction. Cilostazol is not indicated for use in the setting of acute myocardial infarction. Repeated oral administration of cilostazol to dogs has produced cardiovascular lesions that included endocardial hemorrhage, fibrosis of the left ventricle, changes in the smooth muscle of coronary artery walls, and intimal thickening of the coronary arteries. Left ventricular outflow tract obstruction has been reported in patients with sigmoid shaped intraventricular septum. Monitor patients for new systolic murmur or cardiac symptoms after beginning cilostazol therapy.

    Pregnancy

    Cilostazol is classified as pregnancy category C. There are no well-controlled, adequate clinical studies in pregnant women. In rats, cilostazol has been associated with cardiovascular, renal, and skeletal anomalies when administered in doses of 1000 mg/kg/day. Increased incidences of ventricular septal defects and retarded ossification also occurred at doses of 150 mg/kg/day (5 times the maximum recommended human dosage on a systemic exposure basis). When cilostazol was administered during late pregnancy and lactation in rats, doses of 150 mg/kg/day were associated with low birth weights and stillbirths.

    Breast-feeding

    Cilostazol is excreted into the breast milk of rats. Because many drugs are excreted in human milk and because of the potential for serious adverse events in breast-feeding infants from cilostazol, discontinue cilostazol or discontinue breast-feeding.

    Children

    The safety and efficacy of cilostazol in children have not been established.

    Renal failure, renal impairment

    Elimination of cilostazol's metabolites is altered in patients with severe renal impairment (serum creatinine > 2.5 mg/dl) or renal failure. Since one of cilostazol's metabolites accounts for a significant portion of cilostazol's pharmacologic activity, caution should be used when administering cilostazol to these patients. In manufacturer studies, the pharmacokinetics or pharmacologic effects of cilostazol in patients with mild to moderate renal impairment did not differ from those patients with normal renal function.

    Hepatic disease

    Cilostazol is hepatically metabolized to both active and inactive metabolites. Since cilostazol has not been studied in patients with moderate or severe hepatic disease or cirrhosis, cilostazol should be used with caution in these populations.

    Tobacco smoking

    Tobacco smoking appears to decrease cilostazol serum concentrations by roughly 20%. There were no statistically significant differences in absolute claudication distance (ACD) at the end of cilostazol treatment during clinical trials in those patients with peripheral arterial disease who were smokers versus those who were not. However, it is unknown if tobacco smoking would contribute to a decreased clinical response to cilostazol when the drug is administered for other uses or when the clinical response to cilostazol is measured by parameters other than ACD. Given the adverse effects that tobacco smoking may have on the peripheral vasculature, patients taking cilostazol should be advised not to smoke.

    Geriatric

    During clinical studies of cilostazol, no overall differences in safety or effectiveness were observed and other reported clinical experience has not identified differences in response for geriatric patients vs. younger adults; however, greater sensitivity of some older individuals cannot be ruled out. The drug is contraindicated in patients with congestive heart failure of any severity. According to the Beers Criteria, cilostazol is considered a potentially inappropriate medication (PIM) for use in geriatric patients with heart failure and should be avoided due to the potential to increase mortality in older adults with heart failure. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities; platelet inhibitors may increase the risk of bleeding. Common side effects of platelet inhibitors include headache, dizziness, and vomiting. Concurrent use with anticoagulants or NSAIDs may increase the risk of bleeding.

    ADVERSE REACTIONS

    Severe

    peptic ulcer / Delayed / 0-2.0
    hematemesis / Delayed / 0-2.0
    myocardial infarction / Delayed / 0-2.0
    atrial flutter / Early / 0-2.0
    stroke / Early / 0-2.0
    atrial fibrillation / Early / 0-2.0
    cardiac arrest / Early / 0-2.0
    ventricular tachycardia / Early / 0-2.0
    heart failure / Delayed / 0-2.0
    ocular hemorrhage / Delayed / 0-2.0
    retinal hemorrhage / Delayed / 0-2.0
    retroperitoneal bleeding / Delayed / 0-2.0
    visual impairment / Early / 0-2.0
    agranulocytosis / Delayed / 0-1.0
    thrombosis / Delayed / Incidence not known
    intracranial bleeding / Delayed / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    azotemia / Delayed / Incidence not known

    Moderate

    palpitations / Early / 5.0-10.0
    peripheral edema / Delayed / 7.0-9.0
    sinus tachycardia / Rapid / 4.0-4.0
    cholelithiasis / Delayed / 0-2.0
    esophagitis / Delayed / 0-2.0
    melena / Delayed / 0-2.0
    gastritis / Delayed / 0-2.0
    colitis / Delayed / 0-2.0
    supraventricular tachycardia (SVT) / Early / 0-2.0
    peripheral vasodilation / Rapid / 0-2.0
    hypotension / Rapid / 0-2.0
    orthostatic hypotension / Delayed / 0-2.0
    premature ventricular contractions (PVCs) / Early / 0-2.0
    hemoptysis / Delayed / 0-2.0
    vaginal bleeding / Delayed / 0-2.0
    furunculosis / Delayed / 0-2.0
    vaginitis / Delayed / 0-2.0
    anemia / Delayed / 0-2.0
    cystitis / Delayed / 0-2.0
    polycythemia / Delayed / 0-2.0
    diabetes mellitus / Delayed / 0-2.0
    hyperlipidemia / Delayed / 0-2.0
    amblyopia / Delayed / 0-2.0
    hyperuricemia / Delayed / 0-2.0
    edema / Delayed / 0-2.0
    gout / Delayed / 0-2.0
    bone pain / Delayed / 0-2.0
    conjunctivitis / Delayed / 0-2.0
    QT prolongation / Rapid / 0-1.0
    hypertension / Early / 2.0
    angina / Early / 2.0
    hematuria / Delayed / 2.0
    dyspnea / Early / 2.0
    hematoma / Early / Incidence not known
    leukopenia / Delayed / Incidence not known
    bleeding / Early / Incidence not known
    subdural hematoma / Early / Incidence not known
    platelet dysfunction / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    hot flashes / Early / Incidence not known
    chest pain (unspecified) / Early / Incidence not known

    Mild

    headache / Early / 27.0-34.0
    diarrhea / Early / 12.0-19.0
    infection / Delayed / 10.0-14.0
    rhinitis / Early / 7.0-12.0
    dizziness / Early / 9.0-10.0
    pharyngitis / Delayed / 7.0-10.0
    nausea / Early / 6.0-7.0
    back pain / Delayed / 6.0-7.0
    dyspepsia / Early / 6.0-6.0
    abdominal pain / Early / 4.0-5.0
    cough / Delayed / 3.0-4.0
    flatulence / Early / 2.0-3.0
    myalgia / Early / 2.0-3.0
    vertigo / Early / 1.0-3.0
    anorexia / Delayed / 0-2.0
    syncope / Early / 0-2.0
    ecchymosis / Delayed / 0-2.0
    epistaxis / Delayed / 0-2.0
    purpura / Delayed / 0-2.0
    urticaria / Rapid / 0-2.0
    xerosis / Delayed / 0-2.0
    tinnitus / Delayed / 0-2.0
    malaise / Early / 0-2.0
    diplopia / Early / 0-2.0
    anxiety / Delayed / 0-2.0
    increased urinary frequency / Early / 0-2.0
    chills / Rapid / 0-2.0
    fever / Early / 0-2.0
    insomnia / Early / 0-2.0
    sinusitis / Delayed / 0-2.0
    arthralgia / Delayed / 0-2.0
    rash / Early / 2.0
    influenza / Delayed / 2.0
    hypoesthesia / Delayed / 2.0
    vomiting / Early / 2.0
    paresthesias / Delayed / 2.0
    asthenia / Delayed / 2.0
    pruritus / Rapid / Incidence not known

    DRUG INTERACTIONS

    Abciximab: (Moderate) Because cilostazol is a platelet aggregation inhibitor, a potential additive risk for bleeding exists if cilostazol is given with other agent that affect hemostasis such as platelet glycoprotein IIb/IIIa inhibitors including abciximab, eptifibatide, and tirofiban.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Use caution with the coadministration of aspirin and cilostazol. Although the short-term (<= 4 days) coadministration of aspirin and cilostazol increased the inhibition of ADP-induced platelet aggregation by 22% to 37% compared to aspirin or cilostazol use alone, no clinically significant effect on PT, aPTT, or bleeding time was observed compared to aspirin alone. In clinical trials, there was no apparent increase in hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to aspirin alone. The effects of long-term coadministration are unknown. Monitor for bleeding during concomitant therapy.
    Ado-Trastuzumab emtansine: (Moderate) Use caution if coadministration of platelet inhibitors with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Altretamine: (Moderate) An additive risk of bleeding may occur when platelet inhibitors is used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as altretamine.
    Aminolevulinic Acid: (Minor) Agents, such as platelet inhibitors, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Amiodarone: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with amiodarone, and monitor for an increase in cilostazol-related adverse reactions. Cilostazol is a CYP3A4 substrate. Amiodarone is a moderate CYP3A4 inhibitor both in vitro and in vivo. Coadministration with another moderate CYP3A4 inhibitor increased the Cmax and AUC of cilostazol (single dose) by 47% and 73%, respectively; the AUC of 4-trans-hydroxycilostazol increased by 141%.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with clarithromycin. Monitor for an increase in cilostazol-related adverse reactions. Clarithromycin is a strong CYP3A4 inhibitor and cilostazol is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the cilostazol AUC by 117%.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with clarithromycin. Monitor for an increase in cilostazol-related adverse reactions. Clarithromycin is a strong CYP3A4 inhibitor and cilostazol is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the cilostazol AUC by 117%. (Major) When significant CYP2C19 inhibitors, such as omeprazole, are administered concomitantly with cilostazol, the cilostazol dosage should be reduced by 50%. Cilostazol is metabolized by the CYP2C19 hepatic isoenzyme and appears to have pharmacokinetic interactions with many medications that are potent inhibitors of CYP2C19. When given concurrently with omeprazole, cilostazol AUC is increased by 26% and the Cmax is increased by 18%; the AUC of the active metabolite 3,4-dehydro-cilostazol is increased by 69% and the Cmax is increased by 29%.
    Amprenavir: (Major) Concurrent administration of cilostazol with protease inhibitors can result in elevated cilostazol plasma concentrations; the manufacturer recommends prescribers consider up to a 50% reduction in cilostazol dosage during concurrent administration. Cilostazol is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Anagrelide: (Moderate) Because anagrelide and cilostazol inhibit platelet aggregation, a potential additive risk for bleeding exists if they are coadminsitered.
    Antimetabolites: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antimetabolites.
    Antithrombin III: (Moderate) The safety of cilostazol has not been established with concomitant administration of anticoagulants. Because cilostazol is a platelet aggregation inhibitor, concomitant administration with similar acting drugs could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution. Patients on anticoagulants should be monitored for changes in response to anticoagulation therapy if cilostazol is administered concurrently.
    Antithymocyte Globulin: (Moderate) An increased risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia, such as antithymocyte globulin. Platelet inhibitors should be used cautiously in patients with thrombocytopenia following the administration of antithymocyte globulin or other drugs that cause significant thrombocytopenia due to the increased risk of bleeding.
    Apixaban: (Major) The concomitant use of apixaban and platelet inhibitors (e.g, aspirin) may increase the risk of bleeding. In the ARISTOTLE trial (comparative trial of apixaban and warfarin in patients with nonvalvular atrial fibrillation), concomitant use of aspirin increased the bleeding risk of apixaban from 1.8%/year to 3.4%/year. If given concomitantly, patients should be educated about the signs and symptoms of bleeding and be instructed to report them immediately or go to an emergency room.
    Aprepitant, Fosaprepitant: (Major) Use caution if cilostazol and aprepitant, fosaprepitant are used concurrently and monitor for an increase in cilostazol-related adverse effects for several days after administration of a multi-day aprepitant regimen; a dose adjustment of cilostazol may be necessary. Cilostazol is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of cilostazol. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Argatroban: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., clopidogrel, platelet glycoprotein IIb/IIIa inhibitors, ticlopidine, etc.) in combination with argatroban.
    Arsenic Trioxide: (Moderate) Because cilostazol inhibits platelet aggregation, a potential additive risk for bleeding exists if cilostazol is given in combination with other drugs that affect hemostasis. Agents that cause clinically significant thrombocytopenia could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
    Aspirin, ASA: (Moderate) Use caution with the coadministration of aspirin and cilostazol. Although the short-term (<= 4 days) coadministration of aspirin and cilostazol increased the inhibition of ADP-induced platelet aggregation by 22% to 37% compared to aspirin or cilostazol use alone, no clinically significant effect on PT, aPTT, or bleeding time was observed compared to aspirin alone. In clinical trials, there was no apparent increase in hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to aspirin alone. The effects of long-term coadministration are unknown. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Use caution with the coadministration of aspirin and cilostazol. Although the short-term (<= 4 days) coadministration of aspirin and cilostazol increased the inhibition of ADP-induced platelet aggregation by 22% to 37% compared to aspirin or cilostazol use alone, no clinically significant effect on PT, aPTT, or bleeding time was observed compared to aspirin alone. In clinical trials, there was no apparent increase in hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to aspirin alone. The effects of long-term coadministration are unknown. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Use caution with the coadministration of aspirin and cilostazol. Although the short-term (<= 4 days) coadministration of aspirin and cilostazol increased the inhibition of ADP-induced platelet aggregation by 22% to 37% compared to aspirin or cilostazol use alone, no clinically significant effect on PT, aPTT, or bleeding time was observed compared to aspirin alone. In clinical trials, there was no apparent increase in hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to aspirin alone. The effects of long-term coadministration are unknown. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Use caution with the coadministration of aspirin and cilostazol. Although the short-term (<= 4 days) coadministration of aspirin and cilostazol increased the inhibition of ADP-induced platelet aggregation by 22% to 37% compared to aspirin or cilostazol use alone, no clinically significant effect on PT, aPTT, or bleeding time was observed compared to aspirin alone. In clinical trials, there was no apparent increase in hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to aspirin alone. The effects of long-term coadministration are unknown. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Use caution with the coadministration of aspirin and cilostazol. Although the short-term (<= 4 days) coadministration of aspirin and cilostazol increased the inhibition of ADP-induced platelet aggregation by 22% to 37% compared to aspirin or cilostazol use alone, no clinically significant effect on PT, aPTT, or bleeding time was observed compared to aspirin alone. In clinical trials, there was no apparent increase in hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to aspirin alone. The effects of long-term coadministration are unknown. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Carisoprodol: (Moderate) Use caution with the coadministration of aspirin and cilostazol. Although the short-term (<= 4 days) coadministration of aspirin and cilostazol increased the inhibition of ADP-induced platelet aggregation by 22% to 37% compared to aspirin or cilostazol use alone, no clinically significant effect on PT, aPTT, or bleeding time was observed compared to aspirin alone. In clinical trials, there was no apparent increase in hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to aspirin alone. The effects of long-term coadministration are unknown. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Use caution with the coadministration of aspirin and cilostazol. Although the short-term (<= 4 days) coadministration of aspirin and cilostazol increased the inhibition of ADP-induced platelet aggregation by 22% to 37% compared to aspirin or cilostazol use alone, no clinically significant effect on PT, aPTT, or bleeding time was observed compared to aspirin alone. In clinical trials, there was no apparent increase in hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to aspirin alone. The effects of long-term coadministration are unknown. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Use caution with the coadministration of aspirin and cilostazol. Although the short-term (<= 4 days) coadministration of aspirin and cilostazol increased the inhibition of ADP-induced platelet aggregation by 22% to 37% compared to aspirin or cilostazol use alone, no clinically significant effect on PT, aPTT, or bleeding time was observed compared to aspirin alone. In clinical trials, there was no apparent increase in hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to aspirin alone. The effects of long-term coadministration are unknown. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Dipyridamole: (Moderate) Because cilostazol and dipyridamole inhibit platelet aggregation, a potential additive risk for bleeding exists if they are coadminsitered. (Moderate) Use caution with the coadministration of aspirin and cilostazol. Although the short-term (<= 4 days) coadministration of aspirin and cilostazol increased the inhibition of ADP-induced platelet aggregation by 22% to 37% compared to aspirin or cilostazol use alone, no clinically significant effect on PT, aPTT, or bleeding time was observed compared to aspirin alone. In clinical trials, there was no apparent increase in hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to aspirin alone. The effects of long-term coadministration are unknown. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Omeprazole: (Major) When significant CYP2C19 inhibitors, such as omeprazole, are administered concomitantly with cilostazol, the cilostazol dosage should be reduced by 50%. Cilostazol is metabolized by the CYP2C19 hepatic isoenzyme and appears to have pharmacokinetic interactions with many medications that are potent inhibitors of CYP2C19. When given concurrently with omeprazole, cilostazol AUC is increased by 26% and the Cmax is increased by 18%; the AUC of the active metabolite 3,4-dehydro-cilostazol is increased by 69% and the Cmax is increased by 29%. (Moderate) Use caution with the coadministration of aspirin and cilostazol. Although the short-term (<= 4 days) coadministration of aspirin and cilostazol increased the inhibition of ADP-induced platelet aggregation by 22% to 37% compared to aspirin or cilostazol use alone, no clinically significant effect on PT, aPTT, or bleeding time was observed compared to aspirin alone. In clinical trials, there was no apparent increase in hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to aspirin alone. The effects of long-term coadministration are unknown. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Oxycodone: (Moderate) Use caution with the coadministration of aspirin and cilostazol. Although the short-term (<= 4 days) coadministration of aspirin and cilostazol increased the inhibition of ADP-induced platelet aggregation by 22% to 37% compared to aspirin or cilostazol use alone, no clinically significant effect on PT, aPTT, or bleeding time was observed compared to aspirin alone. In clinical trials, there was no apparent increase in hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to aspirin alone. The effects of long-term coadministration are unknown. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Pravastatin: (Moderate) Use caution with the coadministration of aspirin and cilostazol. Although the short-term (<= 4 days) coadministration of aspirin and cilostazol increased the inhibition of ADP-induced platelet aggregation by 22% to 37% compared to aspirin or cilostazol use alone, no clinically significant effect on PT, aPTT, or bleeding time was observed compared to aspirin alone. In clinical trials, there was no apparent increase in hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to aspirin alone. The effects of long-term coadministration are unknown. Monitor for bleeding during concomitant therapy.
    Atazanavir: (Major) Concurrent administration of cilostazol with protease inhibitors can result in elevated cilostazol plasma concentrations; the manufacturer recommends prescribers consider up to a 50% reduction in cilostazol dosage during concurrent administration. Cilostazol is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Atazanavir; Cobicistat: (Major) Concurrent administration of cilostazol with protease inhibitors can result in elevated cilostazol plasma concentrations; the manufacturer recommends prescribers consider up to a 50% reduction in cilostazol dosage during concurrent administration. Cilostazol is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together. (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with cobicistat. Monitor for an increase in cilostazol-related adverse reactions. Cobicistat is a strong CYP3A4 inhibitor and cilostazol is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the cilostazol AUC by 117%.
    Betrixaban: (Major) Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if betrixaban and platelet inhibitors are used concomitantly. Coadministration of betrixaban and platelet inhibitors may increase the risk of bleeding.
    Bexarotene: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including bexarotene.
    Bivalirudin: (Moderate) When used as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI), bivalirudin is intended for use with aspirin (300 to 325 mg/day PO) and has been studied only in patients receiving concomitant aspirin. Generally, an additive risk of bleeding may be seen in patients receiving other platelet inhibitors (other than aspirin). In clinical trials in patients undergoing PTCA, patients receiving bivalirudin with heparin, warfarin, or thrombolytics had increased risks of major bleeding events compared to those receiving bivalirudin alone. According to the manufacturer, the safety and effectiveness of bivalirudin have not been established when used in conjunction with platelet inhibitors other than aspirin. However, bivalirudin has been safely used as an alternative to heparin in combination with provisional use of platelet glycoprotein IIb/IIIa inhibitors during angioplasty (REPLACE-2). In addition, two major clinical trials have evaluated the use of bivalirudin in patients receiving streptokinase following acute myocardial infarction (HERO-1, HERO-2). Based on the these trials, bivalirudin may be considered an alternative to heparin therapy for use in combination with streptokinase for ST-elevation MI. Bivalirudin has not been sufficiently studied in combination with other more specific thrombolytics.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering cilostazol with boceprevir due to an increased potential for cilostazol-related adverse events. If cilostazol dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of cilostazol. Cilostazol is metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated cilostazol plasma concentrations.
    Cenobamate: (Major) Reduce cilostazol dose to 50 mg twice daily when coadministered with cenobamate. Coadministration increases systemic exposure of cilostazol active metabolites. Cilostazol is a CYP2C19 substrate; cenobamate is a moderate CYP2C19 inhibitor. Coadministration of another CYP2C19 inhibitor did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%.
    Ceritinib: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with ceritinib. Monitor for an increase in cilostazol-related adverse reactions. Ceritinib is a strong CYP3A4 inhibitor and cilostazol is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the cilostazol AUC by 117%.
    Chlorambucil: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as chlorambucil.
    Cimetidine: (Minor) Cilostazol is extensively metabolized by the CYP3A4 hepatic isoenzyme and appears to interact with medications that are potent inhibitors of this enzyme, including cimetidine. When significant CYP3A4 inhibitors are administered concomitantly, the cilostazol adult dosage should be reduced by 50%.
    Ciprofloxacin: (Major) Reduce cilostazol dose to 50 mg PO twice daily when administered with ciprofloxacin. Coadministration of moderate CYP3A4 inhibitors, such as ciprofloxacin, can increase exposure to cilostazol, a CYP3A4 substrate.
    Citalopram: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
    Cladribine: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Clarithromycin: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with clarithromycin. Monitor for an increase in cilostazol-related adverse reactions. Clarithromycin is a strong CYP3A4 inhibitor and cilostazol is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the cilostazol AUC by 117%.
    Clofarabine: (Moderate) Due to the thrombocytopenic effects of antineoplastics an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Clopidogrel: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of cilostazol and clopidogrel. Both agents are platelet inhibitors; therefore, concomitant use may increase the risk of bleeding. Platelet aggregation returns to normal within 96 hours of discontinuing cilostazol.
    Cobicistat: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with cobicistat. Monitor for an increase in cilostazol-related adverse reactions. Cobicistat is a strong CYP3A4 inhibitor and cilostazol is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the cilostazol AUC by 117%.
    Collagenase: (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Conivaptan: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as cilostazol, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with cilostazol. Treatment with cilostazol may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Crizotinib: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with crizotinib and monitor for an increase in cilostazol-related adverse reactions. Cilostazol is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased the Cmax and AUC of cilostazol (single dose) by 47% and 73%, respectively; the AUC of 4-trans-hydroxycilostazol increased by 141%.
    Dabigatran: (Moderate) The safety of cilostazol has not been established with concomitant administration of anticoagulants. Because cilostazol is a platelet aggregation inhibitor, concomitant administration with similar acting drugs could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution. Patients on anticoagulants should be monitored for changes in response to anticoagulation therapy if cilostazol is administered concurrently.
    Dalteparin: (Moderate) The safety of cilostazol has not been established with concomitant administration of anticoagulants. Because cilostazol is a platelet aggregation inhibitor, concomitant administration with similar acting drugs could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution. Patients on anticoagulants should be monitored for changes in response to anticoagulation therapy if cilostazol is administered concurrently.
    Danaparoid: (Moderate) The safety of cilostazol has not been established with concomitant administration of anticoagulants. Because cilostazol is a platelet aggregation inhibitor, concomitant administration with similar acting drugs could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution. Patients on anticoagulants should be monitored for changes in response to anticoagulation therapy if cilostazol is administered concurrently.
    Danazol: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with platelet inhibitors.
    Darunavir: (Major) Concurrent administration of cilostazol with protease inhibitors can result in elevated cilostazol plasma concentrations; the manufacturer recommends prescribers consider up to a 50% reduction in cilostazol dosage during concurrent administration. Cilostazol is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Darunavir; Cobicistat: (Major) Concurrent administration of cilostazol with protease inhibitors can result in elevated cilostazol plasma concentrations; the manufacturer recommends prescribers consider up to a 50% reduction in cilostazol dosage during concurrent administration. Cilostazol is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together. (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with cobicistat. Monitor for an increase in cilostazol-related adverse reactions. Cobicistat is a strong CYP3A4 inhibitor and cilostazol is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the cilostazol AUC by 117%.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Concurrent administration of cilostazol with protease inhibitors can result in elevated cilostazol plasma concentrations; the manufacturer recommends prescribers consider up to a 50% reduction in cilostazol dosage during concurrent administration. Cilostazol is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together. (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with cobicistat. Monitor for an increase in cilostazol-related adverse reactions. Cobicistat is a strong CYP3A4 inhibitor and cilostazol is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the cilostazol AUC by 117%.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Concurrent administration of cilostazol with protease inhibitors can result in elevated cilostazol plasma concentrations; the manufacturer recommends prescribers consider up to a 50% reduction in cilostazol dosage during concurrent administration. Cilostazol is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Dasatinib: (Moderate) Monitor for evidence of bleeding if coadministration of dasatinib and cilostazol is necessary. Dasatinib can cause serious and fatal bleeding. Concomitant platelet inhibitors may increase the risk of hemorrhage.
    Defibrotide: (Severe) Coadministration of defibrotide with antithrombotic agents like platelet inhibitors is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
    Delavirdine: (Major) Cilostazol is extensively metabolized by the cytochrome P450 CYP 3A4 hepatic isoenzyme and appears to have pharmacokinetic interactions with many medications that are potent inhibitors of CYP3A4, such as delaviridine.
    Denileukin Diftitox: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as denileukin difitox.
    Desirudin: (Moderate) The safety of cilostazol has not been established with concomitant administration of anticoagulants. Because cilostazol is a platelet aggregation inhibitor, concomitant administration with similar acting drugs could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution. Patients on anticoagulants should be monitored for changes in response to anticoagulation therapy if cilostazol is administered concurrently.
    Desvenlafaxine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
    Diltiazem: (Major) Diltiazem can potentially inhibit the CYP3A4 metabolism of cilostazol. The coadministration of diltiazem and cilostazol increases the AUC of cilostazol by approximately 40%, presumably by inhibition of CYP3A4 metabolism. When diltiazem or other significant CYP3A4 inhibitors are coadministered with cilostazol, the manufacturer recommends that the cilostazol dosage be reduced by 50%.
    Dipyridamole: (Moderate) Because cilostazol and dipyridamole inhibit platelet aggregation, a potential additive risk for bleeding exists if they are coadminsitered.
    Dronedarone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Cilostazol is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Drotrecogin Alfa: (Major) Treatment with drotrecogin alfa should be carefully considered in patients who are receiving or have received any platelet inhibitors within 7 days. These patients are at increased risk of bleeding during drotrecogin alfa therapy.
    Duloxetine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
    Duvelisib: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with duvelisib, and monitor for an increase in cilostazol-related adverse reactions. Cilostazol is a CYP3A4 substrate; duvelisib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the Cmax and AUC of cilostazol (single dose) by 47% and 73%, respectively; the AUC of 4-trans-hydroxycilostazol increased by 141%.
    Edoxaban: (Major) Coadministration of edoxaban and platelet inhibitors should be avoided due to an increased risk of bleeding during concurrent use. Occasionally, short-term coadministration may be necessary in patients transitioning to and from edoxaban. Long-term coadminstration is not recommended. Promptly evaluate any signs or symptoms of blood loss in patients on concomitant therapy.
    Efavirenz: (Major) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as cilostazol.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as cilostazol.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as cilostazol.
    Elbasvir; Grazoprevir: (Major) Administering cilostazol with grazoprevir may result in elevated cilostazol plasma concentrations. Cilostazol is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with cobicistat. Monitor for an increase in cilostazol-related adverse reactions. Cobicistat is a strong CYP3A4 inhibitor and cilostazol is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the cilostazol AUC by 117%.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with cobicistat. Monitor for an increase in cilostazol-related adverse reactions. Cobicistat is a strong CYP3A4 inhibitor and cilostazol is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the cilostazol AUC by 117%.
    Enoxaparin: (Moderate) The safety of cilostazol has not been established with concomitant administration of anticoagulants. Because cilostazol is a platelet aggregation inhibitor, concomitant administration with similar acting drugs could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution. Patients on anticoagulants should be monitored for changes in response to anticoagulation therapy if cilostazol is administered concurrently.
    Eptifibatide: (Moderate) Because cilostazol is a platelet aggregation inhibitor, a potential additive risk for bleeding exists if cilostazol is given with other agent that affect hemostasis such as platelet glycoprotein IIb/IIIa inhibitors including abciximab, eptifibatide, and tirofiban.
    Erythromycin: (Major) Erythromycin can inhibit the hepatic metabolism of cilostazol, increasing it's serum concentrations and potentially causing toxicity. When erythromycin or other significant CYP3A4 inhibitors are coadministered with cilostazol, the manufacturer recommends that the cilostazol dosage be reduced by 50%.
    Erythromycin; Sulfisoxazole: (Major) Erythromycin can inhibit the hepatic metabolism of cilostazol, increasing it's serum concentrations and potentially causing toxicity. When erythromycin or other significant CYP3A4 inhibitors are coadministered with cilostazol, the manufacturer recommends that the cilostazol dosage be reduced by 50%.
    Escitalopram: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs), including escitalopram, due to platelet serotonin depletion. There may be an increased risk of a bleeding complication in patients receiving platelet inhibitors, such as cilostazol. Patients receiving this combination should be monitored for signs and symptoms of bleeding.
    Esomeprazole: (Major) Cilostazol is metabolized by the CYP2C19 hepatic isoenzyme and appears to have pharmacokinetic interactions with many medications that are potent inhibitors of CYP2C19, such as esomeprazole. When given concurrently with omeprazole, another CYP2C19 inhibitor, cilostazol AUC is increased by 26% and the Cmax is increased by 18%; the AUC of the active metabolite 3,4-dehydro-cilostazol is increased by 69% and the Cmax is increased by 29%. When administered concomitantly with esomeprazole, the cilostazol dosage should be reduced by 50%.
    Esomeprazole; Naproxen: (Major) Cilostazol is metabolized by the CYP2C19 hepatic isoenzyme and appears to have pharmacokinetic interactions with many medications that are potent inhibitors of CYP2C19, such as esomeprazole. When given concurrently with omeprazole, another CYP2C19 inhibitor, cilostazol AUC is increased by 26% and the Cmax is increased by 18%; the AUC of the active metabolite 3,4-dehydro-cilostazol is increased by 69% and the Cmax is increased by 29%. When administered concomitantly with esomeprazole, the cilostazol dosage should be reduced by 50%.
    Estramustine: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as estramustine.
    Fedratinib: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with fedratinib, and monitor for an increase in cilostazol-related adverse reactions. Cilostazol is a CYP3A4 substrate. fedratinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the Cmax and AUC of cilostazol (single dose) by 47% and 73%, respectively; the AUC of 4-trans-hydroxycilostazol increased by 141%.
    Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) Because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with other platelet inhibitors. Theoretically, the risk of bleeding may be increased.
    Fluconazole: (Major) Decrease cilostazol dose to one half of the recommended dosage when coadministered with fluconazole. Coadministration may increase cilostazol serum concentrations and increase the risk for adverse reactions. Cilostazol is extensively metabolized by hepatic isoenzyme CYP3A4; fluconazole is a moderate inhibitor of CYP3A4.
    Fludarabine: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Fluoxetine: (Major) Cilostazol is extensively metabolized by the CYP3A4 hepatic isoenzyme and appears to have pharmacokinetic interactions with many medications that are potent inhibitors of CYP3A4, including fluoxetine. These agents have been shown to increase both cilostazol AUC and Cmax when administered concurrently. When significant CYP3A4 inhibitors, such as fluoxetine, are administered concomitantly with cilostazol, the manufacturer recommends that the cilostazol dosage be reduced by 50%.
    Fluoxetine; Olanzapine: (Major) Cilostazol is extensively metabolized by the CYP3A4 hepatic isoenzyme and appears to have pharmacokinetic interactions with many medications that are potent inhibitors of CYP3A4, including fluoxetine. These agents have been shown to increase both cilostazol AUC and Cmax when administered concurrently. When significant CYP3A4 inhibitors, such as fluoxetine, are administered concomitantly with cilostazol, the manufacturer recommends that the cilostazol dosage be reduced by 50%.
    Fluvoxamine: (Major) Decrease cilostazol dose to one half of the recommended dosage when coadministered with fluvoxamine. Coadministration may increase cilostazol serum concentrations and increase the risk for adverse reactions. Cilostazol is extensively metabolized by hepatic isoenzyme CYP3A4; fluvoxamine is a moderate inhibitor of CYP3A4. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased cilostazol Cmax by 94% and AUC by 117%.
    Folate analogs: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Fondaparinux: (Moderate) The safety of cilostazol has not been established with concomitant administration of anticoagulants. Because cilostazol is a platelet aggregation inhibitor, concomitant administration with similar acting drugs could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution. Patients on anticoagulants should be monitored for changes in response to anticoagulation therapy if cilostazol is administered concurrently.
    Food: (Severe) Coadministration with food increases both the AUC and the Cmax of cilostazol, particularly if the meal has a high fat content. Cilostazol is recommended to be administered on an empty stomach, at least one-half hour before or two hours after food.
    Fosamprenavir: (Major) Concurrent administration of cilostazol with protease inhibitors can result in elevated cilostazol plasma concentrations; the manufacturer recommends prescribers consider up to a 50% reduction in cilostazol dosage during concurrent administration. Cilostazol is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Garlic, Allium sativum: (Moderate) Use together with caution. Garlic produces clinically significant antiplatelet effects, and a risk for bleeding may occur if platelet inhibitors are given in combination with garlic.
    Ginger, Zingiber officinale: (Moderate) Ginger inhibits thromboxane synthetase, a platelet aggregation inducer, and is a prostacyclin agonist so additive bleeding may occur if platelet inhibitors are given in combination with ginger, zingiber officinale.
    Ginkgo, Ginkgo biloba: (Major) Use Ginkgo biloba with caution in patients taking platelet inhibitors, as it can produce clinically-significant antiplatelet effects. A compound found in Ginkgo biloba, ginkgolide-B, may act as a selective antagonist of platelet activating factor (PAF). Although a review of Ginkgo biloba in 1992 stated that no known drug interactions exist, spontaneous hyphema has been reported in an elderly male who began taking Ginkgo while stabilized on daily aspirin. After ginkgo was stopped, no further bleeding was noted despite continuing the aspirin therapy. Other clinical data exist that describe spontaneous subdural hematomas associated with chronic Ginkgo biloba ingestion.
    Grapefruit juice: (Major) While the effects have not been systematically evaluated, grapefruit juice may inhibit cilostazol metabolism by inhibiting cytochrome P450 3A4 in enterocytes. Grapefruit juice inhibits the cytochrome P-450 3A4 isozyme in the gut wall. Grapefruit juice contains furanocoumarins that are metabolized by CYP3A4 to reactive intermediates. These intermediates form a covalent bond to the active site of the CYP3A4 enzyme, causing irreversible inactivation (mechanism-based inhibition). Consequently, CYP3A4 activity in the gut wall is inhibited until de novo synthesis returns the enzyme to its previous level. Grapefruit juice increases the Cmax of cilostazol by about 50%, but has no effect on cilostazol AUC. The clinical significance of the interaction is unknown. It is possible that cilostazol induced side effects could be increased in some individuals.
    Green Tea: (Moderate) Green tea has demonstrated antiplatelet and fibrinolytic actions in animals. It is possible that the use of green tea may increase the risk of bleeding if co administered with aspirin. Caution and careful monitoring of clinical and/or laboratory parameters are warranted with this combination.
    Heparin: (Moderate) The safety of cilostazol has not been established with concomitant administration of anticoagulants. Because cilostazol is a platelet aggregation inhibitor, concomitant administration with similar acting drugs could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution. Patients on anticoagulants should be monitored for changes in response to anticoagulation therapy if cilostazol is administered concurrently.
    Ibritumomab Tiuxetan: (Major) During and after therapy, avoid the concomitant use of Yttrium (Y)-90 ibrutumomab tiuxetan with drugs that interfere with platelet function such as platelet inhibitors; the risk of bleeding may be increased. If coadministration with platelet inhibitors is necessary, monitor platelet counts more frequently for evidence of thrombocytopenia.
    Ibrutinib: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as cilostazol may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
    Icosapent ethyl: (Moderate) Icosapent ethyl is an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA). Because omega-3 fatty acids inhibit platelet aggregation, caution is advised when icosapent ethyl is used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 36 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant icosapent ethyl therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with cilostazol, a CYP3A substrate, as cilostazol toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Iloprost: (Moderate) When used concurrently with platelet inhibitors, inhaled iloprost may increase the risk of bleeding.
    Imatinib: (Major) Imatinib is a potent inhibitor of cytochrome P450 (CYP) 3A4 and may increase concentrations of other drugs metabolized by this enzyme, inlcuding cilostazol. Consider up to a 50% reduction in cilostazol dosage when coadministered with imatinib. The combination may also cause an additive risk of bleeding.
    Indinavir: (Major) Concurrent administration of cilostazol with protease inhibitors can result in elevated cilostazol plasma concentrations; the manufacturer recommends prescribers consider up to a 50% reduction in cilostazol dosage during concurrent administration. Cilostazol is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Inotersen: (Moderate) Use caution with concomitant use of inotersen and cilostazol due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of cilostazol in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
    Intravenous Lipid Emulsions: (Moderate) Because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with other platelet inhibitors. Theoretically, the risk of bleeding may be increased.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with cilostazol may result in increased serum concentrations of cilostazol. Cilostazol is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isoniazid, INH: (Major) Decrease cilostazol dose to one-half of the recommended dosage when coadministered with isoniazid. Coadministration may increase cilostazol serum concentrations and increase the risk for adverse reactions. Cilostazol is a CYP2C19 substrate; isoniazid is a moderate CYP2C19 inhibitor. Coadministration of another CYP2C19 inhibitor did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Decrease cilostazol dose to one-half of the recommended dosage when coadministered with isoniazid. Coadministration may increase cilostazol serum concentrations and increase the risk for adverse reactions. Cilostazol is a CYP2C19 substrate; isoniazid is a moderate CYP2C19 inhibitor. Coadministration of another CYP2C19 inhibitor did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%.
    Isoniazid, INH; Rifampin: (Major) Decrease cilostazol dose to one-half of the recommended dosage when coadministered with isoniazid. Coadministration may increase cilostazol serum concentrations and increase the risk for adverse reactions. Cilostazol is a CYP2C19 substrate; isoniazid is a moderate CYP2C19 inhibitor. Coadministration of another CYP2C19 inhibitor did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%.
    Itraconazole: (Major) Decrease cilostazol dose to one half of the recommended dosage when coadministered with itraconazole. Coadministration may increase cilostazol serum concentrations and increase the risk for adverse reactions. Cilostazol is extensively metabolized by hepatic isoenzyme CYP3A4; itraconazole is a strong inhibitor of CYP3A4.In a drug interaction study, coadministration of another strong CYP3A4 inhibitor increased cilostazol Cmax by 94% and AUC by 117%.
    Ketoconazole: (Major) Decrease cilostazol dose to one half of the recommended dosage when coadministered with ketoconazole. Coadministration may increase cilostazol serum concentrations and increase the risk for adverse reactions. Cilostazol is extensively metabolized by hepatic isoenzyme CYP3A4; ketoconazole is a strong inhibitor of CYP3A4. In a drug interaction study, coadministration of ketoconazole and cilostazol increased cilostazol Cmax by 94% and AUC by 117%.
    Lefamulin: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with oral lefamulin, and monitor for an increase in cilostazol-related adverse reactions. Cilostazol is a CYP3A4 substrate. Oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration with another moderate CYP3A4 inhibitor increased the Cmax and AUC of cilostazol (single dose) by 47% and 73%, respectively; the AUC of 4-trans-hydroxycilostazol increased by 141%.
    Lepirudin: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., clopidogrel, platelet glycoprotein IIb/IIIa inhibitors, ticlopidine, etc.) in combination with lepirudin.
    Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of cilostazol; monitor for potential reduction in efficacy. Cilostazol is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of cilostazol; monitor for potential reduction in efficacy. Cilostazol is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Letermovir: (Major) Reduce the dose of cilostazol to 50 mg PO twice daily if coadministered with letermovir due to increased cilostazol exposure and risk for adverse events. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Cilostazol is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. The AUC of cilostazol and its metabolite 4-trans-hydroxycilostazol have been increased by up to 73% and 141%, respectively in the presence of moderate CYP3A4 inhibitors; a strong CYP3A4 inhibitor increased the cilostazol AUC by 117%.
    Levomilnacipran: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of levomilnacipran and platelet inhibitors. Serotonin-norepinephrine reuptake inhibitors (SNRIs) affect platelet activation; therefore, concomitant use may increase the risk of bleeding.
    Lomitapide: (Major) Concomitant use of lomitapide and cilostazol may significantly increase the serum concentration of lomitapide. Therefore, the lomitapide dose should not exceed 30 mg/day PO during concurrent use. Cilostazol is a weak CYP3A4 inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors.
    Lomustine, CCNU: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as lomustine.
    Lopinavir; Ritonavir: (Major) Concurrent administration of cilostazol with protease inhibitors can result in elevated cilostazol plasma concentrations; the manufacturer recommends prescribers consider up to a 50% reduction in cilostazol dosage during concurrent administration. Cilostazol is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Lovastatin: (Moderate) Cilostazol may interact with lovastatin, but it is not clear if the interaction could be clinically significant. In healthy volunteers, peak plasma concentrations of lovastatin did not change with co-administration of cilostazol. However, peak plasma concentrations and the AUC of lovastatin's active metabolite did increase. Also, the peak plasma concentrations and AUC of cilostazol were decreased by roughly 15% when lovastatin was co-administered.
    Lovastatin; Niacin: (Moderate) Cilostazol may interact with lovastatin, but it is not clear if the interaction could be clinically significant. In healthy volunteers, peak plasma concentrations of lovastatin did not change with co-administration of cilostazol. However, peak plasma concentrations and the AUC of lovastatin's active metabolite did increase. Also, the peak plasma concentrations and AUC of cilostazol were decreased by roughly 15% when lovastatin was co-administered.
    Luliconazole: (Moderate) Theoretically, luliconazole may increase the side effects of cilostazol, which is a CYP2C19 and CYP3A4 substrate. Monitor patients for adverse effects of cilostazol, such as increased bleeding. In vitro, therapeutic doses of luliconazole inhibit the activity of CYP2C19 and CYP3A4 and small systemic concentrations may be noted with topical application, particularly when applied to patients with moderate to severe tinea cruris. No in vivo drug interaction trials were conducted prior to the approval of luliconazole.
    Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may reduce the efficacy of cilostazol by decreasing its systemic exposure; caution and close monitoring are advised if these drugs are used together. Cilostazol is extensively metabolized by CYP3A4 and, to a lesser extent, CYP2C19. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest lumacaftor; ivacaftor may induce CYP2C19.
    Mercaptopurine, 6-MP: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Methoxsalen: (Minor) Agents that affect platelet function, such as platelet inhibitors, could decrease the efficacy of methoxsalen when used during photodynamic therapy.
    Methylsulfonylmethane, MSM: (Moderate) Increased effects from concomitant anticoagulant drugs including increased bruising or blood in the stool have been reported in patients taking methylsulfonylmethane, MSM. Although these effects have not been confirmed in published medical literature or during clinical studies, clinicians should consider using methylsulfonylmethane, MSM with caution in patients who are taking anticoagulants or antiplatelets including clopidogrel until data confirming the safety of these drug combinations are available. During one of the available, published clinical trials in patients with osteoarthritis, those patients with bleeding disorders or using anticoagulants or antiplatelets were excluded from enrollment. Patients who choose to consume methylsulfonylmethane, MSM while receiving clopidogrel should be observed for increased bleeding.
    Mifepristone: (Moderate) Mifepristone is a strong inhibitor of CYP3A4. Use of mifepristone may lead to an increase in serum levels of drugs that are CYP3A4 substrates, such as cilostazol. Strong CYP3A4 inhibitors have significantly increased the systemic exposure of cilostazol and/or its major metabolites. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration. If use together is medically necessary, use the lowest dose of cilostazol necessary (e.g., 50 mg PO twice daily), with appropriate monitoring and follow-up. Side effects of cilostazol may include unusual bleeding or bruising, diarrhea, dizziness, edema (such as swelling of the ankles or legs), headache, or upset stomach.
    Milnacipran: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of milnacipran and platelet inhibitors. Serotonin-norepinephrine reuptake inhibitors (SNRIs) affect platelet activation; therefore, concomitant use may increase the risk of bleeding.
    Mitotane: (Moderate) Use caution if mitotane and cilostazol are used concomitantly, and monitor for decreased efficacy of cilostazol and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and cilostazol is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of cilostazol.
    Mycophenolate: (Moderate) Platelet Inhibitors inhibit platelet aggregation and should be used cautiously in patients with thrombocytopenia, as mycophenolate can also cause thrombocytopenia.
    Nefazodone: (Major) Decrease cilostazol dose to one half of the recommended dosage when coadministered with nefazodone. Coadministration may increase cilostazol serum concentrations and increase the risk for adverse reactions. Cilostazol is extensively metabolized by hepatic isoenzyme CYP3A4; nefazodone is a strong inhibitor of CYP3A4. In a drug interaction study, coadministration of another strong CYP3A4 inhibitor and cilostazol increased cilostazol Cmax by 94% and AUC by 117%.
    Nelarabine: (Moderate) Due to the thrombocytopenic effects of nelarabine, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Nelfinavir: (Major) Concurrent administration of cilostazol with protease inhibitors can result in elevated cilostazol plasma concentrations; the manufacturer recommends prescribers consider up to a 50% reduction in cilostazol dosage during concurrent administration. Cilostazol is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Nicardipine: (Minor) Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates, such as cilostazol.
    Nilotinib: (Moderate) Concomitant use of nilotinib, an moderate CYP3A4 inhibitor, and cilostazol, a CYP3A4 substrate, may result in increased cilostazol levels. A cilostazol dose reduction may be necessary if these drugs are used together.
    Nonsteroidal antiinflammatory drugs: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, and prolong bleeding time. If NSAIDs are administered with platelet inhibitors, these pharmacodynamic effects may be increased. The manufacturer of clopidogrel advises that caution be used when used in combination with NSAIDs as an increase in occult GI blood loss occurred when clopidogrel was used concomitantly with naproxen
    Obinutuzumab: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Concurrent administration of cilostazol with protease inhibitors can result in elevated cilostazol plasma concentrations; the manufacturer recommends prescribers consider up to a 50% reduction in cilostazol dosage during concurrent administration. Cilostazol is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Omeprazole: (Major) When significant CYP2C19 inhibitors, such as omeprazole, are administered concomitantly with cilostazol, the cilostazol dosage should be reduced by 50%. Cilostazol is metabolized by the CYP2C19 hepatic isoenzyme and appears to have pharmacokinetic interactions with many medications that are potent inhibitors of CYP2C19. When given concurrently with omeprazole, cilostazol AUC is increased by 26% and the Cmax is increased by 18%; the AUC of the active metabolite 3,4-dehydro-cilostazol is increased by 69% and the Cmax is increased by 29%.
    Omeprazole; Amoxicillin; Rifabutin: (Major) When significant CYP2C19 inhibitors, such as omeprazole, are administered concomitantly with cilostazol, the cilostazol dosage should be reduced by 50%. Cilostazol is metabolized by the CYP2C19 hepatic isoenzyme and appears to have pharmacokinetic interactions with many medications that are potent inhibitors of CYP2C19. When given concurrently with omeprazole, cilostazol AUC is increased by 26% and the Cmax is increased by 18%; the AUC of the active metabolite 3,4-dehydro-cilostazol is increased by 69% and the Cmax is increased by 29%.
    Omeprazole; Sodium Bicarbonate: (Major) When significant CYP2C19 inhibitors, such as omeprazole, are administered concomitantly with cilostazol, the cilostazol dosage should be reduced by 50%. Cilostazol is metabolized by the CYP2C19 hepatic isoenzyme and appears to have pharmacokinetic interactions with many medications that are potent inhibitors of CYP2C19. When given concurrently with omeprazole, cilostazol AUC is increased by 26% and the Cmax is increased by 18%; the AUC of the active metabolite 3,4-dehydro-cilostazol is increased by 69% and the Cmax is increased by 29%.
    Oritavancin: (Major) Cilostazol is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of cilostazol may be reduced if these drugs are administered concurrently.
    Paroxetine: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
    Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and cilostazol, a CYP3A4 substrate, may cause an increase in systemic concentrations of cilostazol. Use caution when administering these drugs concomitantly.
    Pegaspargase: (Moderate) Due to the risk of bleeding and coagulopathy during pegaspargase therapy, patients should receive other agents that may increase the risk of bleeding (e.g., anticoagulants, NSAIDs, platelet inhibitors, or thrombolytic agents) with caution.
    Pentosan: (Moderate) The safety of cilostazol has not been established with concomitant administration of anticoagulants. Because cilostazol is a platelet aggregation inhibitor, concomitant administration with similar acting drugs could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution. Patients on anticoagulants should be monitored for changes in response to anticoagulation therapy if cilostazol is administered concurrently.
    Pentostatin: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Pentoxifylline: (Moderate) A potential additive risk for bleeding exists if platelet inhibitors are given in combination with other agents that affect hemostasis such as pentoxifylline.
    Phentermine; Topiramate: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as cilostazol may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation. In addition, cilostazol is metabolized by the cytochrome P450 CYP2C19 hepatic isoenzyme and may interact with medications that are inhibitors of CYP2C19, including topiramate.
    Photosensitizing agents (topical): (Minor) Agents, such as platelet inhibitors, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Platelet Glycoprotein IIb/IIIa Inhibitors: (Moderate) Because cilostazol is a platelet aggregation inhibitor, a potential additive risk for bleeding exists if cilostazol is given with other agent that affect hemostasis such as platelet glycoprotein IIb/IIIa inhibitors including abciximab, eptifibatide, and tirofiban.
    Posaconazole: (Moderate) Posaconazole and cilostazol should be coadministered with caution due to an increased potential for cilostazol-related adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of cilostazol. These drugs used in combination may result in elevated cilostazol plasma concentrations, causing an increased risk for cilostazol-related adverse events.
    Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Moderate) Prasterone is contraindicated for use in patients with active deep vein thrombosis, pulmonary embolism or history of these conditions. Prasterone is also contraindicated in patients with active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions. Thus, patients receiving anticoagulation due to a history of these conditions are not candidates for prasterone treatment. DHEA is converted to androgens and estrogens within the human body and thus may affect hemostasis via androgenic or estrogenic effects. Estrogens increase the production of clotting factors VII, VIII, IX, and X. Androgens, such as testosterone, increase the synthesis of several anticoagulant and fibrinolytic proteins. Because of the potential effects on coagulation, patients receiving prasterone or DHEA concurrently with preventative anticoagulants (e.g., warfarin or heparin) or other platelet inhibitors, including aspirin, ASA should be monitored for side effects or the need for dosage adjustments.
    Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Moderate) Prasterone is contraindicated for use in patients with active deep vein thrombosis, pulmonary embolism or history of these conditions. Prasterone is also contraindicated in patients with active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions. Thus, patients receiving anticoagulation due to a history of these conditions are not candidates for prasterone treatment. DHEA is converted to androgens and estrogens within the human body and thus may affect hemostasis via androgenic or estrogenic effects. Estrogens increase the production of clotting factors VII, VIII, IX, and X. Androgens, such as testosterone, increase the synthesis of several anticoagulant and fibrinolytic proteins. Because of the potential effects on coagulation, patients receiving prasterone or DHEA concurrently with preventative anticoagulants (e.g., warfarin or heparin) or other platelet inhibitors, including aspirin, ASA should be monitored for side effects or the need for dosage adjustments.
    Prasugrel: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of cilostazol and prasugrel. Both agents are platelet inhibitors; therefore, concomitant use may increase the risk of bleeding. Platelet aggregation returns to normal within 96 hours of discontinuing cilostazol.
    Protease inhibitors: (Major) Concurrent administration of cilostazol with protease inhibitors can result in elevated cilostazol plasma concentrations; the manufacturer recommends prescribers consider up to a 50% reduction in cilostazol dosage during concurrent administration. Cilostazol is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Purine analogs: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Ranolazine: (Moderate) Ranolazine inhibits CYP3A isoenzymes and may theoretically increase plasma concentrations of CYP3A4 substrates, like cilostazol, potentially leading to adverse reactions.
    Ribociclib: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with ribociclib. Monitor for an increase in cilostazol-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor and cilostazol is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the cilostazol AUC by 117%.
    Ribociclib; Letrozole: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with ribociclib. Monitor for an increase in cilostazol-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor and cilostazol is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the cilostazol AUC by 117%.
    Riociguat: (Moderate) Coadministration of riociguat and phosphodiesterase inhibitors, including specific phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil) and nonspecific phosphodiesterase inhibitors (dipyridamole or theophylline, aminophylline) is contraindicated due to the risk of hypotension. Clinical experience with other phosphodidesterase inhibitors (e.g., milrinone, cilostazol, and roflumilast) is limited. The addition of riociguat to a stable sildenafil regimen (20 mg three times a day) resulted in additive hemodynamic effects in an exploratory interaction study in 7 patients with pulmonary arterial hypertension (PAH). Among patients with PAH on stable sildenafil treatment and riociguat there was one death, possibly related to the combination of these drugs, and a high rate of discontinuation for hypotension.
    Ritonavir: (Major) Concurrent administration of cilostazol with protease inhibitors can result in elevated cilostazol plasma concentrations; the manufacturer recommends prescribers consider up to a 50% reduction in cilostazol dosage during concurrent administration. Cilostazol is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Rivaroxaban: (Major) Avoid concurrent administration of platelet inhibitors such as clopidogrel with rivaroxaban unless the benefit outweighs the risk of increased bleeding. An increase in bleeding time to 45 minutes was observed in two drug interaction studies where clopidogrel (300 mg loading dose followed by 75 mg daily maintenance dose) and rivaroxaban (15 mg single dose) were coadministered in healthy subjects. In the first study, the increase in bleeding time to 45 minutes was observed in approximately 45% of patients. Approximately 30% of patients in the second study had the event. The change in bleeding time was approximately twice the maximum increase seen with either drug alone. No change in the pharmacokinetic parameters of either drug were noted.
    Rufinamide: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as cilostazol, may occur during concurrent use with rufinamide.
    Saquinavir: (Major) Concurrent administration of cilostazol with protease inhibitors can result in elevated cilostazol plasma concentrations; the manufacturer recommends prescribers consider up to a 50% reduction in cilostazol dosage during concurrent administration. Cilostazol is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Selumetinib: (Moderate) Closely monitor for bleeding if coadministration of selumetinib and platelet inhibitors is necessary as concurrent use may increase the bleeding risk; adjust the platelet inhibitor dose as appropriate. Selumetinib contains vitamin E which can inhibit platelet aggregation.
    Sertraline: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
    Simeprevir: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of cilostazol, which is a CYP3A4 substrate. Monitor patients for adverse effects of cilostazol, such as increased bleeding.
    Sodium Hyaluronate, Hyaluronic Acid: (Moderate) Increased bruising or bleeding at the injection site may occur when using hyaluronate sodium with platelet inhibitors especially if used within the 3 weeks prior to the procedure.
    St. John's Wort, Hypericum perforatum: (Moderate) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system. Co-administration of St. John's wort could decrease the efficacy of some medications metabolized by these enzymes, including cilostazol.
    Sulfinpyrazone: (Major) Sulfinpyrazone, when used as a uricosuric agent should be avoided when possible with concurrent platelet inhibitors due to potential for additive antiplatelet effects and increased bleeding risk.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering cilostazol with telaprevir due to an increased potential for cilostazol-related adverse events. If cilostazol dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of cilostazol. Cilostazol is metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated cilostazol plasma concentrations.
    Telithromycin: (Major) Concentrations of cilostazol may be increased with concomitant use of telithromycin. Cilostazol is a CYP3A4 substrate and telithromycin is a strong CYP3A4 inhibitor. Patients should be monitored for increased side effects.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and cilostazol is necessary, as the systemic exposure of cilostazol may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of cilostazol; consider increasing the dose of cilostazol if necessary. Cilostazol is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Thioguanine, 6-TG: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Thrombolytic Agents: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
    Ticagrelor: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of cilostazol and ticagrelor. Both agents are platelet inhibitors; therefore, concomitant use may increase the risk of bleeding. Platelet aggregation returns to normal within 96 hours of discontinuing cilostazol.
    Ticlopidine: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of cilostazol and ticlopidine. Both agents are platelet inhibitors; therefore, concomitant use may increase the risk of bleeding. Additionally, ticlopidine may increase serum concentrations of cilostazol. Cilostazol is a CYP2C19 substrate and ticlopidine is a potent CYP2C19 inhibitor. Platelet aggregation returns to normal within 96 hours of discontinuing cilostazol.
    Tinzaparin: (Moderate) The safety of cilostazol has not been established with concomitant administration of anticoagulants. Because cilostazol is a platelet aggregation inhibitor, concomitant administration with similar acting drugs could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution. Patients on anticoagulants should be monitored for changes in response to anticoagulation therapy if cilostazol is administered concurrently.
    Tipranavir: (Major) Concurrent administration of cilostazol with protease inhibitors can result in elevated cilostazol plasma concentrations; the manufacturer recommends prescribers consider up to a 50% reduction in cilostazol dosage during concurrent administration. Cilostazol is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Tirofiban: (Moderate) Because cilostazol is a platelet aggregation inhibitor, a potential additive risk for bleeding exists if cilostazol is given with other agent that affect hemostasis such as platelet glycoprotein IIb/IIIa inhibitors including abciximab, eptifibatide, and tirofiban.
    Tobacco: (Moderate) Tobacco smoking appears to decrease cilostazol serum concentrations by roughly 20%. There were no statistically significant differences in absolute claudication distance (ACD) at the end of cilostazol treatment during clinical trials in those patients with peripheral arterial disease who were smokers versus those who were not. However, it is unknown if tobacco smoking would contribute to a decreased clinical response to cilostazol when the drug is administered for other uses or when the clinical response to cilostazol is measured by parameters other than ACD. Given the adverse effects that tobacco smoking may have on the peripheral vasculature, patients taking cilostazol should be advised not to smoke tobacco.
    Topiramate: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as cilostazol may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation. In addition, cilostazol is metabolized by the cytochrome P450 CYP2C19 hepatic isoenzyme and may interact with medications that are inhibitors of CYP2C19, including topiramate.
    Trandolapril; Verapamil: (Major) Cilostazol clearance may be impaired by inhibitors of the CYP3A4 hepatic microsomal isoenzyme, including verapamil. When verapamil is coadministered with cilostazol, the manufacturer recommends that the cilostazol dosage be reduced by 50%.
    Trazodone: (Moderate) Platelet aggregation may be impaired by trazodone due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking trazodone concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Treprostinil: (Moderate) Monitor patients for signs and symptoms of bleeding if treprostinil is administered with cilostazol. Treprostinil inhibits platelet aggregation; cilostazol is a platelet inhibitor. Coadministration increases the risk of bleeding.
    Tretinoin, ATRA: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as tretinoin.
    Tucatinib: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with tucatinib and monitor for an increase in cilostazol-related adverse reactions. Concurrent use may increase cilostazol exposure. Cilostazol is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the cilostazol AUC by 117%.
    Vemurafenib: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as cilostazol, could be expected with concurrent use. Use caution, and monitor therapeutic effects of cilostazol when coadministered with vemurafenib.
    Venlafaxine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
    Verapamil: (Major) Cilostazol clearance may be impaired by inhibitors of the CYP3A4 hepatic microsomal isoenzyme, including verapamil. When verapamil is coadministered with cilostazol, the manufacturer recommends that the cilostazol dosage be reduced by 50%.
    Verteporfin: (Moderate) Use caution if coadministration of verteporfin with platelet inhibitors is necessary due to the risk of decreased verteporfin efficacy. Verteporfin is a light-activated drug. Once activated, local damage to neovascular endothelium results in a release of procoagulant and vasoactive factors resulting in platelet aggregation, fibrin clot formation, and vasoconstriction. Concomitant use of drugs that decrease platelet aggregation could decrease the efficacy of verteporfin therapy.
    Vilazodone: (Moderate) Patients should be instructed to monitor for signs and symptoms of bleeding while taking vilazodone concurrently with salicylates or other platelet inhibitors and to promptly report any bleeding events to the practitioner. Platelet aggregation may be impaired by vilazodone due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., aspirin, cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors).
    Vorapaxar: (Moderate) Because vorapaxar and cilostazol inhibit platelet aggregation, a potential additive risk for bleeding exists if they are coadminsitered.
    Voriconazole: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with voriconazole. Monitor for an increase in cilostazol-related adverse reactions. Voriconazole is a strong CYP3A4 inhibitor and cilostazol is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the cilostazol AUC by 117%.
    Vorinostat: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of cilostazol and vorinostat. Due to the thrombocytopenic effects of vorinostat, an additive risk of bleeding may occur in patients taking platelet inhibitors. Platelet aggregation returns to normal within 96 hours of discontinuing cilostazol.
    Vortioxetine: (Moderate) Platelet aggregation may be impaired by vortioxetine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymosis to life-threatening hemorrhages. Patients should be instructed to monitor for signs and symptoms of bleeding while taking vortioxetine concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Warfarin: (Moderate) The safety of cilostazol has not been established with concomitant administration of heparin, other anticoagulants, or thrombolytic agents. Because cilostazol is a platelet aggregation inhibitor, concomitant administration with similar acting drugs could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution. While both cilostazol and warfarin are metabolized by cytochrome P450 CYP3A4 and CYP2C19, administration of cilostazol with a single dose of warfarin (25 mg) in healthy volunteers did not affect warfarin metabolism or effect changes in pro-times, bleeding times, or platelet aggregation. However, the effect of concomitant multiple dosing of cilostazol and warfarin has not been evaluated. Patients on anticoagulants should be monitored for changes in response to anticoagulation therapy if cilostazol is administered concurrently. Regularly monitor the INR and other clinical parameters during the chronic concomitant administration of warfarin and cilostazol. Although the risk of bleeding is increased when clopidogrel is used concomitantly with thrombolytic agents, it is common to see patients receive these drugs simultaneously.
    Zafirlukast: (Moderate) Cilostazol is extensively metabolized by the cytochrome P450 CYP3A4 hepatic isoenzyme and metabolism may be inhibited by zafirlukast, an inhibitor of CYP3A4.

    PREGNANCY AND LACTATION

    Pregnancy

    Cilostazol is classified as pregnancy category C. There are no well-controlled, adequate clinical studies in pregnant women. In rats, cilostazol has been associated with cardiovascular, renal, and skeletal anomalies when administered in doses of 1000 mg/kg/day. Increased incidences of ventricular septal defects and retarded ossification also occurred at doses of 150 mg/kg/day (5 times the maximum recommended human dosage on a systemic exposure basis). When cilostazol was administered during late pregnancy and lactation in rats, doses of 150 mg/kg/day were associated with low birth weights and stillbirths.

    Cilostazol is excreted into the breast milk of rats. Because many drugs are excreted in human milk and because of the potential for serious adverse events in breast-feeding infants from cilostazol, discontinue cilostazol or discontinue breast-feeding.

    MECHANISM OF ACTION

    The pharmacologic effects of cilostazol are multifactorial and include antithrombotic, antiplatelet, and vasodilatory actions. The actions of cilostazol with respect to peripheral arterial disease may be particularly significant within the microcirculation. Cilostazol inhibits platelet aggregation caused by ADP, arachidonic acid, collagen, epinephrine, thrombin, and shear stress; it is 10—30 times more potent than aspirin in this regard, but cilostazol does not inhibit prostaglandin I2 synthesis. Cilostazol and its metabolites reversibly inhibit platelet aggregation via inhibition of phosphodiesterase (PDE) type III activity. This action suppresses degradation of cyclic AMP and increases levels of cyclic AMP in platelets. Cyclic AMP levels are also increased in the vascular tissue, promoting vasodilation. The vasodilatory actions of cilostazol are greater on femoral arteries than on vertebral, carotid, or superior mesenteric arteries. Renal arteries do not vasodilate in response to cilostazol administration.
     
    Cilostazol favorably alters the lipid profile, decreasing plasma triglycerides by roughly 15% and increasing HDL cholesterol by roughly 10%. Cilostazol also decreases remnant lipoprotein particles (RLPs) of plasma chylomicrons and VLDLs, a lipid fraction that has been shown to contribute to platelet aggregation. The exact mechanism by which cilostazol induces these favorable effects on lipoproteins is currently unknown, but it is possibly due to actions of increased cyclic AMP.
     
    Finally, cilostazol inhibits the proliferation of vascular smooth muscle cells in vitro; this action may be mediated by increases in cyclic AMP. In addition, cilostazol suppresses intracellular heparin-binding EGF-like growth factor in smooth muscle cells. In theory, by interfering with the proliferation of smooth muscle cells, cilostazol may potentially inhibit the initiation and progression of atherosclerosis..

    PHARMACOKINETICS

    Cilostazol is administered orally. It is extensively metabolized in the liver by the CYP3A4 and, to a lesser extent, CYP2C19 isoenzymes. Two metabolites are active. The primary metabolite, 3,4-dehydro-cilostazol, is 4—7 times more pharmacologically active than cilostazol and appears to account for at least 50% of the cilostazol's activity. The second metabolite, 4'-trans-hydroxy-cilostazol, is one-fifth as active as the parent compound. Cilostazol and its metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. Cilostazol and its metabolites are further metabolized in the liver; the primary route of elimination is the urine (74%) and feces (20%). No measurable amount of cilostazol is excreted unchanged and less than 2% of the dose is excreted as 3,4-dehydro-cilostazol. The apparent elimination half-lives of cilostazol and its metabolites are roughly 11—13 hours.
     
    Affected cytochrome P450 isoenzymes: CYP3A4, CYP2C19

    Oral Route

    The absolute bioavailability of cilostazol after oral administration is not known. However, administration with a high fat meal increases cilostazol AUC by 25% and Cmax by 90%. Cilostazol is 95—98% protein bound, primarily to albumin.