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Cilostazol

Pronunciation

Pronunciation: sil-OH-sta-zol
Class: Aggregation inhibitor

Trade Names

Pletal
- Tablets 50 mg
- Tablets 100 mg

Pharmacology

Inhibits cellular phosphodiesterase and exhibits a higher specificity for phosphodiesterase III.

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Pharmacokinetics

Absorption

A high-fat meal increases C max approximately 90% and AUC 25%.

Distribution

95% to 98% protein bound, predominantly to albumin.

Metabolism

Extensively metabolized in the liver by CYP3A4 and, to a lesser extent, CYP2C19. Two of the metabolites are active.

Elimination

The t ½ is approximately 11 to 13 h. Approximately 74% is excreted in the urine and 20% in the feces as metabolites.

Special Populations

Renal Function Impairment

Severe renal function impairment increases metabolic levels and alters protein binding of the parent and metabolites.

Hepatic Function Impairment

Patients with moderate or severe hepatic function impairment have not been studied.

Smoking

Smoking decreased exposure approximately 20%.

Indications and Usage

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

Contraindications

CHF of any severity; hypersensitivity to any components of the product; patients with hemostatic disorders or active pathologic bleeding (eg, bleeding ulcer, intracranial bleeding).

Dosage and Administration

Intermittent Claudication
Adults

PO 100 mg twice daily, taken at least 30 min before or 2 h after breakfast and dinner. Consider a dosage reduction to 50 mg twice daily during coadministration of CYP2C19 inhibitors such as omeprazole or CYP3A4 inhibitors such as diltiazem, erythromycin, itraconazole, and ketoconazole.

Storage/Stability

Store at 59° to 86°F.

Drug Interactions

Aspirin

Short-term (up to 4 days) coadministration of aspirin with cilostazol showed a 22% to 37% increase in inhibition of adenosine diphosphate–induced ex vivo platelet aggregation compared with aspirin alone.

Moderate inhibitors of CYP3A4 (eg, clarithromycin, diltiazem, erythromycin, grapefruit juice)

Cilostazol plasma concentrations may be elevated, increasing the pharmacologic and adverse reactions.

Omeprazole

Coadministration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased 69%.

CYP-450 system

Cilostazol could have pharmacokinetic interactions because of effects of other drugs on its metabolism by CYP3A4 or CYP2C19.

Platelet function inhibitors

Cilostazol could have pharmacodynamic interactions with other platelet function inhibitors.

Strong inhibitors of CYP3A4 (eg, fluoxetine, fluvoxamine, itraconazole, ketoconazole, nefazodone)

Cilostazol plasma concentrations may be elevated, increasing the pharmacologic and adverse reactions.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Palpitation (10%); tachycardia (4%); atrial fibrillation, atrial flutter, cerebral infarct, cerebral ischemia, CHF, heart arrest, hemorrhage, hypotension, MI, myocardial ischemia, nodal arrhythmia, postural hypotension, supraventricular tachycardia, syncope, varicose vein, vasodilation, ventricular extrasystoles, ventricular tachycardia (less than 2%); QTc prolongation, subacute thrombosis, torsades de pointes (postmarketing).

CNS

Headache (34%); dizziness (10%); vertigo (3%); anxiety, insomnia, malaise, neuralgia (less than 2%); cerebral hemorrhage, cerebrovascular accident, intracranial hemorrhage (postmarketing).

Dermatologic

Dry skin, furunculosis, skin hypertrophy, urticaria (less than 2%); pruritus, skin drug eruption (dermatitis medicamentosa), skin eruptions including Stevens-Johnson syndrome, subcutaneous hemorrhage (postmarketing).

EENT

Rhinitis (12%); pharyngitis (10%); amblyopia, blindness, conjunctivitis, diplopia, ear pain, eye hemorrhage, retinal hemorrhage, tinnitus (less than 2%).

Endocrine

Diabetes mellitus (less than 2%).

GI

Diarrhea (19%); abnormal stools (15%); nausea (7%); dyspepsia (6%); abdominal pain (5%); flatulence (3%); anorexia, colitis, duodenal ulcer, duodenitis, esophageal hemorrhage, esophagitis, gastritis, gastroenteritis, gum hemorrhage, hematemesis, increased gamma-glutamyltransferase, melena, peptic ulcer, periodontal abscess, rectal hemorrhage, stomach ulcer, tongue edema (less than 2%); GI hemorrhage (postmarketing).

Genitourinary

Albuminuria, cystitis, urinary frequency, vaginal hemorrhage, vaginitis (less than 2%).

Hematologic-Lymphatic

Anemia, ecchymosis, iron deficiency anemia, polycythemia, purpura (less than 2%); agranulocytosis, bleeding tendency, granulocytopenia, leukopenia, thrombocytopenia (postmarketing).

Hepatic

Cholelithiasis (less than 2%); hepatic function impairment/abnormal LFTs, jaundice (postmarketing).

Lab Tests

Decreased platelet count, decreased WBC, increased blood glucose, increased blood uric acid, increased BUN (postmarketing).

Metabolic-Nutritional

Peripheral edema (9%); gout, hyperlipemia, hyperuricemia, increased creatinine, (less than 2%).

Musculoskeletal

Back pain (7%); myalgia (3%); arthralgia, bone pain, bursitis, neck rigidity, pelvic pain (less than 2%).

Respiratory

Increased cough (4%); asthma, epistaxis, hemoptysis, pneumonia, sinusitis (less than 2%); interstitial pneumonia, pulmonary hemorrhage (postmarketing).

Miscellaneous

Infection (14%); chills, face edema, fever, generalized edema, retroperitoneal hemorrhage (less than 2%); chest pain, extradural hematoma, hot flushes, pain, subdural hematoma (postmarketing).

Precautions

Warnings

Contraindicated for use in CHF patients of any severity. Cilostazol and metabolites are inhibitors of phosphodiesterase III. Such activity has been shown to decrease survival of patients with class III to IV CHF.


Monitor

Monitor patient for signs and symptoms of bleeding, especially those concurrently on other anticoagulants. Assess patient for adverse cardiac signs and symptoms and for signs of CHF.


Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy in children have not been established.

Renal Function

Use with caution in patients with severe renal function impairment (Ccr less than 25 mL/min).

Hepatic Function

Use with caution.

Hematologic toxicity

Thrombocytopenia or leukopenia progressing to agranulocytosis has been reported; however, agranulocytosis was reversible on immediate discontinuation of cilostazol.

Overdosage

Symptoms

Cardiac arrhythmias, diarrhea, hypotension, severe headache, tachycardia.

Patient Information

  • Instruct patient to take cilostazol as directed and to read the patient package insert before starting therapy or restarting therapy.
  • Advise patient to inform health care provider if taking or planning to take any OTC medications because there is a potential for drug interactions.
  • Advise patient that beneficial effects of cilostazol may not be immediate; relief of symptoms may require 2 to 12 wk.
  • Instruct patient to avoid consuming grapefruit juice to avoid drug/food interactions.
  • Advise smokers of risks, including potential interaction with the drug, and the benefits of not smoking.
  • Warn patient, especially patient with underlying heart disease, of the uncertainty concerning the CV risk with long-term use. Instruct patient to report adverse cardiac symptoms immediately to health care provider before taking next dose.
  • Advise patient not to take aspirin or an NSAID without informing health care provider.
  • Instruct patient to inform primary caregiver of any adverse reactions.
  • Warn women of childbearing potential to avoid becoming pregnant and apprise them of the potential hazard to the fetus.
  • Warn breast-feeding mothers of the danger of transferring the drug to the baby through mother's milk and possible infant effects. Patients decide to discontinue the drug or breast-feeding in collaboration with health care provider.
  • Instruct patient to report any unusual reaction or concern to health care provider.

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