CILOSTAZOL — cilostazol tablet
STAT RX USA LLC
Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV congestive heart failure. Cilostazol is contraindicated in patients with congestive heart failure of any severity.
DESCRIPTION Cilostazol is a quinolinone derivative that inhibits cellular phosphodiesterase (more specific for phosphodiesterase III). The empirical formula of cilostazol is C20 H27 N5 O2 , and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H -tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1. The structural formula is:
Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in methanol and ethanol, and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.
Cilostazol tablets for oral administration are available as 50 mg or 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: carboxymethylcellulose calcium, corn starch, hypromellose, magnesium stearate and microcrystalline cellulose.
Mechanism of Action:
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) phosphodiesterase III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in cAMP in platelet and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including thrombin, ADP, collagen, arachidonic acid, epinephrine, and shear stress. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in triglycerides of 29.3 mg/dL (15%) and an increase in HDL-cholesterol of 4.0 mg/dL ( ≅10%).
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, carotid, or superior mesenteric arteries. Renal arteries were not responsive to the effects of cilostazol.
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with Holter monitors, numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained ventricular tachycardia events than did placebo-treated patients; the increases were not dose-related.
Pharmacokinetics:Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).
The mean ± SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below:
Plasma Protein and Erythrocyte Binding: Cilostazol is 95%-98% protein bound, predominantly to albumin. The mean percent binding for 3,4-dehydro-cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.
Metabolism and Excretion:
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol’s metabolism are CYP3A4 and, to a lesser extent, CYP2C19. The enzyme responsible for metabolism of 3,4-dehydro-cilostazol, the most active of the metabolites, is unknown.
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.
Age and Gender: The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50-to-80-year-old age range.
Smokers: Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.
Hepatic Impairment: The pharmacokinetics of cilostazol and its metabolites were similar in subjects with mild hepatic disease as compared to healthy subjects.
Patients with moderate or severe hepatic impairment have not been studied.
Renal Impairment: The total pharmacologic activity of cilostazol and its metabolites was similar in subjects with mild to moderate renal impairment and in normal subjects. Severe renal impairment increases metabolite levels and alters protein binding of the parent and metabolites. The expected pharmacologic activity, however, based on plasma concentrations and relative PDE III inhibiting potency of parent drug and metabolites, appeared little changed. Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95%-98%).
Pharmacokinetic and Pharmacodynamic Drug-Drug Interactions: Cilostazol could have pharmacodynamic interactions with other inhibitors of platelet function and pharmacokinetic interactions because of effects of other drugs on its metabolism by CYP3A4 or CYP2C19. A reduced dose of cilostazol should be considered when taken concomitantly with CYP3A4 or CYP2C19 inhibitors. Cilostazol does not appear to inhibit CYP3A4 (see Pharmacokinetic and Pharmacodynamic Drug-Drug Interactions, Lovastatin).
Aspirin: Short-term (≤ 4 days) coadministration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% — 37% when compared to either aspirin or cilostazol alone. Short-term (≤ 4 days) coadministration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term coadministration of aspirin with cilostazol had no clinically significant impact on PT, aPTT, or bleeding time compared to aspirin alone. Effects of long-term coadministration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was coadministered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75-81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.
Warfarin: The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2, and CYP2C19, and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time, or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.
Clopidogrel: Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.
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