PLETAL®

Oral Cilostazol cuts stent restenosis in bare-metal stents: extensive safety record.(Rx): An article from: Internal Medicine News



(PLAY-tal)
(cilostazol) (sil-OS-tah-zol)
Tablets
CONTRAINDICATIONCilostazol 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. PLETAL is
contraindicated in patients with congestive heart failure of any severity.

DESCRIPTIONPLETAL (cilostazol) is a quinolinone derivative that inhibits cellular phosphodiesterase (more specific for phosphodiesterase
III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1Htetrazol-
5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.
The structural formula is:

CILOSTAZOL
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.

PLETAL tablets for oral administration are available in 50 mg triangular and 100 mg round, white debossed tablets. Each tablet,
in addition to the active ingredient, contains the following inactive ingredients: carboxymethylcellulose calcium, corn starch,
hydroxypropyl methylcellulose 2910, magnesium stearate, and microcrystalline cellulose.

CLINICAL PHARMACOLOGY
Mechanism of Action:The mechanism of the effects of PLETAL on the symptoms of intermittent claudication is not fully understood. PLETAL 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 platelets and blood vessels,
leading to inhibition of platelet aggregation and vasodilation, respectively.

PLETAL 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 PLETAL. After 12
weeks, as compared to placebo, PLETAL 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%).

Cardiovascular Effects:
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:PLETAL (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 PLETAL. 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 PLETAL 100 mg b.i.d. is shown
below:

Distribution: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-dehydrocilostazol.

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.

Special Populations: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 PLETAL (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 PLETAL increased the inhibition of ADP-induced ex vivo platelet
aggregation by 22% - 37% when compared to either aspirin or PLETAL alone. Short-term (<4 days) coadministration of aspirin
with PLETAL increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to PLETAL
alone and by 48% compared to aspirin alone. However, short-term coadministration of aspirin with PLETAL 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 PLETAL 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.

Inhibitors of CYP3A4:Strong Inhibitors of CYP3A4: A priming dose of ketoconazole 400 mg (a strong inhibitor of CYP3A4), was given one day prior
to coadministration of single doses of ketoconazole 400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by
94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as itraconazole, fluconazole, miconazole, fluvoxamine,
fluoxetine, nefazodone, and sertraline, would be expected to have a similar effect (see DOSAGE AND ADMINISTRATION).
Moderate Inhibitors of CYP3A4

1. Erythromycin and other macrolide antibiotics: Erythromycin is a moderately strong inhibitor of CYP3A4. Coadministration
of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%.
Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other
macrolide antibiotics (e.g., clarithromycin), but not all (e.g., azithromycin), would be expected to have a similar effect (see
DOSAGE AND ADMINISTRATION).

2. Diltiazem: Diltiazem 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC
increased ~40% (see DOSAGE AND ADMINISTRATION).

3. Grapefruit Juice: Grapefruit juice increased the Cmax of cilostazol by ~50%, but had no effect on AUC.

Inhibitors of CYP2C19:Omeprazole: Coadministration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure
to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 (see
DOSAGE AND ADMINISTRATION).

Quinidine:Concomitant administration of quinidine with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.

Lovastatin:The concomitant administration of lovastatin with cilostazol decreases cilostazol Css, max and AUCτ by 15%. There is also a
decrease, although nonsignificant, in cilostazol metabolite concentrations. Coadministration of cilostazol with lovastatin
increases lovastatin and ß-hydroxi lovastatin AUC approximately 70%. This is most likely clinically insignificant.

CLINICAL STUDIES

The ability of PLETAL (cilostazol) to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998), and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.

Compared to patients treated with placebo, patients treated with PLETAL 50 or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exerciselimiting symptoms supervened (maximal walking distance). The effect of PLETAL on walking distance was seen as early as the first on-therapy observation point of two or four weeks.

The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.