Pletal Information
Pletal ()
Pletal () Description
Pletal () (cilostazol) is a quinolinone derivative that inhibits cellular phosphodiesterase (more specific for phosphodiesterase III). The empirical formula of cilostazol is CHNO, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1)-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.
Pletal () (cilostazol) 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.
Pletal () Clinical Pharmacology
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%).
Pletal () is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in C 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:
Pletal () Clinical Studies
The ability of Pletal () 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 exercise-limiting 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.
Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with Pletal () 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.
The corresponding changes in the placebo group were –10% to 41%.
The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either Pletal () 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age, and concomitant use of beta blockers or calcium channel blockers. Pletal () has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers, or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.
A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8 to 8.4%) on cilostazol and 6.8% (95% CI of 1.9 to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which is the study hypothesis.
Pletal () Indications And Usage
Pletal () is indicated for the reduction of symptoms of intermittent claudication, as indicated by an increased walking distance.
Pletal () Precautions
Please refer to the patient package insert.
Patients should be advised:
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.
Special caution is advised when Pletal () is used in such patients.
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%).
Special caution is advised when Pletal () is used in patients with severe renal impairment: estimated creatinine clearance
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation, and mouse bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the Chinese Hamster Ovary Cell assay.
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males, and about 5 times in females, the exposure in humans at the MRHD.
Pletal () Adverse Reactions
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. Pletal () (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on Pletal () and 134 days for patients on placebo.
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with Pletal () 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with Pletal () 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included palpitation and diarrhea, both 1.1% for cilostazol (all doses) versus 0.1% for placebo.
The most commonly reported adverse events, occurring in ≥2% of patients treated with Pletal () 50 or 100 mg b.i.d., are shown in the table (below).
Other events seen with an incidence of ≥2%, but occurring in the placebo group at least as frequently as in the 100 mg b.i.d. group were: asthenia, hypertension, vomiting, leg cramps, hypesthesia, paresthesia, dyspnea, rash, hematuria, urinary tract infection, flu syndrome, angina pectoris, arthritis, and bronchitis.
Less frequent adverse events (
Pletal () Overdosage
Information on acute overdosage with Pletal () in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe headache, diarrhea, hypotension, tachycardia, and possibly cardiac arrhythmias. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by hemodialysis or peritoneal dialysis. The oral LD of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.
Pletal () Dosage And Administration
The recommended dosage of Pletal () is 100 mg b.i.d. taken at least half an hour before or two hours after breakfast and dinner. A dose of 50 mg b.i.d. should be considered during coadministration of such inhibitors of CYP3A4 as ketoconazole, itraconazole, erythromycin and diltiazem, and during coadministration of such inhibitors of CYP2C19 as omeprazole.
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.
Pletal () How Supplied
Pletal () is supplied as 50 mg and 100 mg tablets. The 50 mg tablets are white, triangular, debossed with Pletal () 50, and provided in bottles of 60 tablets (NDC #59148-003-16).
The 100 mg tablets are white, round, debossed with Pletal () 100, and provided in bottles of 60 tablets (NDC #59148-002-16).
Pletal ()
Pletal () Principal Display Panel - Mg Bottle Label
Pletal () Principal Display Panel - Mg Bottle Label
