Cilostazol (Pletal)
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Cilostazol (Pletal)

PLETAL
(cilostazol) Tablets

CONTRAINDICATION

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. Pletal (cilostazol) is contraindicated in patients with congestive heart failure of any severity.

DRUG DESCRIPTION

Pletal (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-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1. The structural formula is:

PLETAL (PLAY-tal)  Structural Formula Illustration

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.

What are the possible side effects of cilostazol (Pletal)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have any of these serious side effects:

  • severe headache;
  • bloody urine, painful urination;
  • fever, chills, body aches, flu symptoms;
  • chest pain;
  • feeling short of breath, even with mild exertion; or
  • swelling of your ankles or feet.

Less serious side effects may include:

  • fast or pounding heartbeats;
  • diarrhea,...

Read All Potential Side Effects and See Pictures of Pletal »

What are the precautions when taking cilostazol (Pletal)?

Before taking cilostazol, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: bleeding disorders (such as bleeding ulcers, bleeding in the eye/brain), congestive heart failure, other heart disease (such as heart attack, chest pain, fast/irregular heartbeat), stroke, kidney disease, liver disease, blood disorders (such as hemophilia, low platelet counts).

This drug may make you dizzy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such...

Read All Potential Precautions of Pletal »

Last reviewed on RxList: 12/19/2007
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

Pletal (cilostazol) is indicated for the reduction of symptoms of intermittent claudication, as indicated by an increased walking distance.

DOSAGE AND ADMINISTRATION

The recommended dosage of Pletal (cilostazol) 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.

Discontinuation of Therapy: The available data suggest that the dosage of Pletal (cilostazol) can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).

HOW SUPPLIED

Pletal (cilostazol) is supplied as 50 mg and 100 mg tablets. The 50 mg tablets are white, triangular, debossed with Pletal (cilostazol) 50, and provided in bottles of 60 tablets (NDC #59148-003-16).

The 100 mg tablets are white, round, debossed with Pletal (cilostazol) 100, and provided in bottles of 60 tablets (NDC #59148-002-16).

Storage

Store Pletal (cilostazol) tablets at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [See USP Controlled Room Temperature].

Manufactured for : Otsuka America Pharmaceutical, Inc. Rockville, MD 20850. Manufactured by : Otsuka America Pharmaceutical, Inc.Tokushima 771-0192, Japan. FDA revision date: 11/13/2007

Last reviewed on RxList: 12/19/2007
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. Pletal (cilostazol) (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on Pletal (cilostazol) and 134 days for patients on placebo.

The only adverse event resulting in discontinuation of therapy in ≥ 3% of patients treated with Pletal (cilostazol) 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 (cilostazol) 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 (cilostazol) 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.

Most Commonly Reported AEs (Incidence ≥ 2%) in Patients on Pletal (cilostazol) (PLT) 50 mg b.i.d. or 100 mg b.i.d. and Occurring at a Rate in the 100 mg b.i.d. Group Higher Than in Patients on Placebo

Adverse Events (AEs) by Body System PLT 50 mg b.i.d.
(N=303) %
PLT 100 mg b.i.d.
(N=998) %
Placebo
(N=973) %
BODY AS A WHOLE
Abdominal pain 4 5 3
Back pain 6 7 6
Headache 27 34 14
Infection 14 10 8
CARDIOVASCULAR
Palpitation 5 10 1
Tachycardia 4 4 1
DIGESTIVE
Abnormal stools 12 15 4
Diarrhea 12 19 7
Dyspepsia 6 6 4
Flatulence 2 3 2
Nausea 6 7 6
METABOLIC & NUTRITIONAL
Peripheral edema 9 7 4
MUSCULO-SKELETAL
Myalgia 2 3 2
NERVOUS
Dizziness 9 10 6
Vertigo 3 1 1
RESPIRATORY
Cough increased 3 4 3
Pharyngitis 7 10 7
Rhinitis 12 7 5

Less frequent adverse events ( < 2%) that were experienced by patients exposed to Pletal (cilostazol) 50 mg b.i.d. or 100 mg b.i.d. in the eight controlled clinical trials and that occurred at a frequency in the 100 mg b.i.d. group greater than in the placebo group, regardless of suspected drug relationship, are listed below.

Body as a whole: Chills, face edema, fever, generalized edema, malaise, neck rigidity, pelvic pain, retroperitoneal haemorrhage.
Cardiovascular: Atrial fibrillation, atrial flutter, cerebral infarct, cerebral ischemia, congestive heart failure, heart arrest, haemorrhage, hypotension, myocardial infarction, myocardial ischemia, nodal arrhythmia, postural hypotension, supraventricular tachycardia, syncope, varicose vein, vasodilation, ventricular extrasystoles, ventricular tachycardia.
Digestive
:
Anorexia, cholelithiasis, colitis, duodenal ulcer, duodenitis, esophageal haemorrhage, esophagitis, increased GGT, gastritis, gastroenteritis, gum haemorrhage, hematemesis, melena, peptic ulcer, periodontal abscess, rectal haemorrhage, stomach ulcer, tongue edema.
Endocrine
:
Diabetes mellitus.
Hemic and Lymphatic
: Anemia, ecchymosis, iron deficiency anemia, polycythemia, purpura.
Metabolic and Nutritional
:
Increased creatinine, gout, hyperlipemia, hyperuricemia.
Musculoskeletal
:
Arthralgia, bone pain, bursitis.
Nervous
:
Anxiety, insomnia, neuralgia.
Respiratory
:
Asthma, epistaxis, hemoptysis, pneumonia, sinusitis.
Skin and Appendages
:
Dry skin, furunculosis, skin hypertrophy, urticaria.
Special Senses
:
Amblyopia, blindness, conjunctivitis, diplopia, ear pain, eye haemorrhage, retinal haemorrhage, tinnitus.
Urogenital
:
Albuminuria, cystitis, urinary frequency, vaginal haemorrhage, vaginitis.

Post-Marketing Experience

The following events have been reported spontaneously from worldwide post-marketing experience since the launch of Pletal (cilostazol) in the US.

  • Blood and lymphatic system disorders:
  • Cardiac disorders:
    • Torsades de pointes, QTc prolongation (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. complete atrioventricular block, cardiac failure and bradyarrythmia, when treated with cilostazol. Cilostazol was used “off label” due to its positive chronotropic action)
  • Gastrointestinal disorders:
    • Gastrointestinal haemorrhage
  • General disorders and administration site conditions:
    • Pain, chest pain, hot flushes
  • Hepatobiliary disorders:
    • Hepatic dysfunction/abnormal liver function tests, jaundice
  • Injury, poisoning and procedural complications:
    • Extradural haematoma and subdural haematoma
  • Investigations:
  • Nervous system disorders:
    • Intracranial haemorrhage, cerebral haemorrhage, cerebrovascular accident
  • Respiratory, thoracic and mediastinal disorders:
    • Pulmonary haemorrhage, interstitial pneumonia
  • Skin and subcutaneous tissue disorders:
    • Haemorrhage subcutaneous, pruritus, skin eruptions including Stevens-Johnson syndrome, skin drug eruption (dermatitis medicamentosa)
  • Vascular disorders:
    • Subacute thrombosis (these cases of subacute thrombosis occurred in patients treated with aspirin and “off label” use of cilostazol for prevention of thrombotic complication after coronary stenting)

Read the Pletal (cilostazol) Side Effects Center for a complete guide to possible side effects »

DRUG INTERACTIONS

Since Pletal (cilostazol) is extensively metabolized by cytochrome P-450 isoenzymes, caution should be exercised when Pletal (cilostazol) is coadministered with inhibitors of CYP3A4 such as ketoconazole and erythromycin or inhibitors of CYP2C19 such as omeprazole. Pharmacokinetic studies have demonstrated that omeprazole and erythromycin significantly increased the systemic exposure of cilostazol and/or its major metabolites. Population pharmacokinetic studies showed higher concentrations of cilostazol among patients concurrently treated with diltiazem, an inhibitor of CYP3A4 (see CLINICAL PHARMACOLOGY, Pharmacokinetic and Pharmacodynamic Drug-Drug Interactions). Pletal (cilostazol) does not, however, appear to cause increased blood levels of drugs metabolized by CYP3A4, as it had no effect on lovastatin, a drug with metabolism very sensitive to CYP3A4 inhibition.

Use with other antiplatelet agents

Pletal (cilostazol) inhibits platelet aggregation but in a reversible manner. Caution is advised in patients at risk of bleeding from surgery or pathologic processes. Platelet aggregability returns to normal within 96 hours of stopping Pletal (cilostazol) . Caution is advised in patients receiving both Pletal (cilostazol) and any other antiplatelet agent, or in patients with thrombocytopenia.

Cardiovascular Toxicity

Repeated oral administration of cilostazol to dogs (30 or more mg/kg/day for 52 weeks, 150 or more mg/kg/day for 13 weeks, and 450 mg/kg/day for 2 weeks), produced cardiovascular lesions that included endocardial haemorrhage, hemosiderin deposition and fibrosis in the left ventricle, haemorrhage in the right atrial wall, haemorrhage and necrosis of the smooth muscle in the wall of the coronary artery, intimal thickening of the coronary artery, and coronary arteritis and periarteritis. At the lowest dose associated with cardiovascular lesions in the 52-week study, systemic exposure (AUC) to unbound cilostazol was less than that seen in humans at the maximum recommended human dose (MRHD) of 100 mg b.i.d. Similar lesions have been reported in dogs following the administration of other positive inotropic agents (including PDE III inhibitors) and/or vasodilating agents. No cardiovascular lesions were seen in rats following 5 or 13 weeks of administration of cilostazol at doses up to 1500 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were only about 1.5 and 5 times (male and female rats, respectively) the exposure seen in humans at the MRHD. Cardiovascular lesions were also not seen in rats following 52 weeks of administration of cilostazol at doses up to 150 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were about 0.5 and 5 times (male and female rats, respectively) the exposure in humans at the MRHD. In female rats, cilostazol AUCs were similar at 150 and 1500 mg/kg/day. Cardiovascular lesions were also not observed in monkeys after oral administration of cilostazol for 13 weeks at doses up to 1800 mg/kg/day. While this dose of cilostazol produced pharmacologic effects in monkeys, plasma cilostazol levels were less than those seen in humans given the MRHD, and those seen in dogs given doses associated with cardiovascular lesions.

Last reviewed on RxList: 12/19/2007
This monograph has been modified to include the generic and brand name in many instances.

WARNINGS

No information provided.

PRECAUTIONS

Hematologic adverse reactions

Rare cases have been reported of thrombocytopenia or leukopenia progressing to agranulocytosis when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.

Use with Clopidogrel

There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and clopidogrel, a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and clopidogrel, caution is advised for checking bleeding times during coadministration.

Hepatic Impairment

Patients with moderate or severe hepatic impairment have not been studied in clinical trials.

Special caution is advised when Pletal (cilostazol) is used in such patients.

Renal Impairment

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 (cilostazol) is used in patients with severe renal impairment: estimated creatinine clearance < 25 ml/min.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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 in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro 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.

Pregnancy

Pregnancy Category C: In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights, and increased incidences of cardiovascular, renal, and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib, and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD, and exposure to 3,4-dehydro-cilostazol was barely detectable.

When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).

There are no adequate and well-controlled studies in pregnant women.

Nursing Mothers

Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue Pletal (cilostazol) .

Pediatric Use

The safety and effectiveness of Pletal (cilostazol) in pediatric patients have not been established.

Geriatric Use

Of the total number of subjects (n = 2274) in clinical studies of Pletal (cilostazol) , 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism, and elimination of cilostazol and its metabolites.

Last reviewed on RxList: 12/19/2007
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

Information on acute overdosage with Pletal (cilostazol) 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 LD50 of cilostazol is > 5.0 g/kg in mice and rats and > 2.0 g/kg in dogs.

CONTRAINDICATIONS

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. Pletal (cilostazol) is contraindicated in patients with congestive heart failure of any severity.

Pletal (cilostazol) is contraindicated in patients with haemostatic disorders or active pathologic bleeding, such as bleeding peptic ulcer and intracranial bleeding. Pletal (cilostazol) inhibits platelet aggregation in a reversible manner.

Pletal (cilostazol) is contraindicated in patients with known or suspected hypersensitivity to any of its components.

Last reviewed on RxList: 12/19/2007
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism of the effects of Pletal (cilostazol) on the symptoms of intermittent claudication is not fully understood. Pletal (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 platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.

Pletal (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 Pletal (cilostazol) . After 12 weeks, as compared to placebo, Pletal (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%).

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 (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 Pletal (cilostazol) 100 mg b.i.d. is shown below:

The mean ± SEM plasma concentration-time profile at steady state after multiple dosing of Pletal 100 mg b.i.d - illustration
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-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.

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

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 β-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 (cilostazol) 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 (cilostazol) 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.

percent mean improvement in maximal walking distance - Illustration

Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with Pletal (cilostazol) 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 (cilostazol) 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 (cilostazol) 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 was the a priori study hypothesis.

Last reviewed on RxList: 12/19/2007
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

Please refer to the patient package insert. Patients should be advised:

  • to read the patient package insert for Pletal (cilostazol) carefully before starting therapy and to reread it each time therapy is renewed in case the information has changed.
  • to take Pletal (cilostazol) at least one-half hour before or two hours after food.
  • that the beneficial effects of Pletal (cilostazol) on the symptoms of intermittent claudication may not be immediate. Although the patient may experience benefit in 2 to 4 weeks after initiation of therapy, treatment for up to 12 weeks may be required before a beneficial effect is experienced.

Last reviewed on RxList: 12/19/2007
This monograph has been modified to include the generic and brand name in many instances.

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PATIENT INFORMATION

Please refer to the patient package insert. Patients should be advised:

  • to read the patient package insert for Pletal (cilostazol) carefully before starting therapy and to reread it each time therapy is renewed in case the information has changed.
  • to take Pletal (cilostazol) at least one-half hour before or two hours after food.
  • that the beneficial effects of Pletal (cilostazol) on the symptoms of intermittent claudication may not be immediate. Although the patient may experience benefit in 2 to 4 weeks after initiation of therapy, treatment for up to 12 weeks may be required before a beneficial effect is experienced.

Last reviewed on RxList: 12/19/2007
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Pletal Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

CILOSTAZOL - ORAL

(sye-LOE-sta-zol)

COMMON BRAND NAME(S): Pletal

WARNING: Medications similar to cilostazol have shortened the lives of people with a certain type of heart disease (congestive heart failure). Therefore, do not use cilostazol if you have congestive heart failure.

USES: Cilostazol is used to improve the symptoms of a certain blood flow problem in the legs (intermittent claudication). Cilostazol can decrease the muscle pain/cramps that occur during exercise/walking. Claudication pain is caused by too little oxygen getting to the muscles. Cilostazol can increase blood flow and the amount of oxygen that gets to the muscles.

Cilostazol is an "anti-platelet" and a vasodilator. It works by preventing certain blood cells (platelets) from sticking together and by widening blood vessels in the legs. This helps the blood to move more easily and increases blood flow.

HOW TO USE: Read the Patient Information Leaflet if available from your pharmacist before you start taking cilostazol and each time you get a refill. If you have any questions, ask your doctor or pharmacist.

Take this medication by mouth as directed by your doctor, usually twice daily without food, at least 30 minutes before or 2 hours after breakfast and dinner. Dosage is based on your medical condition, response to treatment, and other medications you may be taking. Be sure to tell your doctor and pharmacist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

Avoid eating grapefruit or drinking grapefruit juice while using this medication unless your doctor or pharmacist says you may do so. Grapefruit can increase the chance of side effects with this medicine. Ask your doctor or pharmacist for more details.

Use this medication regularly in order to get the most benefit from it. Remember to use it at the same times each day.

Your symptoms may improve in 2-4 weeks, but it may take up to 12 weeks to notice a benefit from this drug.

Tell your doctor if your condition persists or worsens.

Disclaimer

Pletal Consumer (continued)

SIDE EFFECTS: Headache, diarrhea, runny nose, and dizziness may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these serious side effects occur: fast/pounding/irregular heartbeat, swelling of the hands/feet.

Tell your doctor immediately if any of these unlikely but serious side effects occur: easy bruising/bleeding, black or bloody stools, vomit that looks like coffee grounds, signs of infection (such as fever, persistent sore throat).

Get medical help right away if any of these rare but serious side effects occur: chest/jaw/left arm pain, fainting, vision changes, weakness on one side of the body, slurred speech, confusion.

A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the Pletal (cilostazol) Side Effects Center for a complete guide to possible side effects »

PRECAUTIONS: Before taking cilostazol, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: bleeding disorders (such as bleeding ulcers, bleeding in the eye/brain), congestive heart failure, other heart disease (such as heart attack, chest pain, fast/irregular heartbeat), stroke, kidney disease, liver disease, blood disorders (such as hemophilia, low platelet counts).

This drug may make you dizzy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Limit alcoholic beverages.

Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is unknown if this medication passes into breast milk. Consult your doctor before breast-feeding.

Disclaimer

Pletal Consumer (continued)

DRUG INTERACTIONS: Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.

Some products that may interact with this drug include: "blood thinners" (such as heparin, warfarin), other "anti-platelet" drugs (such as clopidogrel, dipyridamole, ticlopidine), tipranavir.

Other medications can affect the removal of cilostazol from your body, which may affect how cilostazol works. Examples include diltiazem, omeprazole, azole antifungals (such as ketoconazole, itraconazole, fluconazole, miconazole), macrolide antibiotics (such as erythromycin, clarithromycin), certain antidepressants (such as nefazodone, fluvoxamine, fluoxetine, sertraline) among others.

Check all prescription and nonprescription medicine labels carefully since many contain pain relievers/fever reducers (nonsteroidal anti-inflammatory drugs or NSAIDs such as ibuprofen, naproxen, or aspirin) which can increase the risk of bleeding/anti-platelet effect when used with cilostazol. Low-dose aspirin (usually 81-325 milligrams per day) as prescribed by your doctor for specific medical reasons such as heart attack or stroke prevention should be continued. Consult your doctor or pharmacist for more details.

OVERDOSE: If overdose is suspected, contact a poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: severe headache, very fast/irregular heartbeat, or severe dizziness.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests may be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

Talk with your doctor about an exercise program to improve walking and decrease pain.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature away from light and moisture. Do not store in the bathroom. Keep all medications away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (US) or 1-800-668-1507 (Canada).

Information last revised November 2010. Copyright(c) 2010 First Databank, Inc.

Pletal Patient Information Including Side Effects

Brand Names: Pletal

Generic Name: cilostazol (Pronunciation: sil OS tah zol)

What is cilostazol (Pletal)?

Cilostazol widens arteries that supply blood to the legs. Cilostazol also improves circulation by keeping platelets in the blood from sticking together and clotting.

Cilostazol is used to treat the symptoms of intermittent claudication. This condition causes reduced blood flow to the legs, leading to pain while walking. Cilostazol improves your ability to walk longer distances without pain.

Cilostazol may also be used for other purposes not listed in this medication guide.

Cilostazol 100 mg-APO

round, white, imprinted with APO, CIL 100

Cilostazol 100 mg-MYL

round, white, imprinted with M C42

Cilostazol 100 mg-ROX

round, white, imprinted with 54 757

Cilostazol 100 mg-TEV

round, white, imprinted with 7231, 9 3

Cilostazol 50 mg-AND

round, white, imprinted with G, CL 50

Cilostazol 50 mg-APO

round, white, imprinted with APO, CIL 50

Cilostazol 50 mg-MYL

round, white, imprinted with M C41

Cilostazol 50 mg-ROX

round, white, imprinted with 54 521

Cilostazol 50 mg-SAN

round, white, imprinted with E 123

Cilostazol 50 mg-TEV

rectangular, white, imprinted with 7230, 9 3

What are the possible side effects of cilostazol (Pletal)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have any of these serious side effects:

  • severe headache;
  • bloody urine, painful urination;
  • fever, chills, body aches, flu symptoms;
  • chest pain;
  • feeling short of breath, even with mild exertion; or
  • swelling of your ankles or feet.

Less serious side effects may include:

  • fast or pounding heartbeats;
  • diarrhea, vomiting;
  • weakness, dizziness;
  • leg cramps;
  • numbness or tingling;
  • joint pain; or
  • cough, runny or stuffy nose.

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

Read the Pletal (cilostazol) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about cilostazol (Pletal)?

Do not take cilostazol if you have congestive heart failure. Cilostazol can make this condition worse.

It may take up to 12 weeks of using cilostazol before your symptoms improve. For best results, keep using the medication as directed. Talk with your doctor if your symptoms do not improve after 4 weeks of treatment.

Grapefruit and grapefruit juice may interact with cilostazol. The interaction could lead to potentially dangerous effects. Discuss the use of grapefruit products with your doctor. Do not increase or decrease the amount of grapefruit products in your diet without first talking to your doctor.

Take cilostazol on an empty stomach, at least 30 minutes before or 2 hours after food.

Side Effects Centers

Pletal Patient Information including How Should I Take

What should I discuss with my healthcare provider before taking cilostazol (Pletal)?

Do not take cilostazol if you have congestive heart failure. Cilostazol can make this condition worse.

Before using cilostazol, tell your doctor if you have:

  • heart disease; or
  • liver disease.

If you have any of these conditions, you may need a dose adjustment or special tests to safely take this medication.

FDA pregnancy category C. This medication may be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

Cilostazol can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take cilostazol (Pletal)?

Take this medication exactly as it was prescribed for you. Do not take the medication in larger amounts, or take it for longer than recommended by your doctor.

Take each dose with a full glass of water.

Cilostazol is usually taken twice a day, at least 30 minutes before or 2 hours after breakfast or dinner. Take cilostazol at the same times each day. Follow your doctor's instructions.

It may take up to 12 weeks of using cilostazol before your symptoms improve. For best results, keep using the medication as directed. Talk with your doctor if your symptoms do not improve after 4 weeks of treatment.

Store cilostazol at room temperature away from moisture, heat, and light.

Side Effects Centers

Pletal Patient Information including If I Miss a Dose

What happens if I miss a dose (Pletal)?

Take the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take extra medicine to make up the missed dose.

What happens if I overdose (Pletal)?

Seek emergency medical attention if you think you have used too much of this medicine.

Overdose symptoms may include a severe headache, diarrhea, feeling light-headed, fainting, and fast or uneven heartbeats.

What should I avoid while taking cilostazol (Pletal)?

Grapefruit and grapefruit juice may interact with cilostazol. The interaction could lead to potentially dangerous effects. Discuss the use of grapefruit products with your doctor. Do not increase or decrease the amount of grapefruit products in your diet without first talking to your doctor.

What other drugs will affect cilostazol (Pletal)?

Before taking cilostazol, tell your doctor if you are using any of the following drugs:

  • clopidogrel (Plavix);
  • omeprazole (Prilosec, Zegerid) or esomeprazole (Nexium);
  • erythromycin (E.E.S., Ery-Tab, E-Mycin, Erythrocin) or clarithromycin (Biaxin);
  • ketoconazole (Nizoral), fluconazole (Diflucan), or itraconazole (Sporanox);
  • diltiazem (Cardizem, Tiazac); or
  • fluvoxamine (Luvox), fluoxetine (Prozac), sertraline (Zoloft), or nefazodone (Serzone).

This list is not complete and there may be other drugs that can interact with cilostazol. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

Where can I get more information?

Your pharmacist has more information about cilostazol.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2012 Cerner Multum, Inc. Version: 3.05. Revision date: 12/15/2010.

Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.

Healthwise

Side Effects Centers

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