Cilostazol (PLETAAL®): Complete Drug Monograph

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The information in this article is intended for educational and informational purposes only and should not replace the prescribing information, official product labeling, or individualized advice from a qualified healthcare professional.

Because some of the supplied product information is from an older document, product-specific details such as packaging, local manufacturer/marketing authorization information, formulations, and regulatory indications should be verified against the current official labeling applicable to the country of use.

Summary

Cilostazol is an oral phosphodiesterase-3 (PDE3) inhibitor with both antiplatelet and vasodilatory effects. It inhibits platelet aggregation and promotes vasodilation by selectively inhibiting PDE3 in platelets and vascular smooth muscle.

Its currently established U.S. indication is the reduction of symptoms of intermittent claudication, demonstrated by increased walking distance.

In Japan, Pletaal (cilostazol) is also indicated for improvement of ischemic symptoms associated with chronic arterial obstruction and for secondary prevention of cerebral infarction, excluding cardiogenic cerebral embolism. Otsuka continues to list Pletaal as an antiplatelet agent with peripheral vasodilator effects.

A critical safety point is that cilostazol is contraindicated in patients with heart failure of any severity.

Brand Name

PLETAAL®

The active pharmaceutical ingredient is cilostazol.

Pletaal was developed by Otsuka Pharmaceutical and was launched in Japan in 1988. Otsuka describes Pletaal as an antiplatelet agent with peripheral vasodilator effects.

The product is also marketed under the name Pletal® in some markets.

Category

Pharmacological category:

• Antiplatelet agent
• Phosphodiesterase-3 (PDE3) inhibitor
• Peripheral vasodilator

Cilostazol inhibits platelet aggregation while also producing vasodilation. Otsuka describes Pletaal as an antiplatelet drug that inhibits platelet aggregation and has peripheral vasodilator effects.

Active Ingredient

Cilostazol

Non-proprietary name: Cilostazol (JAN)

Chemical name:

6-[4-(1-Cyclohexyl-1H-tetrazol-5-yl) butyloxy]-3,4-dihydroquinolin-2(1H)-one

Molecular formula:

C₂₀H₂₇N₅O₂

Molecular weight:

369.46

Physical description:

Cilostazol occurs as white to pale yellowish-white crystals or crystalline powder. It is slightly soluble in methanol, ethanol (99.5%), and acetonitrile and is practically insoluble in water.

Melting point:

158–162°C.

Pharmaceutical Form & Strength

The supplied Pletaal product information lists:

• Pletaal Tablets 50 mg
• Pletaal Tablets 100 mg

The supplied document describes packaging as boxes containing 20 tablets, arranged in two strips of 10 tablets each.

Current U.S. cilostazol labeling also recognizes 50 mg and 100 mg tablets.

Otsuka also manufactures Pletaal OD (orally disintegrating) tablets 50 mg and 100 mg in Japan.

Manufacturer & Marketing Authorization Holder

The supplied Egyptian product document states:

Produced by:
Egypt Otsuka Pharmaceutical Co. S.A.E.

Under Licence Of:
OTSUKA PHARMACEUTICAL CO., LTD.
2-9 Kanda Tsukasa-machi
Chiyoda-ku, Tokyo 101-8535, Japan

The supplied document identifies this information in its second version dated February 2007.

Important: These manufacturer/licensing details are retained from the supplied historical document. They should not automatically be interpreted as the current Egyptian marketing authorization or manufacturing arrangement without checking the current Egyptian regulatory/product documentation.

Otsuka currently identifies Pletaal as one of its pharmaceutical products.

Mechanism of Action

Cilostazol exerts its principal pharmacological effects through selective inhibition of phosphodiesterase type 3 (PDE3).

The supplied pharmacological data state that cilostazol:

• selectively inhibits PDE3 in platelets and vascular smooth muscle;
• inhibits platelet aggregation;
• produces vasodilation;
• inhibits thromboxane A₂ production in activated human platelets;
• inhibits platelet procoagulant activity.

The antiplatelet and vasodilatory effects are attributed to PDE3 inhibition.

By inhibiting PDE3, cilostazol increases intracellular cyclic nucleotide signaling, contributing to inhibition of platelet activation and relaxation of vascular smooth muscle.

The supplied experimental data also report that cilostazol inhibited serotonin release from platelets without affecting serotonin or adenosine uptake by platelets and inhibited platelet aggregation induced by thromboxane A₂.

Spectrum of Activity

Cilostazol is not an antimicrobial drug, so a conventional antimicrobial spectrum does not apply.

Its pharmacological activity is instead directed toward:

• platelet aggregation pathways;
• vascular smooth muscle;
• peripheral blood flow;
• thrombotic processes associated with platelet activation.

In vitro, cilostazol inhibited platelet aggregation induced by ADP, collagen, arachidonic acid, epinephrine, and thrombin and also inhibited shear-stress-induced platelet aggregation.

Pharmacokinetics

Absorption

Following a single oral dose of cilostazol 100 mg in fasted healthy individuals, plasma concentrations rose promptly and reached a maximum concentration of approximately 763.9 ng/mL at 3 hours.

Food substantially increases exposure. Administration of a single 50 mg dose in the fed state produced approximately:

• 2.3-fold higher Cmax
• 1.4-fold higher AUC

compared with administration in the fasted state.

For the U.S. formulation, the recommended administration is therefore at least 30 minutes before or 2 hours after breakfast and dinner.

Distribution and Protein Binding

Cilostazol is highly protein bound.

The supplied data report:

• Cilostazol: >95%
• Active metabolite OPC-13015: 97.4%
• Active metabolite OPC-13213: 53.7%

Metabolism

Cilostazol undergoes extensive hepatic metabolism.

The principal metabolic pathways involve:

• CYP3A4
• CYP2D6
• CYP2C19

with CYP3A4 being the major enzyme among those identified in vitro.

Two active metabolites were identified:

• OPC-13015, the dehydrated metabolite
• OPC-13213, the hydroxylated metabolite

Half-Life

The supplied pharmacokinetic study estimated plasma half-life using a two-compartment model at:

• approximately 2.2 hours in the α-phase;
• approximately 18.0 hours in the β-phase.

Renal Impairment

In patients with severe renal impairment, repeated oral administration of Pletaal 100 mg daily for 8 days produced:

• a 29% decrease in cilostazol Cmax;
• a 39% decrease in cilostazol AUC;
• a 173% increase in OPC-13213 Cmax;
• a 209% increase in OPC-13213 AUC.

In patients with mild-to-moderate renal impairment, cilostazol and OPC-13213 concentrations were similar to those observed in healthy individuals.

Hepatic Impairment

In patients with mild-to-moderate hepatic impairment, plasma concentrations following a single 100 mg dose were reported to be similar to those in healthy individuals:

• Cmax decreased by approximately 7%;
• AUC increased by approximately 8%.

Indications

1. Intermittent Claudication

The current U.S. labeling indicates cilostazol for the reduction of symptoms of intermittent claudication, demonstrated by increased walking distance.

Clinical benefit may begin within 2–4 weeks, although treatment for up to 12 weeks may be required before a beneficial effect is fully assessed. If symptoms do not improve after three months, current U.S. labeling recommends discontinuation.

2. Chronic Arterial Occlusive Disease

The supplied Pletaal information reports clinical use for ischemic symptoms associated with chronic arterial occlusive disease, including:

• ulceration;
• pain;
• coldness of the extremities.

The Japanese Pletaal information continues to list improvement of ischemic symptoms such as ulceration, pain, and coldness associated with chronic arterial obstruction.

3. Secondary Prevention After Cerebral Infarction

Pletaal is approved in Japan for prevention of recurrence after cerebral infarction, excluding cardiogenic cerebral embolism. Otsuka states that this additional indication was approved in Japan in 2003.

The supplied historical clinical information also describes a placebo-controlled study involving 1,034 patients with cerebral infarction. The annual incidence of cerebral infarction was reported as:

• 3.43% with Pletaal
• 5.75% with placebo

The estimated risk reduction per person-year relative to placebo was 40.3%.

However, regulatory indications vary by country. Therefore, the indication applicable to a particular patient should always be confirmed against the local approved product labeling.

Administration

For the currently available U.S. labeling:

Recommended dose:

100 mg orally twice daily.

It should be taken:

• at least 30 minutes before breakfast and dinner, or
• at least 2 hours after breakfast and dinner.

The dose should be reduced to:

50 mg twice daily

when cilostazol is administered with strong or moderate inhibitors of CYP3A4 or inhibitors of CYP2C19, including examples such as:

• ketoconazole;
• itraconazole;
• erythromycin;
• diltiazem;
• ticlopidine;
• fluconazole;
• omeprazole.

The exact approved dosage may differ according to the indication and national product labeling.

Method of Preparation

For standard Pletaal tablets, no special preparation or reconstitution is required.

The medication is administered orally as a tablet.

For orally disintegrating Pletaal OD formulations, the dosage form is specifically designed to disintegrate orally. Otsuka introduced Pletaal OD 50 mg and 100 mg tablets in Japan.

Patients should follow the administration instructions for the specific formulation supplied to them.

Contraindications

1. Heart Failure

Cilostazol is contraindicated in patients with heart failure of any severity.

This is a major and current safety warning.

Cilostazol and several of its metabolites inhibit PDE3, and drugs with this pharmacological effect have been associated with decreased survival in patients with advanced heart failure.

2. Hypersensitivity

Cilostazol is contraindicated in patients with a history of hypersensitivity to cilostazol or any component of the formulation.

Hypersensitivity reactions may include serious reactions such as anaphylaxis and angioedema.

3. Active or Significant Bleeding

The supplied Pletaal information lists patients with hemorrhage among the contraindicated populations, including examples such as:

• hemophilia;
• increased capillary fragility;
• intracranial hemorrhage;
• gastrointestinal hemorrhage;
• urinary tract hemorrhage;
• hemoptysis;
• vitreous hemorrhage.

The rationale given is that the bleeding tendency may be increased.

Current labeling also advises avoiding use in patients with hemostatic disorders or active pathological bleeding.

4. Pregnancy

The supplied Pletaal labeling lists women who are pregnant or may possibly become pregnant among the contraindicated populations.

Pregnancy-related use should therefore be evaluated according to current local labeling and specialist advice.

Warnings & Precautions

Cardiovascular Effects

Cilostazol may increase heart rate and may cause:

• tachycardia;
• palpitations;
• tachyarrhythmias;
• hypotension.

It may also exacerbate angina pectoris or increase the risk of myocardial infarction in patients with ischemic heart disease.

The supplied Pletaal warning specifically states that patients should be closely monitored for symptoms of angina, such as chest pain, because increased pulse rate may induce angina pectoris.

Arrhythmias and Angina

Particular caution is appropriate in patients with underlying cardiovascular disease.

The supplied clinical data reported angina pectoris in:

• 6/516 patients receiving Pletaal;
• 0/518 patients receiving placebo

in the cerebral infarction prevention study.

Hematological Effects

Current labeling warns of the possibility of:

• thrombocytopenia;
• leukopenia;
• progression to agranulocytosis.

Monitoring of platelet and white blood cell counts may therefore be appropriate when clinically indicated.

Bleeding

Because cilostazol inhibits platelet aggregation, bleeding risk should be considered, particularly in patients with active bleeding, bleeding disorders, or concomitant medications that affect hemostasis.

Drug Interactions

Cilostazol is extensively metabolized by CYP3A4, with additional contributions from CYP2D6 and CYP2C19.

CYP3A4 Inhibitors

Important CYP3A4 inhibitors can increase cilostazol exposure.

The supplied pharmacokinetic studies found:

Erythromycin

Coadministration of cilostazol 100 mg with erythromycin 500 mg three times daily for seven days increased:

• cilostazol Cmax by 47%;
• cilostazol AUC by 87%.

Ketoconazole

Coadministration of ketoconazole 400 mg with cilostazol 100 mg increased:

• Cmax by 94%;
• AUC by 129%.

Diltiazem

Diltiazem 180 mg increased cilostazol:

• Cmax by 34%;
• AUC by 44%.

Current U.S. labeling recommends reducing cilostazol to 50 mg twice daily with strong or moderate CYP3A4 inhibitors such as ketoconazole, itraconazole, erythromycin, and diltiazem.

CYP2C19 Inhibitors

Current labeling also recommends reducing the cilostazol dose to 50 mg twice daily with CYP2C19 inhibitors such as:

• ticlopidine;
• fluconazole;
• omeprazole.

The supplied study found that repeated administration of omeprazole 40 mg once daily for seven days increased cilostazol:

• Cmax by 18%;
• AUC by 26%.

Grapefruit Juice

A single 100 mg dose of cilostazol taken with 240 mL of grapefruit juice increased:

• Cmax by 46%;
• AUC by 14%.

Therefore, grapefruit products should be considered when evaluating potential increases in cilostazol exposure.

Lovastatin

Coadministration of a single dose of lovastatin 80 mg with cilostazol 100 mg increased lovastatin AUC by 64% compared with lovastatin alone.

Warfarin

The supplied data state that Pletaal did not inhibit the metabolism or pharmacological effects of R- or S-warfarin when administered with a single 25 mg dose of warfarin.

Nevertheless, patients receiving antithrombotic combinations should be assessed individually for bleeding risk.

Side Effects

Potential adverse effects of cilostazol include cardiovascular, gastrointestinal, neurological, and hematological reactions.

Clinically important reactions include:

• headache;
• diarrhea;
• abnormal stools;
• dizziness;
• palpitations;
• tachycardia;
• hypotension;
• angina pectoris;
• tachyarrhythmias;
• bleeding;
• hypersensitivity reactions.

Serious reactions may include:

• myocardial infarction;
• congestive heart failure exacerbation;
• ventricular tachycardia;
• significant bleeding;
• thrombocytopenia;
• leukopenia;
• agranulocytosis;
• anaphylaxis;
• angioedema.

Current labeling specifically emphasizes tachycardia, palpitations, tachyarrhythmias, hypotension, worsening angina or myocardial infarction, hematological abnormalities, and bleeding-related precautions.

Use in Special Populations

Pregnancy

The supplied Pletaal labeling lists pregnancy and possible pregnancy as contraindications.

Cilostazol should therefore not be used during pregnancy unless its use is specifically supported by the applicable current regulatory labeling and specialist assessment.

Lactation

The available product information should be checked for the specific formulation and country.

Because regulatory labeling can differ, breastfeeding decisions should be based on current official product information and clinical assessment.

Renal Impairment

Mild-to-moderate renal impairment produced pharmacokinetic findings broadly similar to those in healthy individuals in the supplied study.

Severe renal impairment produced substantially altered exposure to the active metabolite OPC-13213, including increases in Cmax and AUC of 173% and 209%, respectively.

Patients with significant renal impairment should therefore be assessed carefully.

Hepatic Impairment

Mild-to-moderate hepatic impairment resulted in relatively similar cilostazol exposure compared with healthy subjects, with a 7% decrease in Cmax and an 8% increase in AUC.

Older Adults

Older patients may be more susceptible to cardiovascular adverse effects and drug interactions because of the higher prevalence of cardiovascular disease and polypharmacy. Individual clinical assessment is appropriate.

Clinical Pharmacology and Experimental Findings

Antiplatelet Action

In vitro studies showed that cilostazol:

• inhibited platelet aggregation induced by ADP;
• inhibited collagen-induced aggregation;
• inhibited arachidonic-acid-induced aggregation;
• inhibited epinephrine-induced aggregation;
• inhibited thrombin-induced aggregation;
• inhibited shear-stress-induced platelet aggregation;
• inhibited ADP- and epinephrine-induced primary aggregation;
• demonstrated a dispersing effect on human platelet aggregates;
• inhibited thromboxane A₂ production in activated human platelets;
• inhibited platelet procoagulant activity.

In vivo studies showed inhibition of ADP- and collagen-induced platelet aggregation in animal models. In patients with chronic arterial occlusion or cerebral infarction, oral cilostazol prevented platelet aggregation induced by ADP, collagen, arachidonic acid, and epinephrine.

The platelet-inhibitory effect appeared promptly in humans and persisted during repeated administration.

Following discontinuation, platelet aggregability returned toward baseline as plasma cilostazol concentrations declined, without a rebound increase in platelet aggregation.

Antithrombotic Action

Experimental studies reported that cilostazol:

• reduced mortality from experimentally induced pulmonary embolism in mice;
• suppressed progression of peripheral thrombotic circulatory insufficiency in canine hind limbs;
• inhibited thrombotic occlusion of prosthetic femoral arterial grafts in dogs;
• inhibited electrically induced carotid arterial thrombus formation in pigs;
• reduced experimentally induced cerebral infarct size in rabbits;
• reduced the frequency of ischemic attacks in patients with transient ischemic attacks.

Vasodilating Action

Experimental and clinical studies reported that cilostazol:

• inhibited KCl- and prostaglandin F₂α-induced contraction of isolated femoral, middle cerebral, and basilar arteries in dogs;
• increased blood flow in femoral, vertebral, common carotid, and internal carotid arteries in anesthetized dogs;
• increased cerebral cortical blood flow in anesthetized dogs and cats;
• increased cerebral cortical and hypothalamic blood flow in conscious rats;
• increased blood flow in occluded ankle and calf regions in patients with chronic arterial occlusion;
• increased skin temperature and cutaneous blood flow in the extremities of patients with chronic arterial occlusion;
• increased cerebral blood flow in patients with ischemic cerebrovascular disease as determined by the xenon-inhalation method.

Effects on Vascular Cells

Experimental studies reported that cilostazol:

• suppressed ³H-thymidine uptake in cultured human vascular smooth muscle cells;
• suppressed depletion of lactate dehydrogenase from cultured human endothelial cells stimulated with homocysteine or lipopolysaccharide.

Clinical Studies

Chronic Arterial Occlusive Disease

Pletaal tablets were studied in 226 patients with chronic arterial occlusive disease in open and double-blind studies.

For ischemic symptoms including:

• ulceration;
• pain;
• coldness of the extremities;

the drug was judged effective or very effective in 66.1% (119/180) of patients and slightly effective or better in 85.0% (153/180).

Cerebral Infarction

Pletaal tablets were studied in 1,034 patients with cerebral infarction in a placebo-controlled double-blind study.

The annual incidence of cerebral infarction was:

• 3.43% in the Pletaal group;
• 5.75% in the placebo group.

There were 30 recurrences in the Pletaal group versus 56 in the placebo group during the reported observation periods.

The estimated risk reduction per person-year for Pletaal relative to placebo was 40.3%.

The annual mortality rates were estimated at:

• 0.92% with Pletaal;
• 0.82% with placebo;

with no significant difference reported in this study.

Angina pectoris was reported in 6/516 patients receiving Pletaal and 0/518 receiving placebo.

Nonclinical Safety Findings

The supplied historical nonclinical data reported cardiovascular changes in dogs and monkeys during intravenous repeated-dose toxicity studies.

In one-week intravenous repeated-dose studies:

• changes in the left ventricular endocardium;
• right atrial epicardium;
• coronary arteries

were observed in dogs.

Mild hemorrhagic changes in the left ventricular endocardium were observed in monkeys.

The supplied document notes that similar cardiac changes have also been reported with other PDE inhibitors and vasodilators and that dogs are considered particularly sensitive to these changes.

The supplied document also reports that the mean survival time of stroke-prone spontaneously hypertensive rats receiving 0.3% cilostazol in the diet was shorter than that of controls:

• 40.2 weeks vs. 43.5 weeks.

In a clinical study evaluating Pletaal for prevention of recurrent cerebral infarction, diabetes mellitus either developed or worsened in:

• 11/520 patients receiving Pletaal;
• 1/523 patients receiving placebo.

These historical findings should be interpreted within the context of the original study design and current regulatory labeling rather than used alone to determine clinical risk.

Storage Conditions

The supplied product information states:

Store at room temperature, below 30°C.

The storage instructions on the actual marketed package should always be followed because formulation-specific requirements may differ.

Additional Sections

Prescription Status

The supplied Egyptian product document identifies Pletaal as a:

Prescription-only Drug.

Physical and Chemical Properties

Chemical formula: C₂₀H₂₇N₅O₂

Molecular weight: 369.46

Melting point: 158–162°C

Appearance: White to pale yellowish-white crystals or crystalline powder.

Solubility: Slightly soluble in methanol, ethanol (99.5%), and acetonitrile; practically insoluble in water.

Effect on Platelet Aggregation After Discontinuation

An important pharmacodynamic observation from the supplied data is that after cilostazol discontinuation, platelet aggregability returned toward baseline as the plasma concentration declined, without a rebound increase in platelet aggregation.

Product Development

Pletaal was independently discovered and developed by Otsuka Pharmaceutical and was launched in Japan in 1988 for ischemic symptoms associated with chronic arterial obstruction. Secondary prevention of cerebral infarction, excluding cardiogenic cerebral embolism, was approved in Japan in 2003.

Pletaal OD 50 mg and 100 mg orally disintegrating tablets were subsequently introduced in Japan in 2010.

Frequently Asked Questions (FAQ)

What is cilostazol used for?

Cilostazol is primarily used to reduce symptoms of intermittent claudication by increasing walking distance. In certain countries, including Japan, Pletaal also has approved indications involving chronic arterial obstruction and secondary prevention of recurrent cerebral infarction.

Is cilostazol an anticoagulant?

No. Cilostazol is primarily an antiplatelet drug and PDE3 inhibitor. It inhibits platelet aggregation rather than directly acting as a conventional anticoagulant such as warfarin or heparin.

Does cilostazol dilate blood vessels?

Yes. In addition to inhibiting platelet aggregation, cilostazol has vasodilatory effects mediated largely through PDE3 inhibition in vascular smooth muscle.

Can cilostazol be used in heart failure?

No. Cilostazol is contraindicated in heart failure of any severity. This is one of the most important safety points in the current labeling.

How should cilostazol be taken?

The current U.S. labeling recommends 100 mg twice daily, taken at least 30 minutes before or 2 hours after breakfast and dinner.

Why is the dose reduced with some antibiotics and other medicines?

Cilostazol is metabolized predominantly by CYP3A4 and also by CYP2C19. Drugs that inhibit these enzymes can increase cilostazol exposure. With specified CYP3A4 or CYP2C19 inhibitors, the current U.S. labeling recommends reducing the dose to 50 mg twice daily.

Can cilostazol cause a fast heartbeat?

Yes. Tachycardia, palpitations, tachyarrhythmias, and hypotension are recognized risks. Cilostazol may also worsen angina in susceptible patients.

Can cilostazol increase bleeding?

Yes. Because it inhibits platelet aggregation, bleeding risk must be considered, particularly in patients with active bleeding, bleeding disorders, or concomitant drugs affecting hemostasis.

Does food affect cilostazol absorption?

Yes. Food can substantially increase exposure. The supplied pharmacokinetic data showed a 2.3-fold increase in Cmax and a 1.4-fold increase in AUC when a 50 mg dose was administered in the fed state compared with fasting.

Can grapefruit juice affect cilostazol?

Yes. In the supplied study, 240 mL of grapefruit juice increased cilostazol Cmax by 46% and AUC by 14%.

How quickly does cilostazol work?

For intermittent claudication, some patients may respond within 2–4 weeks, although up to 12 weeks may be needed to assess benefit adequately. If symptoms remain unimproved after three months, current U.S. labeling recommends discontinuation.

Is Pletaal available as an orally disintegrating tablet?

Yes. Otsuka has marketed Pletaal OD 50 mg and 100 mg orally disintegrating tablets in Japan.

References

1. DailyMed — Cilostazol Tablets, U.S. prescribing information. Current labeling includes the boxed warning against use in heart failure, indications, dosage, dose reductions for CYP3A4/CYP2C19 inhibitors, contraindications, and cardiovascular/hematological warnings.
2. Otsuka Pharmaceutical Co., Ltd. — Pletaal pharmaceutical product information. Otsuka currently identifies Pletaal as an antiplatelet agent with peripheral vasodilator effects.
3. Otsuka Pharmaceutical — Pletaal OD patient information. Provides current Japanese product information for Pletaal OD 50 mg and 100 mg and lists Japanese indications.
4. Otsuka Pharmaceutical — Pletaal development and CSPS II information. Documents the development of cilostazol/Pletaal and its use in secondary prevention of cerebral infarction in Japan.
5. Supplied Pletaal product document — Egypt Otsuka Pharmaceutical Co. S.A.E., second version February 2007. Used for the historical Egyptian product information, pharmacokinetic data, pharmacological studies, clinical studies, physical/chemical properties, packaging, storage, manufacturer and licensing information.

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