Side effects of cilostazol

Contents

Cilostazol

Cilostazol is the generic form of the brand name prescription drug Pletal, used to treat intermittent claudication.

Intermittent claudication is a condition characterized by narrowing of blood vessels in the legs, which causes leg pain that worsens with walking and improves when resting.

The drug is in a class of medicines known as platelet-aggregation inhibitors. It works by widening blood vessels to improve blood flow to the legs and decreasing the ability of platelets to form clots.

Cilostazol is manufactured as Pletal by Otsuka America Pharmaceutical Co.

The Food and Drug Administration (FDA) approved the medicine in 1999.

Cilostazol Warnings

Cilostazol contains a black-box warning because similar medications have caused an increased risk of death in people with congestive heart failure.

Tell your doctor if you have or have ever had any type of heart failure before taking this drug.

Also, tell your doctor if you have or have ever had:

  • Bleeding problems or a disorder that causes an inability to form blood clots
  • Any active bleeding (especially a peptic ulcer or brain bleeding)
  • Low blood platelet levels
  • Liver disease
  • Kidney disease
  • Allergies to medications, foods, or other substances

Tell your doctor or dentist you’re taking this medication before any type of surgical procedure, and let your healthcare provider know if you’ve had a recent surgery before starting on cilostazol.

In rare instances, this drug can lower your body’s ability to fight infection. Avoid contact with people who have colds or infections.

Cilostazol should be used with extreme caution in children. Safety and effectiveness in kids hasn’t been confirmed.

Older adults may be more sensitive to the side effects of cilostazol.

This medicine controls symptoms of intermittent claudication, but it doesn’t cure the condition.

Continue to take cilostazol even if you feel well. Don’t stop taking the drug without first talking to your doctor.

You might notice improvements within two to four weeks of starting on cilostazol, but it can take up to 12 weeks for you to experience the full benefits of the medicine.

Be sure to keep all doctor and laboratory appointments while taking cilostazol.

Pregnancy and Cilostazol

It’s not known whether cilostazol is safe to take during pregnancy.

Talk to your doctor before taking this medicine if you’re pregnant or plan to become pregnant.

It’s also not known whether the medication passes into breast milk or could harm a breastfeeding baby.

Don’t breastfeed while taking cilostazol without first talking to your doctor.

Pletal

SIDE EFFECTS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

  • Patients with Heart Failure
  • Tachycardia
  • Left Ventricular Outflow Tract Obstruction
  • Hematologic Adverse Reactions
  • Hemostatic Disorders or Active Pathologic Bleeding

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse reactions were assessed in eight placebo-controlled clinical trials involving patients exposed to either 50 or 100 mg twice daily 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 most frequent adverse reaction resulting in discontinuation of therapy in more than 3% of patients treated with PLETAL was headache . Other frequent causes of discontinuation included palpitation and diarrhea, both 1.1% for PLETAL (all doses) versus 0.1% for placebo.

The most common adverse reactions, occurring in at least 2% of patients treated with PLETAL 50 or 100 mg twice daily, are shown in Table 1.

Table 1: Most Common Adverse Reactions in Patients on PLETAL (PLT) 50 or 100 mg Twice Daily(Incidence at least 2% and Occurring More Frequently (≥ 2%) in the 100 mg Twice Daily Group than on Placebo)

Less frequent clinical significant adverse reactions (less than 2%) that were experienced by patients treated with PLETAL 50 mg twice daily or 100 mg twice daily in the eight controlled clinical trials and that occurred at a frequency in the 100 mg twice daily group greater than in the placebo group are listed below.

Body as a whole: fever, generalized edema, malaise

Cardiovascular: atrial fibrillation, heart failure, myocardial infarction, nodal arrhythmia, supraventricular tachycardia, ventricular extrasystoles, ventricular tachycardia

Digestive: anorexia, melena

Hematologic and Lymphatic: anemia

Metabolic and Nutritional: increased creatinine, hyperuricemia

Nervous: insomnia

Respiratory: epistaxis

Skin and Appendages: urticaria

Special Senses: conjunctivitis, retinal hemorrhage, tinnitus

Urogenital: urinary frequency

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of PLETAL. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood And Lymphatic System Disorders

Aplastic anemia, granulocytopenia, pancytopenia, bleeding tendency

Cardiac Disorders

Torsade de pointes and QTc prolongation in patients with cardiac disorders (e.g. complete atrioventricular block, heart failure; and bradyarrythmia), angina pectoris.

Gastrointestinal Disorders

Gastrointestinal hemorrhage, vomiting, flatulence, nausea

General Disorders And Administration Site Conditions

Pain, chest pain, hot flushes

Hepatobiliary Disorders

Hepatic dysfunction/abnormal liver function tests, jaundice

Immune System Disorders

Anaphylaxis, angioedema, and hypersensitivity

Investigations

Blood glucose increased, blood uric acid increased, increase in BUN (blood urea increased), blood pressure increase

Nervous System Disorders

Intracranial hemorrhage, cerebral hemorrhage, cerebrovascular accident, extradural hematoma and subdural hematoma

Renal And Urinary Disorders

Hematuria

Respiratory, Thoracic And Mediastinal Disorders

Pulmonary hemorrhage, interstitial pneumonia

Skin And Subcutaneous Tissue Disorders

Hemorrhage subcutaneous, pruritus, skin eruptions including Stevens-Johnson syndrome, skin drug eruption (dermatitis medicamentosa), rash.

Vascular Disorders

Subacute stent thrombosis, hypertension.

Read the entire FDA prescribing information for Pletal (Cilostazol)

Before taking cilostazol

Some medicines are not suitable for people with certain conditions, and sometimes a medicine may only be used if extra care is taken. For these reasons, before you start taking cilostazol it is important that your doctor knows:

  • If you have a heart condition or high blood pressure.
  • If you have high blood sugar levels (diabetes mellitus).
  • If you know you are at risk of bleeding – for example, if you have a stomach ulcer or if you have had surgery recently.
  • If you have any problems with the way your liver works or the way your kidneys work.
  • If you are pregnant or breast-feeding.
  • If you are taking any other medicines. This includes any medicines you are taking which are available to buy without a prescription, as well as herbal and complementary medicines.
  • If you have ever had an allergic reaction to a medicine.

How to take cilostazol

  • Before you start this treatment, read the manufacturer’s printed information leaflet from inside your pack. It will give you more information about cilostazol and will provide you with a full list of side-effects which you may experience from taking it.
  • Take the tablets exactly as your doctor tells you to. It is usual to take one tablet twice a day, in the morning and evening. The usual strength of tablet is 100 mg, although a lower strength of tablet may be appropriate at times if you are also taking certain other medicines. Your doctor will tell you which is the right strength for you, and this will also be printed on the label of the pack of tablets to remind you.
  • Swallow the tablets with a drink of water. Ideally, you should take the tablets 30 minutes before meals. If this is not possible, wait until two hours afterwards.
  • If you forget to take a dose, don’t worry, just remember to take your next dose when it is due. Do not take two doses together to make up for a forgotten dose.

Getting the most from your treatment

  • Try to keep your regular appointments with your doctor. This is so your doctor can check on your progress and assess how cilostazol is working for you.
  • If you are a smoker, you should try to stop. Smoking can narrow your blood vessels further and will make your condition worse. Your doctor or pharmacist can advise you about how to quit smoking.
  • Keep your home warm. The cold cuts down the blood supply to your skin even before you feel cold. If you go out in the cold, wrap up well in warm clothing, especially gloves and socks.
  • Regular exercise will help to improve your circulation – your doctor will advise you on what type of exercise is suitable for you.
  • Try to take good care of your hands and feet. Examine your hands, legs and feet regularly for any signs of damage or infection. If you notice any changes, see your doctor.

Can cilostazol cause problems?

Along with their useful effects, most medicines can cause unwanted side-effects although not everyone experiences them. The table below contains some of the most common ones associated with cilostazol. You will find a full list in the manufacturer’s information leaflet supplied with your medicine. The unwanted effects often improve as your body adjusts to the new medicine, but speak with your doctor or pharmacist if any of the following continue or become troublesome.

Very common cilostazol side-effects (these affect more than 1 in 10 people) What can I do if I experience this?
Headache Ask your pharmacist to recommend a suitable painkiller. If the headache continues, speak with your doctor
Diarrhoea Drink plenty of water to replace lost fluids
Common cilostazol side-effects (these affect less than 1 in 10 people) What can I do if I experience this?
Feeling dizzy or tired Do not drive and do not use tools or machines
Feeling sick (nausea) or being sick (vomiting), indigestion, abdominal pain, wind (flatulence) Stick to simple meals – avoid rich or spicy foods
Lack of appetite, fast heartbeat, chest pain, runny nose, swollen ankles or feet, itchy skin rash If you are concerned about any of these, speak with your doctor

Important: cilostazol has been associated with blood disorders in a few people. If you experience any bruising or bleeding, or if you develop a sore throat or a high temperature, you should let your doctor know straightaway so that your blood can be checked.

If you experience any other symptoms which you think may be due to the tablets, speak with your doctor or pharmacist for advice.

How to store cilostazol

  • Keep all medicines out of the reach and sight of children.
  • Store in a cool, dry place, away from direct heat and light.

Important information about all medicines

If you buy any medicines, check with a pharmacist that they are safe to take with your other medicines.

If you are having an operation or dental treatment, tell the person carrying out the treatment which medicines you are taking.

Never take more than the prescribed dose. If you suspect that you or someone else might have taken an overdose of this medicine, go to the accident and emergency department of your local hospital. Take the container with you, even if it is empty.

This medicine is for you. Never give it to other people even if their condition appears to be the same as yours.

Do not keep out-of-date or unwanted medicines. Take them to your local pharmacy which will dispose of them for you.

If you have any questions about this medicine ask your pharmacist.

Cilostazol (Pletal): risks of cardiovascular and bleeding events

Article date: April 2013

Cilostazol (Pletal) is a phosphodiesterase type 3 inhibitor indicated for the improvement of walking distances in patients with intermittent claudication, who do not have rest pain and who do not have evidence of peripheral tissue necrosis (Fontaine stage II). The effects of cilostazol include antiplatelet activity and vasodilation.

A review of the benefits and risks of cilostazol was triggered by reports of adverse reactions (mainly cardiac and haemorrhagic), and by the potential for drug interactions.

Efficacy of cilostazol

In clinical trials, cilostazol provided an average improvement in maximum walking distance of 87 m (approximately 66% increase) compared with 44 m for placebo; average baseline walking distance was 133 m. The studies measured walking distance using a graded treadmill test, and therefore the actual improvement on flat ground is expected to be greater.

Safety review of cilostazol

Safety data from the efficacy trials and a phase IV long-term safety study (CASTLE) were reviewed. The most commonly reported reactions were relatively minor (headaches, diarrhoea, palpitations, dizziness), and the clinical trials did not raise serious safety concerns. However cilostazol has been shown to increase heart rate by about 5 to 7 beats per minute, and this may put some patients at increased risk of cardiac events (eg, those with stable coronary disease). Contraindications have been revised to exclude patients at greatest risk of cardiac adverse events.

The CASTLE trial had a primary endpoint of all-cause mortality and included more than 1400 patients. Although the trial was terminated early due to a low event rate and high drop-out, it was considered to provide some reassurance on cardiovascular safety. No increase in bleeding risk was found with cilostazol alone or combined with one other antiplatelet treatment (clopidogrel or aspirin). However, there was a higher frequency of bleeding events when cilostazol was combined with both clopidogrel and aspirin.

Cilostazol is mainly metabolised via CYP3A4 and CYP2C19. Exposure to cilostazol is increased if it is taken concomitantly with medicines that inhibit these enzymes.

Pharmacokinetic data from interaction studies has been reviewed and a dose reduction (to 50 mg twice a day) is now recommended when cilostazol is taken with strong inhibitors of these enzymes. The increase in overall pharmacological activity when cilostazol is taken with ketoconazole or erythromycin is around 35%; when taken with omeprazole it is increased by about 47%.

Conclusions of the review

The benefit provided by cilostazol is clinically relevant in some patients and the risks associated with treatment in these patients are manageable. However, in patients with some cardiovascular conditions or those receiving two or more other antiplatelet or anticoagulant treatments, the risks of cilostazol outweigh the benefits.

Advice for healthcare professionals:

  • cilostazol is restricted to second-line treatment where lifestyle modifications (eg, smoking cessation and exercise regimens) and other appropriate interventions have failed to provide sufficient improvement. Lifestyle changes should continue during treatment
  • cilostazol is contraindicated in patients with:
    • unstable angina
    • recent myocardial infarction
    • coronary intervention (within 6 months)
    • history of severe tachyarrhythmia
    • those receiving 2 or more other antiplatelet or anticoagulant treatments
  • advise patients to take cilostazol 30 minutes before breakfast and evening meal
  • reassess patients after 3 months of starting cilostazol and consider stopping treatment if there is no clinically relevant improvement in walking distance
  • adose reduction to 50 mg twice a day is recommended when cilostazol is taken in combination with any of the following:
    • erythromycin
    • clarithromycin
    • ketoconazole
    • itraconazole; omeprazole
    • any strong inhibitors of CYP3A4 or CYP2C1
  • reassess patients currently receiving long-term treatment with cilostazol at a routine appointment, in order to advise on treatment continuation, dose change, or cessation

Further information

EMA

BNF section 2.6.4: Peripheral vasodilators and related drugs

Article citation: Drug Safety Update April 2013, vol 6, issue 9: A2.

Generic Name: cilostazol (sye LOE sta zol)
Brand Name: Pletal

Medically reviewed by Drugs.com on Jul 18, 2019 – Written by Cerner Multum

  • Overview
  • Side Effects
  • Dosage
  • Professional
  • Interactions
  • More

What is Pletal?

Pletal is a vasodilator that works by relaxing the muscles in your blood vessels to help them dilate (widen). This medicine dilates arteries that supply blood to your legs. This medicine also improves circulation by keeping platelets in the blood from sticking together and clotting.

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

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

Important Information

Do not take Pletal if you have congestive heart failure.

Before taking this medicine

Do not take Pletal if you have congestive heart failure. This medicine can make this condition worse.

To make sure Pletal is safe for you, tell your doctor if you have:

  • liver or kidney disease;

  • heart disease; or

  • if you smoke.

It is not known whether Pletal will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether cilostazol passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

How should I take Pletal?

Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Pletal is usually taken twice a day on an empty stomach, at least 30 minutes before or 2 hours after breakfast or dinner.

Take the medicine at the same time each day.

It may take up to 12 weeks before your symptoms improve. Keep using the medication as directed and tell your doctor if your symptoms do not improve after 4 weeks of treatment.

Store at room temperature away from moisture and heat.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while taking Pletal?

Grapefruit and grapefruit juice may interact with Pletal and lead to unwanted side effects. Discuss the use of grapefruit products with your doctor.

Pletal side effects

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

Call your doctor at once if you have:

  • chest pain, pounding heartbeats or fluttering in your chest;

  • a light-headed feeling, like you might pass out;

  • fever, chills, body aches, flu symptoms;

  • bloody urine, painful urination;

  • shortness of breath, even with mild exertion; or

  • swelling of your ankles or feet.

Common side effects may include:

  • headache, dizziness;

  • diarrhea, abnormal bowel movements;

  • upset stomach; or

  • runny nose.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Pletal?

Sometimes it is not safe to use certain medications at the same time. Some drugs can affect your blood levels of other drugs you take, which may increase side effects or make the medications less effective.

Many drugs can interact with Pletal. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide. Tell your doctor about all your current medicines and any medicine you start or stop using.

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.

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Copyright 1996-2018 Cerner Multum, Inc. Version: 5.01.

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  • Intermittent Claudication

CLINICAL PHARMACOLOGY

Mechanism Of Action

PLETAL and several of its metabolites inhibit phosphodiesterase III activity and suppress 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.

Cardiovascular Effects

Cilostazol affects both vascular beds and cardiovascular function. It produces heterogeneous 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 cynomolgus 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 twice daily, respectively.

Pharmacodynamics

Cilostazol’s effects on platelet aggregation were evaluated in both healthy subjects and in patients with stable symptoms of cerebral thrombosis, cerebral embolism, transient ischemic attack, or cerebral arteriosclerosis over a range of doses from 50 mg every day to 100 mg three times a day. Cilostazol significantly inhibited platelet aggregation in a dose-dependent manner. The effects were observed as early as 3 hours post-dose and lasted up to 12 hours following a single dose. Following chronic administration and withdrawal of cilostazol, the effects on platelet aggregation began to subside 48 hours after withdrawal and returned to baseline by 96 hours with no rebound effect. A cilostazol dosage of 100 mg twice daily consistently inhibited platelet aggregation induced with arachidonic acid, collagen and adenosine diphosphate (ADP). Bleeding time was not affected by cilostazol administration.

Effects on circulating plasma lipids have been examined in patients taking PLETAL. After 12 weeks, as compared to placebo, PLETAL 100 mg twice daily produced a reduction in triglycerides of 29.3 mg/dL (15%) and an increase in HDL-cholesterol of 4.0 mg/dL (≅10%).

Drug Interactions

Aspirin

Short-term (less than or equal to 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 (less than or equal to 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 frequency of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.

Cilostazol did not inhibit 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 pharmacodynamics of both drugs is unknown.

Pharmacokinetics

PLETAL 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 subjects and patients with intermittent claudication due to peripheral arterial disease (PAD). Figure 1 shows the mean plasma concentration-time profile at steady state after multiple dosing of PLETAL 100 mg twice daily.

Figure 1: Mean Plasma Concentration-time Profile at Steady State after Multiple Dosing of PLETAL 100 mg Twice Daily


Distribution

Cilostazol is 95 -98% protein bound, predominantly to albumin. The 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 healthy volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.

Metabolism

Cilostazol is eliminated predominantly 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 (20% as active as cilostazol).

Elimination

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 (50 to 80 years) or gender.

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 healthy subjects. Severe renal impairment increases metabolite levels and alters protein binding of the parent. 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%).

Cilostazol does not appear to inhibit CYP3A4.

Cilostazol did not inhibit the metabolism of R-and S-warfarin after a single 25-mg dose of warfarin.

Clopidogrel

Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.

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, voriconazole, clarithromycin, ritonavir, saquinavir, and nefazodone would be expected to have a similar effect .

Moderate Inhibitors Of CYP3A4

Erythromycin and other macrolide antibiotics

Erythromycin is a moderately strong inhibitor of CYP3A4. Coadministration of erythromycin 500 mg every 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-hydroxycilostazol by 141% .

Diltiazem

Diltiazem 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40% .

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 .

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-hydroxylovastatin AUC approximately 70% and is not expected to be clinically significant.

Animal Toxicology And/Or Pharmacology

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 hemorrhage, hemosiderin deposition and fibrosis in the left ventricle, hemorrhage in the right atrial wall, hemorrhage 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 twice daily. 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.

Clinical Studies

The ability of PLETAL to improve walking distance in patients with stable intermittent claudication was studied in eight, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration involving 2,274 patients using dosages of 50 mg twice daily (n=303), 100 mg twice daily (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 twice daily 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.

Figure 2 depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.

Figure 2: Percent Mean Improvement in Maximal Walking Distance at Study End for the EightRandomized, Double-Blind, Placebo-Controlled Clinical Trials


Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with PLETAL 100 mg twice daily, expressed as the 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 twice daily or 50 mg twice daily 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 was the a priori study hypothesis.

Identification

Are you a new drug developer? Contact us to learn more about our customized products and solutions. Stay in the know! As part of our commitment to providing the most up-to-date drug information, we will be releasing #DrugBankUpdates with our newly added curated drug pages. #DrugBankUpdates Name Cilostazol Accession Number DB01166 (APRD00155) Type Small Molecule Groups Approved, Investigational Description

Cilostazol is a quinolinone derivative and antiplatelet agent with vasodilating properties that has been used in the symptomatic treatment of intermittent claudication in patients with peripheral ischaemia. It is marketed under the brand name Pletal by Otsuka Pharmaceutical Co.. Cilostazol works by inhibiting both primary and secondary aggregation and reducing calcium-induced contractions.

Structure 3D Download Similar Structures

Structure for Cilostazol (DB01166)

× Close Synonyms External IDs OPC 13013 / OPC 21 / OPC-13013 / OPC-21 Product Images Prescription Products

Name Dosage Strength Route Labeller Marketing Start Marketing End
Unlock Additional Data
Cilostazol Tablet 50 mg/1 Oral TEVA PHARMACEUTICALS USA 2007-01-08 2007-01-08 US
Pletal Tablet 100 mg/1 Oral Physicians Total Care, Inc. 1999-01-15 2011-07-31 US
Pletal Tablet 50 mg/1 Oral Physicians Total Care, Inc. 1999-01-15 2011-07-31 US
Pletal Tablet 100 mg/1 Oral Otsuka Pharmaceutical Co., Ltd. 1999-01-15 2016-06-30 US
Pletal Tablet 50 mg/1 Oral Otsuka Pharmaceutical Co., Ltd. 1999-01-15 2017-11-30 US

Additional Data Available

  • Application Number Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Generic Prescription Products

Name Dosage Strength Route Labeller Marketing Start Marketing End
Unlock Additional Data
Cilostazol Tablet 100 mg/1 Oral bryant ranch prepack 2004-11-23 2017-01-30 US
Cilostazol Tablet 50 mg/1 Oral NCS HealthCare of KY, Inc dba Vangard Labs 2009-11-04 2010-05-04 US
Cilostazol Tablet 100 mg/1 Oral Core Pharma, Llc 2006-09-06 2012-11-01 US
Cilostazol Tablet 100 mg/1 Oral Slate Run Pharmaceuticals 2018-01-01 Not applicable US
Cilostazol Tablet 100 mg/1 Oral Avera McKennan Hospital 2015-04-01 2018-05-22 US
Cilostazol Tablet 50 mg/1 Oral Nucare Pharmaceuticals, Inc. 2012-04-24 Not applicable US
Cilostazol Tablet 100 mg/1 Oral Lake Erie Medical Dba Quality Care Produts Llc 2012-10-24 Not applicable US
Cilostazol Tablet 100 mg/1 Oral Teva Pharmaceuticals USA, Inc. 2012-10-24 Not applicable US
Cilostazol Tablet 100 mg/1 Oral Ncs Health Care Of Ky, Inc Dba Vangard Labs 2012-03-23 Not applicable US
Cilostazol Tablet 100 mg/1 Oral Actavis Totowa LLC 2006-09-01 2008-08-20 US

Additional Data Available

  • Application Number Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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International/Other Brands Pletaal Categories UNII N7Z035406B CAS number 73963-72-1 Weight Average: 369.4607
Monoisotopic: 369.216475133 Chemical Formula C20H27N5O2 InChI Key RRGUKTPIGVIEKM-UHFFFAOYSA-N InChI InChI=1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26) IUPAC Name 6–1,2,3,4-tetrahydroquinolin-2-one SMILES O=C1CCC2=C(N1)C=CC(OCCCCC1=NN=NN1C1CCCCC1)=C2

Pharmacology

Indication

Indicated for the alleviation of symptoms of intermittent claudication (pain in the legs that occurs with walking and disappears with rest).

Associated Conditions

  • Intermittent Claudication

Pharmacodynamics

Cilostazol reduces the symptoms of intermittent claudication, as indicated by an increased walking distance. Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. The pain occurs due to reduced blood flow to the legs.

Mechanism of action

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.

Target Actions Organism
AcGMP-inhibited 3′,5′-cyclic phosphodiesterase A inhibitor Humans

Unlock Additional Data Additional Data Available Adverse Effects

Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.

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Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

Learn more Additional Data Available Blackbox Warnings

Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

Learn more Absorption

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.

Volume of distribution Not Available Protein binding

95-98%

Metabolism

Hepatic. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol.

Route of elimination

Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. 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.

Half life

11-13 hours.

Clearance Not Available Toxicity

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

Affected organisms

  • Humans and other mammals

Pathways

Pathway Category
Cilostazol Action Pathway Drug action

Pharmacogenomic Effects/ADRs Not Available

Interactions

Drug Interactions This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

  • All Drugs
  • Approved
  • Vet approved
  • Nutraceutical
  • Illicit
  • Withdrawn
  • Investigational
  • Experimental
Drug Interaction
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(R)-warfarin The risk or severity of bleeding can be increased when Cilostazol is combined with (R)-warfarin.
(S)-Warfarin The risk or severity of bleeding can be increased when Cilostazol is combined with (S)-Warfarin.
1-(2-Phenylethyl)-4-phenyl-4-acetoxypiperidine The metabolism of Cilostazol can be decreased when combined with 1-(2-Phenylethyl)-4-phenyl-4-acetoxypiperidine.
2,5-Dimethoxy-4-ethylamphetamine The risk or severity of Tachycardia can be increased when Cilostazol is combined with 2,5-Dimethoxy-4-ethylamphetamine.
2,5-Dimethoxy-4-ethylthioamphetamine The risk or severity of Tachycardia can be increased when Cilostazol is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
4-Bromo-2,5-dimethoxyamphetamine The risk or severity of Tachycardia can be increased when Cilostazol is combined with 4-Bromo-2,5-dimethoxyamphetamine.
4-hydroxycoumarin The risk or severity of bleeding can be increased when Cilostazol is combined with 4-hydroxycoumarin.
4-Methoxyamphetamine The metabolism of 4-Methoxyamphetamine can be decreased when combined with Cilostazol.
5-methoxy-N,N-dimethyltryptamine The metabolism of 5-methoxy-N,N-dimethyltryptamine can be decreased when combined with Cilostazol.
6-Deoxyerythronolide B The metabolism of Cilostazol can be decreased when combined with 6-Deoxyerythronolide B.

Additional Data Available

  • Extended Description Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions

  • Grapefruit and grapefruit juice should be avoided throughout treatment, grapefruit can significantly increase serum levels of this product.
  • Take on an empty stomach, a lipid rich meal will increase absorption.

Synthesis Reference

Marioara Mendelovici, “Processes for preparing cilostazol.” U.S. Patent US20020099213, issued July 25, 2002.

US20020099213 General References Not Available External Links Human Metabolome Database HMDB0015297 KEGG Drug D01896 PubChem Compound 2754 PubChem Substance 46506317 ChemSpider 2652 BindingDB 50225508 ChEBI 31401 ChEMBL CHEMBL799 Therapeutic Targets Database DAP000191 PharmGKB PA164746334 RxList RxList Drug Page Drugs.com Drugs.com Drug Page Wikipedia Cilostazol ATC Codes B01AC23 — Cilostazol

  • B01AC — Platelet aggregation inhibitors excl. heparin
  • B01A — ANTITHROMBOTIC AGENTS
  • B01 — ANTITHROMBOTIC AGENTS
  • B — BLOOD AND BLOOD FORMING ORGANS

MSDS (35.9 KB)

Clinical Trials

Clinical Trials

Phase Status Purpose Conditions Count
0 Completed Basic Science Migraine With Aura / Stroke 1
1 Active Not Recruiting Treatment Healthy Volunteers 1
1 Active Not Recruiting Treatment Intermittent Claudication 1
1 Completed Not Available Healthy Volunteers 3
1 Completed Not Available Therapeutic Equivalency, Healthy 1
1 Completed Basic Science Healthy Volunteers 1
1 Completed Basic Science Therapeutic Equivalency 1
1 Completed Treatment Healthy Volunteers 2
1 Completed Treatment Intermittent Claudication 2
1 Completed Treatment Pain 1
1 Completed Treatment Peripheral Artery Disease (PAD) 1
1 Recruiting Treatment Dyslipidemia / Peripheral Artery Disease (PAD) 1
2 Active Not Recruiting Treatment Mild Cognitive Impairment (MCI) 1
2 Completed Basic Science Contraception 1
2 Completed Prevention Cerebral Small Vessels Disease / Cognitive Impairments / Stroke 1
2 Completed Treatment Intermittent Claudication 2
2 Completed Treatment Vasospastic Angina 1
2 Recruiting Prevention Small Vessel Cerebrovascular Disease 1
2 Unknown Status Treatment Peripheral Artery Disease (PAD) 1
2, 3 Recruiting Prevention Cerebral Small Vessels Disease / Stroke, Lacunar 1
3 Completed Prevention Cerebral Infarctions 2
3 Completed Treatment Cerebrovascular Diseases 1
3 Completed Treatment Coronary Artery Disease 1
3 Completed Treatment Vasospastic Angina 2
3 Recruiting Prevention Peripheral Arterial Disease (PAD) 1
3 Terminated Treatment Recurrent Vestibulopathy 1
3 Unknown Status Treatment Atherosclerosis / Cardiovascular Heart Disease / Peripheral Vascular Disease Patient 1
3 Unknown Status Treatment Coronary Artery Stenosis / High Post-Treatment Platelet Reactivity / Late Platelet Aggregation / Maximal Platelet Aggregation 1
4 Active Not Recruiting Prevention Intracranial Hemorrhages / Ischemia, Brain 1
4 Active Not Recruiting Treatment Carotid Atherosclerosis / Type 2 Diabetes Mellitus 1
4 Active Not Recruiting Treatment Cerebral Small Vessels Disease 1
4 Active Not Recruiting Treatment Intracranial Hemorrhages / Ischemia, Brain 1
4 Completed Other Intermittent Claudication / Peripheral Arterial Disease (PAD) / Peripheral Vascular Disease Patient 1
4 Completed Prevention Cerebral Infarctions 1
4 Completed Prevention Noncardioembolic Cerebral Infarction 1
4 Completed Treatment Acute Coronary Syndromes (ACS) 1
4 Completed Treatment Acute Coronary Syndromes (ACS) / Clopidogrel Low Responsiveness / Percutaneous Coronary Intervention 1
4 Completed Treatment Acute Coronary Syndromes (ACS) / Ischemic Heart Disease 1
4 Completed Treatment Alzheimer Dementia (AD) 1
4 Completed Treatment Arteriosclerosis Obliterans / Type 2 Diabetes Mellitus 1
4 Completed Treatment Atherosclerosis Cerebral Infarction 1
4 Completed Treatment Atherosclerosis / Cerebral Infarctions 1
4 Completed Treatment Cardiovascular Heart Disease 1
4 Completed Treatment Cerebral Infarctions 3
4 Completed Treatment Chronic Kidney Disease (CKD) / Stable Angina (SA) 1
4 Completed Treatment Coronary Artery Disease 3
4 Completed Treatment Coronary Artery Disease / Percutaneous Coronary Intervention 1
4 Completed Treatment Dementia, Vascular / Stroke 1
4 Completed Treatment Diabetes Complications / Type 2 Diabetes Mellitus 1
4 Completed Treatment Diabetic Nephropathies 1
4 Completed Treatment Healthy Volunteers 1
4 Completed Treatment Hemodialysis Patients / Peripheral Vascular Disease Patient 1
4 Completed Treatment Hyperlipidemias 1
4 Completed Treatment Myocardial Infarction 1
4 Completed Treatment Peripheral Arterial Disease (PAD) 1
4 Completed Treatment Polyneuropathies 1
4 Completed Treatment Raynaud’s Phenomenon 2
4 Completed Treatment Stroke, Ischemic 1
4 Not Yet Recruiting Prevention Type 2 Diabetes Mellitus 1
4 Recruiting Health Services Research Peripheral Artery Disease (PAD) / Stroke, Ischemic / Type 2 Diabetes Mellitus 1
4 Recruiting Prevention Aneurysmal Subarachnoid Hemorrhage 1
4 Recruiting Treatment Acute Myocardial Infarction (AMI) 1
4 Recruiting Treatment Aneurysm, Cerebral / Endovascular Procedures 1
4 Recruiting Treatment Coronary Artery Disease 2
4 Recruiting Treatment Critical Limb Ischemia (CLI) 1
4 Recruiting Treatment Severe Hypercholesterolemia 1
4 Terminated Treatment Claudication (Finding) / Peripheral Arterial Disease (PAD) 1
4 Terminated Treatment Coronary Artery Disease 1
4 Unknown Status Prevention Arteriosclerosis Obliterans 1
4 Unknown Status Prevention Type 2 Diabetes Mellitus 1
4 Unknown Status Treatment Angioplasty, Transluminal, Percutaneous Coronary 1
4 Unknown Status Treatment Chronic Occlusive Arterial Disease 1
4 Unknown Status Treatment Metabolic Syndromes / Type 2 Diabetes Mellitus 1
Not Available Completed Health Services Research Drug Drug Interaction (DDI) 1
Not Available Completed Health Services Research Migraine 1
Not Available Completed Treatment Claudication 1
Not Available Completed Treatment Clopidogrel Non-Responsiveness 1
Not Available Completed Treatment Coronary Heart Disease (CHD) 1
Not Available Completed Treatment In-stent Restenosis After Carotid Artery Stenting 1
Not Available Completed Treatment Intermittent Claudication 2
Not Available Completed Treatment Migraine 2
Not Available Completed Treatment Tinnitus 1
Not Available Recruiting Other Migraine / Migraine Without Aura 1
Not Available Recruiting Treatment Major Depressive Disorder (MDD) 1
Not Available Unknown Status Treatment Mild Cognitive Impairment (MCI) 1

Pharmacoeconomics

Manufacturers Not Available Packagers

  • Alphapharm Party Ltd.
  • Apotex Inc.
  • Breckenridge Pharmaceuticals
  • Corepharma LLC
  • Diversified Healthcare Services Inc.
  • Eon Labs
  • Heartland Repack Services LLC
  • Murfreesboro Pharmaceutical Nursing Supply
  • Mylan
  • Otsuka America
  • Physicians Total Care Inc.
  • Prasco Labs
  • Resource Optimization and Innovation LLC
  • Roxane Labs
  • Stat Rx Usa
  • Teva Pharmaceutical Industries Ltd.
  • UDL Laboratories
  • United Research Laboratories Inc.
  • Vangard Labs Inc.

Dosage forms

Form Route Strength
Tablet Conjunctival; Oral 100 mg/1
Tablet Oral 100 mg/1
Tablet Oral 50 mg/1

Prices

Unit description Cost Unit
Pletal 100 mg tablet 2.51USD tablet
Pletal 50 mg tablet 2.39USD tablet
Cilostazol 100 mg tablet 1.86USD tablet
Cilostazol 50 mg tablet 1.86USD tablet

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only. Patents Not Available

Properties

State Solid Experimental Properties

Property Value Source
melting point (°C) 160 °C PhysProp
logP 2.3 Not Available

Predicted Properties

Property Value Source
Water Solubility 0.0324 mg/mL ALOGPS
logP 3.38 ALOGPS
logP 3.31 ChemAxon
logS -4.1 ALOGPS
pKa (Strongest Acidic) 14.42 ChemAxon
pKa (Strongest Basic) -0.51 ChemAxon
Physiological Charge 0 ChemAxon
Hydrogen Acceptor Count 5 ChemAxon
Hydrogen Donor Count 1 ChemAxon
Polar Surface Area 81.93 Å2 ChemAxon
Rotatable Bond Count 7 ChemAxon
Refractivity 117.13 m3·mol-1 ChemAxon
Polarizability 41.15 Å3 ChemAxon
Number of Rings 4 ChemAxon
Bioavailability 1 ChemAxon
Rule of Five Yes ChemAxon
Ghose Filter Yes ChemAxon
Veber’s Rule No ChemAxon
MDDR-like Rule Yes ChemAxon

Predicted ADMET features

Property Value Probability
Human Intestinal Absorption + 1.0
Blood Brain Barrier + 0.9909
Caco-2 permeable 0.5666
P-glycoprotein substrate Non-substrate 0.5361
P-glycoprotein inhibitor I Inhibitor 0.7886
P-glycoprotein inhibitor II Inhibitor 0.8387
Renal organic cation transporter Non-inhibitor 0.5794
CYP450 2C9 substrate Non-substrate 0.7887
CYP450 2D6 substrate Non-substrate 0.7734
CYP450 3A4 substrate Substrate 0.7407
CYP450 1A2 substrate Non-inhibitor 0.9045
CYP450 2C9 inhibitor Non-inhibitor 0.9071
CYP450 2D6 inhibitor Non-inhibitor 0.9231
CYP450 2C19 inhibitor Non-inhibitor 0.9026
CYP450 3A4 inhibitor Inhibitor 0.7959
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.9486
Ames test Non AMES toxic 0.5436
Carcinogenicity Non-carcinogens 0.9085
Biodegradation Not ready biodegradable 0.9636
Rat acute toxicity 1.9002 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.7518
hERG inhibition (predictor II) Non-inhibitor 0.7075

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST) Not Available Spectra

Taxonomy

Description This compound belongs to the class of organic compounds known as hydroquinolones. These are compounds containing a hydrogenated quinoline bearing a ketone group. Kingdom Organic compounds Super Class Organoheterocyclic compounds Class Quinolines and derivatives Sub Class Quinolones and derivatives Direct Parent Hydroquinolones Alternative Parents Hydroquinolines / Alkyl aryl ethers / Benzenoids / Tetrazoles / Heteroaromatic compounds / Secondary carboxylic acid amides / Lactams / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compoundsOrganic oxides / Hydrocarbon derivatives / Carbonyl compounds show 3 more Substituents Tetrahydroquinolone / Tetrahydroquinoline / Alkyl aryl ether / Benzenoid / Azole / Heteroaromatic compound / Tetrazole / Carboxamide group / Lactam / Secondary carboxylic acid amideCarboxylic acid derivative / Ether / Azacycle / Hydrocarbon derivative / Organic oxide / Organic nitrogen compound / Organopnictogen compound / Carbonyl group / Organic oxygen compound / Organonitrogen compound / Organooxygen compound / Aromatic heteropolycyclic compound show 12 more Molecular Framework Aromatic heteropolycyclic compounds External Descriptors tetrazoles, lactam (CHEBI:31401)

Targets

Kind Protein Organism Humans Pharmacological action Yes Actions Inhibitor General Function Metal ion binding Specific Function Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes. Gene Name PDE3A Uniprot ID Q14432 Uniprot Name cGMP-inhibited 3′,5′-cyclic phosphodiesterase A Molecular Weight 124978.06 Da

Enzymes

Kind Protein Organism Humans Pharmacological action Unknown Actions Substrate General Function Oxygen binding Specific Function Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un… Gene Name CYP3A5 Uniprot ID P20815 Uniprot Name Cytochrome P450 3A5 Molecular Weight 57108.065 Da

  1. Suri A, Forbes WP, Bramer SL: Effects of CYP3A inhibition on the metabolism of cilostazol. Clin Pharmacokinet. 1999;37 Suppl 2:61-8.
  2. Flockhart Table of Drug Interactions

Kind Protein Organism Humans Pharmacological action Unknown Actions Substrate General Function Oxygen binding Specific Function Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un… Gene Name CYP3A7 Uniprot ID P24462 Uniprot Name Cytochrome P450 3A7 Molecular Weight 57525.03 Da

  1. Suri A, Forbes WP, Bramer SL: Effects of CYP3A inhibition on the metabolism of cilostazol. Clin Pharmacokinet. 1999;37 Suppl 2:61-8.
  2. Flockhart Table of Drug Interactions

Kind Protein Organism Humans Pharmacological action Unknown Actions Substrate General Function Steroid hydroxylase activity Specific Function Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im… Gene Name CYP2C19 Uniprot ID P33261 Uniprot Name Cytochrome P450 2C19 Molecular Weight 55930.545 Da Kind Protein Organism Humans Pharmacological action Unknown Actions Substrate General Function Vitamin d3 25-hydroxylase activity Specific Function Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react… Gene Name CYP3A4 Uniprot ID P08684 Uniprot Name Cytochrome P450 3A4 Molecular Weight 57342.67 Da

  1. Suri A, Forbes WP, Bramer SL: Effects of CYP3A inhibition on the metabolism of cilostazol. Clin Pharmacokinet. 1999;37 Suppl 2:61-8.
  2. Flockhart Table of Drug Interactions
  3. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers

Kind Protein Organism Humans Pharmacological action Unknown Actions Substrate General Function Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen Specific Function Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un… Gene Name CYP1A2 Uniprot ID P05177 Uniprot Name Cytochrome P450 1A2 Molecular Weight 58293.76 Da Kind Protein Organism Humans Pharmacological action Unknown Actions Substrate General Function Steroid hydroxylase activity Specific Function Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic… Gene Name CYP2D6 Uniprot ID P10635 Uniprot Name Cytochrome P450 2D6 Molecular Weight 55768.94 Da ×Unlock Data

There is additional data available for commercial users including Adverse Effects, Contraindications, and Blackbox Warnings. Contact us to learn more about these and other features.

Learn more

Drug created on June 13, 2005 07:24 / Updated on February 02, 2020 00:26

Pletal Tablet

Precautions

See also Warning section.

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: serious/active bleeding (such as bleeding ulcers, bleeding in the eye/brain), blood disorders (such as hemophilia, low platelet counts), heart disease (such as heart attack, chest pain, fast/irregular heartbeat), stroke, kidney disease.

This drug may make you dizzy. Alcohol or marijuana (cannabis) can make you more dizzy. Do not drive, use machinery, or do anything that needs alertness until you can do it safely. Limit alcoholic beverages. Talk to your doctor if you are using marijuana (cannabis).

To lower the chance of getting cut, bruised, or injured, use caution with sharp objects like razors and nail cutters, and avoid activities such as contact sports.

This medicine may cause stomach bleeding. Daily use of alcohol while using this medicine may increase your risk for stomach bleeding. Limit alcoholic beverages. Ask your doctor or pharmacist about how much alcohol you may safely drink.

Cilostazol may cause a condition that affects the heart rhythm (QT prolongation). QT prolongation can rarely cause serious (rarely fatal) fast/irregular heartbeat and other symptoms (such as severe dizziness, fainting) that need medical attention right away.

The risk of QT prolongation may be increased if you have certain medical conditions or are taking other drugs that may cause QT prolongation. Before using cilostazol, tell your doctor or pharmacist of all the drugs you take and if you have any of the following conditions: certain heart problems (heart failure, slow heartbeat, QT prolongation in the EKG), family history of certain heart problems (QT prolongation in the EKG, sudden cardiac death).

Low levels of potassium or magnesium in the blood may also increase your risk of QT prolongation. This risk may increase if you use certain drugs (such as diuretics/”water pills”) or if you have conditions such as severe sweating, diarrhea, or vomiting. Talk to your doctor about using cilostazol safely.

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

Older adults may be more sensitive to the side effects of this drug, especially swelling of the hands/feet (fluid retention) or QT prolongation (see above).

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.

Patient Education

Taking Cilostazol for Peripheral Arterial Disease (PAD)

Cilostazol is a medicine that can relieve claudication. Claudication is a common symptom of peripheral arterial disease (PAD). It causes pain in your legs when you walk or exercise. This happens because of reduced blood flow to your leg muscles.

How cilostazol works

Cilostazol works by improving blood flow in the smallest blood vessels. This lets you walk farther without pain. You can then be more active and do more of the things you like to do. Cilostazol can be used safely with many medicines. These include medicines used to reduce the risk of heart attack and stroke. But some medicines can affect how cilostazol works in your body. So your healthcare provider needs to know what other medicines you take. You may need to use cilostazol for 1 to 3 months before it starts to work. If you see no improvement after using it for 3 months, then your provider will likely take you off it. You should not use cilostazol if you have heart failure.

Taking cilostazol safely

Before taking cilostazol, tell your provider about any medicines you are taking. This includes:

  • All prescription medicines

  • Over-the-counter medicines such as aspirin or ibuprofen

  • Herbs, vitamins, and other supplements

Avoid grapefruit or grapefruit juice when taking cilostazol. These may cause a harmful interaction. Also tell your provider if you have a history of heart failure, liver disease, or any other health problems. Always take medicines as directed.

Tips for taking cilostazol

  • Have a routine. Take cilostazol when you get up each morning. Or take it when getting ready for bed at night.

  • Don’t skip doses. You must take this medicine daily for it to work.

  • Take on an empty stomach. Take it either 1 hour before a meal or 3 hours after, with a full glass of water.

  • Keep track of what you take. A pillbox with the days of the week marked can help, especially if you take several medicines. Or use a list or chart to keep track.

When to call your healthcare provider

Cilostazol can cause side effects. If you have problems, changing your dose may help. Call your provider or get medical help right away if you have any of the following:

  • Rapid or irregular heartbeat

  • Chest pain

  • Shortness of breath

  • Loose bowel movements or diarrhea

  • Bloody or painful urine

  • Severe headache

  • Fever, chills, or flu symptoms

  • Upset stomach

  • Allergic reaction such as hives, rash, or swelling of your face, lips, tongue, or throat

What to know about blood thinners for heart disease

People taking blood thinners should let their doctors know about any other medications that they are taking. Some blood thinners also interact with certain foods.

In general, combining blood thinners with other drugs that cause bleeding further increases a person’s risk of bleeding.

Antiplatelet medications

Other substances that may interact with aspirin or antiplatelet medications include:

  • diuretics
  • nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen (Advil)
  • steroid drugs
  • alcohol

As well as interacting with other drugs that thin the blood, Plavix and Effient may interact with opioids. Plavix also interacts with omeprazole (Prilosec), which reduces stomach acid.

Brilinta can interact with digoxin (Lanoxin) and with high doses of simvastatin (Zocor) and lovastatin (Altoprev).

A doctor will closely monitor people who take blood thinners.

Warfarin

Doctors who prescribe warfarin must warn the person about the many drug and food interactions that occur with this anticoagulant.

Some substances that interact with warfarin include:

  • antibiotics
  • antifungals
  • botanical or herbal products
  • other anticoagulants and antiplatelet agents
  • foods containing vitamin K

People need to do frequent blood tests when taking warfarin. Doctors will use the blood test to check a person’s International Normalized Ratio (INR).

The INR test provides important information to help doctors determine the appropriate dosage of warfarin. Drug and food interactions can cause changes in a person’s INR.

An INR reading that is too low puts people at risk of clotting, whereas a reading that is too high indicates an increased risk of bleeding. The correct reading for someone on anticoagulants is 2–3.

Doctors may also tell people taking warfarin to pay attention to the vitamin K content in the foods that they eat. People taking warfarin should not avoid vitamin K altogether, but they may need to limit their intake of it.

Learn more about vitamin K, diet, and warfarin in this article.

Heparin

Anyone who takes heparin or low molecular weight heparin should avoid any drugs that increase the risk of major bleeding.

If someone requires other blood thinners while taking heparin, doctors will need to monitor the person closely for signs of bleeding.

Newer direct oral anticoagulants

Compared with warfarin, newer direct oral anticoagulants have fewer drug interactions and may be safer options, although more, long-term clinical use is necessary to confirm this.

These drugs also do not require people to make dietary changes or have INR monitoring. Researchers note, however, that newer direct oral anticoagulants may be more expensive than warfarin for many people.

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