Cilostazol

(sil oh' sta zol)

PCaution when used during lactation - Caution when used during pregnancy

LCaution when used during lactation - Caution when used during lactation

Molecule Info

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Indication(s) & Dosage

Cilostazol is indicated for the reduction of symptoms of intermittent claudication, as indicated by an increased walking distance.

Peripheral vascular disease  Adult: 100 mg bid. May reduce dose in patients taking enzyme inhibitors concurrently.

Administration

Should be taken on an empty stomach.  Take at least ½ hr before or 2 hr after meals.

Overdosage

Symptoms include: severe headache, diarrhoea, hypotension, tachycardia, and possibly cardiac arrhythmias.  Careful observation and supportive treatment are recommended.

Contraindications

Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III to IV congestive heart failure. Cilostazol is contraindicated in patients with congestive heart failure of any severity.

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

Cilostazol tablets are contraindicated in patients with known or suspected hypersensitivity to any of their components.

Special Precautions

Congestive heart disease.  Concurrent therapy with clopidogrel has not been studied for safety or efficacy.  Pregnancy and lactation.

Adverse Drug Reaction(s)

Headache, dizziness, palpitations, diarrhoea, abnormal stools; pain, infection; peripheral oedema, nausea, vomiting, other cardiac arrhythmias, chest pain, rhinitis, pharyngitis, ecchymosis and skin rash.

Drug Interactions

Co-admin with drugs that affect CYP3A4 or CYP2C19 may influence the pharmacokinetics of cilostazol.

Pregnancy Category (FDA)

Category C: Either studies in animals have revealed adverse effects on the foetus and there are no controlled studies in women or studies in women and animals are not available.  Drugs should be given only if the potential benefit justifies the potential risk to the foetus.

Storage

Oral:  Store at 25°C.

Pharmacology

Mechanism of Action:

The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites arecyclic AMP (cAMP) phosphodiesterase III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in cAMP in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.

Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including thrombin, ADP, collagen, arachidonic acid, epinephrine, and shear stress. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in triglycerides of 29.3 mg/dL (15%) and an increase in HDL-cholesterol of 4.0 mg/dL ( =10%).

Cardiovascular Effects:

Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, carotid or superior mesenteric arteries. Renal arteries were not responsive to the effects of cilostazol.

In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with Holter monitors, numerically more cilostazol-treated patients had increases in ventricular premature beats andnon-sustained ventricular tachycardia events than did placebo-treated patients;the increases were not dose-related.

Pharmacokinetics:

Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolizedby 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 (PDEIII inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11 to 13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).

Distribution:

Plasma Protein and Erythrocytes Binding:

Cilostazol is 95% to 98% protein bound, predominantly to albumin. The mean percent binding for 3,4-dehydro-cilostazol is 97.4% and for 4′-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.

Metabolism and Excretion:

Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol’s metabolism are CYP3A4 and, to a lesser extent, CYP2C19. The enzyme responsible for metabolism of 3,4-dehydro-cilostazol, the most active of the metabolites, is unknown.

Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4 to 7 times as active as cilostazol), and 4% was 4′-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4′-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.

Special Populations:

Age and Gender:

The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50-to-80-year-old age range

Smokers:

Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.

Hepatic Impairment:

The pharmacokinetics of cilostazol and its metabolites were similar in subjects with mild hepatic disease as compared to healthy subjects.

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

Renal Impairment:

The total pharmacologic activity of cilostazol and its metabolites was similar in subjects with mild to moderate renal impairment and in normal subjects. Severe renal impairment increases metabolite levels and alters protein binding of the parent and metabolites. The expected pharmacologic activity, however, based on plasma concentrations and relative PDE III inhibiting potency of parent drug and metabolites, appeared little changed. Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).

Pharmacokinetic and Pharmacodynamic Drug-Drug Interactions:

Cilostazol could have pharmacodynamic interactions with other inhibitors of platelet function and pharmacokinetic interactions because of effects of other drugs on its metabolism by CYP3A4 or CYP2C19. A reduced dose of cilostazol should be considered when taken concomitantly with CYP3A4 or CYP2C19 inhibitors. Cilostazoldoes not appear to inhibit CYP3A4 (see Pharmacokinetic and Pharmacodynamic Drug-Drug Interactions, Lovastatin).

Aspirin:

Short-term (≤4 days) coadministration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (≤4 days) coadministration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term coadministration of aspirin with cilostazol had no clinically significant impact on PT, aPTT, or bleeding time compared to aspirin alone. Effects of long-term coadministration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was coadministered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 to 81 mg daily for 137 days (107 patients) and325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.

Warfarin:

The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2, and CYP2C19, and in the metabolism of S-warfarin, CYP2C9.

Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time, or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.

Clopidogrel:

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

Inhibitors of CYP3A4:

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

Moderate Inhibitors of CYP3A4

1. Erythromycin and other macrolide antibiotics:

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

2. Diltiazem:

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

3. Grapefruit Juice:

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

Inhibitors 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 AUC, by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Coadministration of cilostazol with lovastatin increases lovastatin and β-hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.

CLINICAL EFFICACY

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

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

 

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Brand/Product Info


Total Products : 5     
Brand Name Manufacturer/Marketer Composition Dosage Form Pack Size & Price
CILOSTA 100 Square Pharmaceuticals Ltd. Cilostazol 100mg Tablet 3x10's: 362.70 MRP
INCLAUD ACI Ltd. Cilostazol 100mg Tablet 20's: 240.00 MRP
VASOSIL IBN SINA Pharmaceutical Industry Ltd. Cilostazol 50 & 100mg Tablet 50mg x30's, 100mg x20's: 450.00, 500.00 IP
ZOCIL 100 Beximco Pharmaceuticals Ltd Cilostazol 100 mg Tablet 20's: 240.00 MRP
ZOCIL 50 Beximco Pharmaceuticals Ltd Cilostazol 50mg Tablet 30's: 210.00 MRP

Gen. MedInfo

IMPORTANT WARNING:

Medications similar to cilostazol caused an increased risk of death in patients with congestive heart failure.  Tell your doctor if you have or have ever had congestive heart failure.  Your doctor will probably tell you not to take cilostazol.

 

Talk to your doctor about the risks of taking cilostazol.

Why is this medication prescribed?

Cilostazol is used to reduce the symptoms of intermittent claudication.  Cilostazol is in a class of medications called platelet-aggregation inhibitors. It works by improving blood flow to the legs.

How should this medicine be used?

Cilostazol comes as a tablet to take by mouth.  It is usually taken twice a day, at least 30 minutes before or 2 hours after breakfast and dinner.  Take cilostazol at around the same times every day.  Follow the directions on the prescription label carefully, and ask your Doctor to explain any part you do not understand.  Take cilostazol exactly as directed.  Do not take more or less of it or take it more often than prescribed by your doctor. Cilostazol controls the symptoms of intermittent claudication but does not cure it.  Although you may notice improvements in 2 to 4 weeks, it may take up to 12 weeks before you notice the full benefit of cilostazol.  Continue taking cilostazol even if you feel well.  Do not stop taking cilostazol without talking to your doctor.

Other uses for this medicine

This medication is sometimes prescribed for other uses; ask your Doctor for more information.

What special precautions should I follow?

Before taking cilostazol,

  • tell your Doctor if you are allergic to cilostazol, any other medications, or any of the ingredients in cilostazol.  Ask your Doctor for a list of the ingredients.
  • tell your Doctor what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take.  Be sure to mention any of the following: anticoagulants such as warfarin; aspirin; antifungal medications such as fluconazole, itraconazole, and ketoconazole; antiplatelet medications such as clopidogrel, prasugrel, and ticlopidine; clarithromycin; diltiazem; erythromycin; fluoxetine; fluvoxamine; nefazadone; omeprazole; and sertraline.  Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor if you have bleeding ulcers, bleeding in the brain, bleeding from any other part of your body, a low number of platelets in your blood, or any other condition that causes severe bleeding.  Your doctor will probably tell you not to take cilostazol.
  • tell your doctor if you have or have ever had heart, kidney, or liver disease.
  • tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding.  If you become pregnant while taking cilostazol, consult your doctor.

 What should I do if I forget a dose?

Take the missed dose as soon as you remember it.  However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule.  Do not take a double dose to make up for a missed one.

What side effects can this medication cause?

Cilostazol may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

  • headache
  • diarrhea
  • dizziness
  • heartburn
  • nausea
  • stomach pain
  • muscle pain
  • fast or irregular heartbeat
  • unusual bleeding or bruising
  • swelling of the arms, hands, feet, ankles, or lower legs

Some side effects can be serious. If you experience any of the following symptoms, consult your doctor immediately:

If you experience a serious side effect, you or your doctor may send a report to the Office of Directorate General, Drugs Administration.

What storage conditions are needed for this medicine?

Keep this medication in the container it came in, tightly closed, and out of reach of children.  Store it at room temperature and away from excess heat and moisture.  Throw away any medication that is outdated or no longer needed.  Talk to your Doctor about the proper disposal of your medication.

In case of emergency/overdose

In case of overdose, consult your Doctor.  If the victim has collapsed or is not breathing, consultlocal medical emergency services..

Symptoms of overdose may include the following:

  • severe headache
  • dizziness
  • fainting
  • diarrhea
  • fast or irregular heartbeat

What other information should I know?

Keep all appointments with your doctor.

Do not let anyone else take your medication.  

It is important for you to keep a written list of all of the prescription and nonprescription medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements.  You should bring this list with you each time you visit a doctor or if you are admitted to a hospital.  It is also important information to carry with you in case of emergencies. 

Source: U.S. Natl. Library of Medicine

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