Cilostazol

Cilostazol is a Quinolinone derivative belonging to Antiplatelet Agents and Hematologic Class.

Cilostazol is used in the treatment of Intermittent claudication. It is also used in the treatment of Elective PCI with bare metal or drug-eluting stent placement (alternative agent); Secondary prevention of non-cardioembolic ischemic stroke or transient ischemic attack (TIA).

Cilostazol Increased absorption if taken with a high-fat meal. The Plasma protein binding is about 95-98% (Cilostazol); 97.4% (3, 4-dehydrocilostazol), 66% (4'-trans-hydroxycilostazol) and gets extensively metabolised in the liver mainly by CYP3A4, to a lesser extent by CYP2C19, and to an even lesser extent by CYP1A2 and CYP2D6 and gets excreted Via urine (74%), feces (20%) as metabolites. Elimination half-life: Approx 11-13 hours.

Cilostazol shows common side effects like Headache, dizziness, diarrhea, sore throat, runny nose, sneezing, joint pain, etc.

Cilostazol is available in the form of an Oral Tablet and Suspension

Cilostazol is available in India, Germany, Italy, Netherlands, and Sweden.

Cilostazol and its metabolites are inhibitors of phosphodiesterase III. As a result, cyclic AMP is increased, leading to reversible inhibition of platelet aggregation, vasodilation, and inhibition of vascular smooth muscle cell proliferation.

The onset of Action of Cilostazol was within 2 to 4 weeks; it may require up to 12 weeks.

The Duration of Action of Cilostazol is within 11 to 13 hours

The Tmax of Cilostazol is approximately 1.78 ± 0.67 hrs, and Cmax is within 1585±301 ng-Equiv/ml.

Cilostazol is available in the form of Oral Tablet.

Oral: Administer 30 minutes before or 2 hours after meals (breakfast and dinner).

Cilostazol is used in the treatment of Intermittent claudication. It is also used in the treatment of Elective PCI with bare metal or drug eluting stent placement (alternative agent); Secondary prevention of noncardioembolic ischemic stroke or transient ischemic attack (TIA).

Cilostazol inhibits phosphodiesterase-III (PDE-III) resulting to increased cyclic adenosine monophosphate (cAMP) thereby leading to reversible inhibition of platelet aggregation, vasodilation, and inhibition of vascular smooth muscle cell proliferation.

Cilostazol is approved for use in the following clinical indications

• Intermittent claudication: Reduction of symptoms of intermittent claudication, as indicated by an increased walking distance.
• Although not approved, there have been certain off label use documented for Cilostazol which include:

Elective PCI with bare metal or drug-eluting stent placement (alternative agent); Secondary prevention of noncardioembolic ischemic stroke or transient ischemic attack (TIA)

Cilostazol is available in various strengths as 50 mg, 100 mg

Cilostazol is available in the form of Oral Tablet.

• Dosage Adjustment in Kidney Patient

No dosage adjustment is necessary. Severe renal impairment increases metabolite concentrations; use with caution.

End-stage renal disease (ESRD) on dialysis: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). Not dialyzable

• Dosage Adjustment in Hepatic impairment Patient

Mild impairment: No dosage adjustment necessary.

Moderate to severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); use with caution.

Cilostazol is contraindicated in patients with

• Congestive heart failure (of any grade or severity), history of ventricular tachycardia, fibrillation or multifocal ventricular ectopic beats, severe tachyarrhythmia; unstable angina pectoris, myocardial infarction or coronary intervention within the last 6 months; prolonged QTc interval, known predisposition to bleeding (e.g. active peptic ulceration, recent haemorrhagic stroke, proliferative diabetic retinopathy, uncontrolled hypertension) or any active or uncontrolled bleeding.
• Severe renal (CrCl ≤25 mL/min) and moderate or severe hepatic impairment. Pregnancy and lactation. Concomitant use with ≥2 additional antiplatelet or anticoagulant agents (e.g. aspirin, clopidogrel, heparin, warfarin, dabigatran, rivaroxaban or apixaban).

Concerns related to adverse effects:

• Cardiovascular effects: May induce tachycardia, palpitation, tachyarrhythmia, and/or hypotension. Left ventricular outflow tract obstruction has been reported in patients with sigmoid shaped interventricular septum; monitor for the development of a new systolic murmur or cardiac symptoms after initiating therapy.

• Hematologic effects: Cases of thrombocytopenia or leukopenia progressing to agranulocytosis, reversible upon discontinuation, have been reported when not immediately discontinued; monitor platelets and white blood cell counts periodically.

Disease-related concerns:

• Hemostatic disorders: Avoid use in patients with active pathological bleeding or hemostatic disorders (has not been studied).

• Cardiovascular disease: Cilostazol is contraindicated in patients with heart failure of any severity. Phosphodiesterase inhibitors have caused decreased survival compared with placebo in patients with class III to IV heart failure. Patients with a history of ischemic heart disease may be at increased risk for exacerbation of angina pectoris or myocardial infarction.

• Hepatic impairment: Use with caution in patients with moderate to severe hepatic impairment (has not been studied).

• Renal impairment: Use with caution in patients with severe renal impairment.

Cilostazol may cause liver problems, and using it with substantial quantities of ethanol may increase that risk.

There is no available information on the presence of Cilostazol in human milk, the effects of the drug on the breastfed infant, or the effects on milk production. Cilostazol is present in the milk of rats and is therefore likely to be present in human milk. Because of the potential for serious adverse reactions in breastfed infants, such as disruption of infant lipid metabolism, women should not breastfeed during treatment with Cilostazol and for 5 days after the final dose.

Teratogenic Effects

Pregnancy Category C.

Cilostazol has been shown to be teratogenic in rats at doses that are greater than 5-times the human MRHD on a body surface area basis. There are no adequate and well-controlled studies in pregnant women.

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

Taking Cilostazol with a high-fat meal may increase peak concentration by 90% and increase AUC by 25%. Grapefruit juice may increase serum levels of Cilostazol and enhance toxic effects. Management: Administer Cilostazol on an empty stomach 30 minutes before or 2 hours after meals. Concurrent ingestion of grapefruit juice may require therapy modification; Consult drug interactions database for more detailed information.

• Common Adverse effects

Tachycardia, palpitation, tachyarrhythmia, hypotension, thrombocytopenia, leucopenia, agranulocytosis. Cardiac disorders: Angina pectoris, ventricular extrasystoles. Gastrointestinal disorders: Diarrhoea, nausea, vomiting, dyspepsia, flatulence, abdominal pain, abnormal faeces

• Less Common Adverse effects:

Diarrhoea, nausea, vomiting, dyspepsia, flatulence, abdominal pain, abnormal faeces.

• Rare Adverse effects

Pancytopenia, aplastic anaemia.

• Increased serum concentration with strong or moderate inhibitors of CYP3A4 (e.g., erythromycin, ketoconazole, itraconazole, diltiazem) or CYP2C19 (e.g. omeprazole, fluconazole, ticlopidine). Increased serum concentrations of CYP3A4 substrates (e.g. lovastatin, Cilostazol, atorvastatin) or other CYP3A4 substrates with narrow therapeutic index (e.g. cisapride, halofantrine, pimozide, ergot alkaloids).
• Potentially Fatal: Increased risk of bleeding when used concomitantly with antiplatelet or anticoagulant agents (e.g. aspirin, clopidogrel, heparin, warfarin, dabigatran, rivaroxaban or apixaban).

The common side effects of Cilostazol include the following

Common

Geriatric Use

Of the total number of subjects (n = 2,274) in clinical studies of cilostazol , 56 percent were 65 years old and over, while 16 percent were 75 years old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be excluded. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism, and elimination of Cilostazol and its metabolites.

Symptoms: Severe Headache, diarrhoea, hypotension, tachycardia, cardiac arrhythmias.

Management: Supportive treatment. Perform gastric lavage or induce vomiting as necessary to empty stomach contents.

Pharmacodynamic

Cilostazol , as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action and the Principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration, correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response

Pharmacokinetics

• 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.

• Distribution

Plasma protein binding: 95-98% (Cilostazol); 97.4% (3, 4-dehydrocilostazol), 66% (4’-trans-hydroxycilostazol).

• Metabolism

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.

• Excretion

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.

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