Cilostazol

Description

Cilostazol, USP is a quinolinone derivative that inhibits cellular phosphodiesterase, with a more specific action on phosphodiesterase III. The empirical formula of cilostazol is C20H27N5O2, and it has a molecular weight of 369.46 g/mol. The chemical structure is identified as 6-4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy-3,4-dihydro-2(1H)-quinolinone, with a CAS number of 73963-72-1. Cilostazol appears as white to off-white crystals or as a crystalline powder. It is slightly soluble in methanol and ethanol, and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH. Cilostazol Tablets, USP are formulated for oral administration and are available in strengths of 50 mg and 100 mg. Each tablet contains the following inactive ingredients: carboxymethyl cellulose calcium, magnesium stearate, methylcellulose, microcrystalline cellulose, pregelatinized starch, and purified water.

Uses and Indications

Cilostazol tablets are indicated for the reduction of symptoms associated with intermittent claudication, as evidenced by an increase in walking distance.

There are no teratogenic or nonteratogenic effects associated with the use of cilostazol.

Dosage and Administration

Cilostazol tablets are recommended to be administered at a dosage of 100 mg twice daily. It is essential that the tablets are taken at least half an hour before or two hours after meals, specifically breakfast and dinner, to ensure optimal absorption.

In cases where cilostazol is coadministered with CYP3A4 inhibitors, such as ketoconazole, itraconazole, erythromycin, and diltiazem, or with CYP2C19 inhibitors, including ticlopidine, fluconazole, and omeprazole, the dosage should be reduced to 50 mg twice daily. This adjustment is crucial to mitigate potential drug interactions and enhance patient safety.

Contraindications

Use of cilostazol is contraindicated in patients with heart failure of any severity due to the potential for exacerbation of the condition. Additionally, cilostazol should not be administered to individuals with a known hypersensitivity to cilostazol or any of its components, as this may lead to serious allergic reactions.

Warnings and Precautions

Patients receiving treatment with cilostazol should be closely monitored for several cardiovascular and hematological risks.

Cardiovascular Risks Cilostazol may induce tachycardia, palpitations, tachyarrhythmias, or hypotension. Healthcare professionals should be vigilant for exacerbations of angina pectoris or myocardial infarction, particularly in patients with a history of ischemic heart disease. Additionally, left ventricular outflow tract obstruction has been reported in patients with a sigmoid-shaped interventricular septum, necessitating careful assessment in this population.

Hematological Monitoring There is a risk of thrombocytopenia or leukopenia that may progress to agranulocytosis. Regular monitoring of platelet and white blood cell counts is recommended to detect any significant changes early.

Contraindications Cilostazol is contraindicated in patients with heart failure of any severity. The drug, along with its metabolites, acts as an inhibitor of phosphodiesterase III, and its use has been associated with decreased survival rates in patients with class III-IV heart failure compared to placebo.

Hemostatic Disorders Cilostazol should be avoided in patients with hemostatic disorders or those experiencing active pathological bleeding, as the risks may outweigh the benefits in these populations.

Healthcare professionals are advised to consider these warnings and precautions when prescribing cilostazol to ensure patient safety and optimal therapeutic outcomes.

Side Effects

Patients receiving cilostazol may experience a range of adverse reactions. Common adverse reactions reported include headache, diarrhea, abnormal stools, and palpitations.

Serious adverse reactions associated with cilostazol include risks of tachycardia, palpitation, tachyarrhythmia, and hypotension. Additionally, patients with a history of ischemic heart disease may experience exacerbations of angina pectoris or myocardial infarction. It is important to note that cilostazol is contraindicated in patients with heart failure of any severity, as it has been associated with decreased survival compared to placebo in patients with class III-IV heart failure.

Other significant risks include thrombocytopenia or leukopenia, which may progress to agranulocytosis; therefore, monitoring of platelet and white blood cell counts is recommended. Cilostazol should also be avoided in patients with hemostatic disorders or active pathologic bleeding.

Left ventricular outflow tract obstruction has been reported in patients with a sigmoid-shaped interventricular septum. Hypersensitivity reactions to cilostazol or any components of cilostazol tablets have also been noted.

In cases of overdosage, patients may exhibit signs and symptoms consistent with excessive pharmacologic effects, including severe headache, diarrhea, hypotension, tachycardia, and potentially cardiac arrhythmias.

Drug Interactions

Strong and moderate inhibitors of CYP3A4 and CYP2C19 are known to increase the exposure to cilostazol. It is recommended to reduce the dose of cilostazol when co-administered with these inhibitors to mitigate the risk of adverse effects associated with elevated drug levels.

No information regarding drug and laboratory test interactions has been provided.

Packaging & NDC

The table below lists all NDC Code configurations of Cilostazol, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness of cilostazol in pediatric patients have not been established. Therefore, its use in this population is not recommended.

Geriatric Use

In clinical studies involving cilostazol, 56 percent of the total subjects (n = 2,274) were aged 65 years and older, with 16 percent being 75 years and older. No overall differences in safety or effectiveness were observed between these elderly patients and their younger counterparts.

While other reported clinical experiences have not identified significant differences in responses between geriatric patients and younger individuals, it is important to note that greater sensitivity in some older patients cannot be excluded.

Pharmacokinetic studies have shown no age-related effects on the absorption, distribution, metabolism, and elimination of cilostazol and its metabolites. Therefore, no specific dosage adjustments are recommended based solely on age. However, healthcare providers should remain vigilant in monitoring elderly patients for any potential increased sensitivity to the medication.

Pregnancy

Cilostazol has demonstrated teratogenic effects in animal studies, particularly in rats, where doses exceeding 5 times the human maximum recommended human dose (MRHD) on a body surface area basis resulted in significant fetal abnormalities. In a rat developmental toxicity study, administration of 1000 mg cilostazol/kg/day led to decreased fetal weights and an increased incidence of cardiovascular, renal, and skeletal anomalies, including ventricular septal defects, aortic arch and subclavian artery abnormalities, renal pelvic dilation, the presence of a 14th rib, and retarded ossification. At a lower dose of 150 mg/kg/day, which corresponds to approximately 5 times the MRHD based on systemic exposure, similar findings of ventricular septal defects and retarded ossification were observed.

In rabbits, a developmental toxicity study revealed an increased incidence of sternum ossification retardation at doses as low as 150 mg/kg/day. Notably, in nonpregnant rabbits receiving this dose, the systemic exposure to unbound cilostazol was significantly lower than that observed in humans at the MRHD, with levels of 3,4-dehydro-cilostazol being barely detectable.

Furthermore, when cilostazol was administered to rats during late pregnancy and lactation, there was an increased incidence of stillbirths and decreased birth weights in offspring at doses of 150 mg/kg/day, again reflecting a systemic exposure approximately 5 times that of humans at the MRHD.

Given the absence of adequate and well-controlled studies in pregnant women, cilostazol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Healthcare professionals are advised to counsel women of childbearing potential regarding the risks associated with cilostazol and to consider alternative therapies when appropriate.

Lactation

Transfer of cilostazol into milk has been reported in rats. Due to the potential for serious adverse reactions in nursing infants from cilostazol and the fact that many drugs are excreted in human milk, it is recommended that lactating mothers either discontinue nursing or discontinue cilostazol.

Renal Impairment

There is no information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution and consider the lack of specific guidance when prescribing to patients with reduced kidney function.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there is no information available regarding dosage adjustments, special monitoring requirements, or precautions for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population.

Overdosage

In cases of acute overdose, patients may exhibit a range of signs and symptoms, including severe headache, diarrhea, hypotension, tachycardia, and potentially cardiac arrhythmias. These manifestations necessitate prompt recognition and management.

The oral LD50 of cilostazol has been established as greater than 5 g per kg in both mice and rats, and greater than 2 g per kg in dogs. This information underscores the importance of understanding the dosage thresholds that may lead to toxicity.

Due to cilostazol's high protein-binding characteristics, it is unlikely that the drug can be effectively removed through hemodialysis or peritoneal dialysis. Therefore, these methods are not recommended for managing overdose cases.

In the event of an overdose, it is crucial for healthcare professionals to carefully observe the patient and provide supportive treatment as needed. Continuous monitoring and symptomatic management are essential to address any complications that may arise during the course of treatment.

Nonclinical Toxicology

No teratogenic effects were observed in the studies conducted. However, cilostazol demonstrated a reversible contraceptive effect in female mice at a dose of 300 mg/kg, which is approximately 7.4-fold greater than the Maximum Recommended Human Dose (MRHD) on a body surface area basis. This effect has not been replicated in other animal species. In contrast, cilostazol did not impact the fertility or mating performance of male and female rats at doses up to 1000 mg/kg/day. At this dosage, systemic exposures to unbound cilostazol were less than 1.5 times in males and about 5 times in females compared to human exposure at the MRHD.

Long-term dietary administration of cilostazol to male and female rats and mice for up to 104 weeks at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies resulted in systemic exposures that were less than those observed in humans at the MRHD of the drug. Cilostazol was negative in assays for bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation, and mouse in vivo bone marrow chromosomal aberrations. However, it was associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.

Repeated oral administration of cilostazol to dogs at doses of 30 mg/kg/day or more for 52 weeks, 150 mg/kg/day or more for 13 weeks, and 450 mg/kg/day for 2 weeks resulted in cardiovascular lesions. These lesions included endocardial hemorrhage, hemosiderin deposition and fibrosis in the left ventricle, hemorrhage in the right atrial wall, and necrosis of the smooth muscle in the coronary artery wall, along with intimal thickening and coronary arteritis. At the lowest dose associated with cardiovascular lesions in the 52-week study, systemic exposure to unbound cilostazol was less than that seen in humans at the MRHD of 100 mg twice daily. Similar cardiovascular lesions have been reported in dogs following the administration of other positive inotropic agents and/or vasodilating agents.

No cardiovascular lesions were observed in rats after 5 or 13 weeks of cilostazol administration at doses up to 1500 mg/kg/day, with systemic exposures being approximately 1.5 and 5 times (male and female rats, respectively) those seen in humans at the MRHD. Additionally, no cardiovascular lesions were noted in rats after 52 weeks of cilostazol administration at doses up to 150 mg/kg/day, where systemic exposures were about 0.5 and 5 times (male and female rats, respectively) the human MRHD. In female rats, cilostazol AUCs were comparable at doses of 150 and 1500 mg/kg/day. Furthermore, cardiovascular lesions were not observed in monkeys after 13 weeks of oral administration of cilostazol at doses up to 1800 mg/kg/day. Although this dose produced pharmacologic effects in monkeys, plasma cilostazol levels remained below those seen in humans at the MRHD and those observed in dogs at doses associated with cardiovascular lesions.

Postmarketing Experience

During post-approval use of cilostazol, various adverse reactions have been reported voluntarily from a population of an unknown size. Due to the nature of these reports, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders have included aplastic anemia, granulocytopenia, pancytopenia, and a bleeding tendency.

Cardiac disorders reported include torsade de pointes and QTc prolongation, particularly in patients with pre-existing cardiac conditions such as complete atrioventricular block, heart failure, and bradyarrhythmia, as well as angina pectoris.

Gastrointestinal disorders have encompassed gastrointestinal hemorrhage, vomiting, flatulence, and nausea.

General disorders and administration site conditions have involved pain, chest pain, and hot flushes.

Hepatobiliary disorders have been noted, including hepatic dysfunction or abnormal liver function tests and jaundice.

Immune system disorders reported include anaphylaxis, angioedema, and hypersensitivity reactions.

Investigations have indicated increases in blood glucose, blood uric acid, blood urea nitrogen (BUN), and blood pressure.

Nervous system disorders have included intracranial hemorrhage, cerebral hemorrhage, cerebrovascular accidents, extradural hematoma, and subdural hematoma.

Renal and urinary disorders have reported hematuria.

Respiratory, thoracic, and mediastinal disorders have included pulmonary hemorrhage and interstitial pneumonia.

Skin and subcutaneous tissue disorders have involved subcutaneous hemorrhage, pruritus, skin eruptions including Stevens-Johnson syndrome, skin drug eruptions (dermatitis medicamentosa), and rash.

Vascular disorders have included subacute stent thrombosis and hypertension.

Patient Counseling

Healthcare providers should advise patients that cilostazol is contraindicated in individuals with heart failure of any severity. It is important to communicate that cilostazol and its metabolites inhibit phosphodiesterase III, and that several drugs with this mechanism have been associated with decreased survival in patients with class III-IV heart failure.

Patients may begin to notice a response to cilostazol therapy as early as 2 to 4 weeks after initiation; however, it may take up to 12 weeks to experience a beneficial effect. If patients do not see improvement in their symptoms after 3 months, they should discontinue the use of cilostazol tablets.

When cilostazol is coadministered with CYP3A4 inhibitors such as ketoconazole, itraconazole, erythromycin, and diltiazem, or CYP2C19 inhibitors such as ticlopidine, fluconazole, and omeprazole, healthcare providers should recommend reducing the dose to 50 mg twice daily.

It is essential to inform patients that cilostazol inhibits platelet aggregation in a reversible manner and has not been studied in individuals with hemostatic disorders or active pathologic bleeding. Therefore, cilostazol should be avoided in these populations.

Healthcare providers should monitor patients for thrombocytopenia or leukopenia, which could progress to agranulocytosis, by periodically checking platelet and white blood cell counts.

Patients should be made aware that cilostazol may induce tachycardia, palpitations, tachyarrhythmia, or hypotension, with an expected increase in heart rate of approximately 5 to 7 bpm. Those with a history of ischemic heart disease may be at increased risk for exacerbations of angina pectoris or myocardial infarction.

Additionally, left ventricular outflow tract obstruction has been reported in patients with a sigmoid-shaped interventricular septum. Healthcare providers should monitor for the development of a new systolic murmur or any cardiac symptoms after starting cilostazol.

To report any suspected adverse reactions, patients should be directed to contact Chartwell RX, LLC at 1-845-232-1683 or the FDA at 1-800-FDA-1088 or visit www.fda.gov/medwatch.

Storage and Handling

Cilostazol tablets are supplied in various package configurations. The recommended storage conditions for cilostazol tablets are at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. It is essential to ensure that the tablets are kept in their original container to maintain their integrity and efficacy. Special handling requirements should be observed to prevent exposure to extreme temperatures or humidity.

Additional Clinical Information

The recommended dosage of cilostazol tablets is 100 mg administered twice daily, taken at least half an hour before or two hours after meals. In cases where cilostazol is coadministered with CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, erythromycin, diltiazem) or CYP2C19 inhibitors (e.g., ticlopidine, fluconazole, omeprazole), the dosage should be reduced to 50 mg twice daily.

Postmarketing experience has revealed various adverse effects across multiple systems. Blood and lymphatic system disorders may include aplastic anemia, granulocytopenia, pancytopenia, and a bleeding tendency. Cardiac disorders reported include torsade de pointes and QTc prolongation, particularly in patients with pre-existing cardiac conditions, as well as angina pectoris. Gastrointestinal issues such as hemorrhage, vomiting, flatulence, and nausea have also been noted. General disorders may manifest as pain, chest pain, and hot flushes. Hepatobiliary disorders include hepatic dysfunction and jaundice. Immune system reactions can involve anaphylaxis, angioedema, and hypersensitivity. Investigations have shown increases in blood glucose, blood uric acid, BUN, and blood pressure. Neurological complications may consist of intracranial hemorrhage, cerebral hemorrhage, cerebrovascular accidents, and hematomas. Renal and urinary disorders may present as hematuria, while respiratory issues include pulmonary hemorrhage and interstitial pneumonia. Skin reactions can range from subcutaneous hemorrhage and pruritus to severe conditions like Stevens-Johnson syndrome and dermatitis medicamentosa. Lastly, vascular disorders may involve subacute stent thrombosis and hypertension.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Cilostazol as submitted by Chartwell RX, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)