Cilostazol

Description

Cilostazol 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 369.47 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, while being practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH. Cilostazol is formulated as tablets for oral administration, available in strengths of 50 mg and 100 mg, presented as round, white tablets. Each tablet contains inactive ingredients including corn starch, croscarmellose sodium, magnesium stearate, and silicon dioxide.

Uses and Indications

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

Limitations of Use: The safety and efficacy of cilostazol have not been established in patients with severe renal impairment or in those with congestive heart failure.

Dosage and Administration

The recommended dosage of cilostazol is 100 mg administered twice daily. It is essential that the medication is 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 necessary 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 hypersensitivity to cilostazol or any components of cilostazol tablets, as this may lead to serious allergic reactions.

Warnings and Precautions

Patients receiving cilostazol should be closely monitored for several significant risks associated with its use.

Cardiovascular Risks Cilostazol may induce tachycardia, palpitations, tachyarrhythmias, or hypotension. There is an increased risk of exacerbations of angina pectoris or myocardial infarction in individuals with a history of ischemic heart disease. Additionally, left ventricular outflow tract obstruction has been reported in patients with a sigmoid-shaped interventricular septum.

Hematologic Concerns There is a potential risk of thrombocytopenia or leukopenia, which may progress to agranulocytosis. It is essential to monitor platelet and white blood cell counts regularly to detect any hematologic abnormalities early.

Contraindications Cilostazol is contraindicated in patients with heart failure of any severity. The drug and its metabolites act as inhibitors of phosphodiesterase III, and the use of similar pharmacologic agents has been associated with decreased survival in patients with class III-IV heart failure. Furthermore, cilostazol should not be used in patients with hemostatic disorders or those experiencing active pathological bleeding.

Healthcare professionals are advised to remain vigilant regarding these warnings and to implement appropriate monitoring protocols to ensure patient safety during cilostazol therapy.

Side Effects

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

Serious adverse reactions have been noted, particularly in patients with pre-existing conditions. 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. Additionally, there are risks of tachycardia, palpitations, tachyarrhythmia, and hypotension. Patients with a history of ischemic heart disease may experience exacerbations of angina pectoris or myocardial infarction.

Other significant risks include left ventricular outflow tract obstruction, particularly in patients with a sigmoid-shaped interventricular septum. There is also a potential for hematologic adverse reactions, such as thrombocytopenia or leukopenia, which may progress to agranulocytosis; therefore, monitoring of platelet and white blood cell counts is recommended. Cilostazol should be avoided in patients with hemostatic disorders or active pathologic bleeding, as well as in those with hypersensitivity to cilostazol or any of its components.

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 significantly increase the exposure to cilostazol. It is recommended to reduce the dosage of cilostazol tablets in patients concurrently using these inhibitors to mitigate the risk of adverse effects associated with elevated drug levels.

No information is available regarding drug and laboratory test interactions.

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 elderly patients and their younger counterparts. Additionally, other reported clinical experiences have not identified significant differences in responses between geriatric patients and younger individuals; however, 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, while no specific dosage adjustments are recommended based solely on age, healthcare providers should remain vigilant in monitoring elderly patients for any potential increased sensitivity to the medication.

Pregnancy

Cilostazol is classified as a Pregnancy Category C medication. Animal studies have demonstrated teratogenic effects in rats at doses exceeding five times the maximum recommended human dose (MRHD) on a body surface area basis. Specifically, in a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day resulted in 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 five times the MRHD on a systemic exposure basis, similar findings of increased ventricular septal defects and retarded ossification were observed.

In a rabbit developmental toxicity study, an increased incidence of sternum ossification retardation was noted at doses as low as 150 mg/kg/day. It is important to note that in nonpregnant rabbits receiving this dose, the systemic exposure to unbound cilostazol was significantly lower than that observed in humans at the MRHD, with exposure to 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 of offspring at doses of 150 mg/kg/day, again corresponding to five times the MRHD on a systemic exposure basis. Given the lack of adequate and well-controlled studies in pregnant women, healthcare professionals should weigh the potential risks and benefits of cilostazol use in pregnant patients and those of childbearing potential.

Lactation

Cilostazol has not been studied in adequate and well-controlled trials in lactating mothers. Animal studies indicate that when cilostazol was administered to rats during late pregnancy and lactation, there was an increased incidence of stillborn offspring and decreased birth weights at doses of 150 mg/kg/day, which is five times the maximum recommended human dose (MRHD) based on systemic exposure.

Due to the lack of human data and the potential risks observed in animal studies, healthcare professionals should exercise caution when considering cilostazol for use in lactating mothers. The effects on breastfed infants are not well characterized, and the decision to use cilostazol should involve a careful assessment of the benefits and risks.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions outlined 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. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

In cases of acute overdosage with cilostazol, the available information in humans is limited. However, it is anticipated that the signs and symptoms will reflect excessive pharmacologic effects. These may include severe headache, diarrhea, hypotension, tachycardia, and potentially cardiac arrhythmias.

Management of an overdose should involve careful observation of the patient, along with the provision of supportive treatment as necessary. Given cilostazol's high protein-binding characteristics, it is important to note that effective removal of the drug through hemodialysis or peritoneal dialysis is unlikely.

Toxicological studies indicate that the oral LD50 of cilostazol is greater than 5 g per kg in mice and rats, and greater than 2 g per kg in dogs. This information may assist healthcare professionals in assessing the severity of an overdose and determining appropriate management strategies.

Nonclinical Toxicology

Cilostazol has been evaluated for its nonclinical toxicology profile through various studies assessing teratogenicity, fertility, carcinogenicity, and mutagenicity.

No information is available regarding teratogenic effects associated with cilostazol.

In terms of non-teratogenic effects, 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 observed in other animal species. Additionally, cilostazol did not impact the fertility or mating performance of male and female rats at doses up to 1000 mg/kg/day. At this high dose, 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.

Animal studies involving 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.

Cilostazol was found to be 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, among others. 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.

No cardiovascular lesions were observed in rats following 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. Similarly, no cardiovascular lesions were noted in rats after 52 weeks of administration at doses up to 150 mg/kg/day, with systemic exposures being 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.

Cardiovascular lesions were also absent in monkeys after oral administration of cilostazol for 13 weeks at doses up to 1800 mg/kg/day. Although this dose produced pharmacologic effects in monkeys, plasma cilostazol levels remained lower than those observed in humans receiving the MRHD and those seen in dogs at doses associated with cardiovascular lesions.

Postmarketing Experience

Cilostazol tablets have been associated with serious side effects, including cardiovascular events such as fast heart rate, palpitations, irregular heartbeat, and low blood pressure. Additionally, severe allergic reactions, including anaphylaxis and angioedema, have been reported. Symptoms of a severe allergic reaction may include hives, swelling of the face, lips, mouth, or tongue, difficulty breathing or wheezing, and dizziness, necessitating immediate medical attention.

Changes in blood cell counts, specifically thrombocytopenia and leukopenia, have also been observed. It is recommended that healthcare providers conduct regular blood tests to monitor these parameters during treatment with cilostazol tablets.

The most frequently reported side effects include headache, abnormal stools, and diarrhea. Healthcare professionals and patients are encouraged to report any adverse events to the FDA at 1-800-FDA-1088.

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling (Patient Information) thoroughly. It is important for patients to take cilostazol tablets at least one-half hour before or two hours after food to ensure optimal absorption.

Patients should discuss with their healthcare provider before taking any CYP3A4 or CYP2C19 inhibitors, such as omeprazole, as these may interact with cilostazol. They should be informed that the beneficial effects of cilostazol on the symptoms of intermittent claudication may not be immediate; while some patients may experience benefits within 2 to 4 weeks, treatment for up to 12 weeks may be necessary before a beneficial effect is observed. Patients should discontinue cilostazol if symptoms do not improve after 3 months.

It is crucial to inform patients that cilostazol can cause serious side effects, including heart problems, and that they should not take cilostazol if they have any form of heart failure. Patients should also be advised to inform their doctor if they consume grapefruit juice, as it can increase the levels of cilostazol in the body, potentially leading to side effects.

Patients should disclose any other medical conditions they have, as well as if they are pregnant, planning to become pregnant, or breastfeeding. They must inform their healthcare provider about all medications they are taking, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Patients should take cilostazol exactly as prescribed by their healthcare provider, who may adjust the dosage if necessary. They should be made aware that cilostazol may cause serious side effects, including heart problems and severe allergic reactions such as anaphylaxis and angioedema. Patients should seek immediate medical attention if they experience signs or symptoms of a severe allergic reaction.

Patients are encouraged to report any side effects that are bothersome or do not resolve to their healthcare provider. They should store cilostazol tablets at room temperature, between 68°F to 77°F (20°C to 25°C), and keep them out of the reach of children. Lastly, patients should be informed that medications are sometimes prescribed for purposes other than those listed in the Patient Information leaflet, and they should not use cilostazol for any condition for which it was not prescribed or share it with others.

Storage and Handling

Cilostazol tablets are supplied in various package configurations. The recommended storage temperature for cilostazol tablets is 25°C (77°F), with permissible excursions between 15°C and 30°C (59°F to 86°F) in accordance with USP Controlled Room Temperature guidelines. It is essential to ensure that the tablets are stored in a suitable container to maintain their integrity and efficacy. Special handling requirements should be observed to prevent exposure to conditions outside the specified temperature range.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

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

View full prescribing information (PDF)