Cilostazol

Description

Cilostazol is a quinolinone derivative that inhibits cellular phosphodiesterase, specifically phosphodiesterase III. The empirical formula of cilostazol is C20H27N5O2, with a molecular weight of 369.47 g/mol. Its chemical structure is defined as 6-4-(1-cyclohexyl-1H-tetrazol-5-yl) butoxy-3,4-dihydro-2(1H)-quinolinone, and it is identified by CAS-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: There are no teratogenic or nonteratogenic effects noted in the available data.

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 optimize 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 ensure 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 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.

Left Ventricular Outflow Tract Obstruction Patients with a sigmoid-shaped interventricular septum may experience left ventricular outflow tract obstruction.

Hematological Concerns There is a risk of thrombocytopenia or leukopenia, which can progress to agranulocytosis. It is essential to monitor platelet and white blood cell counts regularly to detect any hematological abnormalities 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 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 these conditions may exacerbate the risks associated with the medication.

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

Side Effects

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

Cilostazol is contraindicated in patients with heart failure of any severity due to the potential for decreased survival compared to placebo in patients with class III-IV heart failure. The pharmacologic action of cilostazol and its metabolites as phosphodiesterase III inhibitors poses significant risks, including tachycardia, palpitations, tachyarrhythmia, and hypotension. Additionally, patients with a history of ischemic heart disease may experience exacerbations of angina pectoris or myocardial infarction.

Other notable adverse reactions include the risk of left ventricular outflow tract obstruction, particularly in patients with a sigmoid-shaped interventricular septum. There is also a risk of hematologic abnormalities such as thrombocytopenia or leukopenia, which can 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 regarding drug and laboratory test interactions is available.

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, a total of 2,274 subjects were evaluated, of which 56 percent were aged 65 years and older, and 16 percent were aged 75 years and older. The data indicate that there are no overall differences in safety or effectiveness between elderly patients and their younger counterparts.

While the clinical experience has not identified significant differences in responses to cilostazol between geriatric and younger patients, it is important to note that greater sensitivity to the drug in some older individuals cannot be excluded. Therefore, healthcare providers should remain vigilant when prescribing cilostazol to elderly patients, considering the potential for increased sensitivity.

Pharmacokinetic studies have shown no age-related effects on the absorption, distribution, metabolism, and elimination of cilostazol and its metabolites. However, due to the variability in responses among elderly patients, careful monitoring is recommended to ensure optimal therapeutic outcomes. No specific dosage adjustments are indicated based solely on age; nonetheless, clinicians should exercise caution and consider individual patient factors when treating geriatric patients with cilostazol.

Pregnancy

Cilostazol is classified as Pregnancy Category C. Animal studies have demonstrated teratogenic effects in rats at doses exceeding 5 times the maximum recommended human dose (MRHD) on a body surface area basis. In a rat developmental toxicity study, administration of 1000 mg/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 approximately 5 times the MRHD based on systemic exposure, similar anomalies were observed, including increased incidences of ventricular septal defects and retarded ossification.

In a rabbit developmental toxicity study, an increased incidence of sternum ossification retardation was noted 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 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 in offspring at doses of 150 mg/kg/day, again corresponding to 5 times the MRHD on a systemic exposure basis.

Due to the lack of adequate and well-controlled studies in pregnant women, the potential risks associated with cilostazol use during pregnancy should be carefully weighed against the benefits. Healthcare providers are advised to consider alternative treatments for pregnant patients or those planning to become pregnant.

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

There is no specific information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in this patient population.

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 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 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 to mitigate adverse effects.

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 capacity, it is unlikely that the drug can be effectively removed through hemodialysis or peritoneal dialysis. Therefore, standard renal clearance methods may not be applicable in cases of overdose.

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

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

No teratogenic effects have been reported 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 observed in other animal species. In contrast, cilostazol did not affect 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.

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.

Cilostazol was tested negative in several mutagenicity assays, including bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation, and mouse in vivo bone marrow chromosomal aberration assays. However, it was associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.

In terms of animal pharmacology and toxicology, 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. Notably, 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.

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 lower than those seen in humans at the MRHD and those observed in dogs at doses associated with cardiovascular lesions.

Postmarketing Experience

Postmarketing experience has identified several adverse events associated with cilostazol tablets, reported voluntarily or through surveillance programs.

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

Serious cardiovascular events have also been reported, including fast heart rate, palpitations, irregular heartbeat, and low blood pressure.

Severe allergic reactions, such as anaphylaxis and angioedema, have been documented. Patients experiencing symptoms indicative of a severe allergic reaction, including hives, facial swelling, difficulty breathing, or dizziness, should seek immediate medical attention.

The most frequently reported side effects include headache, abnormal stools, and diarrhea.

Patients are encouraged to consult their healthcare provider for medical advice regarding side effects and may report any adverse events to the FDA at 1-800-FDA-1088.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling (Patient Information) prior to starting cilostazol tablets and each time they receive a refill, as there may be new information available. 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 be informed to discuss with their doctor before taking any CYP3A4 or CYP2C19 inhibitors, such as omeprazole, as these may affect the efficacy and safety of cilostazol. Additionally, patients should be made aware 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 may need to continue for up to 12 weeks before a noticeable improvement is observed. If symptoms do not improve after 3 months, patients should discontinue the use of cilostazol tablets and consult their doctor.

Patients should also inform their doctor if they consume grapefruit juice, as it can increase the concentration of cilostazol in the body, potentially leading to side effects. It is essential for patients to disclose any other medical conditions they may have, as well as if they are pregnant, planning to become pregnant, breastfeeding, or planning to breastfeed, since the effects of cilostazol on unborn babies and breast milk are not fully understood.

Healthcare providers should encourage patients to provide a complete list of all medications they are taking, including prescription and over-the-counter drugs, vitamins, and herbal supplements. If patients are unsure about potential interactions, they should ask their doctor or pharmacist for a list of medicines that may interact with cilostazol. Maintaining an updated list of medications is crucial for safe and effective treatment.

Patients must take cilostazol tablets exactly as prescribed by their doctor, who will determine the appropriate dosage and timing. It is critical to adhere to the instruction of taking cilostazol tablets 30 minutes before meals or 2 hours after meals.

Finally, patients should be advised to contact their doctor for medical advice regarding any side effects they may experience. They may also report side effects to the FDA at 1-800-FDA-1088.

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 AvPAK. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)