Cilostazol

Description

Cilostazol, USP is a quinolinone derivative that inhibits cellular phosphodiesterase, specifically phosphodiesterase III. Its chemical structure is 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 is formulated as tablets for oral administration, available in strengths of 50 mg and 100 mg, which are round, white, and debossed. Each tablet contains inactive ingredients including crospovidone, lactose monohydrate, magnesium stearate, and povidone.

Uses and Indications

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

Limitations of Use: There are no teratogenic or nonteratogenic effects associated with cilostazol as per the available data.

Dosage and Administration

The recommended dosage of cilostazol tablets is 100 mg administered twice daily. It is essential that the tablets be 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 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 cardiovascular and hematological complications.

Cardiovascular Risks Cilostazol is associated with an increased risk of tachycardia, palpitations, tachyarrhythmias, and hypotension. Healthcare professionals should exercise caution when prescribing this medication to patients with a history of ischemic heart disease, as it may exacerbate angina pectoris or precipitate myocardial infarction.

Left Ventricular Outflow Tract Obstruction There have been reports of left ventricular outflow tract obstruction in patients with a sigmoid-shaped interventricular septum. Clinicians should evaluate the cardiac anatomy of patients prior to initiating treatment.

Hematological Monitoring Patients may experience thrombocytopenia or leukopenia, which can 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 medication, along with its metabolites, acts as an inhibitor of phosphodiesterase III, and its use has been linked to decreased survival rates in patients with class III-IV heart failure compared to placebo. Additionally, cilostazol should not be used in patients with hemostatic disorders or those experiencing active pathological bleeding, as this may exacerbate bleeding risks.

Healthcare professionals are advised to consider these warnings and precautions carefully to ensure patient safety during treatment with cilostazol.

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, palpitations, 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 left ventricular outflow tract obstruction, particularly in patients with a sigmoid-shaped interventricular septum. There is also a risk of 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.

In cases of acute overdose, signs and symptoms may include severe headache, diarrhea, hypotension, tachycardia, and potentially cardiac arrhythmias, reflecting excessive pharmacologic effects.

Drug Interactions

Strong and moderate inhibitors of CYP3A4 and CYP2C19 significantly 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 is available regarding interactions with other drugs or laboratory tests.

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

The safety and effectiveness of cilostazol in pediatric patients have not been established. Therefore, its use in this population is not recommended until further data are available to support its use.

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 the available clinical experience has not identified significant differences in responses between geriatric patients and younger individuals, it is important to note that greater sensitivity to the drug may be present in some older patients. Therefore, healthcare providers should exercise caution and consider individual patient factors when prescribing cilostazol to the elderly.

Pharmacokinetic studies have shown no age-related effects on the absorption, distribution, metabolism, and elimination of cilostazol and its metabolites. However, ongoing monitoring of geriatric patients is recommended to ensure optimal therapeutic outcomes and to address any potential variations in response to treatment.

Pregnancy

Cilostazol is classified as a Pregnancy Category C medication. Animal studies have demonstrated teratogenic effects, with evidence of fetal harm at doses significantly higher than the maximum recommended human dose (MRHD) on a body surface area basis. In a rat developmental toxicity study, oral administration of cilostazol at 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, and retarded ossification. At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was approximately five times that observed in humans receiving the MRHD. Additionally, increased incidences of ventricular septal defects and retarded ossification were noted at a lower dose of 150 mg/kg/day, which also corresponds to five times the MRHD based on systemic exposure.

In a separate rabbit developmental toxicity study, an increased incidence of sternum ossification retardation was observed at doses as low as 150 mg/kg/day. Notably, the systemic exposure to unbound cilostazol in nonpregnant rabbits at this dose was considerably lower than that seen in humans at the MRHD, with minimal detection of the metabolite 3,4-dehydro-cilostazol.

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 reflecting a systemic exposure equivalent to five times the MRHD.

Given the lack 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 treatments 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 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 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 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 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, 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 teratogenic effects, fertility, carcinogenicity, mutagenicity, and general animal pharmacology.

No information regarding teratogenic effects is available in the insert. However, non-teratogenic effects have been observed. In female mice, cilostazol induced a reversible contraceptive effect 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 demonstrated 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 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.

In terms of carcinogenicity, 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 has been tested for mutagenicity and was found to be negative in 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.

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 produced cardiovascular lesions. These lesions included endocardial hemorrhage, hemosiderin deposition and fibrosis in the left ventricle, hemorrhage in the right atrial wall, necrosis of the smooth muscle in the coronary artery wall, intimal thickening of the coronary artery, and coronary arteritis and periarteritis. 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 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 following 5 or 13 weeks of cilostazol administration at doses up to 1500 mg/kg/day. At this dose, systemic exposures to unbound cilostazol were approximately 1.5 and 5 times (male and female rats, respectively) the exposure seen in humans at the MRHD. Additionally, cardiovascular lesions were not seen in rats after 52 weeks of cilostazol 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 similar at doses of 150 and 1500 mg/kg/day.

Cardiovascular lesions were also not observed 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 were lower than those seen in humans given the MRHD and those seen in dogs given doses associated with cardiovascular lesions.

Postmarketing Experience

Cilostazol tablets have been associated with serious side effects reported through voluntary and surveillance programs. These include cardiovascular events such as fast heart rate, palpitations, irregular heartbeat, and low blood pressure. Additionally, severe allergic reactions, including anaphylaxis and angioedema, have been documented. Signs of a severe allergic reaction may include hives, swelling of the face, lips, mouth, or tongue, difficulty breathing or wheezing, and dizziness. Changes in blood cell counts, specifically thrombocytopenia or leukopenia, have also been reported, necessitating regular blood tests to monitor these parameters during treatment.

Commonly reported side effects of cilostazol tablets include headache, abnormal stools, and diarrhea. Patients are advised to inform their healthcare provider of any side effects that are bothersome or persistent. This summary does not encompass all potential side effects associated with cilostazol tablets. For further information, patients should consult their healthcare provider or pharmacist. Side effects can also be reported to the FDA at 1-800-FDA-1088.

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling (Patient Information) prior to starting cilostazol and each time they receive a refill, as there may be new information. It is important for patients to take cilostazol at least one-half hour before or two hours after food to ensure optimal absorption.

Healthcare providers should encourage patients to discuss with their doctor before taking any CYP3A4 or CYP2C19 inhibitors, such as omeprazole, as these may interact with cilostazol. Patients 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 after initiating therapy, it may take up to 12 weeks to observe a beneficial effect. Patients should discontinue cilostazol if symptoms do not improve after 3 months.

Patients must inform their doctor if they consume grapefruit juice, have any other medical conditions, or are pregnant, planning to become pregnant, breastfeeding, or planning to breastfeed. It is also essential for patients to disclose all medications they are taking, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Patients should take cilostazol tablets exactly as prescribed by their doctor, who will provide specific instructions regarding dosage and timing. The doctor may adjust the dose if necessary. Patients should be advised to call their doctor for medical advice regarding any side effects and may report side effects to the FDA at 1-800-FDA-1088.

Cilostazol tablets should be stored at a temperature between 68°F to 77°F (20°C to 25°C) and kept out of the reach of children. Patients should not use cilostazol tablets for any condition for which they were not prescribed and should not share their medication with others, even if they have similar symptoms, as it may cause harm.

Storage and Handling

The product is supplied in a tight, light-resistant, child-resistant container, as defined by the United States Pharmacopeia (USP). It is essential to store the product at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines.

Healthcare professionals are advised to ensure that this medication, along with all other medications, is kept out of the reach of children to prevent accidental ingestion or misuse.

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 Slate Run Pharmaceuticals, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)