Cilostazol

Description

Cilostazol, USP is a quinolinone derivative that functions as a selective inhibitor of phosphodiesterase III. The chemical structure of Cilostazol is designated as 6-4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy-3,4-dihydro-2(1H)-quinolinone, with a CAS number of 73963-72-1. Its molecular formula is C20H27N5O2, and it has a molecular weight of 369.46.

Cilostazol appears as white to off-white crystals or a crystalline powder. It exhibits slight solubility in methanol and ethanol, while being practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH. Cilostazol is formulated as oral tablets, available in two strengths: 50 mg pillow-shaped and 100 mg round, both of which are white to off-white and debossed. Each tablet contains inactive ingredients including colloidal silicon dioxide, corn starch, crospovidone, magnesium stearate, microcrystalline cellulose, and povidone. The formulation meets the USP Dissolution Test 3 criteria.

Uses and Indications

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

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

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 severe allergic reactions.

Warnings and Precautions

Patients receiving treatment with this medication should be closely monitored for cardiovascular and hematological complications.

Cardiovascular Risks There is a significant risk 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 essential for healthcare professionals to assess the cardiovascular status of these patients regularly.

Left Ventricular Outflow Tract Obstruction Patients with a sigmoid-shaped interventricular septum may be at risk for left ventricular outflow tract obstruction. Clinicians should evaluate the anatomical structure of the heart in patients prior to initiating treatment.

Hematological Monitoring There is a risk of thrombocytopenia or leukopenia, which can progress to agranulocytosis. Regular monitoring of platelet and white blood cell counts is recommended to detect any hematological abnormalities early.

Contraindications This medication is contraindicated in patients with heart failure of any severity. Cilostazol and its metabolites are known 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.

Hemostatic Disorders The use of this medication should be avoided 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 and optimize 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 be at risk for exacerbations of angina pectoris or myocardial infarction. There have also been reports of left ventricular outflow tract obstruction in patients with a sigmoid-shaped interventricular septum.

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. Furthermore, there are risks of thrombocytopenia or leukopenia that may progress to agranulocytosis; therefore, monitoring of platelet and white blood cell counts is recommended. The use of cilostazol should be avoided in patients with hemostatic disorders or active pathologic bleeding.

In cases of acute overdose, severe headache, diarrhea, hypotension, tachycardia, and possibly cardiac arrhythmias may occur.

Drug Interactions

The concomitant use of cilostazol with strong and moderate inhibitors of CYP3A4 and CYP2C19 may lead to increased exposure to cilostazol. It is recommended to reduce the dose of cilostazol in patients receiving these inhibitors to mitigate the risk of adverse effects associated with elevated drug levels.

Healthcare professionals should monitor patients closely for signs of cilostazol toxicity and adjust the dosage accordingly based on clinical response and tolerability.

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 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 cannot be excluded in some older individuals. Therefore, healthcare providers should exercise caution 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 remain vigilant in assessing the individual needs and responses of geriatric patients during treatment.

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 fetal anomalies. 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. Notably, at this dose, systemic exposure to unbound cilostazol was approximately five times that observed in humans receiving the MRHD.

Further findings from the same study indicated that at a lower dose of 150 mg/kg/day, which corresponds to five times the MRHD on a systemic exposure basis, there were also increased incidences of ventricular septal defects and retarded ossification. In a separate rabbit developmental toxicity study, retardation of ossification of the sternum 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 seen in humans at the MRHD, with exposure to its metabolite, 3,4-dehydrocilostazol, being barely detectable.

Additionally, 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 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. Women of childbearing potential should be advised to use effective contraception while receiving cilostazol.

Lactation

Cilostazol has been shown to affect reproductive outcomes in animal studies. When 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.

There are no available data on the excretion of cilostazol in human breast milk or its effects on breastfed infants. Therefore, caution is advised when cilostazol is administered to lactating mothers.

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 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

Acute overdosage with cilostazol in humans is not well-documented; 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.

In the event of an overdose, it is crucial for the patient to be carefully observed. Supportive treatment should be administered as necessary to manage symptoms and maintain patient stability.

Due to cilostazol's high protein-binding characteristics, it is unlikely that effective removal of the drug can be achieved through hemodialysis or peritoneal dialysis.

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, suggesting a relatively high threshold for acute toxicity in these animal models.

Nonclinical Toxicology

Cilostazol has been evaluated for its nonclinical toxicology profile through various studies in animal models.

Teratogenic effects have not been reported in the available data. However, non-teratogenic effects were observed in female mice, where 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.

Animal toxicology 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 the human exposure at the MRHD of the drug.

Cilostazol was 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.

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. 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) the exposure 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, where systemic exposures were about 0.5 and 5 times (male and female rats, respectively) the human MRHD. Additionally, 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 were lower than those seen in humans at the MRHD and 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

Advise patients to read the FDA-approved patient labeling (Patient Information) carefully to understand the medication's use and potential risks. Patients should be instructed to take cilostazol at least one-half hour before or two hours after food to ensure optimal absorption.

It is important for patients to discuss with their healthcare provider before taking any CYP3A4 or CYP2C19 inhibitors, such as omeprazole, as these may interact with cilostazol. Inform patients 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.

Patients must be made aware that cilostazol tablets can cause serious side effects, including heart problems. Advise patients not to take cilostazol if they have any form of heart failure. Additionally, instruct patients to inform their healthcare provider if they consume grapefruit juice, as it can increase the levels of cilostazol in the body, potentially leading to side effects.

Patients should also be encouraged to inform their healthcare provider about any other medical conditions they may have, as well as if they are pregnant, planning to become pregnant, breastfeeding, or planning to breastfeed. It is essential for patients to disclose all medications they are taking, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Instruct patients to take cilostazol tablets exactly as prescribed by their healthcare provider, adhering to the timing of administration—30 minutes before meals or 2 hours after meals. Patients should be informed about the possible side effects of cilostazol, which include serious reactions such as heart problems and severe allergic reactions (anaphylaxis, angioedema). Advise patients to contact their healthcare provider for medical advice regarding side effects and to report any adverse effects to the FDA at 1-800-FDA-1088.

Finally, instruct patients to store cilostazol tablets at a temperature between 68° to 77°F (20° to 25°C) and to keep them out of the reach of children to ensure safety.

Storage and Handling

The product is supplied in a tight, light-resistant container that complies with USP standards and includes a child-resistant closure as required. 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 Teva Pharmaceuticals USA, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)