Cilostazol

Description

Cilostazol is a quinolinone derivative that inhibits cellular phosphodiesterase, specifically phosphodiesterase III. The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.47 g/mol. The chemical structure is described 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 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 doses are taken at least half an hour before or two hours after 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. Additionally, left ventricular outflow tract obstruction has been reported in patients with a sigmoid-shaped interventricular septum, necessitating careful evaluation of cardiac function prior to initiation of therapy.

Hematological Monitoring There is a risk of thrombocytopenia or leukopenia that may progress to agranulocytosis in patients taking cilostazol. Regular monitoring of platelet and white blood cell counts is recommended to detect any significant hematological 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 in patients with class III-IV heart failure has been associated with decreased survival compared to placebo. Furthermore, cilostazol should be avoided in patients with hemostatic disorders or those experiencing active pathological bleeding, as it may exacerbate these conditions.

Healthcare professionals are advised to assess the overall risk-benefit profile for each patient before prescribing cilostazol, ensuring appropriate monitoring and management strategies are in place.

Side Effects

Patients may experience a range of adverse reactions while using cilostazol tablets. Common adverse reactions include headache, diarrhea, abnormal stools, and palpitations.

Serious warnings are associated with cilostazol, particularly its contraindication in patients with heart failure of any severity. Cilostazol and its metabolites act as inhibitors of phosphodiesterase III, and several drugs with similar pharmacologic effects have been linked to decreased survival in patients with class III-IV heart failure compared to those receiving placebo.

Additional risks include tachycardia, palpitations, tachyarrhythmia, and hypotension. Patients with a history of ischemic heart disease may experience 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.

Monitoring is advised for potential hematologic adverse reactions, including thrombocytopenia or leukopenia that may progress to agranulocytosis; therefore, regular assessment 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, such as 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 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 in children and adolescents.

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. As such, no specific dosage adjustments are recommended solely based on age. However, ongoing monitoring of elderly patients is advised to ensure safety and efficacy during treatment.

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 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 approximately 5 times the MRHD based on systemic exposure, similar anomalies were observed, including increased incidences of ventricular septal defects and retarded ossification.

In rabbits, a developmental toxicity study indicated that doses as low as 150 mg/kg/day were associated with an increased incidence of sternum ossification retardation. 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. 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. Women of childbearing potential should be advised to use effective contraception while receiving cilostazol.

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

There is no information available regarding the use of this medication in patients with hepatic impairment. Consequently, there are no dosage adjustments, special monitoring requirements, or precautions specified for individuals with compromised liver function. Healthcare professionals should exercise caution and consider the lack of data when prescribing this medication to patients with liver problems.

Overdosage

In cases of acute overdose, healthcare professionals should be vigilant for a range of signs and symptoms. These may include severe headache, diarrhea, hypotension, tachycardia, and potentially cardiac arrhythmias. Prompt recognition of these symptoms is crucial for effective 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 need for careful dosing and monitoring in clinical practice to prevent overdose situations.

Due to cilostazol's high protein-binding characteristics, it is important to note that conventional methods of removal, such as hemodialysis or peritoneal dialysis, are unlikely to be effective. Therefore, management of an overdose should focus on supportive care and symptomatic treatment rather than reliance on dialysis.

Healthcare professionals are advised to monitor the patient closely and provide appropriate interventions based on the symptoms presented.

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 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. However, this effect has not been observed 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 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 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.

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, as well as 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 cardiovascular lesions have been reported in dogs following the administration of other positive inotropic agents and/or vasodilating agents.

In contrast, 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 (for male and female rats, respectively) the exposure seen in humans at the MRHD. Furthermore, cardiovascular lesions were not observed 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 (for male and female rats, respectively) the human MRHD. In female rats, cilostazol AUCs were similar at both 150 and 1500 mg/kg/day.

Additionally, cardiovascular lesions were not seen 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 observed in humans receiving the MRHD and those seen in dogs given doses associated with cardiovascular lesions.

Postmarketing Experience

Postmarketing experience with cilostazol tablets has identified several serious side effects. Reports indicate that cilostazol may be associated with cardiovascular issues, including fast heart rate, palpitations, irregular heartbeat, and low blood pressure. Additionally, severe allergic reactions such as anaphylaxis and angioedema have been documented. Symptoms of these reactions may include hives, facial swelling, difficulty breathing, and dizziness, necessitating immediate medical attention.

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

Commonly reported side effects include headache, abnormal stools, and diarrhea. Patients are advised to consult their healthcare provider for any side effects experienced and may report 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 to instruct patients to take cilostazol tablets at least one-half hour before or two hours after food to ensure optimal absorption.

Healthcare providers should discuss with patients the necessity of consulting 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 may experience benefits within 2 to 4 weeks, treatment for up to 12 weeks may be required before a noticeable improvement is observed. Patients should discontinue cilostazol if symptoms do not improve after 3 months.

It is critical to inform patients that cilostazol should not be taken if they have any form of heart failure. Additionally, patients should be advised to inform their doctor if they consume grapefruit juice, as this can increase the levels of cilostazol in the body and lead to side effects.

Patients must disclose any other medical conditions they have, as well as if they are pregnant, planning to become pregnant, breastfeeding, or planning to breastfeed. The safety of cilostazol during pregnancy and breastfeeding is not established, and a discussion with their doctor is essential to determine the best course of action.

Patients should be reminded to inform their doctor about all medications they are taking, including prescription and over-the-counter drugs, vitamins, and herbal supplements. It is important for patients to take cilostazol exactly as prescribed by their doctor, who will provide specific instructions regarding dosage and timing.

Patients should be vigilant for any signs or symptoms of a severe allergic reaction, such as hives, swelling of the face, lips, mouth, or tongue, trouble breathing or wheezing, and dizziness, and should seek immediate medical attention if these occur. Lastly, patients should report any side effects that are bothersome or do not resolve to their healthcare provider.

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

View full prescribing information (PDF)