Cilostazol

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

No teratogenic or nonteratogenic effects are mentioned in the provided text.

Dosage and Administration

The recommended dosage of cilostazol tablets is 100 mg administered twice daily. It is essential that the tablets are taken at least half an hour before or two hours after meals, specifically breakfast and dinner.

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.

Healthcare professionals should ensure that patients adhere to these guidelines to optimize therapeutic outcomes and minimize potential drug interactions.

Contraindications

Cilostazol is contraindicated in patients with heart failure of any severity. Additionally, it should not be used in individuals who have a hypersensitivity to cilostazol or any components of cilostazol tablets.

Warnings and Precautions

Risks of tachycardia, palpitation, tachyarrhythmia, or hypotension are associated with the use of Cilostazol. Patients with a history of ischemic heart disease may experience exacerbations of angina pectoris or myocardial infarction. Additionally, left ventricular outflow tract obstruction has been reported in patients with a sigmoid-shaped interventricular septum.

There is a risk of thrombocytopenia or leukopenia that may progress to agranulocytosis; therefore, it is essential to monitor platelet and white blood cell counts regularly. Cilostazol should be avoided in patients with hemostatic disorders or active pathologic bleeding.

Serious Warnings Cilostazol is contraindicated in patients with heart failure of any severity. The drug and several of its metabolites are inhibitors of phosphodiesterase III, and the use of such drugs has been associated with decreased survival compared to placebo in patients with class III-IV heart failure.

Monitoring Requirements

• Regular monitoring of platelets and white blood cell counts is recommended to detect potential hematological issues early.

No additional general precautions, emergency medical help instructions, or specific instructions to stop taking the medication and contact a doctor were explicitly listed in the provided data.

Side Effects

Common adverse reactions observed in patients taking cilostazol include:

• Headache

• Diarrhea

• Abnormal stools

• Palpitation

Cilostazol is contraindicated in patients with heart failure of any severity. This warning is significant as cilostazol and its metabolites are phosphodiesterase III inhibitors, which have been associated with decreased survival in patients with class III-IV heart failure compared to placebo.

Additional adverse reactions and important considerations include:

• Risks of tachycardia, palpitation, tachyarrhythmia, or hypotension.

• Potential exacerbations of angina pectoris or myocardial infarction in patients with a history of ischemic heart disease.

• Reports of left ventricular outflow tract obstruction in patients with a sigmoid-shaped interventricular septum.

• Risks of thrombocytopenia or leukopenia, which may progress to agranulocytosis; monitoring of platelet and white blood cell counts is recommended.

• Avoidance of cilostazol in patients with hemostatic disorders or active pathologic bleeding.

• Hypersensitivity reactions to cilostazol or any components of cilostazol tablets.

In cases of overdose, signs and symptoms may include severe headache, diarrhea, hypotension, tachycardia, and possibly cardiac arrhythmias, which are indicative of 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.

No specific drug and laboratory test interactions have been provided for cilostazol.

Pediatric Use

Safety and effectiveness of cilostazol in pediatric patients have not been established. There are no available data to support its use in this population.

Geriatric Use

In clinical studies of cilostazol, 56 percent of subjects were aged 65 years and older, and 16 percent were aged 75 years and older, with no overall differences in safety or effectiveness observed between these geriatric patients and younger subjects. While clinical experience has not identified significant differences in responses between elderly and younger patients, it is important to note that greater sensitivity in some older individuals cannot be excluded. Pharmacokinetic studies have shown no age-related effects on the absorption, distribution, metabolism, and elimination of cilostazol and its metabolites. Therefore, no specific dosage adjustments are recommended for geriatric patients based solely on age. However, careful monitoring is advised due to the potential for increased sensitivity in this population.

Pregnancy

Cilostazol is classified as a Pregnancy Category C medication. Animal studies have demonstrated teratogenic effects in rats at doses exceeding 5 times the human maximum recommended human dose (MRHD) on a body surface area basis. There are no adequate and well-controlled studies in pregnant women to assess the safety of cilostazol during pregnancy.

In a rat developmental toxicity study, administration of 1000 mg cilostazol/kg/day resulted in decreased fetal weights and increased incidences 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 5 times that observed in humans at 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 5 times the MRHD on a systemic exposure basis.

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

Furthermore, 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, again reflecting 5 times the MRHD on a systemic exposure basis.

Given these findings, healthcare providers should exercise caution when considering cilostazol for use in pregnant patients, weighing the potential risks to fetal outcomes against the benefits of treatment.

Lactation

Cilostazol is known to transfer into breast milk, as evidenced by studies in rats. Due to the potential for serious adverse reactions in breastfed infants, it is recommended that lactating mothers either discontinue nursing or discontinue the use of cilostazol.

In animal studies, administration of cilostazol during late pregnancy and lactation resulted in an increased incidence of stillborn offspring and decreased birth weights at doses significantly higher than the maximum recommended human dose (MRHD). There are no adequate and well-controlled studies in pregnant women, which further underscores the need for caution when considering cilostazol in lactating mothers.

Renal Impairment

Patients with renal impairment have no specific information regarding dosage adjustments, monitoring, or safety considerations for the use of Cilostazol. The available data does not provide guidance on the management of this medication in individuals with reduced kidney function. Therefore, healthcare professionals should exercise caution and consider individual patient circumstances when prescribing Cilostazol to patients with renal impairment, as the lack of specific recommendations necessitates careful clinical judgment.

Hepatic Impairment

Patients with hepatic impairment have no specific information regarding dosage adjustments, special monitoring, or precautions when using Cilostazol. The available data does not provide guidance on the use of this medication in individuals with liver problems. Therefore, healthcare professionals should exercise caution and consider individual patient factors when prescribing Cilostazol to patients with hepatic impairment.

Overdosage

In cases of acute overdose with cilostazol, the signs and symptoms may include severe headache, diarrhea, hypotension, tachycardia, and potentially cardiac arrhythmias. The oral LD50 of cilostazol is reported to be greater than 5 g per kg in mice and rats, and greater than 2 g per kg in dogs, indicating a significant margin of safety in animal models.

Due to cilostazol's high protein-binding characteristics, it is unlikely that the drug can be effectively removed through hemodialysis or peritoneal dialysis. Therefore, management of an overdose should focus on careful observation of the patient and the provision of supportive treatment as necessary. Monitoring for the aforementioned symptoms is essential to ensure appropriate intervention and care.

Nonclinical Toxicology

Teratogenic Effects

No teratogenic effects were reported in the available studies.

Non-Teratogenic Effects

Cilostazol has been shown to cause 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 dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and approximately 5 times in females compared to human exposure at the MRHD.

Carcinogenesis, Mutagenesis

Long-term dietary administration of cilostazol to male and female rats and mice for up to 104 weeks at doses of 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 studies were, on a systemic exposure basis, lower than the human exposure at the MRHD. Cilostazol tested negative in various 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.

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 these lesions in the 52-week study, systemic exposure (AUC) 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, with systemic exposures being about 0.5 and 5 times (male and female rats, respectively) the human exposure at the MRHD.

In female rats, cilostazol AUCs were comparable 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 at the MRHD and in dogs given doses associated with cardiovascular lesions.

Storage and Handling

Cilostazol tablets are supplied in a tight, light-resistant container with a child-resistant closure, as defined in the USP.

Cilostazol tablets should be stored at a temperature range of 20° to 25°C (68° to 77°F), with excursions permitted from 15°C to 30°C (59°F to 86°F) see USP Controlled Room Temperature.

It is important to keep this and all medications out of the reach of children.