Cilostazol

Pharmacokinetic interaction (increased plasma concentrations of active metabolite 3,4-dehydro-cilostazol) with CYP2C19 inhibitors, including omeprazole; use with caution and consider reduced dosage.

Potential pharmacokinetic interaction (increased plasma lovastatin concentrations and decreased plasma cilostazol concentration) with lovastatin, a substrate for CYP3A4, although unlikely to be clinically important.

Pharmacokinetic interaction (increased plasma cilostazol concentrations); use with caution and consider reduced dosage. Potential pharmacokinetic interaction (increased plasma cilostazol concentrations, decreased clearance) with other inhibitors of CYP3A4 isoenzyme, including, but not limited to, certain azole antifungals (e.g., fluconazole, itraconazole, ketoconazole, miconazole), certain macrolide antibiotics (e.g., erythromycin or clarithromycin but not azithromycin), certain selective serotonin-reuptake inhibitors (e.g., fluoxetine, fluvoxamine, nefazodone, sertraline), certain antiretroviral agents (e.g., indinavir), metronidazole, diltiazem, and danazol.

Potentially additive antiplatelet effects with clopidogrel and cilostazol. Caution is advised and bleeding times should be monitored during such concomitant therapy. Pharmacokinetic interaction unlikely.

For more Interactions (Complete) data for Cilostazol (10 total), please visit the HSDB record page.

In publications of the multiple, large prospective trials of cilostazol therapy, rates of serum ALT elevations during therapy were not provided. Furthermore, there were no reported instances of clinically apparent acute liver injury. Since its approval and wide scale use, there have been no published reports of hepatotoxicity attributed to cilostazol. Nevertheless, the current product label mentions that instances of serum enzyme elevations and hepatitis have been reported to the sponsor. The time of onset, clinical pattern and course of liver test abnormalities during cilostazol therapy have not been reported.

Cilostazol is a generally well-tolerated oral medication. Common side effects of cilostazol therapy reportedly include headache (34%), diarrhea (19%), and palpitations (10%). A slight elevation in heart rate of 5 to 7 beats/min may also occur with the administration of cilostazol. These side effects are mild to moderate in intensity, transient, or alleviated with symptomatic treatment and seldom demand treatment withdrawal. Cilostazol may induce tachycardia, tachyarrhythmia, and hypotension. Postmarketing research has shown cilostazol to induce thrombocytopenia or leukopenia, progressing to agranulocytosis when drug administration is not immediately discontinued. Agranulocytosis is reversible with immediate discontinuation of the drug.

IDENTIFICATION AND USE: Cilostazol forms colorless, needle-like crystals. As the oral drug Pletal, it is indicated for the reduction of symptoms of intermittent claudication. HUMAN EXPOSURE AND TOXICITY: The signs and symptoms of an acute overdose may include severe headache, diarrhea, hypotension, tachycardia, and possibly cardiac arrhythmias. ANIMAL STUDIES: No cardiovascular lesions were seen in rats following 5 or 13 weeks of administration of cilostazol at doses up to 1500 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were only about 1.5 and 5 times (male and female rats, respectively) the exposure seen in humans at the maximum recommended human dose (MRHD). Repeated oral administration of cilostazol to dogs produced cardiovascular lesions that included endocardial hemorrhage, hemosiderin deposition and fibrosis in the left ventricle, hemorrhage in the right atrial wall, hemorrhage and necrosis of the smooth muscle in the wall of the coronary artery, intimal thickening of the coronary artery, and coronary arteritis and periarteritis. At the lowest dose associated with cardiovascular lesions in the 52-week study, AUC to unbound cilostazol was less than that seen in humans at the MRHD of 100 mg twice daily. In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights, and increased incidences of cardiovascular, renal, and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib, and retarded ossification). Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation, and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay. Dietary administration of cilostazol to rats and mice for up to 104 weeks revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug.

The oral lethal dose of cilostazol is over 5 g/kg in rats and mice and more than 2 g/kg in dogs. There is a lack of data on acute overdosage with cilostazol in humans. The signs and symptoms of an acute cilostazol overdose can present as a severe headache, diarrhea, hypotension, tachycardia, and possibly cardiac arrhythmia. In an overdose, patients require careful observation and supportive treatment. Cilostazol is highly protein-bound and unlikely to be efficiently removed by hemodialysis or peritoneal dialysis. Emptying the stomach by gastric lavage may be appropriate if needed.

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of December 17, 2015: http://actor.epa.gov/dashboard/]

/SIGNS AND SYMPTOMS/ Cilostazol may induce tachycardia, palpitation, tachyarrhythmia or hypotension. The increase in heart rate associated with cilostazol is approximately 5 to 7 bpm. Patients with a history of ischemic heart disease may be at risk for exacerbations of angina pectoris or myocardial infarction.

/SIGNS AND SYMPTOMS/ The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe headache, diarrhea, hypotension, tachycardia, and possibly cardiac arrhythmias.

/CASE REPORTS/ Cilostazol, a phosphodiesterase III inhibitor, is known to increase the heart rate; however, its effects on glucose metabolism remain unclear. We observed that the blood glucose level varied in parallel with the heart rate immediately after starting or stopping cilostazol therapy in three patients with type 2 diabetes. This finding indicates that cilostazol induces hyperglycemia and tachycardia in a portion of diabetic patients, presumably via similar pharmacological effects on different organs. Much more attention should be paid to the possible effects of cilostazol on glycemic control, including taking into consideration the risk-benefit ratio of cilostazol use and individual circumstances.

/ALTERNATIVE and IN VITRO TESTS/ Cilostazol, a selective phosphodiesterase 3 (PDE3) inhibitor, is known as an anti-platelet drug and acts directly on platelets. Cilostazol has been shown to exhibit vascular protection in ischemic diseases. Although vascular endothelium-derived prostaglandin I2 (PGI2) plays an important role in vascular protection, it is unknown whether cilostazol directly stimulates PGI2 synthesis in endothelial cells. Here, we elucidate the mechanism of cilostazol-induced PGI2 stimulation in endothelial cells. Human aortic endothelial cells (HAECs) were stimulated with cilostazol and PGI2 accumulation in the culture media was measured. Cilostazol increased PGI2 synthesis via the arachidonic acid pathway. Cilostazol-induced intracellular calcium also promoted PGI2 synthesis via the inositol 1,4,5-trisphosphate receptor. Using RNAi, silencing of PDE3B abolished the induction effect of cilostazol on PGI2 synthesis and intracellular cAMP accumulation. Inhibition of the exchange protein, which was directly activated by cyclic AMP 1 (Epac-1) and its downstream signal the Ras-like small GTPase (Rap-1), abolished cilostazol-induced PGI2 synthesis, but this did not take place via protein kinase A (PKA). Inhibition of downstream signaling, such as mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K) gamma, and phospholipase C (PLC) e, suppressed cilostazol-induced PGI2 synthesis. The PDE3/Epac-1/Rap-1 signaling pathway plays an important role in cilostazol-induced PGI2 synthesis. Namely, stimulation of HAECs with cilostazol induces intracellular calcium elevation via the Rap-1/PLCe/IP3 pathway, along with MAPK activation via direct activation by Epac-1/Rap-1 and indirect activation by Epac-1/Rap-1/PI3Kgamma, resulting in synergistically induced PGI2 synthesis.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Cilostazol

Ambiguous-DILI-concern

5

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Cardiovascular lesions were ... not observed in monkeys after oral administration of cilostazol for 13 weeks at doses up to 1800 mg/kg/day. While this dose of cilostazol produced pharmacologic effects in monkeys, plasma cilostazol levels were less than those seen in humans given the MRHD, and those seen in dogs given doses associated with cardiovascular lesions.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ No cardiovascular lesions were seen in rats following 5 or 13 weeks of administration of cilostazol at doses up to 1500 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were only about 1.5 and 5 times (male and female rats, respectively) the exposure seen in humans at the maximum recommended human dose (MRHD).

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Cilostazol, a selective type III phosphodiesterase inhibitor, has antiplatelet and vasodilating effects. In this study, the effects of cilostazol on lipid metabolism and lipoprotein lipase (LPL) activity were studied in rats. Cilostazol was administered orally at doses of 30 or 100 mg/kg twice a day for 1-2 weeks to rats. Cilostazol decreased the serum triglyceride level in normolipidemic rats. The serum triglyceride level was reduced and HDL cholesterol level was increased by cilostazol in streptozotocin (STZ)-induced diabetic rats. The disappearance of exogenous triglyceride was accelerated by cilostazol in normolipidemic rats. Cilostazol increased post-heparin plasma LPL activity but had no effect on hepatic triglyceride lipase activity in STZ-induced diabetic rats. Cilostazol also increased LPL activity in the heart in STZ-induced diabetic rats. These findings suggest that an increase in LPL activity is responsible for the serum triglyceride lowering and HDL cholesterol elevating effects of cilostazol in rats.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Repeated oral administration of cilostazol to dogs (30 or more mg/kg/day for 52 weeks, 150 or more mg/kg/day for 13 weeks, and 450 mg/kg/day for 2 weeks), produced cardiovascular lesions that included endocardial hemorrhage, hemosiderin deposition and fibrosis in the left ventricle, hemorrhage in the right atrial wall, hemorrhage and necrosis of the smooth muscle in the wall of the coronary artery, 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 (AUC) to unbound cilostazol was less than that seen in humans at the maximum recommended human dose (MRHD) of 100 mg twice daily. Similar lesions have been reported in dogs following the administration of other positive inotropic agents (including PDE III inhibitors) and/or vasodilating agents.

For more Non-Human Toxicity Excerpts (Complete) data for Cilostazol (15 total), please visit the HSDB record page.

WARNING: CONTRAINDICATED IN HEART FAILURE PATIENTS. Pletal is contraindicated in patients with heart failure of any severity. Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV heart failure.

Cilostazol may induce tachycardia, palpitation, tachyarrhythmia or hypotension. The increase in heart rate associated with cilostazol is approximately 5 to 7 bpm. Patients with a history of ischemic heart disease may be at risk for exacerbations of angina pectoris or myocardial infarction.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

LD50 Dog oral > 2 g/kg

LD50 Rat oral > 5 g/kg

LD50 Mouse oral > 5 g/kg

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including cilostazol, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

MEDICATION

Use (kg; approx.) in Germany (2009): >1000