Cilostazol

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Patients with Heart Failure [see Boxed Warning] Tachycardia [see Warnings and Precautions ( 5.1 )] Left Ventricular Outflow Tract Obstruction [see Warnings and Precautions ( 5.2 )] Hematologic Adverse Reactions [see Warnings and Precautions ( 5.3 )] Hemostatic Disorders or Active Pathologic Bleeding [see Warnings and Precautions ( 5.4 )] Most common adverse reactions greater than or equal to 2% and at least twice that for placebo in patients on 100 mg twice daily are headache, diarrhea, abnormal stools, and palpitation ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993; email drugsafety@avkare.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reactions were assessed in eight placebo-controlled clinical trials involving patients exposed to either 50 or 100 mg twice daily cilostazol tablets (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol tablets and 134 days for patients on placebo. The most frequent adverse reaction resulting in discontinuation of therapy in more than 3% of patients treated with cilostazol tablets was headache [50 mg twice daily (1.3%), 100 mg twice daily (3.5%) and placebo (0.3%)]. Other frequent causes of discontinuation included palpitation and diarrhea, both 1.1% for cilostazol tablets (all doses) versus 0.1% for placebo. The most common adverse reactions, occurring in at least 2% of patients treated with cilostazol tablets 50 or 100 mg twice daily, are shown in Table 1. Table 1: Most Common Adverse Reactions in Patients on cilostazol tablets 50 or 100 mg Twice Daily (Incidence at least 2% and Occurring More Frequently (≥ 2%) in the 100 mg Twice Daily Group than on Placebo) Adverse Reactions Placebo (N=973) Cilostazol tablets 50 mg twice daily (N=303) Cilostazol tablets 100 mg twice daily (N=998) Headache 14% 27% 34% Diarrhea 7% 12% 19% Abnormal stools 4% 12% 15% Palpitation 1% 5% 10% Dizziness 6% 9% 10% Pharyngitis 7% 7% 10% Infection 8% 14% 10% Peripheral edema 4% 9% 7% Rhinitis 5% 12% 7% Dyspepsia 4% 6% 6% Abdominal pain 3% 4% 5% Tachycardia 1% 4% 4% Less frequent clinical significant adverse reactions (less than 2%) that were experienced by patients treated with cilostazol 50 mg twice daily or 100 mg twice daily in the eight controlled clinical trials and that occurred at a frequency in the 100 mg twice daily group greater than in the placebo group are listed below. Body as a whole: fever, generalized edema, malaise Cardiovascular: atrial fibrillation, heart failure, myocardial infarction, nodal arrhythmia, supraventricular tachycardia, ventricular extrasystoles, ventricular tachycardia Digestive: anorexia, melena Hematologic and Lymphatic: anemia Metabolic and Nutritional: increased creatinine, hyperuricemia Nervous: insomnia Respiratory: epistaxis Skin and Appendages: urticaria Special Senses: conjunctivitis, retinal hemorrhage, tinnitus Urogenital: urinary frequency 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of cilostazol tablets. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: Aplastic anemia, granulocytopenia, pancytopenia, bleeding tendency Cardiac disorders: Torsade de pointes and QTc prolongation in patients with cardiac disorders (e.g. complete atrioventricular block, heart failure; and bradyarrythmia), angina pectoris. Gastrointestinal disorders: Gastrointestinal hemorrhage, vomiting, flatulence, nausea General disorders and administration site conditions: Pain, chest pain, hot flushes Hepatobiliary disorders: Hepatic dysfunction/abnormal liver function tests, jaundice Immune system disorders: Anaphylaxis, angioedema, and hypersensitivity Investigations: Blood glucose increased, blood uric acid increased, increase in BUN (blood urea increased), blood pressure increase Nervous system disorders: Intracranial hemorrhage, cerebral hemorrhage, cerebrovascular accident, extradural hematoma and subdural hematoma Renal and urinary disorders: Hematuria Respiratory, thoracic and mediastinal disorders: Pulmonary hemorrhage, interstitial pneumonia Skin and subcutaneous tissue disorders: Hemorrhage subcutaneous, pruritus, skin eruptions including Stevens-Johnson syndrome, skin drug eruption (dermatitis medicamentosa), rash Vascular disorders: Subacute stent thrombosis, hypertension.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects Pregnancy Category C. Cilostazol has been shown to be teratogenic in rats at doses that are greater than 5-times the human MRHD on a body surface area basis. There are no adequate and well-controlled studies in pregnant women. 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, 14 th rib, and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD, and exposure to 3,4-dehydro- cilostazol was barely detectable. When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). 8.3 Nursing Mothers Transfer of cilostazol into milk has been reported in rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from cilostazol, discontinue nursing or discontinue cilostazol. 8.4 Pediatric Use Safety and effectiveness of cilostazol in pediatric patients have not been established. 8.5 Geriatric Use Of the total number of subjects (n = 2,274) in clinical studies of cilostazol, 56 percent were 65 years old and over, while 16 percent were 75 years old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be excluded. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism, and elimination of cilostazol and its metabolites. 8.6 Hepatic Impairment No dose adjustment is required in patients with mild hepatic impairment. Patients with moderate or severe hepatic impairment have not been studied in clinical trials and dosing recommendations cannot be provided [see Clinical Pharmacology ( 12.3 )]. 8.7 Renal Impairment No dose adjustment is required in patients with renal impairment. Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95 to 98%) [see Clinical Pharmacology ( 12.3 )].