Source: FDA, National Drug Code (US) Revision Year: 2017
PLETAL is contraindicated in patients with:
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.
Left ventricular outflow tract obstruction has been reported in patients with sigmoid shaped interventricular septum. Monitor patients for the development of a new systolic murmur or cardiac symptoms after starting cilostazol.
Cases of thrombocytopenia or leukopenia progressing to agranulocytosis when PLETAL was not immediately discontinued have been reported. Agranulocytosis is reversible on discontinuation of PLETAL. Monitor platelets and white blood cell counts periodically.
PLETAL inhibits platelet aggregation in a reversible manner. PLETAL has not been studied in patients with hemostatic disorders or active pathologic bleeding. Avoid use of PLETAL in these patients.
The following adverse reactions are discussed in greater detail in other sections of the labeling:
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 PLETAL (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on PLETAL 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 PLETAL 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 PLETAL (all doses) versus 0.1% for placebo.
The most common adverse reactions, occurring in at least 2% of patients treated with PLETAL 50 or 100 mg twice daily, are shown in Table 1.
Table 1. Most Common Adverse Reactions in Patients on PLETAL (PLT) 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) | PLT 50 mg twice daily (N=303) | PLT 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 PLETAL 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
The following adverse reactions have been identified during post-approval use of PLETAL. 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.
Coadministration of strong (e.g., ketoconazole) and moderate (e.g., erythromycin, diltiazem and grapefruit juice) CYP3A4 inhibitors can increase exposure to PLETAL. Reduce PLETAL dose to 50 mg twice daily when coadministered with strong or moderate inhibitors of CYP3A4 [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
Coadministration with CYP2C19 inhibitors (e.g., omeprazole) increases systemic exposure of PLETAL active metabolites. Reduce PLETAL dose to 50 mg twice daily when coadministered with strong or moderate inhibitors of CYP2C19 [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
Pregnancy Category C.
PLETAL 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, 14th 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-dehydrocilostazol 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).
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 PLETAL, discontinue nursing or discontinue PLETAL.
Safety and effectiveness of PLETAL in pediatric patients have not been established.
Of the total number of subjects (n=2,274) in clinical studies of PLETAL, 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.
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 (95-98%) [see Clinical Pharmacology (12.3)].
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)].
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