Tirofiban Hydrochloride

1 INDICATIONS AND USAGE Tirofiban hydrochloride injection is indicated to reduce the rate of thrombotic cardiovascular events (combined endpoint of death, myocardial infarction, or refractory ischemia/repeat cardiac procedure) in patients with non-ST elevation acute coronary syndrome (NSTE-ACS). Tirofiban hydrochloride injection is a platelet aggregation inhibitor indicated to reduce the rate of thrombotic cardiovascular events (combined endpoint of death, myocardial infarction, or refractory ischemia/repeat cardiac procedure) in patients with non-ST elevation acute coronary syndrome (NSTE-ACS). ( 1 )

2 DOSAGE AND ADMINISTRATION Administer intravenously 25 mcg/kg within 5 minutes and then 0.15 mcg/kg/min for up to 18 hours. In patients with creatinine clearance ≤ 60 mL/min, give 25 mcg/kg within 5 minutes and then 0.075 mcg/kg/min. ( 2 ) 2.1 Recommended Dosage The recommended dosage is 25 mcg/kg administered intravenously within 5 minutes and then 0.15 mcg/kg/min for up to 18 hours. 2.2 Administration For intravenous use only. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. To open the 250 mL premixed bag, first tear off its foil overpouch. The plastic may be somewhat opaque because of moisture absorption during sterilization; the opacity will diminish gradually. Check for leaks by squeezing the inner bag firmly; if any leaks are found or sterility is suspect then the solution should be discarded. Do not use unless the solution is clear and the seal is intact. Administration Instructions The bolus dose of tirofiban hydrochloride injection may be administered from the 250 mL premixed bag. Do not dilute. Administer the bolus dose within 5 minutes via IV pump. Immediately following the bolus dose administration, administer the maintenance infusion from the 250 mL premixed bag via an IV pump. Discard any unused portion left in the bag. The recommended bolus volume using 250 mL premixed bag can be calculated using the following equation: Bolus Volume (mL) = 25 mcg/kg X body weight (kg) 50 mcg/mL The recommended infusion rate for patients with CrCl (Creatinine Clearance) > 60 mL/min using the 250 mL premixed bag can be calculated using the following equation: Infusion Rate for CrCl > 60 mL/min (mL/h) = 0.15 mcg/kg/min x body weight (kg) x 60 min/h 50 mcg/mL Example calculation of infusion rate for 60 kg patient with CrCl > 60 mL/min using the 250 mL premixed bag: Infusion Rate for CrCl > 60 mL/min (mL/h) = 0.15 mcg/kg/min x 60 kg x 60 min/h =10.8 mL/h 50 mcg/mL Drug Compatibilities Tirofiban hydrochloride injection can be administered in the same intravenous line as heparin, atropine sulfate, dobutamine, dopamine, epinephrine hydrochloride (HCl), famotidine injection, furosemide, lidocaine, midazolam HCl, morphine sulfate, nitroglycerin, potassium chloride, and propranolol HCl. Do not administer tirofiban hydrochloride injection through the same IV line as diazepam. Do not add other drugs or remove solution directly from bag with a syringe. 2.3 Dose Adjustment for Renal Impairment The recommended dosage in patients with CrCl ≤ 60 mL/min (calculated using the Cockcroft-Gault equation with actual body weight) is 25 mcg/kg intravenously within 5 minutes and then 0.075 mcg/kg/min, for up to 18 hours. The recommended infusion rate for patients with CrCl ≤ 60 mL/min using the 250 mL premixed bag can be calculated using the following equation: Infusion Rate for CrCl ≤ 60 mL/min (mL/h) = 0.075 mcg/kg/min x body weight (kg) x 60 min/h 50 mcg/mL

6 ADVERSE REACTIONS Bleeding is the most commonly reported adverse reaction. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sagent Pharmaceuticals at 1-866-625-1618 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial 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 clinical practice. In the PRISM (Platelet Receptor Inhibition for Ischemic Syndrome Management), PRISM-PLUS (Platelet Receptor Inhibition for Ischemic Syndrome Management — Patients Limited by Unstable Signs and Symptoms) and RESTORE (Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis) trials, 1946 patients received tirofiban hydrochloride injection in combination with heparin and 2002 patients received tirofiban hydrochloride injection alone for about 3 days. Forty-three percent of the population was > 65 years of age and approximately 30% of patients were female. In clinical studies with the recommended regimen (25 mcg/kg bolus followed by a 0.15 mcg/kg/min maintenance infusion), tirofiban hydrochloride injection was administered in combination with aspirin, clopidogrel and heparin or bivalirudin to over 8000 patients for typically ≤ 24 hours. Approximately 30% of the population was > 65 years of age and approximately 25% were female. Bleeding PRISM-PLUS Regimen The incidences of major and minor bleeding using the TIMI criteria in the PRISM-PLUS study are shown below. Table 2 TIMI Major and Minor Bleeding in PRISM-PLUS * 0.4 mcg/kg/min initial infusion; 0.10 mcg/kg/min maintenance infusion. ‡ Major = Hemoglobin drop of > 5.0 g/dL with or without an identified site, intracranial hemorrhage, or cardiac tamponade. § Minor = Hemoglobin drop of > 3.0 g/dL with bleeding from a known site, spontaneous gross hematuria, hematemesis or hemoptysis. PRISM-PLUS (NSTE-ACS) Bleeding (TIMI Criteria)‡ § Tirofiban Hydrochloride Injection* + Heparin (N=773) Heparin alone (N=797) Major Bleeding 1.4% 0.8% Minor Bleeding 10.5% 8.0% Transfusions 4.0% 2.8% The incidence rates of TIMI major bleeding in patients undergoing percutaneous procedures in PRISM-PLUS are shown below. Table 3 TIMI Major Bleeding Associated with Percutaneous Procedures in PRISM-PLUS Tirofiban Hydrochloride Injection + Heparin Heparin alone N % N % Prior to Procedures 773 0.3 797 0.1 Following Angiography 697 1.3 708 0.7 Following PTCA 239 2.5 236 2.2 The incidence rates of TIMI major bleeding in patients undergoing coronary artery bypass graft surgery (CABG) in PRISM-PLUS within one day of discontinuation of tirofiban hydrochloride injection were 17% on tirofiban hydrochloride injection plus heparin (N=29) and 35% on heparin alone (N=31). Recommended (“High-Dose Bolus”) Regimen Rates of major bleeds (including any intracranial, intraocular or retroperitoneal hemorrhage, clinically overt signs of hemorrhage associated with a drop in hemoglobin of > 3 g/dL or any drop in hemoglobin by 4 g/dL, bleeding requiring transfusion of ≥ 2U blood products, bleeding directly resulting in death within 7 days or hemodynamic compromise requiring intervention) were consistent with the rates observed in subjects administered the PRISM-PLUS regimen of tirofiban hydrochloride injection. There was a trend toward greater bleeding in ST segment elevation myocardial infarction (STEMI) patients treated with fibrinolytics prior to administration of tirofiban hydrochloride injection using the recommended regimen during rescue PCI. Non-Bleeding The incidences of non-bleeding adverse events that occurred at an incidence of > 1% and numerically higher than control, regardless of drug relationship, are shown below: Table 4 Non-bleeding Adverse Reactions in PRISM-PLUS Tirofiban Hydrochloride Injection + Heparin (N=1953) % Heparin alone (N=1887)% Body as a Whole Edema/swelling 2 1 Pain, pelvic 6 5 Reaction, vasovagal 2 1 Cardiovascular System Bradycardia 4 3 Dissection, coronary artery 5 4 Musculoskeletal System Pain, leg 3 2 Nervous System/Psychiatric Dizziness 3 2 Skin and Skin Appendage Sweating 2 1 Thrombocytopenia Patients treated with tirofiban hydrochloride injection plus heparin, were more likely to experience decreases in platelet counts than were those on heparin alone. These decreases were reversible upon discontinuation of tirofiban hydrochloride injection. The percentage of patients with a decrease of platelets to < 90,000/mm 3 was 1.5%, compared with 0.6% in the patients who received heparin alone. The percentage of patients with a decrease of platelets to < 50,000/mm 3 was 0.3%, compared with 0.1% of the patients who received heparin alone. 6.2 Post-Marketing Experience The following additional adverse reactions have been identified during post-approval use of tirofiban hydrochloride injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the drug exposure. Hypersensitivity: Severe allergic reactions including anaphylactic reactions have occurred during the first day of tirofiban hydrochloride injection infusion, during initial treatment, and during readministration of tirofiban hydrochloride injection. Some cases have been associated with severe thrombocytopenia (platelet counts < 10,000/mm 3 ). No information is available on the formation of antibodies to tirofiban.

12.3 Pharmacokinetics Tirofiban has a half-life of approximately 2 hours. It is cleared from the plasma largely by renal excretion, with about 65% of an administered dose appearing in urine and about 25% in feces, both largely as unchanged tirofiban. Metabolism appears to be limited. Tirofiban is not highly bound to plasma proteins and protein binding is concentration independent over the range of 0.01 to 25 mcg/mL. The unbound fraction in human plasma is 35%. The steady state volume of distribution of tirofiban ranges from 22 to 42 liters. In healthy subjects, the plasma clearance of tirofiban ranges from 213 to 314 mL/min. Renal clearance accounts for 39 to 69% of plasma clearance. Specific Populations There is no effect on clearance of tirofiban by sex, race, age, or hepatic impairment. Renal Insufficiency Plasma clearance of tirofiban is decreased about 40% in subjects with creatinine clearance < 60 mL/min and > 50% in patients with creatinine clearance < 30 mL/min, including patients requiring hemodialysis [see Dosage and Administration ( 2.3 )]. Tirofiban is removed by hemodialysis.