AGGRASTAT

1 INDICATIONS AND USAGE AGGRASTAT® 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). AGGRASTAT 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).

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 100 mL or 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 Withdraw the bolus dose of AGGRASTAT from the 15 mL premixed bolus vial into a syringe. Alternatively, the bolus dose of AGGRASTAT may be administered from the 100 mL or 250 mL premixed bag. Do not dilute. Administer the bolus dose within 5 minutes via a syringe or IV pump. For patients ≥ 167 kg, it is recommended that the bolus dose be administered via syringe from the 15 mL premixed bolus vial, to ensure that delivery time does not exceed 5 minutes. Immediately following the bolus dose administration, administer the maintenance infusion the 100 mL premixed bag or the 250 mL premixed bag via an IV pump. Discard any unused portion left in the vial or bag. The recommended bolus volume using the 15 mL premixed bolus vial can be calculated using the following equation: The recommended bolus volume using the 100 mL premixed bag or 250 mL premixed bag can be calculated using the following equation: The recommended infusion rate for patients with CrCl (Creatinine Clearance) >60 mL/min using the 100 mL premixed bag or 250 mL premixed bag can be calculated using the following equation: Example calculation of infusion rate for 60 kg patient with CrCl >60 mL/min using the 100 mL premixed bag or 250 mL premixed bag: Drug Compatibilities AGGRASTAT 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 AGGRASTAT through the same IV line as diazepam. Do not add other drugs or remove solution directly from the bag with a syringe. equation-1 equation-2 equation-3 equation-4 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 100 mL premixed vial, 100 mL premixed bag or 250 mL premixed bag can be calculated using the following equation: equation-5

3 DOSAGE FORMS AND STRENGTHS AGGRASTAT is a clear, non-preserved, colorless, isosmotic, sterile premixed injection with sodium chloride for tonicity adjustment available in the following presentations: Table 1 AGGRASTAT Strength and Packaging Strength Volume - Packaging 50 mcg/mL 250 mL - bag 50 mcg/mL 100 mL - bag 250 mcg/mL 15 mL - bolus vial Injection: 12.5 mg/250mL (50 mcg/mL) in 250 mL bag ( 3 ) Injection: 5 mg/100mL (50 mcg/mL) in 100 mL bag. ( 3 ) Injection: 3.75 mg/15mL (250 mcg/mL) in 15 mL bolus vial ( 3 )

4 CONTRAINDICATIONS AGGRASTAT is contraindicated in patients with: Severe hypersensitivity reaction to AGGRASTAT (i.e., anaphylactic reactions) [see Adverse Reactions ( 6.2 )] . A history of thrombocytopenia following prior exposure to AGGRASTAT [see Adverse Reactions ( 6.1 )] . Active internal bleeding or a history of bleeding diathesis, major surgical procedure or severe physical trauma within the previous month [see Adverse Reactions ( 6.1 ) ]. Known hypersensitivity to any component of AGGRASTAT. ( 4 ) History of thrombocytopenia with prior exposure to AGGRASTAT. ( 4 ) Active internal bleeding, or history of bleeding diathesis, major surgical procedure or severe physical trauma within the previous month. ( 4 )

6 ADVERSE REACTIONS Bleeding is the most commonly reported adverse reaction. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Medicure at 1-800-509-0544 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 AGGRASTAT in combination with heparin and 2002 patients received AGGRASTAT 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), AGGRASTAT 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 PRISM-PLUS (NSTE-ACS) Bleeding (TIMI Criteria) 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. AGGRASTAT 0.4 mcg/kg/min initial infusion; 0.10 mcg/kg/min maintenance infusion. + 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 AGGRASTAT + 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 AGGRASTAT were 17% on AGGRASTAT 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 ≥ 2 U 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 AGGRASTAT. There was a trend toward greater bleeding in ST segment elevation myocardial infarction (STEMI) patients treated with fibrinolytics prior to administration of AGGRASTAT 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 AGGRASTAT + 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 AGGRASTAT plus he …

7 DRUG INTERACTIONS Concomitant use of fibrinolytics, anticoagulants and antiplatelet drugs increases the risk of bleeding. Coadministration of fibrinolytics, anticoagulants and antiplatelet agents, increases the risk of bleeding. ( 7 )

8 USE IN SPECIFIC POPULATIONS Renal Insufficiency: Reduce the dose in patients with severe renal insufficiency. ( 8.6 ) 8.1 Pregnancy Risk Summary While published data cannot definitively establish the absence of risk, available published case reports have not established an association with tirofiban use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. Untreated myocardial infarction can be fatal to the pregnant woman and fetus (see Clinical Considerations). Studies with tirofiban HCl at intravenous doses up to 5 mg/kg/day (about 5 and 13 times the maximum recommended daily human dose for rat and rabbit, respectively, when compared on a body surface area basis) have revealed no harm to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Myocardial infarction is a medical emergency in pregnancy which can be fatal to the pregnant woman and fetus if left untreated. Data Animal Data There was no evidence of maternal or developmental toxicity in any of the studies in Table 5. Table 5 Developmental Toxicity Studies Type of Study Species Dose/Exposure 5 mg/kg/day is ~5 and 13 times the maximum recommended daily human dose for rat and rabbit, respectively, when compared on a body surface area basis. Duration/Timing Exposure (1) Range-finding Rat (N=30) 1, 2, 5 mg/kg/day IV (N=10 per group) Once daily from GD 6 through LD 20 (2) Developmental Toxicity Rat (N=66) 1, 2, 5 mg/kg/day IV (N=22 per group) Once daily from GD 6 through GD 20 (3) Developmental Toxicity with Postweaning Evaluation Rat (N=66) 1, 2, 5 mg/kg/day IV (N=22 per group) Once daily from GD 6 through LD 20 (4) Range-finding (non-pregnant) Rabbit (N=21) 1, 2, 5 mg/kg/day IV (N=7 per group) Once daily for 14 days (5) Range-finding (pregnant) Rabbit (N=30) 1, 2, 5 mg/kg/day IV (N=10 per group) Once daily from GD 7 through GD 20 (6) Developmental Toxicity Rabbit (N=60) 1, 2, 5 mg/kg/day (N=20 per group) IV Once daily from GD 7 through GD 20 8.2 Lactation Risk Summary There is no data on the presence of tirofiban in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on human milk production. However, tirofiban is present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for AGGRASTAT and any potential adverse effects on the breastfed child from AGGRASTAT or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Of the total number of patients in controlled clinical studies of AGGRASTAT, 43% were 65 years and over, while 12% were 75 years and over. With respect to efficacy, the effect of AGGRASTAT in the elderly (≥65 years) appeared similar to that seen in younger patients (<65 years). Elderly patients receiving AGGRASTAT with heparin or heparin alone had a higher incidence of bleeding complications than did younger patients, but the incremental risk of bleeding in patients treated with AGGRASTAT in combination with heparin compared to the risk in patients treated with heparin alone was similar regardless of age. No dose adjustment is recommended for the elderly population [see Dosage and Administration ( 2 )] . 8.6 Renal Insufficiency Patients with moderate to severe renal insufficiency have decreased plasma clearance of AGGRASTAT. Reduce the dosage of AGGRASTAT in patients with severe renal insufficiency [see Dosage and Administration ( 2.3 ) and Clinical Pharmacology ( 12.3 )]. Safety and efficacy of AGGRASTAT has not been es …

12.1 Mechanism of Action AGGRASTAT is a reversible antagonist of fibrinogen binding to the GP IIb/IIIa receptor, the major platelet surface receptor involved in platelet aggregation. When administered intravenously, AGGRASTAT inhibits ex vivo platelet aggregation in a dose- and concentration-dependent manner. When given according to the PRISM-PLUS regimen of 0.4 mcg/kg/min over 30 minutes followed by a 0.1 mcg/kg/min maintenance infusion, >90% inhibition of platelet aggregation is attained by the end of the 30-minute infusion. When given according to the recommended regimen of 25 mcg/kg followed by a 0.15 mcg/kg/min maintenance infusion, >90% inhibition of platelet aggregation is attained within 10 minutes. Platelet aggregation inhibition is reversible following cessation of the infusion of AGGRASTAT.

11 DESCRIPTION AGGRASTAT contains tirofiban hydrochloride, a non-peptide antagonist of the platelet GP IIb/IIIa receptor, which inhibits platelet aggregation. Tirofiban hydrochloride monohydrate is chemically described as N- (butylsulfonyl)- O -[4-(4-piperidinyl)butyl]-L-tyrosine monohydrochloride monohydrate. Its molecular formula is C 22 H 36 N 2 O 5 S•HCl•H 2 O and its structural formula is: Tirofiban hydrochloride monohydrate is a white to off-white, non-hygroscopic, free-flowing powder, with a molecular weight of 495.08. It is very slightly soluble in water. AGGRASTAT Injection Premixed is supplied as a sterile solution in water for injection, for intravenous use. The pH of the solution ranges from 5.5 to 6.5 adjusted with hydrochloric acid and/or sodium hydroxide. Each 100 mL of the premixed, isosmotic intravenous injection contains 5.618 mg tirofiban hydrochloride monohydrate equivalent to 5 mg tirofiban (50 mcg/mL) and the following inactive ingredients: 0.9 g sodium chloride, 54 mg sodium citrate dihydrate, and 3.2 mg citric acid anhydrous. Each 250 mL of the premixed, isosmotic intravenous injection contains 14.045 mg tirofiban hydrochloride monohydrate equivalent to 12.5 mg tirofiban (50 mcg/mL) and the following inactive ingredients: 2.25 g sodium chloride, 135 mg sodium citrate dihydrate, and 8 mg citric acid anhydrous. AGGRASTAT Injection Premixed Bolus Vial is supplied as a sterile, isosmotic, concentrated solution for intravenous bolus injection, in 15 mL vials. No dilution is required. Each 15 mL of the premixed, isosmotic intravenous injection bolus vial contains 4.215 mg of tirofiban hydrochloride monohydrate equivalent to 3.75 mg of tirofiban and the following inactive ingredients: 120 mg sodium chloride, 40.5 mg sodium citrate dihydrate, and 2.4 mg citric acid anhydrous and water for injection. structure

10 OVERDOSAGE In clinical trials, inadvertent overdosage with AGGRASTAT occurred in doses up to 2 times the recommended dose for initial infusion doses. Inadvertent overdosage occurred in doses up to 9.8 times the 0.15 mcg/kg/min maintenance infusion rate. The most frequently reported manifestation of overdosage was bleeding, primarily minor mucocutaneous bleeding events and minor bleeding at the sites of cardiac catheterization [see Warnings and Precautions ( 5.1 )]. Overdosage of AGGRASTAT should be treated by assessment of the patient’s clinical condition and cessation or adjustment of the drug infusion as appropriate. AGGRASTAT can be removed by hemodialysis.

16 HOW SUPPLIED/STORAGE AND HANDLING AGGRASTAT is supplied as a clear, non-preserved, colorless, isosmotic, sterile premixed solution with sodium chloride for tonicity adjustment. Table 8 AGGRASTAT Product Details Strength Total Amount Packaging NDC # 50 mcg/mL 12.5 mg/250 mL bag 25208-002-02 50 mcg/mL 5 mg/100 mL bag 25208-002-01 250 mcg/mL 3.75 mg/15 mL bolus vial 25208-001-04 FOR INTRAVENOUS USE ONLY Store AGGRASTAT at controlled room temperature, 25°C (77°F) with excursions permitted between 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Do not freeze. Protect from light during storage.