Tirofiban Hydrochloride

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 )

Tirofiban Hydrochloride Injection is a clear, non-preserved, colorless, isosmotic, sterile premixed injection with sodium chloride for tonicity adjustment available in the following presentations: Table 1 Tirofiban Hydrochloride Injection Strength and Packaging Strength Volume – Packaging 50 mcg/mL 250 mL – bag 50 mcg/mL 100 mL – bag 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 )

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

Tirofiban Hydrochloride Injection can cause serious bleeding. If bleeding cannot be controlled discontinue Tirofiban Hydrochloride Injection. ( 5.1 ) Thrombocytopenia: Discontinue Tirofiban Hydrochloride Injection and heparin. ( 5.2 )

5.1 General Risk of Bleeding Bleeding is the most common complication encountered during therapy with Tirofiban Hydrochloride Injection. Most bleeding associated with Tirofiban Hydrochloride Injection occurs at the arterial access site for cardiac catheterization. Minimize the use of traumatic or potentially traumatic procedures such as arterial and venous punctures, intramuscular injections, nasotracheal intubation, etc. Concomitant use of fibrinolytics, anticoagulants and antiplatelet drugs increases the risk of bleeding.

5.2 Thrombocytopenia Profound thrombocytopenia has been reported with Tirofiban Hydrochloride Injection. Monitor platelet counts beginning about 6 hours after treatment initiation and daily thereafter. If the platelet count decreases to < 90,000/mm 3 , monitor platelet counts to exclude pseudothrombocytopenia. If thrombocytopenia is confirmed, discontinue Tirofiban Hydrochloride Injection and heparin. Previous exposure to a glycoprotein (GP) IIb/IIIa receptor antagonist may increase the risk of developing thrombocytopenia [see Adverse Reactions ( 6.1 )] .

Bleeding is the most commonly reported adverse reaction. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lambda Therapeutics Limited at 1-855-642-2594 or the 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. The incidence rates of TIMI major bleeding in patients undergoing percutaneous procedures in PRISM-PLUS are shown below. PRISM-PLUS (NSTE-ACS) Bleeding (TIMI Criteria)‡ § Tirofiban Hydrochloride * + Heparin (N=773) Heparin alone (N=797) Major Bleeding 1.4% 0.8% Minor Bleeding 10.5% 8.0% Transfusions 4.0% 2.8% Table 3 TIMI Major Bleeding Associated with Percutaneous Procedures in PRISM-PLUS Tirofiban Hydrochloride + 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 ≥ 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 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 + H eparin (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 re-administration 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 hydrochloride

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 )

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 *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. Type of Study Species Dose/Exposure* 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 Tirofiban Hydrochloride Injection and any potential adverse effects on the breastfed child from Tirofiban Hydrochloride Injection 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 Tirofiban Hydrochloride Injection, 43% were 65 years and over, while 12% were 75 years and over. With respect to efficacy, the effect of Tirofiban Hydrochloride Injection in the elderly (≥ 65 years) appeared similar to that seen in younger patients (< 65 years). Elderly patients receiving Tirofiban Hydrochloride Injection 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 Tirofiban Hydrochloride Injection 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 Tirofiban Hydrochloride. Reduce the dosage of Tirofiban Hydrochloride Injection in patients with severe renal insufficiency [see Dosage and Administration ( 2.3 ) and Clinical Pharmacology ( 12.3 )] . Safety and efficacy of Tirofiban Hydrochloride Injection has not been established in patients on hemodialysis.

Tirofiban Hydrochloride 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, Tirofiban Hydrochloride 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 Tirofiban Hydrochloride.