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 )

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

Tirofiban hydrochloride injection 12.5 mg tirofiban per 250 mL (50 mcg per mL) is a clear, non-preserved, colorless, isosmotic, sterile premixed injection with sodium chloride for tonicity adjustment. Injection: 12.5 mg per 250 mL (50 mcg per mL) in 250 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 )

5 WARNINGS AND PRECAUTIONS 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 )] .

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 )

In clinical trials, inadvertent overdosage with tirofiban hydrochloride injection 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 tirofiban hydrochloride injection should be treated by assessment of the patient's clinical condition and cessation or adjustment of the drug infusion as appropriate. Tirofiban hydrochloride injection can be removed by hemodialysis.

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 to 4% and 15 to 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 injection. 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.

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 to 4% and 15 to 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

Safety and effectiveness in pediatric patients have not been established.

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 )] .

Tirofiban hydrochloride injection 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. Tirofiban hydrochloride injection 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 250 mL of the premixed, isosmotic intravenous injection contains 14.045 mg tirofiban hydrochloride monohydrate equivalent to 12.5 mg tirofiban (50 mcg per mL) and the following inactive ingredients: 2.25 g sodium chloride, 135 mg sodium citrate dihydrate, and 8 mg citric acid anhydrous. Structural Formula

12.1 Mechanism of Action Tirofiban hydrochloride injection 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 injection 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 injection.

12.2 Pharmacodynamics Tirofiban hydrochloride injection inhibits platelet function, as demonstrated by its ability to inhibit ex vivo adenosine phosphate (ADP)-induced platelet aggregation and prolong bleeding time in healthy subjects and patients with coronary artery disease. The time course of inhibition parallels the plasma concentration profile of the drug. Following discontinuation of an infusion of tirofiban hydrochloride injection 0.10 mcg/kg/min, ex vivo platelet aggregation returns to near baseline in 4 to 8 hours in approximately 90% of patients with coronary artery disease. The addition of heparin to this regimen does not significantly alter the percentage of subjects with > 70% inhibition of platelet aggregation (IPA), but does increase the average bleeding time, as well as the number of patients with bleeding times prolonged to > 30 minutes. Similar platelet aggregation recovery rates are observed following discontinuation of a 0.15 mcg/kg/min infusion.

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.

Tirofiban hydrochloride injection 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 injection 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 injection.

Tirofiban hydrochloride injection inhibits platelet function, as demonstrated by its ability to inhibit ex vivo adenosine phosphate (ADP)-induced platelet aggregation and prolong bleeding time in healthy subjects and patients with coronary artery disease. The time course of inhibition parallels the plasma concentration profile of the drug. Following discontinuation of an infusion of tirofiban hydrochloride injection 0.10 mcg/kg/min, ex vivo platelet aggregation returns to near baseline in 4 to 8 hours in approximately 90% of patients with coronary artery disease. The addition of heparin to this regimen does not significantly alter the percentage of subjects with > 70% inhibition of platelet aggregation (IPA), but does increase the average bleeding time, as well as the number of patients with bleeding times prolonged to > 30 minutes. Similar platelet aggregation recovery rates are observed following discontinuation of a 0.15 mcg/kg/min infusion.

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.

, Mutagenesis, Impairment of Fertility The carcinogenic potential of tirofiban hydrochloride injection has not been evaluated. Tirofiban HCl was negative in the in vitro microbial mutagenesis and V-79 mammalian cell mutagenesis assays. In addition, there was no evidence of direct genotoxicity in the in vitro alkaline elution and in vitro chromosomal aberration assays. There was no induction of chromosomal aberrations in bone marrow cells of male mice after the administration of intravenous doses up to 5 mg tirofiban/kg (about 3 times the maximum recommended daily human dose when compared on a body surface area basis). Fertility and reproductive performance were not affected in studies with male and female rats given intravenous doses of tirofiban up to 5 mg/kg/day (about 5 times the maximum recommended daily human dose when compared on a body surface area basis).

17 PATIENT COUNSELING INFORMATION Advise patients to watch closely for any signs of bleeding or bruising and to report these to their health care provider when they occur. Advise patients to discuss with their health care provider their use of any other medications, including over-the-counter or herbal products prior to tirofiban hydrochloride injection use. SAGENT ® Mfd. for SAGENT Pharmaceuticals Schaumburg, IL 60195 (USA) Made in India ©2024 Sagent Pharmaceuticals March 2024 SAGENT Pharmaceuticals ®

Storage Conditions Store at 25°C (77°F); excursions permitted between 15° and 30°C (59° and 86°F). [See USP Controlled Room Temperature.] Do not freeze. Protect from light during storage. Discard unused portion. Sterile, Nonpyrogenic, Preservative-free, PVC-free. The container closure is not made with natural rubber latex.