ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Bleeding is the most commonly reported adverse reaction. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Eugia US LLC at 1-866-850-2876 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 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 in combination with heparin and 2002 patients received tirofiban hydrochloride alone for about 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 0.15 mcg/kg/min maintenance infusion), tirofiban hydrochloride 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.BleedingPRISM-PLUS Regimen The incidences of major and minor bleeding using the TIMI criteria in the PRISM-PLUS study are shown below.Table 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 known site, spontaneous gross hematuria, hematemesis or hemoptysis.Bleeding(TIMI Criteria) PRISM-PLUS (NSTE-ACS)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% The incidence rates of TIMI major bleeding in patients undergoing percutaneous procedures in PRISM- PLUS are shown below. Table TIMI Major Bleeding Associated with Percutaneous Procedures in PRISM-PLUS Tirofiban Hydrochloride +HeparinHeparin aloneN 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 were 17% on tirofiban hydrochloride plus heparin (N=29) and 35% on heparin alone (N=31).Recommended (High-Dose Bolus) RegimenRates of major bleeds (including any intracranial, intraocular or retroperitoneal hemorrhage, clinically overt signs of hemorrhage associated with drop in hemoglobin of 3 g/dL or any drop in hemoglobin by g/dL, bleeding requiring transfusion of >= U blood products, bleeding directly resulting in death within days or hemodynamic compromise requiring intervention) were consistent with the rates observed in subjects administered the PRISM-PLUS regimen of tirofiban hydrochloride. There was trend toward greater bleeding in ST segment elevation myocardial infarction (STEMI) patients treated with fibrinolytics prior to administration of tirofiban hydrochloride using the recommended regimen during rescue PCI.Non-BleedingThe 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 Non-bleeding Adverse Reactions in PRISM-PLUS Tirofiban Hydrochloride Heparin (N=1953)%Heparin alone(N=1887)% Body as Whole Edema/swelling 1 Pain, pelvic 5 Reaction, vasovagal 1 Cardiovascular System Bradycardia 3 Dissection, coronary artery 4 Musculoskeletal System Pain, leg 2 Nervous System/Psychiatric Dizziness 2 Skin and Skin Appendage Sweating 1 ThrombocytopeniaPatients treated with tirofiban hydrochloride 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. The percentage of patients with decrease of platelets to 90,000/mm3 was 1.5%, compared with 0.6% in the patients who received heparin alone. The percentage of patients with decrease of platelets to 50,000/mm3 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. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to the drug exposure.Hypersensitivity: Severe allergic reactions including anaphylactic reactions have occurred during the first day of tirofiban hydrochloride infusion, during initial treatment, and during readministration of tirofiban hydrochloride. Some cases have been associated with severe thrombocytopenia (platelet counts 10,000/mm3). No information is available on the formation of antibodies to tirofiban.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Tirofiban hydrochloride injection is clear, non-preserved, colorless, isosmotic, sterile premixed injection with sodium chloride for tonicity adjustment available in the following presentations: Table Tirofiban Hydrochloride Injection Strength and Packaging StrengthVolume Packaging5 mg/100 mL (50 mcg/mL) 100 mL bag 12.5 mg/250 mL (50 mcg/mL) 250 mL bag Injection: mg/100 mL (50 mcg/mL) in 100 mL bag. (3)Injection: 12.5 mg/250 mL (50 mcg/mL) in 250 mL bag. (3). Injection: mg/100 mL (50 mcg/mL) in 100 mL bag. (3). Injection: 12.5 mg/250 mL (50 mcg/mL) in 250 mL bag. (3).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. The carcinogenic potential of tirofiban hydrochloride 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 mg tirofiban/kg (about times the maximum recommended daily human dose when compared on 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 mg/kg/day (about times the maximum recommended daily human dose when compared on body surface area basis).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Tirofiban hydrochloride is 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 dose- and concentration-dependent manner.When given according to the PRISM-PLUS regimen of 0.4 mcg/kg/min over 30 minutes followed by 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 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.. 12.2 Pharmacodynamics. Tirofiban hydrochloride 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 0.10 mcg/kg/min, ex vivo platelet aggregation returns to near baseline in to 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 0.15 mcg/kg/min infusion.. 12.3 Pharmacokinetics. Tirofiban has half-life of approximately 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 InsufficiencyPlasma 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Two large-scale clinical studies established the efficacy of tirofiban hydrochloride in the treatment of patients with NSTE-ACS (unstable angina/non-ST elevation MI). The two studies examined tirofiban hydrochloride alone and added to heparin, prior to and after percutaneous coronary revascularization (if indicated) (PRISM-PLUS) and in comparison to heparin in similar population (PRISM). These trials are discussed in detail below. PRISM-PLUS (Platelet Receptor Inhibition for Ischemic Syndrome Management -- Patients Limited by Unstable Signs and Symptoms)In the double-blind PRISM-PLUS trial, 1570 patients with documented NSTE-ACS within 12 hours of entry into the study were randomized to tirofiban hydrochloride (30 minute initial infusion of 0.4 mcg/kg/min followed by maintenance infusion of 0.10 mcg/kg/min) in combination with heparin (bolus of 5,000 followed by an infusion of 1,000 U/h titrated to maintain an activated partial thromboplastin time (APTT) of approximately times control) or to heparin alone. All patients received concomitant aspirin unless contraindicated. Patients who were medically managed or who underwent revascularization procedures were studied. Patients underwent 48 hours of medical stabilization on study drug therapy, and they were to undergo angiography before 96 hours (and, if indicated, angioplasty/atherectomy, while continuing on tirofiban hydrochloride and heparin for 12 to 24 hours after the procedure). Tirofiban hydrochloride and heparin could be continued for up to 108 hours. Exclusions included contraindications to anticoagulation, decompensated heart failure, platelet count 150,000/mm3, and serum creatinine 2.5 mg/dL. The mean age of the population was 63 years; 32% of patients were female and approximately half of the population presented with non-ST elevation myocardial infarction. On average, patients received tirofiban hydrochloride for 71 hours.A third group of patients was initially randomized to tirofiban hydrochloride alone (no heparin). This arm was stopped when the group was found, at an interim look, to have greater mortality than the other two groups.The primary endpoint of the study was composite of refractory ischemia, new MI and death within days. There was 32% risk reduction in the overall composite primary endpoint. The components of the composite were examined separately and the results are shown in Table 6. Note that the sum of the individual components may be greater than the composite (if patient experiences multiple component events only one event counts towards the composite). Table Primary Outcomes at days in PRISM-PLUS EndpointTirofiban hydrochloride Heparin(n=773)Heparin (n=797)Risk Reductionp-valueDeath, new MI, andrefractory ischemia at days 12.9% 17.9% 32% 0.004 Death 1.9% 1.9% --- --- MI 3.9% 7.0% 47% 0.006 Refractory Ischemia 9.3% 12.7% 30% 0.023 The benefit seen at days was maintained over time. The risk reduction in the composite endpoint at 30 days and months is shown in the Kaplan-Meier curve below. Figure 1. Time to first event of death, new MI, or refractory ischemia in PRISM-PLUSAn analysis of the results by sex suggests that women who are medically managed or who undergo subsequent percutaneous transluminal coronary angioplasty (PTCA)/atherectomy may receive less benefit from tirofiban hydrochloride (95% confidence limits for relative risk of 0.61 to 1.74) than do men (0.43 to 0.89) (p=0.11). This difference may be true treatment difference, the effect of other differences in these subgroups, or chance occurrence.Approximately 90% of patients in the PRISM-PLUS study underwent coronary angiography and 30% underwent angioplasty/atherectomy during the first 30 days of the study. The majority of these patients continued on study drug throughout these procedures. Tirofiban hydrochloride was continued for 12 to 24 hours (average 15 hours) after angioplasty/atherectomy. The effects of tirofiban hydrochloride at Day 30 did not appear to differ among sub-populations that did or did not receive PTCA or CABG, both prior to and after the procedure.PRISM (Platelet Receptor Inhibition for Ischemic Syndrome Management)In the PRISM study, randomized, parallel, double-blind study, 3232 patients with NSTE-ACS intended to be managed without coronary intervention were randomized to tirofiban hydrochloride (initial dose of 0.6 mcg/kg/min for 30 minutes followed by 0.15 mcg/kg/min for 47.5 hours) or heparin (5,000-unit intravenous bolus followed by an infusion of 1,000 U/h for 48 hours). The mean age of the population was 62 years; 32% of the population was female and 25% had non-ST elevation MI on presentation. Thirty percent had no ECG evidence of cardiac ischemia. Exclusion criteria were similar to PRISM-PLUS. The primary endpoint was the composite endpoint of refractory ischemia, MI or death at the end of the 48-hour drug infusion. The results are shown in Table 7.Table Primary Outcomes in PRISM Cardiac Ischemia Events Composite Endpoint (death, MI, orrefractory ischemia)Tirofiban Hydrochloride (n=1616)Heparin (n=1616)Risk Reductionp-value2 Days (end of drug infusion) 3.8% 5.6% 33% 0.015 Days 10.3% 11.3% 10% 0.33 In the PRISM study, no adverse effect of tirofiban hydrochloride on mortality at either or 30 days was detected. This result is different from that in the PRISM-PLUS study, where the arm that included tirofiban hydrochloride without heparin (N=345) was dropped at an interim analysis by the Data Safety Monitoring Committee for increased mortality at days.. tirofiban-figure-1.

CONTRAINDICATIONS SECTION.

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

DESCRIPTION SECTION.

11 DESCRIPTION. Tirofiban hydrochloride injection contains tirofiban hydrochloride, 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 hydrochloride monohydrate.Its molecular formula is C22H36N2O5SoHCloH2O and its structural formula is: Tirofiban hydrochloride monohydrate is off-white, non-hygroscopic, free-flowing powder, with molecular weight of 495.07. It is very slightly soluble in water. Tirofiban hydrochloride injection premixed is supplied as 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 mg tirofiban (50 mcg/mL) and the following inactive ingredients: 0.9 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 sodium chloride, 135 mg sodium citrate dihydrate, and mg citric acid anhydrous.. chemical-structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Administer intravenously 25 mcg/kg within 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 minutes and then 0.075 mcg/kg/min. (2). Administer intravenously 25 mcg/kg within 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 minutes and then 0.075 mcg/kg/min. (2). 2.1 Recommended Dosage. The recommended dosage is 25 mcg/kg administered intravenously within 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 InstructionsThe bolus dose of tirofiban hydrochloride injection may be administered from the 100 mL or 250 mL premixed bag. Do not dilute. Administer the bolus dose within minutes via IV pump.Immediately following the bolus dose administration, administer the maintenance infusion from the 100 mL premixed bag or the 250 mL premixed bag via an IV pump.Discard any unused portion left in the bag.The recommended bolus volume using the 100 mL premixed bag or 250 mL premixed bag can be calculated using the following equation: Bolus Volume 25 mcg/kg body weight (kg) (mL) 50 mcg/mL 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: Infusion Rate for CrCl 60 mL/min 0.15 mcg/kg/min body weight (kg) 60 min/h (mL/h) 50 mcg/mL 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: Infusion Rate for CrCl 60 mL/min 0.15 mcg/kg/min 60 kg 60 min/h 10.8 mL/h (mL/h) 50 mcg/mLDrug CompatibilitiesTirofiban 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 the bag with syringe.. The bolus dose of tirofiban hydrochloride injection may be administered from the 100 mL or 250 mL premixed bag. Do not dilute. Administer the bolus dose within minutes via IV pump.. Immediately following the bolus dose administration, administer the maintenance infusion from the 100 mL premixed bag or the 250 mL premixed bag via an IV pump.. Discard any unused portion left in the bag.. 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 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 bag or 250 mL premixed bag can be calculated using the following equation: Infusion Rate for CrCl <= 60 mL/min 0.075 mcg/kg/min body weight (kg) 60 min/h (mL/h) 50 mcg/mL.

DRUG INTERACTIONS SECTION.

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). Coadministration of fibrinolytics, anticoagulants and antiplatelet agents, increases the risk of bleeding. (7).

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the total number of patients in controlled clinical studies of tirofiban hydrochloride, 43% were 65 years and over, while 12% were 75 years and over. With respect to efficacy, the effect of tirofiban hydrochloride in the elderly (>= 65 years) appeared similar to that seen in younger patients (< 65 years). Elderly patients receiving tirofiban hydrochloride with heparin or heparin alone had higher incidence of bleeding complications than did younger patients, but the incremental risk of bleeding in patients treated with tirofiban hydrochloride 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)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Tirofiban hydrochloride injection is supplied as clear, non-preserved, colorless, isosmotic, sterile premixed solution with sodium chloride for tonicity adjustment. Table Tirofiban Hydrochloride Injection Product Details StrengthTotal AmountPackagingNDC 50 mcg/mL mg/100 mL bag 55150-429-01 50 mcg/mL 12.5 mg/250 mL bag 55150-430-01 FOR INTRAVENOUS USE ONLYStore tirofiban hydrochloride injection at controlled room temperature, 25C (77F) with excursions permitted between 15 to 30C (59 to 86F) [see USP Controlled Room Temperature]. Do not freeze. Protect from light during storage.Discard Unused Portion.

INDICATIONS & USAGE SECTION.

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 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).

INFORMATION FOR PATIENTS SECTION.

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 use. Distributed by: Eugia US LLC 279 Princeton-Hightstown Rd. E. Windsor, NJ 08520 Manufactured by: Eugia Pharma Specialities Limited Hyderabad 500032 India.

LABOR & DELIVERY SECTION.

8.2 Lactation. Risk SummaryThere 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 mothers clinical need for tirofiban hydrochloride and any potential adverse effects on the breastfed child from tirofiban hydrochloride or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Tirofiban hydrochloride is 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 dose- and concentration-dependent manner.When given according to the PRISM-PLUS regimen of 0.4 mcg/kg/min over 30 minutes followed by 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 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. The carcinogenic potential of tirofiban hydrochloride 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 mg tirofiban/kg (about times the maximum recommended daily human dose when compared on 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 mg/kg/day (about times the maximum recommended daily human dose when compared on body surface area basis).

OVERDOSAGE SECTION.

10 OVERDOSAGE. In clinical trials, inadvertent overdosage with tirofiban hydrochloride occurred in doses up to 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 should be treated by assessment of the patients clinical condition and cessation or adjustment of the drug infusion as appropriate.Tirofiban hydrochloride can be removed by hemodialysis.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL mg per 100 mL (50 mcg/mL) Infusion Bag Label. Recommended for Use With Calibrated Infusion Device Rx only NDC 55150-429-01Tirofiban Hydrochloride Injection mg per 100 mL (50 mcg/mL) For Intravenous Infusion Premixed Iso-osmotic Sterile, Nonpyrogenic 100 mL Single-Dose Container. PACKAGE LABEL.PRINCIPAL DISPLAY PANEL mg per 100 mL (50 mcg/mL) Infusion Bag Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness in pediatric patients have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Tirofiban hydrochloride 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 0.10 mcg/kg/min, ex vivo platelet aggregation returns to near baseline in to 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 0.15 mcg/kg/min infusion.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Tirofiban has half-life of approximately 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 InsufficiencyPlasma 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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryWhile 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 mg/kg/day (about and 13 times the maximum recommended daily human dose for rat and rabbit, respectively, when compared on 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 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 to 4% and 15 to 20%, respectively.Clinical ConsiderationsDisease-associated maternal and/or embryo/fetal riskMyocardial infarction is medical emergency in pregnancy which can be fatal to the pregnant woman and fetus if left untreated.DataAnimal DataThere was no evidence of maternal or developmental toxicity in any of the studies in Table 5.Table Developmental Toxicity Studies Type of StudySpeciesDose/ExposureDuration/Timing Exposure(1) Range-finding Rat(N=30) 1, 2, mg/kg/day IV(N=10 per group) Once daily from GD6 through LD 20 (2) Developmental Toxicity Rat(N=66) 1, 2, mg/kg/day IV(N=22 per group) Once daily from GD6 through GD 20 (3) Developmental Toxicity with Postweaning Evaluation Rat(N=66) 1, 2, mg/kg/day IV(N=22 per group) Once daily from GD6 through LD 20 (4) Range-finding (non-pregnant) Rabbit(N=21) 1, 2, mg/kg/day IV(N=7 per group) Once daily for 14 days (5) Range-finding (pregnant) Rabbit(N=30) 1, 2, mg/kg/day IV(N=10 per group) Once daily from GD7 through GD 20 (6) Developmental Toxicity Rabbit(N=60) 1, 2, mg/kg/day(N=20 per group) IV Once daily from GD7 through GD 20 mg/kg/day is ~5 and 13 times the maximum recommended daily human dose for rat and rabbit, respectively, when compared on body surface area basis.

SPL UNCLASSIFIED SECTION.

2.1 Recommended Dosage. The recommended dosage is 25 mcg/kg administered intravenously within minutes and then 0.15 mcg/kg/min for up to 18 hours.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Renal Insufficiency: Reduce the dose in patients with severe renal insufficiency. (8.6) Renal Insufficiency: Reduce the dose in patients with severe renal insufficiency. (8.6) 8.1 Pregnancy. Risk SummaryWhile 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 mg/kg/day (about and 13 times the maximum recommended daily human dose for rat and rabbit, respectively, when compared on 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 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 to 4% and 15 to 20%, respectively.Clinical ConsiderationsDisease-associated maternal and/or embryo/fetal riskMyocardial infarction is medical emergency in pregnancy which can be fatal to the pregnant woman and fetus if left untreated.DataAnimal DataThere was no evidence of maternal or developmental toxicity in any of the studies in Table 5.Table Developmental Toxicity Studies Type of StudySpeciesDose/ExposureDuration/Timing Exposure(1) Range-finding Rat(N=30) 1, 2, mg/kg/day IV(N=10 per group) Once daily from GD6 through LD 20 (2) Developmental Toxicity Rat(N=66) 1, 2, mg/kg/day IV(N=22 per group) Once daily from GD6 through GD 20 (3) Developmental Toxicity with Postweaning Evaluation Rat(N=66) 1, 2, mg/kg/day IV(N=22 per group) Once daily from GD6 through LD 20 (4) Range-finding (non-pregnant) Rabbit(N=21) 1, 2, mg/kg/day IV(N=7 per group) Once daily for 14 days (5) Range-finding (pregnant) Rabbit(N=30) 1, 2, mg/kg/day IV(N=10 per group) Once daily from GD7 through GD 20 (6) Developmental Toxicity Rabbit(N=60) 1, 2, mg/kg/day(N=20 per group) IV Once daily from GD7 through GD 20 mg/kg/day is ~5 and 13 times the maximum recommended daily human dose for rat and rabbit, respectively, when compared on body surface area basis. 8.2 Lactation. Risk SummaryThere 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 mothers clinical need for tirofiban hydrochloride and any potential adverse effects on the breastfed child from tirofiban hydrochloride 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, 43% were 65 years and over, while 12% were 75 years and over. With respect to efficacy, the effect of tirofiban hydrochloride in the elderly (>= 65 years) appeared similar to that seen in younger patients (< 65 years). Elderly patients receiving tirofiban hydrochloride with heparin or heparin alone had higher incidence of bleeding complications than did younger patients, but the incremental risk of bleeding in patients treated with tirofiban hydrochloride 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 in patients with severe renal insufficiency [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. Safety and efficacy of tirofiban hydrochloride has not been established in patients on hemodialysis.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Tirofiban hydrochloride can cause serious bleeding. If bleeding cannot be controlled discontinue tirofiban hydrochloride. (5.1) Thrombocytopenia: Discontinue tirofiban hydrochloride and heparin. (5.2) Tirofiban hydrochloride can cause serious bleeding. If bleeding cannot be controlled discontinue tirofiban hydrochloride. (5.1) Thrombocytopenia: Discontinue tirofiban hydrochloride and heparin. (5.2) 5.1 General Risk of Bleeding. Bleeding is the most common complication encountered during therapy with tirofiban hydrochloride. Most bleeding associated with tirofiban hydrochloride 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. Monitor platelet counts beginning about hours after treatment initiation and daily thereafter. If the platelet count decreases to 90,000/mm3, monitor platelet counts to exclude pseudothrombocytopenia. If thrombocytopenia is confirmed, discontinue tirofiban hydrochloride and heparin. Previous exposure to glycoprotein (GP) IIb/IIIa receptor antagonist may increase the risk of developing thrombocytopenia [see Adverse Reactions (6.1)].