telet 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)] .

ion instructions 1. 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 an iv pump. 2. immediately following the bolus dose administration, administer the maintenance infusion from the 250 ml premixed bag via an iv pump. 3. discard any unused portion left in the bag. the recommended bolus volume using 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 250 ml premixed bags can be calculated using the following equation: example calculation of infusion rate for 60 kg patient with crcl > 60 ml/min using the 250 ml premixed bag: 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. tirofiban-spl-fig-1 tirofiban-spl-fig-2 tirofiban-spl-fig-3 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: tirofiban-spl-fig-4.jpg

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 prism-plus (nste-acs) bleeding (timi criteria)‡ § tirofiban hydrochloride injection * + heparin (n=773) heparin alone (n=797) major bleeding 1.4% 0.8% minor bleeding 10.5% 8.0% transfusions 4.0% 2.8% * 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. table 3 timi major bleeding associated with percutaneous procedures in prism-plus tirofiban hydrochloride injection + heparin heparin alone n % n % prior to procedures 773 0.3 797 0.1 following angiography 697 1.3 708 0.7 following ptca 239 2.5 236 2.2 the incidence rates of timi major bleeding in patients undergoing coronary artery bypass graft surgery (cabg) in prism-plus within one day of discontinuation of tirofiban hydrochloride injection were 17% on tirofiban hydrochloride injection plus heparin (n=29) and 35% on heparin alone (n=31). recommended ("high-dose bolus") regimen rates of major bleeds (including any intracranial, intraocular or retroperitoneal hemorrhage, clinically overt signs of hemorrhage associated with a drop in hemoglobin of > 3 g/dl or any drop in hemoglobin by 4g/dl, bleeding requiring transfusion of ≥ 2u blood products, bleeding directly resulting in death within 7 days or hemodynamic compromise requiring intervention) were consistent with the rates observed in subjects administered the prism-plus regimen of tirofiban hydrochloride injection. there was a trend toward greater bleeding in st segment elevation myocardial infarction (stemi) patients treated with fibrinolytics prior to administration of tirofiban hydrochloride injection using the recommended regimen during rescue pci. non-bleeding the incidences of non-bleeding adverse events that occurred at an incidence of > 1% and numerically higher than control, regardless of drug relationship, are shown below: table 4 non-bleeding adverse reactions in prism-plus tirofiban hydrochloride injection + heparin (n=1953) % heparin alone (n=1887) % body as a whole edema/swelling 2 1 pain, pelvic 6 5 reaction, vasovagal 2 1 cardiovascular system bradycardia 4 3 dissection, coronary artery 5 4 musculoskeletal system pain, leg 3 2 nervous system/psychiatric dizziness 3 2 skin and skin appendage sweating 2 1 thrombocytopenia patients treated with tirofiban hydrochloride injection plus heparin, were more likely to experience decreases in platelet counts than were those on heparin alone. these decreases were reversible upon discontinuation of tirofiban hydrochloride injection. the percentage of patients with a decrease of platelets to < 90,000/mm 3 was 1.5%, compared with 0.6% in the patients who received heparin alone. the percentage of patients with a decrease of platelets to < 50,000/mm 3 was 0.3%, compared with 0.1% of the patients who received heparin alone. 6.2 post-marketing experience the following additional adverse reactions have been identified during post-approval use of tirofiban hydrochloride injection. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the drug exposure. hypersensitivity: severe allergic reactions including anaphylactic reactions have occurred during the first day of tirofiban hydrochloride injection infusion, during initial treatment, and during readministration of tirofiban hydrochloride injection. some cases have been associated with severe thrombocytopenia (platelet counts < 10,000/mm 3 ). no information is available on the formation of antibodies to tirofiban.

round 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* 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 *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. 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.

espectively. 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* 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 *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.

emonstrated 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.

nts requiring hemodialysis [see dosage and administration (2.3)]. tirofiban is removed by hemodialysis.

ial thromoplastin time (aptt) of approximately 2 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 injection and heparin for 12-24 hours after the procedure). tirofiban hydrochloride injection and heparin could be continued for up to 108 hours. exclusions included contraindications to anticoagulation , decompensated heart failure, platelet count < 150,000/mm 3 , 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 injection for 71 hours. a third group of patients was initially randomized to tirofiban hydrochloride injection 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 a composite of refractory ischemia, new mi and death within 7 days. there was a 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 a patient experiences multiple component events only one event counts towards the composite). table 6 primary outcomes at 7 days in prism-plus endpoint tirofiban hydrochloride injection + heparin(n=773) heparin(n=797) risk reduction p-value death, new mi, and refractory ischemia at 7 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 7 days was maintained over time. the risk reduction in the composite endpoint at 30 days and 6 months is shown in the kaplan-meier curve below. figure 1. time to first event of death, new mi, or refractory ischemia in prism-plus an 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 injection (95% confidence limits for relative risk of 0.61-1.74) than do men (0.43-0.89) (p=0.11). this difference may be a true treatment difference, the effect of other differences in these subgroups, or a 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 injection was continued for 12-24 hours (average 15 hours) after angioplasty/atherectomy. the effects of tirofiban hydrochloride injection 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, a randomized, parallel, double-blind study, 3232 patients with nste-acs intended to be managed without coronary intervention were randomized to tirofiban hydrochloride injection (initial dose of 0.6 mcg/kg/min for 30 minutes followed by 0.15 mcg/kg/min for 47.5 hours) or heparin (5000-unit intravenous bolus followed by an infusion of 1000 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 7 primary outcomes in prism – cardiac ischemia events composite endpoint (death, mi, or refractory ischemia) tirofiban hydrochloride injection (n=1616) heparin (n=1616) risk reduction p-value 2 days (end of drug infusion) 3.8% 5.6% 33% 0.015 7 days 10.3% 11.3% 10% 0.33 in the prism study, no adverse effect of tirofiban hydrochloride injection on mortality at either 7 or 30 days was detected. this result is different from that in the prism-plus study, where the arm that included tirofiban hydrochloride injection without heparin (n=345) was dropped at an interim analysis by the data safety monitoring committee for increased mortality at 7 days. tirofiban-spl-fig-3