NDC 68083-145 Tirofiban Hydrochloride

Tirofiban

NDC Product Code 68083-145

NDC 68083-145-01

Package Description: 1 CONTAINER in 1 CARTON > 250 mL in 1 CONTAINER

NDC Product Information

Tirofiban Hydrochloride with NDC 68083-145 is a a human prescription drug product labeled by Gland Pharma Limited. The generic name of Tirofiban Hydrochloride is tirofiban. The product's dosage form is injection, solution and is administered via intravenous form.

Labeler Name: Gland Pharma Limited

Dosage Form: Injection, Solution - A liquid preparation containing one or more drug substances dissolved in a suitable solvent or mixture of mutually miscible solvents that is suitable for injection.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Tirofiban Hydrochloride Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • TIROFIBAN HYDROCHLORIDE 12.5 mg/250mL

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • ANHYDROUS CITRIC ACID (UNII: XF417D3PSL)
  • SODIUM CHLORIDE (UNII: 451W47IQ8X)
  • TRISODIUM CITRATE DIHYDRATE (UNII: B22547B95K)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intravenous - Administration within or into a vein or veins.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Decreased Platelet Aggregation - [PE] (Physiologic Effect)
  • Platelet Aggregation Inhibitor - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Gland Pharma Limited
Labeler Code: 68083
FDA Application Number: ANDA206888 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 04-15-2021 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2022 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Tirofiban Hydrochloride Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

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).

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 Instructions1. 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 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 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:

3 Dosage Forms And Strengths

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

4 Contraindications

  • 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)].

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, oral 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/mm3, 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)].

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. BleedingPRISM-PLUS RegimenThe 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 Bleeding1.4%0.8%Minor Bleeding10.5%8.0%Transfusions4.0%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 + HeparinHeparin alone N%N%Prior to Procedures 773 0.37970.1Following Angiography 6971.37080.7Following PTCA 2392.52362.2 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") RegimenRates 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-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 4 Non-bleeding Adverse Reactions in PRISM-PLUS                  Tirofiban Hydrochloride Injection + Heparin (N=1953)%Heparin alone(N=1887)%Body as a WholeEdema/swelling21Pain, pelvic65Reaction, vasovagal21Cardiovascular SystemBradycardia43Dissection, coronary artery54Musculoskeletal SystemPain, leg32Nervous System/PsychiatricDizziness32Skin and Skin AppendageSweating21Thrombocytopenia  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/mm3 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/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 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/mm3). No information is available on the formation of antibodies to tirofiban.

7 Drug Interactions

Concomitant use of fibrinolytics, anticoagulants and antiplatelet drugs increases the risk of bleeding.

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 women 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 riskMyocardial infarction is a 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 5 Developmental Toxicity StudiesType 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 202) Developmental Toxicity Rat (N=66) 1, 2, 5 mg/kg/day IV (N=22 per group)Once daily from GD 6 through GD 203) Developmental Toxicity with Postweaning EvaluationRat (N=66) 1, 2, 5 mg/kg/day IV (N=22 per group) Once daily from GD 6 through LD 204) Range-finding (non-pregnant)Rabbit (N=21) 1, 2, 5 mg/kg/day IV(N=7 per group) Once daily for 14 days5) Range-finding (pregnant) Rabbit (N=30)1, 2, 5 mg/kg/day IV (N=10 per group) Once daily from GD 7 through GD 206) 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 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 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.

10 Overdosage

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.

11 Description

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 C22H36N2O5S•HCl•H2O 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/mL) and the following inactive ingredients: 2.25 g sodium chloride, 135 mg sodium citrate dihydrate, and 8 mg citric acid anhydrous.

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 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.

13.1 Carcinogenesis, 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).

14 Clinical Studies

Two large-scale clinical studies established the efficacy of tirofiban hydrochloride injection in the treatment of patients with NSTE-ACS (unstable angina/non-ST elevation MI). The two studies examined tirofiban hydrochloride injection alone and added to heparin, prior to and after percutaneous coronary revascularization (if indicated) (PRISM-PLUS) and in comparison to heparin in a 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 injection (30 minute initial infusion of 0.4 mcg/kg/min followed by a maintenance infusion of 0.10 mcg/kg /min) in combination with heparin (bolus of 5,000 U followed by an infusion of 1,000 U/h titrated to maintain an activated partial 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/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 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-PLUSEndpointTirofiban Hydrochloride Injection  + Heparin(N=773)Heparin(N=797)Risk Reductionp-valueDeath, new MI, and refractory ischemia at 7 days12.9%17.9%32%0.004Death1.9 %1.9%------MI3.9%7.0%47%0.006Refractory Ischemia9.3%12.7%30%0.023The 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-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 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 EventsComposite Endpoint (death, MI, or refractory ischemia)Tirofiban Hydrochloride Injection (N=1616)Heparin (N=1616)Risk Reductionp-value2 Days (end of drug infusion)3.8%5.6%33%0.0157 Days10.3%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.

16 How Supplied/Storage And Handling

Tirofiban hydrochloride injection 12.5 mg/250 mL (50 mcg/mL) is supplied as a clear, non-preserved, colorless, isosmotic, sterile premixed solution with sodium chloride for tonicity adjustment and is supplied as follows:NDC 68083-145-01, 250 mL single-dose bag  FOR INTRAVENOUS USE ONLYStore tirofiban hydrochloride injection at 25°C (77°F) with excursions permitted between 15-30°C (59-86°F) (see USP Controlled Room Temperature). Do not freeze. Protect from light during storage.

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.

* Please review the disclaimer below.