Tirofiban Injection Prescribing Information

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 100 mL or the 250 mL premixed bag, first tear off its foil overpouch and remove inner overwrap. 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

1. Withdraw the bolus dose of Tirofiban Hydrochloride Injection from the 100 mL or 250 mL premixed bag into a syringe. Do not dilute. Administer the bolus dose within 5 minutes via a syringe or IV pump.
2. Immediately following the bolus dose administration, administer the maintenance infusion from the 100 mL or 250 mL premixed bag via an IV pump.
3. Discard any unused portion left in the bag.

The recommended bolus volume using the 100 mL or 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 100 mL or 250 mL premixed bag can be calculated using the following equation:

Example calculation of infusion rate for 60 kg patient with CrCl > 60 mL/min using the 100 mL or 250 mL premixed 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 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 100 mL or 250 mL premixed bag can be calculated using the following equation:

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/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.

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.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Of the total number of patients in controlled clinical studies of Tirofiban Hydrochloride Injection, 43% were 65 years and over, while 12% were 75 years and over. With respect to efficacy, the effect of Tirofiban Hydrochloride Injection in the elderly (≥ 65 years) appeared similar to that seen in younger patients (< 65 years). Elderly patients receiving Tirofiban Hydrochloride Injection with heparin or heparin alone had a higher incidence of bleeding complications than did younger patients, but the incremental risk of bleeding in patients treated with Tirofiban Hydrochloride Injection in combination with heparin compared to the risk in patients treated with heparin alone was similar regardless of age. No dose adjustment is recommended for the elderly population [see Dosage and Administration (2)].

8.6 Renal Insufficiency

Patients with moderate to severe renal insufficiency have decreased plasma clearance of Tirofiban Hydrochloride. Reduce the dosage of Tirofiban Hydrochloride Injection in patients with severe renal insufficiency [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

Safety and efficacy of Tirofiban Hydrochloride Injection has not been established in patients on hemodialysis.

12.1 Mechanism of Action

Tirofiban Hydrochloride is a reversible antagonist of fibrinogen binding to the GP IIb/IIIa receptor, the major platelet surface receptor involved in platelet aggregation. When administered intravenously, Tirofiban Hydrochloride inhibits ex vivo platelet aggregation in a dose- and concentration-dependent manner.

When given according to the PRISM-PLUS regimen of 0.4 mcg/kg/min over 30 minutes followed by a 0.1 mcg/kg/min maintenance infusion, > 90% inhibition of platelet aggregation is attained by the end of the 30-minute infusion. When given according to the recommended regimen of 25 mcg/kg followed by a 0.15 mcg/kg/min maintenance infusion, > 90% inhibition of platelet aggregation is attained within 10 minutes. Platelet aggregation inhibition is reversible following cessation of the infusion of Tirofiban Hydrochloride.

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 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 hydrochloride 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 hydrochloride 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 hydrochloride ranges from 213 to 314 mL/min. Renal clearance accounts for 39 to 69% of plasma clearance.

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 hydrochloride up to 5 mg/kg/day (about 5 times the maximum recommended daily human dose when compared on a body surface area basis).

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 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 thromboplastin 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 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 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 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).

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 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.

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.