2.1 Recommended Dosage

The recommended dosage is 25 mcg/kg administered intravenously within 5 minutes and then 0.15 mcg/kg/min for up to 18 hours.

2.2 Administration

For intravenous use only. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
 

To open the 250 mL premixed bag, first tear off its foil overpouch. The plastic may be somewhat opaque because of moisture absorption during sterilization; the opacity will diminish gradually. Check for leaks by squeezing the inner bag firmly; if any leaks are found or sterility is suspect then the solution should be discarded. Do not use unless the solution is clear and the seal is intact.

Administration Instructions
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.

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:

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.

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

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

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

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/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.

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 risk
Myocardial infarction is a medical emergency in pregnancy which can be fatal to the pregnant woman and fetus if left untreated.

Data

Animal Data

There was no evidence of maternal or developmental toxicity in any of the studies in Table 5.

Table 5 Developmental Toxicity Studies

*5 mg/kg/day is ~5 and 13 times the maximum recommended daily human dose for rat and rabbit, respectively, when compared on a body surface area basis.

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.

12.1 Mechanism of Action

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

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

12.2 Pharmacodynamics

Tirofiban hydrochloride injection inhibits platelet function, as demonstrated by its ability to inhibit ex vivo adenosine phosphate (ADP)-induced platelet aggregation and prolong bleeding time in healthy subjects and patients with coronary artery disease. The time course of inhibition parallels the plasma concentration profile of the drug.

Following discontinuation of an infusion of tirofiban hydrochloride injection 0.10 mcg/kg/min, ex vivo platelet aggregation returns to near baseline in 4 to 8 hours in approximately 90% of patients with coronary artery disease. The addition of heparin to this regimen does not significantly alter the percentage of subjects with > 70% inhibition of platelet aggregation (IPA), but does increase the average bleeding time, as well as the number of patients with bleeding times prolonged to > 30 minutes. Similar platelet aggregation recovery rates are observed following discontinuation of a 0.15 mcg/kg/min infusion.

12.3 Pharmacokinetics

Tirofiban has a half-life of approximately 2 hours. It is cleared from the plasma largely by renal excretion, with about 65% of an administered dose appearing in urine and about 25% in feces, both largely as unchanged tirofiban. Metabolism appears to be limited.

Tirofiban is not highly bound to plasma proteins and protein binding is concentration independent over the range of 0.01 to 25 mcg/mL. The unbound fraction in human plasma is 35%. The steady state volume of distribution of tirofiban ranges from 22 to 42 liters.

In healthy subjects, the plasma clearance of tirofiban ranges from 213 to 314 mL/min. Renal clearance accounts for 39 to 69% of plasma clearance.

Specific Populations
There is no effect on clearance of tirofiban by sex, race, age, or hepatic impairment.

Renal Insufficiency
Plasma clearance of tirofiban is decreased about 40% in subjects with creatinine clearance < 60 mL/min and > 50% in patients with creatinine clearance < 30 mL/min, including patients requiring hemodialysis [see Dosage and Administration (2.3)]. Tirofiban is removed by hemodialysis.

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).