AGRIPLAT

Tirofiban prevents the blood from clotting during episodes of chest pain or a heart attack, or while the patient is undergoing a procedure to treat a blocked coronary artery.

It is a non-peptide reversible antagonist of the platelet glycoprotein (GP) IIb/IIIa receptor, and inhibits platelet aggregation.

For treatment, in combination with heparin, of acute coronary syndrome, including patients who are to be managed medically and those undergoing PTCA or atherectomy.

Tirofiban prevents the blood from clotting during episodes of chest pain or a heart attack, or while the patient is undergoing a procedure to treat a blocked coronary artery.

It is a non-peptide antagonist of the platelet glycoprotein (GP) IIb/IIIa receptor, and inhibits platelet aggregation.

When administered

Intravenous, tirofiban inhibits ex vivo platelet aggregation in a dose.

• and concentration-dependent manner.

When given according to the recommended regimen, >90% inhibition is attained by the end of the 30-minute infusion.

Tirofiban has been recently shown in patients with unstable angina to reduce ischemic events at 48 hours following infusion when compared to standard heparin therapy.

appears to be limited.

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.

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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.

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.

Tirofiban hydrochloride injection is contraindicated in patients with: Severe hypersensitivity reaction to tirofiban hydrochloride injection (i.e., anaphylactic reactions) .

A history of thrombocytopenia following prior exposure to tirofiban hydrochloride injection.

Active internal bleeding or a history of bleeding diathesis, major surgical procedure or severe physical trauma within the previous month.

Known hypersensitivity to any component of tirofiban hydrochloride injection.

History of thrombocytopenia with prior exposure to tirofiban hydrochloride injection.

Active internal bleeding, or history of bleeding diathesis, major surgical procedure or severe physical trauma within the previous month.

Administer intravenously 25 mcg/kg within 5 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 5 minutes and then 0.075 mcg/kg/min. 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.

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 IV pump.

Immediately following the bolus dose administration, administer the maintenance infusion from the 250 mL premixed bag via an IV pump.

Discard any unused portion left in the bag.

The recommended bolus volume using 250 mL premixed bag can be calculated using the following equation: Bolus Volume (mL) = 25 mcg/kg X body weight (kg) 50 mcg/mL The recommended infusion rate for patients with CrCl (Creatinine Clearance) > 60 mL/min using the 250 mL premixed bag can be calculated using the following equation: Infusion Rate for CrCl > 60 mL/min (mL/h) = 0.15 mcg/kg/min x body weight (kg) x 60 min/h 50 mcg/mL Example calculation of infusion rate for 60 kg patient with CrCl > 60 mL/min using the 250 mL premixed bag: Infusion Rate for CrCl > 60 mL/min (mL/h) = 0.15 mcg/kg/min x 60 kg x 60 min/h =10.8 mL/h 50 mcg/mL 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: Infusion Rate for CrCl ≤ 60 mL/min (mL/h) = 0.075 mcg/kg/min x body weight (kg) x 60 min/h 50 mcg/mL.

Tirofiban hydrochloride injection is a clear, non-preserved, colorless, isosmotic, sterile premixed solution with sodium chloride for tonicity adjustment and is supplied as follows: NDC Tirofiban Hydrochloride Injection (50 mcg per mL) Package Factor 25021-417-84 12.5 mg per 250 mL Single-Dose Bag 1 bag per carton FOR INTRAVENOUS USE ONLY Storage Conditions Store at 25°C (77°F); excursions permitted between 15° and 30°C (59° and 86°F).

Do not freeze.

Protect from light during storage.

Discard unused portion.

Sterile, Nonpyrogenic, Preservative-free, PVC-free.

The container closure is not made with natural rubber latex.

Store at 25°C (77°F); excursions permitted between 15° and 30°C (59° and 86°F).

Do not freeze.

Protect from light during storage.

Discard unused portion.

Sterile, Nonpyrogenic, Preservative-free, PVC-free.

The container closure is not made with natural rubber latex.

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 woman and fetus.

Studies with tirofiban

HCl at intravenous doses up to 5 mg/kg/day (about 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 to 4% and to 20%, respectively.

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.

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.

Dose/Exposure * Duration/Timing Exposure Range-finding Rat (N=30) 1, 2, 5 mg/kg/day IV (N=10 per group) Once daily from GD 6 through LD 20 Developmental Toxicity Rat (N=66) 1, 2, 5 mg/kg/day IV (N=22 per group) Once daily from GD 6 through GD 20 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 Range-finding (non-pregnant) Rabbit (N=21) 1, 2, 5 mg/kg/day IV (N=7 per group) Once daily for 14 days 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 Developmental Toxicity Rabbit (N=60) 1, 2, 5 mg/kg/day (N=20 per group) IV Once daily from GD 7 through GD 20.

Safety and effectiveness in pediatric patients have not been established.

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.