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BRIEF SUMMARY OF PRESCRIBING INFORMATION

Non-Bleeding

For full prescribing information visit www.medicure.com/aggrastat/pi.pdf

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:

You are encouraged to report negative side effects of prescription drugs to the FDA.
To report SUSPECTED ADVERSE REACTIONS, contact Medicure at 1-800-509-0544
or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Table 3: Non-bleeding Adverse Reactions in PRISM-PLUS

INDICATIONS AND USAGE

AGGRASTAT + heparin (N=1953) %

AGGRASTAT® 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).

Heparin alone (N=1887) %

AGGRASTAT is contraindicated in patients with:
▪ Severe hypersensitivity reaction to AGGRASTAT (i.e., anaphylactic reactions).
▪ A history of thrombocytopenia following prior exposure to AGGRASTAT.
▪ Active internal bleeding or a history of bleeding diathesis, major surgical procedure or severe
physical trauma within the previous month.

Body as a Whole
Edema/swelling
Pain, pelvic
Reaction, vasovagal
Cardiovascular System
Bradycardia
Dissection, coronary artery
Musculoskeletal System
Pain, leg
Nervous System/Psychiatric
Dizziness
Skin & Skin Appendage
Sweating

WARNINGS AND PRECAUTIONS

Thrombocytopenia

General Risk of Bleeding

Patients treated with AGGRASTAT plus heparin, were more likely to experience decreases in platelet
counts than were those on heparin alone. These decreases were reversible upon discontinuation of
AGGRASTAT. 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.

DOSAGE AND ADMINISTRATION
Refer to package insert for administration & dosing instructions by weight and creatinine clearance.
CONTRAINDICATIONS

Bleeding is the most common complication encountered during therapy with AGGRASTAT. Most
bleeding associated with AGGRASTAT 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.
Thrombocytopenia
Profound thrombocytopenia has been reported with AGGRASTAT. 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 AGGRASTAT and heparin. Previous exposure to a glycoprotein (GP) IIb/IIIa
receptor antagonist may increase the risk of developing thrombocytopenia [see Adverse Reactions].
ADVERSE REACTIONS
Clinical Trial Experience
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 AGGRASTAT in combination with heparin and 2002 patients
received AGGRASTAT alone for about 3 days. Forty-three percent of the population was >65 years
o f 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), AGGRASTAT 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 1: TIMI Major and Minor Bleeding in PRISM-PLUS
Bleeding (TIMI Criteria)‡ §
Major Bleeding
Minor Bleeding
Transfusions
*

AGGRASTAT* + heparin (N=773)
1.4%
10.5%
4.0%

Heparin alone (N=797)
0.8%
8.0%
2.8%

2
6
2

1
5
1

4
5

3
4

3

2

3

2

2

1

Post-Marketing Experience
The following additional adverse reactions have been identified during post-approval use of
AGGRASTAT. 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 AGGRASTAT infusion, during initial treatment, and during readministration of
AGGRASTAT. Some cases have been associated with severe thrombocytopenia (platelet counts
<10,000/mm3). No information is available on the formation of antibodies to tirofiban.
USE IN SPECIFIC POPULATIONS
Pregnancy Pregnancy Category B: There are no adequate and well-controlled studies in pregnant
women. Tirofiban has been shown to cross the placenta in pregnant rats and rabbits. 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.
Nursing Mothers It is not known whether tirofiban is excreted in human milk. However, significant
levels of tirofiban were shown to be present in rat milk. Because many drugs are excreted in human
milk, and because of the potential for adverse effects on the nursing infant, discontinue nursing or
discontinue AGGRASTAT.
Pediatric Use Safety and effectiveness in pediatric patients have not been established.
Geriatric Use Of the total number of patients in controlled clinical studies of AGGRASTAT, 43% were
65 years and over, while 12% were 75 and over. With respect to efficacy, the effect of AGGRASTAT
in the elderly (≥65 years) appeared similar to that seen in younger patients (<65 years). Elderly
patients receiving AGGRASTAT 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
AGGRASTAT 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.
Renal Insufficiency Patients with moderate to severe renal insufficiency have decreased plasma
clearance of AGGRASTAT. Reduce the dosage of AGGRASTAT in patients with severe renal
insufficiency [see Dosage and Administration (2) and Clinical Pharmacology (12.3) sections of the
PI]. Safety and efficacy of AGGRASTAT has not been established in patients on hemodialysis.

0.4 mcg/kg/min initial infusion; 0.10 mcg/kg/min maintenance infusion.

‡ Major = Hemoglobin drop of >5.0 g/L with or without an identified site, intracranial hemorrhage, or
cardiac tamponade.

OVERDOSAGE

§ Minor = Hemoglobin drop of >3.0 g/L with bleeding from a known site, spontaneous gross
hematuria, hematemesis or hemoptysis

In clinical trials, inadvertent overdosage with AGGRASTAT 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 incidence rates of TIMI major bleeding in patients undergoing percutaneous procedures in
PRISM-PLUS are shown below.

The most frequently reported manifestation of overdosage was bleeding, primarily minor
mucocutaneous bleeding events and minor bleeding at the sites of cardiac catheterization.

Table 2: TIMI Major Bleeding Associated with Percutaneous Procedures in PRISM-PLUS
AGGRASTAT + heparin
Prior to Procedures
Following Angiography
Following PTCA

N
773
697
239

%
0.3
1.3
2.5

Heparin alone
N
797
708
236

%
0.1
0.7
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 AGGRASTAT were 17% on
AGGRASTAT 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 AGGRASTAT. There
was a trend toward greater bleeding in ST segment elevation myocardial infarction (STEMI) patients
treated with fibrinolytics prior to administration of AGGRASTAT using the recommended regimen
during rescue PCI.
B.P.I. 01

Overdosage of AGGRASTAT should be treated by assessment of the patient’s clinical condition and
cessation or adjustment of the drug infusion as appropriate.
AGGRASTAT can be removed by hemodialysis.
PATIENT COUNSELING INFORMATION
Advise patients to watch closely for any signs of bleeding or bruising.
AGGRASTAT is manufactured for: MEDICURE INTERNATIONAL, INC.
by: BAXTER HEALTHCARE CORPORATION Deerfield, Illinois 60015 USA
Distributed by: MEDICURE PHARMA, INC. Somerset, NJ 08873 USA 1-800-509-0544
*Registered trademark of Medicure International Inc.© 2016
Copyright used under license. All rights reserved.
Intr avia is a registered trademark of Baxter International Inc.