a) Symptoms of overdose

The symptom of overdose most commonly reported was bleeding, usually mucosal bleeding and localised bleeding at the arterial puncture site for cardiac catheterisation but also single cases of intracranial haemorrhages and retroperitoneal bleedings (see sections 4.4 and 5.1).

b) Measures

Overdose with tirofiban hydrochloride should be treated in accordance with the patient's condition and the attending physician's assessment. If treatment of haemorrhage is necessary, the Aggrastat infusion should be discontinued. Transfusions of blood and/or thrombocytes should also be considered. Aggrastat can be removed by haemodialysis.

5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Blood and blood forming organs – antithrombotic agents –antithrombotic agents – Platelet aggregation inhibitors excl. heparin

ATC-Code: B01A C17
Mechanism of action

Tirofiban hydrochloride (tirofiban) is a non-peptidal antagonist of the GP IIb/IIIa receptor, an important platelet surface receptor involved in platelet aggregation. Tirofiban prevents fibrinogen from binding to the GP IIb/IIIa receptor, thus blocking platelet aggregation.

Tirofiban leads to inhibition of platelet function, evidenced by its ability to inhibit ex vivo ADP-induced platelet aggregation and to prolong bleeding time (BT). Platelet function returns to baseline within eight hours after discontinuation.

The extent of this inhibition runs parallel to the tirofiban plasma concentration.
Pharmacodynamic effects

In the 0.4 microgram/kg/min infusion regimen of tirofiban, in the presence of unfractionated heparin and ASA, tirofiban produced a more than 70% (median 89%) inhibition of ex vivo ADP-induced platelet aggregation in 93% of the patients, and a prolongation of the bleeding time by a factor of 2.9 during infusion. Inhibition was achieved rapidly with the 30-minute loading infusion and was maintained over the duration of the infusion.

The tirofiban 25 microgram/kg dose bolus regimen (followed by 18-24 hour maintenance infusion of 0.15 microgram/kg/min), in the presence of unfractionated heparin and oral antiplatelet therapy, produced an average ADP-induced inhibition of maximal aggregation 15 to 60 minutes after onset of treatment of 92% to 95% as measured with light transmission aggregometry (LTA).
Clinical efficacy and safety

PRISM-PLUS study

The double-blind, multicentre, controlled PRISM-PLUS study compared the efficacy of Aggrastat and unfractionated heparin (n=773) versus unfractionated heparin (n=797) in patients with unstable angina (UA) or acute non-Q-wave myocardial infarction (NQWMI) with prolonged repetitive anginal pain or post-infarction angina, accompanied by new transient or persistent ST-T wave changes or elevated cardiac enzymes.

Patients were randomised to either Aggrastat (30 minute loading infusion of 0.4 microgram/kg/min followed by a maintenance infusion of 0.10 microgram/kg/min) and heparin (bolus of 5,000 units (U) followed by an infusion of 1,000 U/hr titrated to maintain an activated partial thromboplastin time (APTT) of approximately two times control), or heparin alone.

All patie