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European Commission final decision


On 18 June 1999, the European Commission issued a Decision valid throughout the European Union for the medicinal product AGGRASTAT/AGRASTAT, which contains Tirofiban. This decision was based on the arbitration assessment report and on the favourable opinion adopted by the Committee for Proprietary Medicinal Products (CPMP) on 25 March 1999. The Marketing Authorisation Holder responsible for this medicinal product is MSD Sharp & Dohme GmbH.

The approved indication is for the prevention of early myocardial infarction in patients presenting with unstable angina (UA) or non-Q-wave myocardial infarction (NQMI) with the last episode of chest pain occurring within 12 hours and with ECG changes and/or elevated cardiac enzymes. Patients most likely to benefit from AGGRASTAT/AGRASTAT treatment are those at high risk of developing myocardial infarction within the first 3-4 days after onset of acute angina symptoms including for instance those that are likely to undergo an early PTCA. AGGRASTAT/AGRASTAT is intended for use with acetylsalicylic acid (ASA) and unfractionated heparin.

In July 1998 MSD Sharp & Dohme GmbH, submitted applications for Mutual Recognition of the Marketing Authorisation granted by the German Competent Authority acting as Reference Member State, for Aggrastat solution for infusion and concentrate for solution for infusion. The Mutual Recognition procedure started on 05 August 1998. The Concerned Member States were Austria, Belgium, Denmark, Finland, France, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, United Kingdom, Spain and Sweden. The Concerned Member State, France not being able to agree with the Mutual Recognition of the Marketing Authorisation granted by the Reference Member State referred the reasons for disagreement to the EMEA on 30 October 1998.

The reasons concerned the enzymatic definition of the Myocardial Infarction component used for the combined endpoint in the PRISM PLUS study, which supported evidence of efficacy and safety of tirofiban at the proposed dosing regimen.

The Reference Member State sent its report to the EMEA on 11 November 1998. The matter was referred to the CPMP on 19 November 1998. The Marketing Authorisation Holder provided written explanations on 18 January and 11 March 1999, and an oral explanation at the March 1999 plenary meeting of the CPMP.

The CPMP adopted a positive opinion on 25 March 1999 recommending the granting of the Marketing Authorisation for Aggrastat with amendments to the Summary of Product Characteristics (SPC) of the Reference Member State. An overall summary of the scientific evaluation is provided, together with Annex I and Annex Ia of the opinion, which contain the amendments to the SPC and the amended SPC. The final Opinion was converted into a Decision by the European Commission on 18 June 1999.

AGGRASTAT/AGRASTAT is supplied in two pharmaceutical forms; a concentrate for solution for infusion containing (0.25 mg/ml) and a solution for infusion (0.05 mg/ml).

The active substance of AGGRASTAT/AGRASTAT is tirofiban hydrochloride. Tirofiban is a nonpeptidal antagonist of the GP IIb/IIIa receptor, an important platelet surface receptor involved in platelet aggregation. Tirofiban hydrochloride prevents fibrinogen from binding to the GP IIb/IIIa receptor, thus blocking platelet aggregation.

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. Tirofiban crosses the placenta in rats and rabbits.

The clinical study PRISM-PLUS, which supported evidence of efficacy and safety of tirofiban at the proposed dosing regimen, investigated the efficacy of AGGRASTAT/AGRASTAT with unfractionated heparine versus unfractionated heparine in patients with unstable angina or acute non-Q-wave myocardial infarction. The combined primary study endpoint was the occurrence of refractory ischemia, myocardial infarction or death at 7 days after the start of tirofiban hydrochloride. At the primary endpoint, there was a 32 % risk reduction (RR) (12.9 % vs. 17.9 %) in the tirofiban hydrochloride group for the combined endpoint (p=0.004): this represents approximately 50 events avoided for 1,000 patients treated. Results of the primary endpoint were principally attributed to the occurrence of myocardial infarction and refractory ischemic conditions. After 30 days the RR for the combined endpoint (death/myocardial infarction/refractory ischemic conditions/readmissions for unstable angina) was 22 % (18.5 % vs. 22.3 %; p=0.029).

The adverse events causally related to AGGRASTAT/AGRASTAT therapy (used concurrently with unfractionated heparin and ASA) most commonly reported was bleeding, which was usually of a milder nature.

In the PRISM-PLUS study, the overall incidence of major bleeding using the TIMI criteria (defined as a haemoglobin drop of >50 g/l with or without an identified site, intracranial haemorrhage, or cardiac tamponade) in patients treated with AGGRASTAT/AGRASTAT in combination with heparin was not significantly higher than in the control group (1.4 % for AGGRASTAT/AGRASTAT in combination with heparin and 0.8 % for the control group which received heparin). There were no reports of intracranial bleeding for AGGRASTAT/AGRASTAT in combination with heparin or in the control group. The incidence of retroperitoneal bleeding reported for AGGRASTAT/AGRASTAT in combination with heparin was 0.0 % and 0.1 % for the control group. The percentage of patients who received a transfusion (including packed red blood cells, fresh frozen plasma, whole blood cryoprecipitates and platelets) was 4.0 % for AGGRASTAT/AGRASTAT and 2.8 % for the control group. The incidence of minor bleeding using the TIMI criteria (defined as a haemoglobin drop of > 30 g/l with bleeding from a known site, spontaneous gross haematuria, haematemesis or haemoptysis) was 10.5 % for AGGRASTAT/AGRASTAT in combination with heparin and 8 % for the control group.

Key facts

Approved name
International non-proprietary name (INN) or common name
Reference number
Article 29(4) referrals

This type of referral is triggered when there is a disagreement between Member States regarding a marketing authorisation application being evaluated in a mutual-recognition or decentralised procedure, on the grounds of a potential serious risk to public health.

European Commission final decision
Opinion date
EC decision date

All documents

Document description

  • Questions and answers (Q&A) - easy-to-understand summary of key issues and Committee conclusions
  • Summary of Opinion - contains the CHMP opinion of the referred medicine(s)
  • List of the medicines affected by the referral (Annex I)
  • Scientific conclusions of the Committee (Annex II)

The following two documents are sometimes available:

  • Changes to the summary of product characteristics, labeling or package leaflet (also known as Annex III) - available when changes havebeen recommended by the Committee
  • Conditions of the marketing authorisation (also known as Annex IV) - available when the Committee recommends measures to be takenfor the marketing authorisation(s) such as safety measures or extra studies

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