Generic Name
Tirofiban

Drug Description
'Aggrastat' Solution:1 ml of solution for infusion contains 56 micrograms of tirofiban hydrochloride monohydrate which is equivalent to 50 micrograms tirofiban.'Aggrastat' Concentrate:1 ml of concentrate for solution for infusion contains 281 micrograms of tirofiban hydrochloride monohydrate which is equivalent to 250 micrograms tirofiban.

Presentation
'Aggrastat' Solution: Solution for Infusion(250 ml bag)A clear, colourless concentrated solution.'Aggrastat' Concentrate: Concentrate for solution for infusion.A clear, colourless concentrated solution.

Indications
'Aggrastat' is indicated for the prevention of early myocardial infarction in patients presenting with unstable angina or non-Q-wave myocardial infarction 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' 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' is intended for use with acetylsalicylic acid and unfractionated heparin.

Adult Dosage
This product is for hospital use only, by specialist physicians experienced in the management of acute coronary syndromes.'Aggrastat' concentrate for solution for infusion must be diluted before use.'Aggrastat' is given intravenously at an initial infusion rate of 0.4 microgram/kg/min for 30 minutes. At the end of the initial infusion, 'Aggrastat' should be continued at a maintenance infusion rate of 0.1 microgram/kg/min. 'Aggrastat' should be given with unfractionated heparin (usually an intravenous bolus of 5,000 units [U] simultaneously with the start of 'Aggrastat' therapy, then approximately 1,000 U per hour, titrated on the basis of the activated thromboplastin time [APTT], which should be about twice the normal value) and ASA, unless contra-indicated.No dosage adjustment is necessary for the elderly.Patients with severe kidney failureIn severe kidney failure (creatinine clearance <30 ml/min) the dosage of 'Aggrastat' should be reduced by 50%.The following table is provided as a guide to dosage adjustment by weight.'Aggrastat' Concentrate for Solution for Infusion must be diluted to the same strength as 'Aggrastat' Injection Premixed, as noted under Instructions for Use.Most patientsMost patientsSevere Kidney FailureSevere Kidney FailurePatient Weight (kg)30-371648238-4520510346-5424612355-6228714463-7032816471-7936918580-87401020588-95441122696-1044812246105-1125213267113-1205614287121-1286015308129-1376416328138-1456817349146-1537218369Start and duration of therapy with 'Aggrastat''Aggrastat' optimally should be initiated within 12 hours after the last anginal episode. The recommended duration should be at least 48 hours. Infusion of 'Aggrastat' and unfractionated heparin may be continued during coronary angiography and should be maintained for at least 12 hours and not more than 24 hours after angioplasty/atherectomy. Once a patient is clinically stable and no coronary intervention procedure is planned by the treating physician, the infusion should be discontinued. The entire duration of treatment should not exceed 108 hours.Concurrent therapy (unfractionated heparin, ASA) Treatment with unfractionated heparin is initiated with an i.v. bolus of 5,000 U and then continued with a maintenance infusion of 1,000 U per hour. The heparin dosage is titrated to maintain an APTT of approximately twice the normal value.Unless contra-indicated, all patients should receive ASA orally before the start of 'Aggrastat'. This medication should be continued at least for the duration of the infusion of 'Aggrastat'.If angioplasty (PTCA) is required, heparin should be stopped after PTCA, and the sheaths should be withdrawn once coagulation has returned to normal, e.g. when the activated clotting time (ACT) is less than 180 seconds (usually 2-6 hours after discontinuation of heparin).AGGRASTAT SOLUTIONInstructions for useDo not withdraw solution directly from the container with a syringe.Directions for use of IntraVia ™† containersTo open: Tear foil overpouch or plastic dust cover down side at slit and remove IntraVia™ container. Some opacity of the plastic due to moisture absorption during the sterilisation process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.†IntraVia is the tradename for the infusion bag used for 'Aggrastat' Solution.Do not use unless solution is clear and seal is intact.Do not add supplementary medication or withdraw solution directly from the bag with a syringe.CAUTION: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed.Preparation for administration1. Suspend container from eyelet support.2. Remove plastic protector from outlet port at bottom of container.3. Attach administration set. Refer to complete directions accompanying set.Use according to the dosage table above.Where the solution and container permit, parenteral drugs should be inspected for visible particles or discoloration before use.'Aggrastat' should only be given intravenously and may be administered with unfractionated heparin through the same infusion tube.It is recommended that 'Aggrastat' be administered with a calibrated infusion set using sterile equipment.Care should be taken to ensure that no prolongation of the infusion of the initial dose occurs and that miscalculation of the infusion rates for the maintenance dose on the basis of the patient's weight is avoided.AGGRASTAT CONCENTRATEInstructions for use'Aggrastat' Concentrate must be diluted before use:1. Draw 50 ml from a 250 ml container of sterile 0.9% saline or 5% glucose in water and replace with 50 ml 'Aggrastat' (from one 50 ml puncture vial) to make up a concentration of 50 microgram/ml. Mix well before use.2. Use according to the dosage table above.FOR BOTH FORMULATIONSWhere the solution and container permit, parenteral drugs should be inspected for visible particles or discoloration before use.'Aggrastat' should only be given intravenously and may be administered with unfractionated heparin through the same infusion tube.It is recommended that 'Aggrastat' be administered with a calibrated infusion set using sterile equipment.Care should be taken to ensure that no prolongation of the infusion of the initial dose occurs and that miscalculation of the infusion rates for the maintenance dose on the basis of the patient's weight is avoided.

Contra Indications
'Aggrastat' is contra-indicated in patients who are hypersensitive to the active substance or to any of the excipients of the preparation or who developed thrombocytopenia during earlier use of a GP IIb/IIIa receptor antagonist.Since inhibition of platelet aggregation increases the bleeding risk, 'Aggrastat' is contra-indicated in patients with:History of stroke within 30 days or any history of haemorrhagic stroke. Known history of intracranial disease (e.g. neoplasm, arteriovenous malformation, aneurysm). Active or recent (within the previous 30 days of treatment) clinically relevant bleeding (e.g. gastro-intestinal bleeding). Malignant hypertension. Relevant trauma or major surgical intervention within the past six weeks. Thrombocytopenia (platelet count <100,000/mm3), disorders of platelet function. Clotting disturbances (e.g. prothrombin time>1.3 times normal or INR [International Normalised Ratio]>1.5). Severe liver failure.

Special Precautions
The administration of 'Aggrastat' alone without unfractionated heparin is not recommended.There is limited experience with concomitant administration of 'Aggrastat' with enoxaparin. The concomitant administration of 'Aggrastat' with enoxaparin is associated with a higher frequency of cutaneous and oral bleeding events, but not in TIMI bleeds**, when compared with the concomitant administration of 'Aggrastat' and unfractionated heparin. An increased risk of serious bleeding events associated with the concomitant administration of 'Aggrastat' and enoxaparin cannot be excluded, particularly in patients given additional unfractionated heparin in conjunction with angiography and/or PCI. The efficacy of 'Aggrastat' in combination with enoxaparin has not been established. The safety and efficacy of 'Aggrastat' with other low molecular weight heparins has not been investigated.There is insufficient experience with the use of tirofiban hydrochloride in the following diseases and conditions, however, an increased risk of bleeding is suspected. Therefore, tirofiban hydrochloride is not recommended in:Traumatic or protracted cardiopulmonary resuscitation, organ biopsy or lithotripsy within the past two weeksSevere trauma or major surgery>6 weeks but <3 months previouslyActive peptic ulcer within the past three monthsUncontrolled hypertension >180/110 mm Hg)Acute pericarditisActive or a known history of vasculitisSuspected aortic dissectionHaemorrhagic retinopathyOccult blood in the stool or haematuriaThrombolytic therapy.Concurrent use of drugs that increase the risk of bleeding to a relevant degree.**TIMI major bleeds are defined as a haemoglobin drop of> 50 g/l with or without an identified site, intracranial haemorrhage, or cardiac tamponade. TIMI minor bleeds are defined as a haemoglobin drop of> 30 g/l by 50 g/l with bleeding from a known site or spontaneous gross haematuria, haematemesis, or haemoptysis. TIMI “loss no site” is defined as a haemoglobin drop> 40 g/l but < 50 g/l without an identified bleeding site.There is no therapeutic experience with tirofiban hydrochloride in patients for whom thrombolytic therapy is indicated (e.g. acute transmural myocardial infarction with new pathological Q-waves or elevated ST-segments or left bundle-branch block in the ECG). Consequently, the use of tirofiban hydrochloride is not recommended in these circumstances.'Aggrastat' infusion should be stopped immediately if circumstances arise that necessitate thrombolytic therapy (including acute occlusion during PTCA) or if the patient must undergo an emergency coronary artery bypass graft (CABG) operation or requires an intra-aortic balloon pump.There are limited efficacy data in patients immediately undergoing PTCA.There is no therapeutic experience with 'Aggrastat' in children, thus, the use of 'Aggrastat' is not recommended in these patients.Other precautionary notes and measuresThere are insufficient data regarding the re-administration of 'Aggrastat'.Patients should be carefully monitored for bleeding during treatment with 'Aggrastat'. If treatment of haemorrhage is necessary, discontinuation of 'Aggrastat' should be considered. In cases of major or uncontrollable bleeding, tirofiban hydrochloride should be discontinued immediately.'Aggrastat' should be used with special caution in the following conditions and patient groups:Recent clinically relevant bleeding (less than one year)Puncture of a non-compressible vessel within 24 hours before administration of 'Aggrastat'Recent epidural procedure (including lumbar puncture and spinal anaesthesia)Severe acute or chronic heart failureCardiogenic shockMild to moderate liver insufficiencyPlatelet count <150,000/mm3, known history of coagulopathy or platelet function disturbance or thrombocytopeniaHaemoglobin concentration less than 11 g/dl or haematocrit <34%.Special caution should be used during concurrent administration of, ticlopidine, clopidogrel, adenosine, dipyridamole, sulfinpyrazone, and prostacyclin.Elderly patients, female patients, and patients with low body weightElderly and/or female patients had a higher incidence of bleeding complications than younger or male patients, respectively. Patients with a low body weight had a higher incidence of bleeding than patients with a higher body weight. For these reasons 'Aggrastat' should be used with caution in these patients and the heparin effect should be carefully monitored.Impaired renal functionThere is evidence from clinical studies that the risk of bleeding increases with decreasing creatinine clearance and hence also reduced plasma clearance of tirofiban. Patients with decreased renal function (creatinine clearance <60ml/min) should therefore be carefully monitored for bleeding during treatment with 'Aggrastat' and the heparin effect should be carefully monitored. In severe kidney failure the 'Aggrastat' dosage should be reduced.Femoral artery lineDuring treatment with 'Aggrastat' there is a significant increase in bleeding rates, especially in the femoral artery area, where the catheter sheath is introduced. Care should be taken to ensure that only the anterior wall of the femoral artery is punctured. Arterial sheaths may be removed when coagulation has returned to normal, e.g. when activated clotting time (ACT) is less than 180 seconds, (usually 2–6 hours after discontinuation of heparin).After removal of the introducer sheath, careful haemostasis should be ensured under close observation.General nursing careThe number of vascular punctures, and intramuscular injections should be minimised during the treatment with 'Aggrastat'. I.V. access should only be obtained at compressible sites of the body. All vascular puncture sites should be documented and closely monitored. The use of urinary catheters, nasotracheal intubation and nasogastric tubes should be critically considered.Monitoring of laboratory valuesPlatelet count, haemoglobin and haematocrit levels should be determined before treatment with 'Aggrastat' as well as within 2-6 hours after start of therapy with 'Aggrastat' and at least once daily thereafter while on therapy (or more often if there is evidence of a marked decrease). In patients who have previously received GPIIb/IIIa receptor antagonists (cross reactivity can occur), the platelet count should be monitored immediately e.g. within the first hour of administration after re-exposure. If the platelet count falls below 90,000/mm3, further platelet counts should be carried out in order to rule out pseudothrombocytopenia. If thrombocytopenia is confirmed, 'Aggrastat' and heparin should be discontinued. Patients should be monitored for bleeding and treated if necessary.In addition, activated thromboplastin time (APTT) should be determined before treatment and the anticoagulant effects of heparin should be carefully monitored by repeated determinations of APTT and the dose should be adjusted accordingly. Potentially life-threatening bleeding may occur especially when heparin is administered with other products affecting haemostasis, such as GPIIb/IIIa receptor antagonists

Interactions
The use of several platelet aggregation inhibitors increases the risk of bleeding, likewise their combination with heparin, warfarin and thrombolytics. Clinical and biological parameters of haemostasis should be regularly monitored.The concomitant administration of 'Aggrastat' and ASA (acetylsalicyclic acid or aspirin) increases the inhibition of platelet aggregation to a greater extent than aspirin alone, as measured by ex vivo APD-induced platelet aggregation test. The concomitant administration of 'Aggrastat' and unfractionated heparin increases the prolongation of the bleeding time to a greater extent as compared to unfractionated heparin alone.With the concurrent use of 'Aggrastat' and unfractionated heparin and ASA there was a higher incidence of bleeding than when only unfractionated heparin and ASA were used together. 'Aggrastat' prolonged bleeding time; however, the combined administration of 'Aggrastat' and ticlopidine did not additionally affect bleeding time.Concomitant use of warfarin with 'Aggrastat' plus heparin was associated with an increased risk of bleeding.'Aggrastat' is not recommended in thrombolytic therapy - concurrent or less than 48 hours before administration of tirofiban hydrochloride or concurrent use of drugs that increase the risk of bleeding to a relevant degree (e.g. oral anticoagulants, other parenteral GP IIb/IIIa inhibitors, dextran solutions). There is insufficient experience with the use of tirofiban hydrochloride in these conditions; however, an increased risk of bleeding is suspected.

Adverse Reactions
BleedingThe adverse event causally related to 'Aggrastat' 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' in combination with heparin was not significantly higher than in the control group. The incidence of major bleeding using the TIMI criteria was 1.4% for 'Aggrastat' in combination with heparin and 0.8% for the control group (which received heparin). 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' in combination with heparin and 8.0% for the control group. There were no reports of intracranial bleeding for 'Aggrastat' in combination with heparin or in the control group. The incidence of retroperitoneal bleeding reported for 'Aggrastat' 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' and 2.8% for the control group.'Aggrastat' given with unfractionated heparin and ASA was associated with gastro-intestinal, haemorrhoidal and post-operative bleeding, epistaxis, gum bleeds and surface dermatorrhagia as well as oozing haemorrhage (haematoma) in the area of intravascular puncture sites (e.g. in cardiac catheter examinations) significantly more often than was unfractionated heparin and ASA alone.Non-bleeding-associated adverse reactions The most common adverse drug reactions (incidence over 1%) associated with 'Aggrastat' given concurrently with heparin, apart from bleeding, were nausea (1.7%), fever (1.5%) and headache (1.1%); nausea, fever and headache occurred with incidences of 1.4%, 1.1% and 1.2%, respectively, in the control group.The incidence of adverse non-bleeding-related events was higher in women (compared to men) and older patients (compared to younger patients). However, the incidences of non-bleeding-related adverse events in these patients were comparable for the 'Aggrastat' with heparin' group and the 'heparin alone' group.[Common: >1/100, <1/10)]Nervous system and psychiatric disorders:Common: headacheGastro-intestinal disorders:Common: nauseaGeneral disorders and administration site conditions:Common: feverInvestigationsThe most common changes of laboratory parameters associated with 'Aggrastat' related to bleeding: reduction of haemoglobin and haematocrit levels and an increased occurrence of occult blood in urine and faeces.Occasionally during 'Aggrastat' therapy an acute fall in the platelet count or thrombocytopenia occurred. The percentage of patients in whom the platelet count fell to below 90,000/mm3 was 1.5%. The percentage of patients in whom the platelet count fell to less than 50,000/mm3 was 0.3%. These decreases were reversible upon discontinuation of 'Aggrastat'. Acute and severe platelet decreases have been observed in patients with no prior history of thrombocytopenia upon re-administration of GPIIb/IIIa receptor antagonists.The following additional adverse reactions have been reported infrequently in post-marketing experience; they are derived from spontaneous reports for which precise incidences cannot be determined:Blood and lymphatic system disorders:Intracranial bleeding, retroperitoneal bleding, haemopericardium, pulmonary (alveolar) haemorrhage, and epidural haematoma in the spinal region. Fatal bleedings have been reported rarely.Acute and/or severe (<20,000/mm3) decreases in platelet counts which may be associated with chills, low-grade fever or bleeding complications (see 'Investigations' above)Immune system disorders:Severe allergic reactions (e.g., bronchospasm, urticaria) including anaphylactic reactions. The reported cases have occurred during initial treatment (also on the first day) and during readministration of tirofiban. Some cases have been associated with severe thrombocytopenia (platelet counts <10,000/mm3).

Manufacturer
Merck Sharp & Dohme Limited

Drug Availability
(POM)

Updated
04 June 2009