Tirofiban

Registered South African indications: 

• Unstable angina or non-Q wave myocardial infarction
• Coronary ischaemic syndromes undergoing coronary angioplasty or atherectomy

Contraindications 

• Hypersensitivity to the active ingredient or any of its excipients
• Severe hepatic impairment
• Thrombocytopenia during earlier use of a GP IIb/IIIa receptor antagonist
• History of stroke within 30 days
• History of haemorrhagic stroke
• Known history of intracranial disease (such as neoplasm, arteriovenous malformation or aneurysm)
• Active or recent clinically relevant bleeding within the previous 30 days of treatment (such as gastrointestinal bleeding)
• Malignant hypertension
• Relevant trauma or major surgical intervention within the past 6 weeks
• Thrombocytopenia (platelet count <100,000/mm³)
• Platelet function disorders
• Clotting disturbances
  - Prothrombin time >1.3 times normal
  - INR >1.5

Cautions

• Pregnancy
• Breastfeeding
• Renal impairment (CrCl <60ml/min)
• Mild to moderate hepatic impairment
• Elderly
• Administration alone without unfractionated heparin
• Traumatic or protracted cardiopulmonary resuscitation, organ biopsy or lithotripsy within the past 2 weeks
• Severe trauma or major surgery >6 weeks but <3 months previously
• Active peptic ulcer within the past 3 months
• Uncontrolled hypertension (>180/110mmHg)
• Acute pericarditis
• Active or a known history of vasculitis
• Suspected aortic dissection
• Occult blood in the stool or haematuria
• Thrombolytic therapy
• Patients requiring emergency coronary artery bypass graft (CABG)
• Patients requiring intra-aortic balloon pump
• Haemorrhagic retinopathy
• Cardiogenic shock
• Re-administration of tirofiban
• Clinically relevant bleeding (<1 year)
• Puncture of a non-compressible vessel within 24hrs before administration
• Recent epidural procedure (including lumbar puncture and spinal anaesthesia)
• Severe acute or chronic cardiac failure
• Platelet count <150000/mm³ 
• Known history of coagulopathy or platelet function disturbance  or thrombocytopenia
• Haemoglobin <11g/dl or haematocrit <34%
• Female patients
• Low body weight
• Patients requiring femoral artery line
• Vascular punctures and IM injections
• Use of urinary catheters, nasotracheal intubation and nasogastric tubes
• Low sodium diet
• Coadministration with agents that increase the risk of bleeding to a relevant degree
• Coadministration with thrombolytic therapy
• Coadministration with ticlopidine, clopidogrel, adenosine, dipyridamole, sulfinpyrazone and prostacyclin

Forms avail. in SA and covered in this monograph: inj

Prevention of early myocardial infarction in acute coronary syndromes without ST elevation (NSTE-ACS) (Additional agent(s) required) 
- Where the last episode of chest pain occurred within 12 hours and with ECG changes and/or elevated cardiac enzymes
- Where management with an early invasive strategy for NSTE-ACS is necessary but no plan to undergo angiography for at least 4 hours and up to 48 hours after diagnosis

• IV: Initial: 0.4μg/kg/min as an infusion for 30min; Maintenance: 0.1μg/kg/min

See additional prescribing points

Reduction of major cardiovascular events in acute myocardial infarction (STEMI) intended for primary PCI (Additional agent(s) required) 
- Where PCI is planned within the first 4 hours of diagnosis

• IV: Initial: 25μg/kg as a bolus over 3min; Maintenance: 0.15μg/kg/min, as an infusion for 12-48hrs

See Additional Prescribing Points 

Not established for use in children below 18 years 

Pregnancy

• Caution; not recommended
• There are no or limited amount of data from the use of tirofiban hydrochloride in pregnant women
• Animal studies are insufficient with respect to the reproductive toxicity. Tirofiban is not recommended during pregnancy unless clearly necessary

Breastfeeding 

• Caution; not recommended
• It is not known whether tirofiban hydrochloride is excreted in human milk
• Available pharmacodynamic/ toxicological data in animals have shown excretion of tirofiban hydrochloride in milk; therefore, a risk to the newborn cannot be excluded
• A decision should be made whether to discontinue breastfeeding or discontinue tirofiban therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman

Fertility

• Fertility and reproductive performance were not affected in studies with male and female rats treated with different doses of tirofiban hydrochloride
• However, animal studies are insufficient to draw conclusions with respect to reproductive toxicity in humans

Renal Impairment 

• CrCl ≥60ml/min: No dose adjustment recommended
• CrCl ≥30-<60ml/min: Caution; no dose adjustment recommended
• CrCl <30ml/min: Caution; dose adjustment recommended
  Recommended dose reduction of 50% (see Adult Dosages)
  Tirofiban is removed by haemodialysis

Hepatic Impairment 

• Mild to moderate: Caution; no dose adjustment recommended
• Severe: Contraindicated 

Elderly

• Caution; no dose adjustment recommended

Porphyria Information

• Not porphyrinogenic (NP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache
• TIMI major and intracranial bleeding 

Cardiovascular Disorders 

• Haemopericardium
• Haematoma

Respiratory Disorders 

• Haemoptysis
• Epistaxis
• Pulmonary (alveolar) haemorrhage

Gastrointestinal Disorders 

• Nausea
• Oral haemorrhage
• Gingival haemorrhage
• Gastrointestinal haemorrhage
• Haematemesis
• Retroperitoneal haemorrhage
• Haemorrhoidal haemorrhage
• Occult blood in stool

Genitourinary Disorders 

• Haematuria

Skin and Subcutaneous Tissue Disorders 

• Ecchymosis

Immune, Blood and Lymphatic System Disorders

• Thrombocytopenia
• Allergic reactions
  - Bronchospasm
  - Urticaria
• Anaphylactic reactions
• Post-operative haemorrhage
• Fever
• Acute and/or severe decrease in platelet count
• Decrease in haematocrit
• Decrease in haemoglobin

Other

• Mild mucocutaneous bleeding
• Mild catheterisation-site bleeding
• Epidural haematoma
• Vessel puncture site haemorrhage

• Thrombolytic agents
• Oral anticoagulants
• Acetylsalicylic acid
• Heparin
• Clopidogrel
• Warfarin
• Ticlopidine
• Adenosine
• Dipyridamole
• Sulfinpyrazone
• Prostacyclin
• Platelet aggregation inhibitors
• Enoxaparin
• Parenteral GPIIb/IIIa inhibitors
• Dextran solutions

• Platelet count
• Activated thromboplastin time (aPTT)
• Haemoglobin
• Haematocrit

Additional observations

• Signs of bleeding

Start and duration of therapy

• In patients who are managed with an early invasive strategy for NSTE-ACS but not planned to undergo angiography for at least 4 hours and up to 48 hours after diagnosis, the 0.4 microgram/kg/min loading dose regimen should be initiated upon diagnosis. The recommended duration of the maintenance infusion should be at least 48 hours. Infusion of tirofiban 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
• If the patient diagnosed with NSTE-ACS and managed with an invasive strategy undergoes angiography within 4 hours after the diagnosis, the tirofiban 25 microgram/kg dose bolus regimen should be initiated at the start of PCI with the infusion continued for 12-24 hours and up to 48 hours. In patients with acute myocardial infarction intended for primary PCI, the 25 microgram/kg dose bolus regimen should be initiated as soon as possible after diagnosis

Concurrent therapy (unfractionated heparin, oral antiplatelet therapy, including acetylsalicylic acid)

• Treatment with unfractionated heparin is initiated with an IV bolus of 50-60 U/kg and then continued with a maintenance infusion of 1000 U per hour. The heparin dosage is titrated to maintain an APTT of approximately twice the normal value
• Unless contraindicated, all patients should receive oral antiplatelet agents, including but not limited to acetylsalicylic acid, before the start of therapy. This medication should be continued at least for the duration of the infusion of tirofiban
• Most studies investigating the administration of tirofiban as an adjunct to PCI have used acetylsalicylic acid in combination with clopidogrel as oral antiplatelet therapy. The efficacy of the combination of tirofiban with either prasugrel or ticagrelor has not been established in randomised controlled trials
• If angioplasty (PCI) is required, heparin should be stopped after PCI, 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)

Instructions for use

• To open, tear foil overpouch at notch and remove inner container. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. Do not use unless solution is clear (no visible particles or discolouration) and seal is intact
• Do not add supplementary medication or withdraw solution directly from the bag with a syringe
• 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
• Tirofiban should only be given intravenously and may be administered with unfractionated heparin through the same infusion tube. It is recommended that tirofiban 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
• Tirofiban concentrate must be diluted before use:
  - Draw 50ml from a 250 ml container of sterile 0.9% saline or 5% glucose in water and replace with 5 ml (from one 50ml puncture vial) to make up a concentration of 50μg/ml. Mix well before use

Coadministration with other medicines

• No incompatibilities have been found with the following IV formulations: atropine sulfate, dobutamine, dopamine, epinephrine HCl, furosemide, heparin, lidocaine, midazolam HCl, morphine sulfate, nitroglycerin, potassium chloride, propranolol HCl and famotidine injection
• Tirofiban should not be administered in the same intravenous line as diazepam

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).

Injection (per 1ml) 0.25mg

• Aggrastet (MSD) originator

Injection (per 1ml) 0.05mg

• Aggrastet (Pharmacare) originator
• Aggreva 0.05mg/ml (Teva Pharmaceuticals)