Tenecteplase

Registered South African indications:

• Thrombolytic treatment of acute phase of myocardial infarction (AMI) 

Contraindications

South African recommendations

• Hypersensitivity to the active substance tenecteplase, gentamicin (a trace residue from the manufacturing process), or to any of the excipients
• Hepatic dysfunction, including hepatic failure, cirrhosis, portal hypertension (oesophageal varices), and active hepatitis. Tenecteplase is metabolised by the liver and no studies in patients with impaired liver function are available at present
• Manifest or recent severe or dangerous bleeding disorder either at present or within the last 6 months
• Patients receiving effective oral anticoagulant treatment, e.g. warfarin sodium (international normalised ratio (INR) >1.3)
• Any history of central nervous system damage (i.e. neoplasm, aneurysm, intracranial or spinal surgery)
• Haemorrhagic stroke or stroke of unknown origin at any time
• Ischaemic stroke or transient ischaemic attack (TIA) in the preceding 6 months
• Known haemorrhagic diathesis
• Severe uncontrolled arterial hypertension
• Major surgery, biopsy of a parenchymal organ, or significant trauma within the past 2 months (this includes any trauma associated with the current acute phase of myocardial infarction (AMI))
• Recent trauma to the head or cranium
• Prolonged or traumatic cardiopulmonary resuscitation (>2mins) in the last 2 weeks
• Active peptic ulceration
• Arterial aneurysm and known arterial/venous malformation
• Neoplasm with increased bleeding risk
• Pregnancy
• Lactation
• Parturition within the previous 3 days
• Previous treatment with tenecteplase
• Subjects >80 years of age or <18 years of age
• Cardiogenic shock
• Acute pericarditis and/or subacute bacterial endocarditis
• Acute pancreatitis

Recommendations in other jurisdictions

• Hypersensitivity to the constituents (tenecteplase or any excipient) or gentamicin (a trace residue from the manufacturing process)
• History of an anaphylactic (i.e. life-threatening) reaction to any of the constituents or gentamicin. If treatment with tenecteplase is nevertheless considered to be necessary, facilities for resuscitation should be immediately available in case of need
• Significant bleeding disorder either at present or within the past 6 months
• Patients receiving effective oral anticoagulant treatment, e.g. warfarin sodium (INR>1.3)
• Any history of central nervous system damage (i.e. neoplasm, aneurysm, intracranial or spinal surgery)
• Known haemorrhagic diathesis
• Severe uncontrolled hypertension
• Major surgery, biopsy of a parenchymal organ, or significant trauma within the past 2 months (this includes any trauma associated with the current AMI)
• Recent trauma to the head or cranium
• Prolonged cardiopulmonary resuscitation (>2mins) within the past 2 weeks
• Acute pericarditis and/or subacute bacterial endocarditis
• Acute pancreatitis
• Severe hepatic dysfunction, including hepatic failure, cirrhosis, portal hypertension (oesophageal varices), and active hepatitis
• Active peptic ulceration
• Arterial aneurysm and known arterial/venous malformation
• Neoplasm with increased bleeding risk
• Any known history of haemorrhagic stroke or stroke of unknown origin
• Known history of ischaemic stroke or transient ischaemic attack in the preceding 6 months
• Dementia

Cautions

South African recommendations

• Renal impairment
• Elderly (>75-≤80 years)
• Systolic blood pressure >160mmHg
• Cerebrovascular disease
• Recent gastrointestinal or genitourinary bleeding (within the past 10 days)
• High likelihood of left heart thrombus (e.g. mitral stenosis with atrial fibrillation)
• Haemostatic defects including those secondary to severe hepatic disease
• Bleeding from recent puncture sites (including catheter insertion sites, arterial and venous puncture sites, cutdown sites and needle puncture sites)
• Use of rigid catheters
• IM injections (within the past 2 days)
• Non-essential handling of the patient
• Low body weight <60kg
• Coadministration with unfractionated heparin
• Coadministration with GPIIb/IIIa antagonists

Recommendations in other jurisdictions

• Pregnancy
• Breastfeeding
• Renal impairment
• Mild and moderate hepatic impairment
• Elderly (>75 years)
• Hypertension (Systolic BP >160mmHg)
• Cerebrovascular disease
• Recent gastrointestinal or genitourinary bleeding (within the past 10 days)
• High likelihood of left heart thrombus (e.g. mitral stenosis with atrial fibrillation)
• Bleeding from recent puncture sites (including catheter insertion sites, arterial and venous puncture sites, cutdown sites and needle puncture sites)
• Use of rigid catheters
• IM injections (within the past 2 days)
• Non-essential handling of the patient
• Weight <60kg
• Coadministration with oral anticoagulants (see additional prescribing points)
• Coadministration with GPIIb/IIIa antagonists

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

Dosages below include:

• South African registered indications and dosages

South African registered indications and dosages

Thrombolytic treatment of acute phase of  myocardial infarction (AMI)

• IV: Admin. on basis of body weight; Max: 10 000U (ten thousand U)/dose (50mg); Dose required should be admin. as a single IV bolus over 5-10secs 

Volume required to admin. the correct dose, can be calculated as below:

Body weight (kg)	Tenecteplase (U)	Tenecteplase (mg)	Corresponding volume of reconstituted solution (ml)
<60	6 000	30	6
≥60-<70	7 000	35	7
≥70-<80	8 000	40	8
≥80-<90	9 000	45	9
≥90	10 000	50	10

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Treatment should be initiated as soon as possible after symptom onset. Insufficient data exist to recommend use of tenecteplase beyond 6-9 hours after the onset of AMI. There is no information on administration later than 9 hours after MI

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Incompatibilities:
Tenecteplase is incompatible with dextrose solution
No other medicinal product should be added to the injection solution or infusion line
Tenecteplase may be administered in a pre-existing intravenous line, containing 0,9 % sodium chloride solution only. If a line is used, this line should be flushed after tenecteplase injection for proper delivery

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Tenecteplase should not be mixed with other medicines, neither in the same infusion-vial nor the same venous line (not even with heparin)

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See additional prescribing points

Contraindicated

Pregnancy

South African recommendations

• Contraindicated
• No experience in pregnant woman is available for tenecteplase

Recommendations in other jurisdictions

• Caution
• There is limited amount of data from the use of tenecteplase in pregnant women
• Nonclinical data performed with tenecteplase have shown bleeding with secondary mortality of dams due to the known pharmacological activity of the active substance and in a few cases abortion and resorption of the foetus occurred (effects only have been observed with repeated dose administration). Tenecteplase is not considered to be teratogenic
• The benefit of treatment must be evaluated against the potential risks in case of myocardial infarction during pregnancy

Breastfeeding

South African recommendations

• Contraindicated
• It is not known if tenecteplase is excreted into breast milk

Recommendations in other jurisdictions

• Caution; not recommended
• It is not known if tenecteplase is excreted in human milk. Breastfeeding should be discarded within the first 24 hours after thrombolytic therapy

Fertility

South African recommendations

• No information available

Recommendations in other jurisdictions

• Clinical data, as well as non-clinical studies on fertility, are not available for tenecteplase

Renal Impairment

South African recommendations

• Caution; no information available

Recommendations in other jurisdictions

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

Hepatic Impairment

South African recommendations

• Contraindicated

Recommendations in other jurisdictions

• Mild to moderate: Caution; no information available 
• Severe: Contraindicated

Elderly

South African recommendations

• >75-≤80 years: Caution; no information available 
• >80 years: Contraindicated 

Recommendations in other jurisdictions

• Caution; no dose adjustment recommended
  Tenecteplase should be administered with caution in the elderly (≥75 years) due to a higher bleeding risk

Porphyria Information

• Not porphyrinogenic (NP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders 

• Intracranial haemorrhage
  - Cerebral haemorrhage
  - Cerebral haematoma
  - Haemorrhagic stroke
  - Haemorrhagic transformation stroke
  - Intracranial haematoma
  - Subarachnoid haemorrhage
• Somnolence
• Aphasia
• Hemiparesis
• Seizures

Cardiovascular Disorders

• Reperfusion arrhythmias
  - Asystole
  - Accelerated idioventricular arrhythmia
  - Arrhythmia
  - Extrasystoles
  - Atrial fibrillation
  - Atrioventricular first degree to atrioventricular block complete
  - Bradycardia
  - Tachycardia
  - Ventricular arrhythmia
  - Ventricular fibrillation
  - Ventricular tachycardia
• Cardiac arrest
• Pericardial haemorrhage
• Haemorrhage
• Embolism (thrombotic embolisation)
• Decreased blood pressure
• Angina pectoris
• Recurrent ischaemia
• Cardiac failure
• Myocardial infarction
• Cardiogenic shock
• Pericarditis
• Mitral valve incompetence
• Pericardial effusion
• Venous thrombosis
• Cardiac tamponade
• Myocardial rupture

Respiratory Disorders

• Epistaxis
• Pulmonary haemorrhage
• Pulmonary oedema
• Pulmonary embolism

Gastrointestinal Disorders

• Gastrointestinal haemorrhage
  - Gastric haemorrhage
  - Gastric ulcer haemorrhage
  - Rectal haemorrhage
  - Haematemesis
  - Melaena
  - Mouth haemorrhage
• Retroperitoneal haemorrhage
  - Retroperitoneal haematoma
• Nausea and vomiting

Genitourinary Disorders

• Urogenital haemorrhage
  - Haematuria
  - Urinary tract haemorrhage

Endocrine and Metabolic Disorders

• Increased body temperature

Skin and Subcutaneous Tissue Disorders

• Ecchymosis
• Injection site haemorrhage
• Puncture site haemorrhage

Immune, Blood and Lymphatic System Disorders

• Anaphylactoid reactions
  - Rash
  - Urticaria
  - Bronchospasm
  - Laryngeal oedema

Sensory Disorders

• Eye haemorrhage

Others

• Fat embolism

• Agents that affect coagulation or platelet function
• Ticlopidine
• Clopidogrel
• Heparin
• GPIIb/IIIa antagonists

None routine. Specific cases may require

• Full blood count
• Activated partial thromboplastin time (aPTT)
• Haemostatic factors
  - Fibrinogen
  - Plasminogen
  - Alpha2-antiplasmin
• ECG

Additional observations

• Signs and symptoms of bleeding

Adjunctive therapy

• Antithrombotic adjunctive therapy is recommended according to the current international guidelines for the management of patients with ST-elevation myocardial infarction

Coronary intervention

• If primary percutaneous coronary intervention (PCI) is scheduled according to the current relevant treatment guidelines, tenecteplase should not be given
• Patients receiving tenecteplase as primary coronary recanalization treatment should be transferred without delay to a coronary intervention capable facility for angiography and timely coronary intervention within 6 - 24 hours or earlier if medically indicated

Bleeding

• Should serious bleeding occur, in particular cerebral haemorrhage, concomitant heparin administration should be terminated immediately. Administration of protamine should be considered if heparin has been administered within 4 hours before the onset of bleeding. In the few patients who fail to respond to these conservative measures, judicious use of transfusion products may be indicated
• Transfusion of cryoprecipitate, fresh frozen plasma, and platelets should be considered with clinical and laboratory reassessment after each administration. A target fibrinogen level of 1g/l is desirable with cryoprecipitate infusion. Antifibrinolytic agents should also be considered

Dysrhythmias

• Coronary thrombolysis may result in dysrhythmias associated with reperfusion. Reperfusion dysrhythmias may lead to cardiac arrest, can be life threatening and may require the use of conventional antidysrhythmic therapies

Instructions for use, handling and disposal

• Tenecteplase should be reconstituted by adding the complete volume of water for injections from the pre-filled syringe of tenecteplase solvent to the vial containing the powder for injection. Ensure that the appropriate vial size is chosen according to the body weight of the patient
• Check that the cap of the vial is still intact
• Remove the flip-off cap from the vial and open the box of the vial adapter
• Remove the tip-cap from the syringe (tenecteplase solvent). Then immediately screw the pre-filled syringe (tenecteplase solvent) on the vial adapter and penetrate the vial stopper in the middle with the spike of the vial adapter
• Add the tenecteplase solvent to the vial by pushing the syringe plunger down slowly to avoid foaming
• Reconstitute by swirling gently
• The reconstituted preparation is a colourless to slightly yellow, clear solution. Only clear solution without particles should be used
• Just before administration, invert the vial with the syringe still attached, so that the syringe is below the vial
• Transfer the appropriate volume of reconstituted solution of tenecteplase into the syringe. This volume is based on the patient’s weight
• Disconnect the syringe from the vial adapter
• Tenecteplase is to be administered to the patient, intravenously over 5-10 seconds. It should not be administered into a line containing dextrose
• Any unused solution should be discarded

Tenecteplase is a recombinant fibrin-specific plasminogen activator. It binds to the fibrin component of the thrombus and selectively converts thrombus-bound plasminogen to plasmin, which degrades the fibrin matrix of the thrombus. Tenecteplase has a higher fibrin specificity and greater resistance to inactivation by its endogenous inhibitor (PAI-1) compared to native t-PA.

Powder for injection (per vial) 40mg

• Metalyse 8 000u (Boehringer Ingelheim) originator

Powder for injection (per vial) 50mg

• Metalyse 10 000u (Boehringer Ingelheim) originator