Alteplase

Registered South African indications:

• Fibrinolytic therapy in acute myocardial infarction
• Thrombolytic (fibrinolytic) treatment in:
  - Acute massive pulmonary embolism with haemodynamic instability
  - Acute ischaemic stroke

Contraindications 

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to gentamicin
• Severe hepatic impairment
  - Severe liver disease, including hepatic failure, cirrhosis, portal hypertension (oesophageal varices) and active hepatitis
• High risk of haemorrhage:
  - Significant bleeding disorder at present or within the past 6 months
  - Known haemorrhagic diathesis
  - Manifest or recent severe or dangerous bleeding
  - Known history of or suspected intracranial haemorrhage
  - Suspected subarachnoid haemorrhage or condition after subarachnoid haemorrhage from aneurysm
  - History of central nervous system damage including neoplasm, aneurysm, intracranial or spinal surgery
  - Traumatic external heart massage, obstetrical delivery, recent puncture of a non-compressible blood-vessel (e.g. subclavian or jugular vein puncture) within the last 10 days
  - Severe uncontrolled arterial hypertension
  - Bacterial endocarditis
  - Pericarditis
  - Acute pancreatitis
  - Documented ulcerative gastrointestinal disease during the last 3 months, oesophageal varices, arterial aneurysm, arterial/venous malformations
  - Neoplasm with increased bleeding risk
  - Major surgery or significant trauma in past 3 months
  - Oral anticoagulant treatment e.g. warfarin sodium (INR>1.3)
• Children <16 years

Acute myocardial infarction and acute pulmonary embolism

• History of haemorrhagic stroke or stroke of unknown origin
• History of ischaemic stroke or transient ischaemic attack in the preceding 6 months, except current acute ischaemic stroke within 4.5 hours

Acute ischaemic stroke

• Symptoms of ischaemic attack beginning >4.5 hours prior to infusion or when time of symptom onset is unknown and could potentially be more than 4.5 hours ago 
• Minor neurological deficit or symptoms rapidly improving before start of infusion
• Severe stroke as assessed clinically (e.g. NIHSS>25) and/or by appropriate imaging techniques
• Seizure at the onset of stroke
• Evidence of intracranial haemorrhage on CT scan
• Symptoms suggestive of subarachnoid haemorrhage, even if CT scan is normal
• Administration of heparin within the previous 48 hours and a thromboplastin time exceeding the upper limit of normal for laboratory
• History of stroke and concomitant diabetes
• Prior stroke within the last 3 months
• Platelet count <100,000mm³
• Systolic blood pressure >185 or diastolic BP >110mmHg, or aggressive management (intravenous pharmacotherapy) necessary to reduce blood pressure to these limits
• Blood glucose <50mg/dl or >400mg/dl (< 2.8mM or > 22.2mM)

South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to gentamicin
• Severe hepatic impairment
  - Severe liver disease, including hepatic failure, cirrhosis, portal hypertension (oesophageal varices) and active hepatitis
• Children <18 years
• Elderly >80 years
• High risk of haemorrhage:
  - Significant bleeding disorder at present or within the past 6 months
  - Known haemorrhagic diathesis
  - History of central nervous system damage including neoplasm, aneurysm, intracranial or spinal surgery, ischaemic stroke in the past 3 months
  - History or evidence or suspicion of intracranial haemorrhage including subarachnoid haemorrhage
  - Uncontrolled arterial hypertension, systolic BP≥180mmHg, diastolic BP≥110mmHg
  - Major surgery, major biopsy, major fracture or significant trauma in the past 6 weeks (this includes any trauma associated with the current acute myocardial infarction), recent trauma to head or cranium
  - Cardiopulmonary resuscitation (>2mins), obstetrical delivery within the past 10 days, recent puncture of a non-compressible blood vessel (e.g. subclavian and jugular vein puncture)
  - Haemorrhagic stroke or stroke of unknown origin at any time
  - Infective endocarditis
  - Pericarditis
  - Acute pancreatitis
  - Documented ulcerative gastrointestinal disease during the last 3 months, oesophageal varices
  - Arterial aneurysm
  - Arterial/venous (A-V) malformations
  - Dissecting aortic aneurism
  - Known or suspected intracranial neoplasm
  - Neoplasm with increased bleeding risk
  - Oral anticoagulant treatment e.g. vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) (INR>1.3)

Acute myocardial infarction and acute pulmonary embolism

• Ischaemic stroke or transient ischaemic attack in the preceding 3 months, except current acute ischaemic stroke within 4.5 hours

Acute ischaemic stroke

• Symptoms of ischaemic attack that began more than 4,5 hours prior to infusion start or when time of symptom onset is unknown
• Symptoms of acute ischaemic stroke that were either rapidly improving or minor before start of infusion
• Severe stroke as assessed clinically (e.g. National Institute of Health Stroke Scale (NIHSS) >25) and/or by appropriate imaging techniques
• Seizure at the onset of stroke
• History of previous stroke or serious head trauma within 3 months
• Combination of previous stroke and diabetes mellitus
• Administration of heparin within 48 hours preceding the onset of stroke with an elevated activated partial thromboplastin time (aPTT) at presentation
• Platelet count <100,000mm³
• Systolic blood pressure >180 or diastolic BP >110mmHg, or aggressive management (IV medication) necessary to reduce blood pressure to these limits
• Blood glucose < 2.78 or > 22.2mmol/L 

Cautions 

International manufacturer recommendations

• Hypersensitivity to natural rubber (a derivative of latex)
• Pregnancy
• Breastfeeding
• Renal impairment
• Mild to moderate hepatic impairment
• Elderly
• Presence of possible bleeding sites (following catheter insertion, arterial and venous puncture cut down and needle puncture)
• Rigid catheters
• Non-essential handling of the patient 
• Small recent traumas including biopsies, puncture of major vessels, intramuscular injections, cardiac massage for resuscitation
• Conditions with an increased risk of haemorrhage not mentioned in contraindications
• Adolescents ≥16 years

Acute myocardial infarction and acute pulmonary embolism

• High doses >100mg
• Systolic blood pressure >160mmHg
• Advanced age
• Coadministration with GPIIb/IIIa antagonists

Acute myocardial infarction

• Risk factors for arrhythmia
• Patients with left heart thrombus e.g. mitral stenosis or atrial fibrillation

Acute ischaemic stroke

• All situations listed in contraindications and in general in all situations involving a high risk of haemorrhage
• Late time-to-treatment onset
• Pre-treated with acetylsalicylic acid particularly with delayed alteplase treatment
• Prior history of stroke
• Uncontrolled diabetes
• Very mild or very severe stroke
• Extensive infarctions
• Advanced age (>80 years)
• Reperfusion of the ischaemic area
• Treatment with platelet aggregation inhibitors within the first 24 hours following thrombolysis with alteplase
• Coadministration with angiotensin-converting enzyme (ACE) inhibitors

South African manufacturer recommendations

• Hypersensitivity to natural rubber (a derivative of latex)
• Pregnancy
• Breastfeeding
• Renal impairment
• Mild to moderate hepatic impairment
• Elderly ≤80 years
• Presence of possible bleeding sites (following catheter insertion sites, arterial and venous puncture sites, cut down sites and needle puncture sites)
• Haemostatic defects including those secondary to severe hepatic or renal disease
• Rigid catheters
• Non-essential handling of the patient 
• Venepunctures
• Recent intramuscular injection or recent traumas, such as biopsies, puncture of major vessels, cardiac massage for resuscitation
• Septic thrombophlebitis or occluded AV cannula at the seriously infected site
• Conditions with an increased risk of haemorrhage not mentioned in contraindications

Acute myocardial infarction and acute pulmonary embolism

• High doses >100mg
• Systolic blood pressure >160mmHg
• Advanced age

Acute myocardial infarction

• Dysrhythmias 
• Patients with left heart thrombus e.g. mitral stenosis or atrial fibrillation
• Coadministration with GPIIb/IIIa antagonists

Acute ischaemic stroke

• All situations listed in contraindications and in general in all situations involving a high risk of haemorrhage
• High doses >90mg
• Pre-treated with acetylsalicylic acid particularly with delayed alteplase treatment
• Prior history of stroke
• Uncontrolled diabetes
• Very mild or very severe stroke
• Extensive infarctions
• Reperfusion of the ischaemic area
• Treatment with platelet aggregation inhibitors within the first 24 hours following thrombolysis with alteplase

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

Dosages below include:

• International manufacturer recommendations
• South African manufacturer recommendations

International manufacturer recommendations

Thrombolytic treatment in acute myocardial infarction
- 90min (accelerated) dose regimen started within 6hrs after symptom onset

• IV: <65kg: 15mg, as a bolus; Then 0.75mg/kg over 30min; Followed by 0.5mg/kg, as an infusion over 60min
• IV: ≥65kg: 15mg, as a bolus; Then 50mg, as an infusion over 30min; Followed by 35mg, as an infusion over 60min; Max total dose: 100mg

- 3hr dose regimen started between 6-12hrs after symptom onset provided that the diagnosis has been clearly confirmed

• IV: <65kg: 10mg, as a bolus; Followed by a constant rate infusion over 3hrs; Max total dose: 1.5mg/kg
• IV: ≥65kg: 10mg, as a bolus; Then 50mg, as an infusion over 60min; Followed by 40mg, as an infusion over 2hrs; Max dose: 100mg over 3hrs

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Actilyse has proven to reduce 30-day-mortality in patients with acute myocardial infarction

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

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Thrombolytic treatment in acute massive pulmonary embolism with haemodynamic instability

• IV: <65kg: 10mg, as bolus given over 1-2 min; Followed by a constant rate infusion over 2hrs; Max total dose: 1.5mg/kg
• IV: ≥65kg: 10mg, as a bolus given over 1-2min; Followed by 90mg, as an infusion over 2hrs; Max total dose: 100mg

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The diagnosis should be confirmed whenever possible by objective means such as pulmonary angiography or non-invasive procedures such as lung scanning. There is no evidence for positive effects on mortality and late morbidity related to pulmonary embolism

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Adjunctive therapy: After treatment with alteplase, heparin therapy should be initiated (or resumed) when aPTT values less than twice the upper limit of normal. The infusion should be adjusted to maintain aPTT between 50-70 seconds (1.5-2.5 fold of the reference value)

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Fibrinolytic treatment in acute ischaemic stroke 

• IV: 0.9mg/kg, with 10% of the total dose administered as an initial IV bolus; Followed by the remainder of the total dose as an infusion over 60min, Max total dose: 90mg

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Treatment must only be performed under the responsibility and follow-up of a physician trained and experienced in neurovascular care

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Treatment must be started as early as possible within 4.5hrs after onset of stroke symptoms and after exclusion of intracranial haemorrhage by appropriate imaging techniques (e.g. cranial computerised tomography or other diagnostic imaging method sensitive for the presence of haemorrhage). The treatment effect is time-dependent; therefore earlier treatment increases the probability of a favourable outcome. Beyond 4.5hrs after onset of stroke symptoms there is a negative benefit risk ratio associated with alteplase administration and so it should not be administered

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Adjunctive therapy: The safety and efficacy of this regimen with concomitant administration of heparin or platelet aggregation inhibitors such as acetylsalicylic acid within the first 24hrs of onset of the symptoms have not been sufficiently investigated. Therefore, administration of intravenous heparin or platelet aggregation inhibitors such as acetylsalicylic acid should be avoided in the first 24hrs after treatment with alteplase due to an increased haemorrhagic risk. If heparin is required for other indications (e.g. prevention of deep vein thrombosis) the dose should not exceed 10,000 IU/day, administered SC

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See additional prescribing points for dosing table

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South African manufacturer's recommendations

Fibrinolytic therapy in acute myocardial infarction
- In whom treatment can be started within 6hrs of symptom onset

• IV: <65kg: 15mg, as a bolus; Then 0.75mg/kg over 30min; Max: 50mg; Followed by 0.5mg/kg, as an infusion over 60min; Max: 35mg; Max total dose: 1.5mg/kg 
• IV: ≥65kg: 15mg, as a bolus; Then 50mg, as an infusion over 30min; Followed by 35mg, as an infusion over 60min; Max total dose: 100mg

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Alteplase should be given as soon as possible after symptom onset

---

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

---

Thrombolytic (fibrinolytic) treatment in acute massive pulmonary embolism with haemodynamic instability

• IV: 10mg, as a bolus given over 1-2min; Followed by 90mg, as an infusion over 2hrs; Max total dose: 100mg

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The total dose should not exceed 1,5mg/kg in patients with a body weight <65kg

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Alteplase should be given as soon as possible after symptom onset

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The diagnosis should be confirmed whenever possible by objective means such as pulmonary angiography or non-invasive procedures such as lung scanning. There is no evidence for positive effects on mortality and late morbidity related to pulmonary embolism in haemodynamically stable patients

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Adjunctive therapy:
After treatment with alteplase, heparin therapy should be initiated (or resumed) when activated partial thromboplastin time (aPTT) values are less than twice the upper limit of normal
The infusion should be adjusted to maintain an activated partial thromboplastin time (aPTT) between 50-70 seconds (1,5-2,5 fold of the reference value)

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Thrombolytic (fibrinolytic) treatment in acute ischaemic stroke

• IV: 0.9mg/kg, with 10% of the total dose administered as an initial IV bolus; Followed by the remainder of the total dose as an infusion over 60min, Max total dose: 90mg

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Only to be used by doctors experienced in the treatment of ischaemic stroke

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Alteplase should be given as soon as possible after symptom onset 

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Treatment must be started as early as possible, but within 4,5 hrs after onset of stroke symptoms and after exclusion of intracranial haemorrhage by appropriate imaging techniques (e.g. cranial computerised tomography or other diagnostic imaging method sensitive for the presence of haemorrhage). The treatment effect is time-dependent; therefore earlier treatment increases the probability of a favourable outcome

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Adjunctive therapy:
The safety and efficacy of this regimen with concomitant administration of heparin and acetylsalicylic acid during the first 24hrs after the symptom-onset has not been investigated sufficiently
Therefore, administration of acetylsalicylic acid or intravenous heparin should be avoided in the first 24hrs after treatment with alteplase. If heparin is required for other indications (e.g. prevention of deep vein thrombosis) the dose should not exceed 10 000 IU/day, administered SC

Paed. forms avail. in SA and covered in this monograph: inj

Dosages below include:

• International manufacturer recommendations
• South African manufacturer recommendations

International manufacturer recommendations

Thrombolytic treatment in acute ischaemic stroke

• <16 years: Contraindicated
• 16-17 years: See adult dosage

South African manufacturer recommendations

• Not established for use in children below 18 years

Pregnancy

International manufacturer recommendations

• Caution
• There is a limited amount of data from the use of alteplase in pregnant women. Nonclinical studies performed with alteplase in doses higher than human doses exhibited foetal immaturity and/or embryotoxicity, secondary to the known pharmacological activity of alteplase. Alteplase is not considered to be teratogenic
• In cases of an acute life-threatening disease, the benefit has to be evaluated against the potential risk

South African manufacturer recommendations

• Caution
• There is very limited experience with the use of alteplase during pregnancy
• Safety in pregnancy has not been established

Breastfeeding

International manufacturer recommendations

• Caution
• It is not known if alteplase is excreted into human milk

South African manufacturer recommendations

• Caution
• There is very limited experience with the use of alteplase during pregnancy
• Safety in pregnancy has not been established

Fertility

International manufacturer recommendations

• Clinical data on fertility are not available for alteplase. Nonclinical studies performed with alteplase showed no adverse effect on fertility

South African manufacturer recommendations

• No information available

Renal Impairment

International manufacturer recommendations

• Caution; no information available 
  Severe renal impairment may result in an increased bleeding risk

South African manufacturer recommendations

• Caution; no information available

Hepatic Impairment

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

Elderly

International manufacturer recommendations

• Caution; no dose adjustment recommended
  The risk of intracranial haemorrhage is increased in elderly patients, therefore risk/benefit evaluation should be carried out carefully

South African manufacturer recommendations

• <80 years: Caution; no information available
  Advanced age, may increase the risk of intracerebral haemorrhage
  As the therapeutic benefit is also increased in elderly patients, the risk-benefit evaluation should be carried out carefully
• >80 years: Contraindicated 

Porphyria Information

• Not porphyrinogenic (NP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Epileptic seizure
• Aphasia
• Speech disorder
• Delirium
• Acute brain syndrome
• Agitation
• Confusion
• Depression
• Psychosis
• Intracerebral haemorrhage
  - Cerebral haemorrhage
  - Cerebral haematoma
  - Haemorrhagic stroke
  - Haemorrhagic transformation of stroke
  - Intracranial haematoma
  - Subarachnoid haemorrhage

Cardiovascular Disorders 

• Recurrent ischaemia
• Angina pectoris
• Hypotension
• Cardiac failure
• Pulmonary oedema
• Cardiogenic shock
• Cardiac arrest
• Reinfarction
• Reperfusion arrhythmias
  - Arrhythmia
  - Extrasystoles
  - First-degree atrioventricular block to complete atrioventricular block
  - Atrial fibrillation
  - Atrial flutter
  - Bradycardia
  - Tachycardia
  - Ventricular arrhythmia
  - Ventricular tachycardia
  - Ventricular fibrillation
  - Electromechanical dissociation
• Mitral regurgitation
• Pulmonary embolism
• Other systemic embolisms
• Cerebral embolism
• Ventricular septal defect
• Decreased blood pressure
• Pericardial haemorrhage

Respiratory Disorders

• Pharyngeal haemorrhage
• Pulmonary haemorrhage
  - Haemoptysis
  - Haemothorax
  - Respiratory tract haemorrhage
• Epistaxis

Gastrointestinal Disorders

• Nausea and vomiting
• Gastrointestinal haemorrhage
  - Gastric haemorrhage
  - Gastric ulcer haemorrhage
  - Rectal haemorrhage
  - Haematemesis
  - Melaena
  - Mouth haemorrhage
  - Gingival bleeding

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
  - Catheter site haematoma
  - Catheter site haemorrhage

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity reactions
  - Rash
  - Urticaria
  - Bronchospasm
  - Angioedema
  - Hypotension
  - Shock
• Serious anaphylaxis
• Retroperitoneal bleeding
  - Retroperitoneal haemorrhage 
• Bleeding in parenchymatous organs 
  - Hepatic haemorrhage 

Sensory Disorders

• Ear haemorrhage
• Eye haemorrhage

Other

• Fat embolism (cholesterol crystal embolisation)

• Coumarin derivatives
• Oral anticoagulants
• Platelet aggregation inhibitors
• Unfractionated heparin
• Low molecular weight heparin
• Agents interfering with coagulation
• Angiotensin-converting enzyme inhibitors
• GPIIb/IIIa antagonists
• Acetylsalicylic acid

Acute ischaemic stroke

• Neurologic examination
• Head CT (without contrast)
• Blood pressure
• Full blood count
• Clotting profile
• Glucose

Pulmonary embolism

• Blood pressure
• Heart rate

ST-elevation myocardial infarction

• Blood pressure
• Serum cardiac biomarkers
• Full blood count
• Clotting profile

Additional investigations (ST-elevation myocardial infarction)

• Evidence of cardiac reperfusion
• Resolution of baseline ECG changes
• Preserved left ventricular function
• Cardiac enzyme washout phenomenon
• Appearance of reperfusion arrhythmias
• Assess for bleeding potential

International manufacturer recommendations

Dosing table for acute ischaemic stroke

By using the recommended standard concentration of 1 mg/ml the volume (ml) to be administered is equal to the recommended dosing value (mg)

Weight (kg)	Total dose (mg)	Bolus dose (mg)	Infusion dose* (mg)
40	36.0	3.6	32.4
42	37.8	3.8	34.0
44	39.6	4.0	35.6
46	41.4	4.1	37.3
48	43.2	4.3	38.9
50	45.0	4.5	40.5
52	46.8	4.7	42.1
54	48.6	4.9	43.7
56	50.4	5.0	45.4
58	52.2	5.2	47.0
60	54.0	5.4	48.6
62	55.8	5.6	50.2
64	57.6	5.8	51.8
66	59.4	5.9	53.5
68	61.2	6.1	55.1
70	63.0	6.3	56.7
72	64.8	6.5	58.3
74	66.6	6.7	59.9
76	68.4	6.8	61.6
78	70.2	7.0	63.2
80	72.0	7.2	64.8
82	73.8	7.4	66.4
84	75.6	7.6	68.0
86	77.4	7.7	69.7
88	79.2	7.9	71.3
90	81.0	8.1	72.9
92	82.8	8.3	74.5
94	84.6	8.5	76.1
96	86.4	8.6	77.8
98	88.2	8.8	79.4
100+	90.0	9.0	81.0

*given in a concentration of 1mg/mL over 60min as a constant rate infusion

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Traceability

• In order to improve traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded in the patient file
• Thrombolytic/fibrinolytic treatment requires adequate monitoring
• Alteplase should only be used under the responsibility and follow-up of physicians trained and experienced in the use of thrombolytic treatments and with the facilities to monitor that use
• It is recommended that when alteplase is administered standard resuscitation equipment and pharmacotherapy is available in all circumstances

South African manufacturer's recommendations

Alternate routes of administration

• Alternate routes of administration include low dose, slow infusion tPA via angiography guided placement of pulmonary artery catheter
• If tPA not available consider the use of  tenecteplase as an alternative

Alteplase a recombinant human tissue-type plasminogen activator, a glycoprotein, which activates plasminogen directly to plasmin. When administered intravenously, alteplase remains relatively inactive in the circulatory system. Once bound to fibrin, it is activated, inducing the conversion of plasminogen to plasmin leading to the dissolution of the fibrin clot.

Powder for injection (per vial) 50mg 

• Actilyse (Boehringer Ingelheim) originator