Alteplase (Activase) - Uses, Dose, MOA, Brands, Side effects

Alteplase (Activase) is used to treat acute ST-elevation Myocardial infarction, acute ischemic stroke, and management of acute massive pulmonary embolism.

Alteplase Recommendations:

Acute ST-elevation Myocardial infarction:

Treatment is indicated in patients with chest pain of more than 20 minutes duration and within 12 hours of the onset of chest pain.

Patients who have ongoing ischemic chest pain may be treated even after 12 hours of the onset of symptoms and prior to 24 hours.

ECG criteria for treating the patient with alteplase include:

ST-segment elevation of greater than 0.1 mV in at least two contiguous precordial leads or two adjacent limb leads
New (or presumably new)left bundle branch block (LBBB)

Alteplase in Acute ischemic stroke:

Patients with ischemic stroke may be treated with alteplase if the patient presents within three hours of stroke symptoms.

Alteplase use in PE (Acute pulmonary embolism):

Patients with acute pulmonary embolism may be treated with alteplase if:

Age of the patient is less than 75 years
Massive pulmonary embolism is documented as defined as:
- Acute pulmonary embolism with sustained hypotension i.e. a systolic blood pressure of less than 90 mmHg for 15 minutes or more or the need for inotropic support.
- Persistent profound bradycardia defines as a heart rate of fewer than 40 beats per minute with signs or symptoms of shock, or pulselessness
- Alteplase may also be considered for submassive pulmonary embolism with new hemodynamic instability, worsening respiratory insufficiency, severe right ventricular dysfunction, or major myocardial necrosis and low risk of bleeding complications.

Alteplase Uses (uncommon):

Patency of a catheter
Acute ischemic stroke presenting 3 to 4.5 hours after symptom onset
Acute limb ischemia
Infected parapneumonic effusion with or without dornase alfa
Prosthetic valve thrombosis

Advantages of alteplase compared to streptokinase include:

Low immunogenicity,
short half-life,
direct activation of plasminogen, and
a strong and specific affinity for fibrin.

Failure of thrombolytic agents especially in newborns and neonates may occur because of the low plasminogen concentrations. These patients may require supplemental plasminogen (in the form of fresh frozen plasma).

Allergy to alteplase or any component of the formulation is a contraindication to its use.

Contraindications to alteplase in the treatment of MI (ST-elevation myocardial infarction) or Pulmonary embolism:

Active internal bleeding;
History of a stroke (ischemic stroke within 3 months)
Recent intracranial or intraspinal surgery or trauma;
Intracranial tumors;
Previous intracranial bleeding
Aneurysms or arteriovenous malformation
known bleeding diathesis
Severe uncontrolled hypertension (relative contraindications in STEMI)
Suspected aortic dissection
Significant facial or closed head trauma within the past 3 months with radiographic evidence of bony fracture or brain injury.

Contraindications to alteplase in the Treatment of acute ischemic stroke:

Evidence of intracranial bleeding or suspicion of subarachnoid hemorrhage on pretreatment evaluation;
intracranial or intraspinal surgery within 3 months;
stroke or serious head injury within 3 months;
history of intracranial hemorrhage;
uncontrolled hypertension at the time of treatment (BP: >185/110 mm Hg)
seizure at the onset of stroke;
active internal bleeding;
intracranial neoplasm;
arteriovenous malformation or an aneurysm;
multilobar cerebral infarction (hypodensity > 1 / 3 cerebral hemisphere; Adams, 2007);
known bleeding diathesis

Alteplase Warnings and Precautions

* Altereplase may cause Perfusion Arrhythmias * Significant bleeding may result including serious internal bleeding.

Conditions that increase bleeding risk:

Recent major surgery (within 10 Days). Examples include CABG, obstetrical birth, organ biopsy and pregnancy.
Evidence of thoracic trauma and prolonged cardiopulmonary resuscitation
Lumbar puncture in one week
Cerebrovascular Disease
Recent gastrointestinal bleeding or genitourinary bleeding
Recent trauma
Uncontrolled Hypertension is defined as hypertension that has a systolic blood pressure (BP) greater than 175mm Hg and/or a diastolicBP>110mm Hg.
High risk of left-heart thrombus (eg mitral stenosis and atrial fibrillation).
Acute pericarditis,
Subacute bacterial heart disease,
Advanced liver disease
Diabetic hemorhagic Retinopathy,
Septic thrombophlebitis

Alteplase precautions:

Patients with acute ischemic strokes, patients with INR greater than 1.7, and those who use anticoagulants that have minimal or no effect on their INR such as dabigatran are advised to avoid using anticoagulants with alteplase.

Patients must have creatinine clearance greater than 50 ml/minute, not have taken dabigatran in the past 48 hours, and a normal coagulation profile.

Aspirin should be avoided for 24 hours following administration of alteplase in patients with acute ischemic stroke.
Patients with acute ischemic stroke should not receive heparin in therapeutic doses within the first 24 hour of administering alteplase.
Deep vein thrombosis prevention can be done with prophylactic doses.
Patients with acute pulmonary embolism may receive therapeutic doses of heparin (but not within the 2-hours alteplase infusion time).
Patients over 75 years of age and pregnant women should not be given this drug.

Alteplase Dose in Adults

Alteplase dose in MI (ST-elevation myocardial infarction):

Two different infusion regimens are being followed. The manufacturer recommends a 3-hour infusion regimen, while the ACC and the AHA prefer the accelerated regimen.

The Accelerated regimen:

Patients greater than 67 kg:
- Administered 15 mg of alteplase as an intravenous bolus over 1 to 2 minutes followed by infusions of 50 mg over 30 minutes, and then 35 mg infusion over 1 hour.
- (Maximum total dose of 100 mg should be given over 1.5 hours)
Patients less than 67 kg:
- Infuse 15 mg as intravenous bolus over 1-2 minutes followed by infusions of 0.75 mg/kg (not to exceed 50 mg) over 30 minutes then 0.5 mg/kg (not to exceed 35 mg) over 1 hour.
- (Maximum total dose should not exceed 100 mg)

All patients with acute ST-elevation Myocardial infarction should receive a chewable non-enteric coated aspirin and intravenous heparin 60 units/ kg bolus (maximum: 4000 units) followed by continuous infusion of 12 units/kg (maximum 1000 units/hour) an adjust a target aPTT of 50-70 seconds.

Alteplase Dose in PE (Acute pulmonary embolism with Right ventricular dysfunction, myocardial necrosis and or clinical worsening):

100 mg of alteplase is infused over 2 hours.
It may also be given as a 10 mg bolus followed by 90 mg over 2 hours.

Alteplase dose in Stroke (Acute ischemic stroke):

Alteplase should be given within 3 hours of the onset of the symptom ( Some patients may benefit even up to 4.5 hours of symptoms onset)

Note: Patients should not receive anticoagulants or antiplatelets within 24 hours of starting alteplase. Aspirin should be started after 24 hours.

Patients less than 100 kg:

Load with 0.09 mg/kg as an intravenous bolus over one minute, followed by 0.81 mg/kg as a continuous intravenous infusion over 60 minutes. (Total recommended dose is 0.9 mg/kg or 90 mg)

Patients weighing greater than 100 kg:

Load with 9 mg as an intravenous bolus over 1 minute, followed by 81 mg as a continuous infusion over 60 minutes.

Alteplase for Central venous catheter clearance:

Patients weighing less than 30 kg:

Retain 110% of the internal lumen volume of the catheter for 0.5 - 2 hours ( Do not exceed 2 mg/2 mL). The dose may be repeated a second time if the catheter remains occluded.

Patients greater than 30 kg:

Retain 2 mg or 2 ml in the catheter for 0.5-2 hours. The dose may be repeated a second time if the catheter remains occluded.

Alteplase for acute peripheral arterial occlusion:

0.001-0.02 mg/kg/hour (maximum dose of 2 mg/hour) intra-arterial for 6 - 48 hours or
0.12-2 mg/hour intra-arterial for 6 - 48 hours

Alteplase for Complicated parapneumonic effusion:

Intrapleural administration of 10 mg in 30 mL saline administered two times a day (with a 1 hour dwell time) for a total of 3 days.
Intrapleural dornase alfa should be given two hours after each dose of alteplase.

Alteplase for Prosthetic Valve thrombosis:

Prosthetic valve thrombosis of the right side or left-sided thrombosis with a thrombus area of less than 0.8 cm 2, or left-sided thrombosis with a thrombus area greater than 0.8 cm2 when contraindications to surgery exist:

Load with 10 mg intravenous bolus, followed by 90 mg over 90 to 180 minutes (without heparin during infusion). This is the high dose regimen.
The Low-dose regimen may be preferred for very small adults. A Loading dose of 20 mg, followed by 10 mg/hour for 3 hours (without heparin during infusion)
After successful thrombolysis, continue heparin infusion followed by warfarin to achieve a target INR of 3.0 - 4.0 for aortic valves and 3.5 to 4.5 for mitral valves.

Alteplase Dose in Childrens

Alteplase Dose in neonates for an occluded catheter:

Central venous catheter:

Use a 1 mg/mL concentration; instill a total of 110% of the internal lumen volume of the catheter solution into the catheter and leave it in the lumen for 2 hours.
Use a 1 mg/ml solution and do not exceed 2 mg in 2 mL. If the catheter remains occluded, instill a second dose.

OR

Dilute 0.5 mg in normal saline to a volume equal to the internal volume of the lumen and instill in each lumen over 1-2 minutes.
Leave the solution inside the lumen for 1-2 hours and then aspirate out followed by flushing the catheter with normals saline.

Alteplase for Systemic thromboses in neonates:

Intravenous dose has not been established in children, however, the dose must be titrated to target fibrinogen of greater than 100-150 mg/dl)
0.1-0.6 mg/kg/ hour for 6 hours. Higher doses (>0.4 mg/kg/ hour may be associated with an increased incidence of serious bleeding like intraventricular bleeding

Alteplase dose in Infants and Children:

For Occluded intravenous catheters (CVC):

Patients less than 10 kg:
- 0.5 mg diluted in normal saline to a volume equal to the internal volume of the lumen.
- Instill in each lumen over 1-2 minutes and leave it inside the lumen for 1-2 hours, then aspirate out of the catheter followed by flushing the catheter with normal saline.
Patients greater than 10 kg:
- 1 mg in 1 mL of normal saline. Use a volume equal to the internal volume of the lumen ( The maximum concentration should be 2 mg in 2 mL per lumen).
- Instill in each of the lumens over 1-2 minutes and leave it inside the lumen for 1-2 hours.
- Then aspirate out of the catheter followed by flushing the catheter with normal saline.

Alteplase dose for SubQ port (PICC lines:

Patients less than 10 kg:
- 0.5 mg diluted with normal saline to a total of 3 mL.
Patients greater than 10 kg:
- 2 mg diluted with NS to 3 mL

Alteplase for the treatment of systemic thromboses:

0.1-0.6 mg/kg/ hour for 6 hours (In some patients, the duration of therapy may be prolonged or reduced)
Initial dose should be started @ 0.1 mg/kg/ hour for 6 hours. ( the patients should be monitored for bleeding and fibrinogen levels should be checked).
If there is no response after 6 hours, the infusion rate should be increased by 0.1 mg/kg/ hour at 6-hour intervals to a maximum of 0.5 mg/kg/ hour (to maintain fibrinogen >100 mg/dL)

Alteplase Dose in kidney disease:

Dose adjustment has not been provided in the manufacturer's labeling

Alteplase dosage in liver disease:

No dose adjustment has been provided in the manufacturer's labeling.

Pregnancy Risk Factor C

Alteplase is not recommended for pregnant women.
You should not use it unless the potential benefits are greater than the risks.
It is also not known if alteplase can be found in breast milk. It should be used with caution. [/bg_collapse]

How to Administer Alteplase?

Parenteral administration (IV Alteplase):

Reconstitute vials with supplied diluent (sterile water for injection). Swirl the vials gently and do not shake it. The final concentration after reconstitution is equivalent to 1 mg/mL.
The concentration of the solution should be 1 mg/ml or 0.5 mg/ml.

Intra-catheter instillation (Alteplase for PICC lines patency):

For catheter patency, reconstitute vial with 2.2 mL of sterile water for injection and allow the vial to stand undisturbed (so large bubbles may dissipate).
swirl the vial gently and do not shake it. The final concentration after reconstitution should be 1 mg/mL.

How to instill the solution into the catheter (PICC line):

Instill the dose (as mentioned previously) into the occluded catheter and leave it inside the lumen. Aspirate blood after 30 minutes from the catheter.
If the catheter is functional, aspirate 3 - 5 ml of blood out of the catheter and gently flush the catheter with Normal saline. Leave alteplase for a total of two hours within the lumen if the catheter is occluded.
A second dose may be repeated if the catheter remains occluded.
Alteplase is stable in normal saline, sterile water for injection but incompatible with bacteriostatic water and ringer lactate and has variable stability in Dextrose water.
Once reconstituted, the solution may be used within 8 hours.
Dilutions to less than 0.5 mg/mL concentrations are not recommended for routine clinical use.
Excessive dilutions i.e. less than 0.5 mg/ml form a precipitate. The solution may be stored at 2°C in plastic syringes (these solutions retain more than 90% of fibrinolytic activity)

Alteplase side effects (Severe side effects):

Rapid: Bradycardia, laryngeal edema, and anaphylaxis,
Early: Stroke, ventricular tachycardia, cholesterol microembolization, coma, cerebral edema, AV block, cardiac arrest, and pulmonary edema
Delayed: Intracranial bleeding (0.4-15.4%), gastrointestinal bleeding, retroperitoneal bleeding, thrombosis, renal failure, myocardial infarction, rhabdomyolysis, seizures, thromboembolism, cardiac tamponade, pericardial effusion, heart failure, pericarditis, and pleural effusion

Alteplase side effects (Moderately severe):

Rapid: Hypotension
Early: bleeding, premature ventricular contractions (PVCs), and hypertension
Delayed: livedo reticularis

Alteplase side effects (Mild):

Rapid: Urticaria
Early: Fever, nausea, vomiting, and rash
Delayed: Ecchymosis, epistaxis, and infection

Monitoring Parameters:

Monitor Blood pressure,
temperature,
Blood CP, reticulocyte percent, platelet count
fibrinogen level,
plasminogen,
fibrinogen degradation products,
D-dimer,
Prothrombin time,
Partial thromboplastin time,
antithrombin III and protein C levels,
urinalysis, and
signs of bleeding when alteplase is used for systemic anticoagulation

When intra-catheter alteplase is used, monitor catheter function (by attempting to aspirate blood), temperature, signs of sepsis, gastrointestinal bleeding, bleeding at the site of injection, and venous thrombosis.

Alteplase Mechanism of Action:

Alteplase binds with fibrin in a cluster or thrombus, activating the entrappedplasminogen to its active form, Plasmin.
Plasmin breaks down fibrinogen and other procoagulant proteins into soluble pieces.

Alteplase is metabolized in the liver and has a half-life of 5 to 72 minutes.