Alteplase

Alteplase is an Anticoagulant agent belonging to the thrombolytic class.

Alteplase is a thrombolytic class for the treatment of Acute ischemic stroke, Pulmonary embolism, and ST-elevation myocardial infarction. It is also used in the treatment of Catheter clearance, hemodialysis catheter; Catheter clearance, peritoneal dialysis catheter; Frostbite; Mechanical prosthetic valve or bioprosthetic valve thrombosis; Parapneumonic effusions, complicated and empyema; Peripheral arterial occlusion, acute; Pulmonary embolism, acute (hemodynamically stable, intermediate to high risk [submassive]); Pulmonary embolism associated with cardiac arrest.

Alteplase is metabolized mainly in the liver with an elimination half-life of 4-5 min (initial); approx 40 min (terminal).

The common side effects are dizziness, drowsiness, headache, weakness, Nausea, strong irregular heartbeat, swelling, and dizziness upon standing.

Alteplase is available in the form of dosage forms, such as Solution Reconstituted and Injection.

Alteplase is available in Austria, Belgium, Denmark, Greece, Spain, USA, and India.

Alteplase is a recombinant tissue plasminogen activator (rt-PA) that converts plasminogen to plasmin in a fibrin-dependent process. In the absence of fibrin, Alteplase converts a limited amount of plasminogen. However, in the presence of fibrin clots, Alteplase binds to fibrin and cleaves the arginine-valine bond at positions 560 and 561 of plasminogen, converting it into its active form, plasmin. Plasmin, in turn, degrades the fibrin matrix of the thrombus and promotes clot dissolution. Alteplase initiates local fibrinolysis with limited systemic proteolysis.

Alteplase is available in the form of dosage forms, such as Solution Reconstituted and Injection.

Alteplase Solution Reconstituted:

Reconstitute to 2 milligrams in 2 milliliters. Next, inject the 2.2 milliliters of sterile water for injection USP into the Alteplase vial, directing the diluent stream into the powder.

Alteplase is a thrombolytic class for the treatment of Acute ischemic stroke, Pulmonary embolism, and ST-elevation myocardial infarction. It is also used in the treatment of Catheter clearance, hemodialysis catheter; Catheter clearance, peritoneal dialysis catheter; Frostbite; Mechanical prosthetic valve or bioprosthetic valve thrombosis; Parapneumonic effusions, complicated and empyema; Peripheral arterial occlusion, acute; Pulmonary embolism, acute (hemodynamically stable, intermediate to high risk [submassive]); Pulmonary embolism associated with cardiac arrest.

Alteplase, a recombinant human tissue plasminogen activator (t-PA), activates fibrin-bound plasminogen into plasmin, initiating fibrinolysis and dissolution of thrombus (fibrin clots).

Alteplase is approved for its use in the following clinical indications:-

• Acute ischemic stroke: Treatment of acute ischemic stroke as soon as possible but within 3 hours of symptom onset.
• Pulmonary embolism: Management of acute massive pulmonary embolism.
• ST-elevation myocardial infarction: Management of ST-elevation myocardial infarction (STEMI) for the lysis of thrombi in coronary arteries. Primary percutaneous coronary intervention (PCI) is the preferred reperfusion strategy. Thrombolytic therapy is an option in centers without PCI capability, followed by transfer to a PCI-capable center.
• Although not approved there have been certain off label use documented for Alteplase which includes:-

Acute ischemic stroke presenting 3 to 4.5 hours after symptom onset; Catheter clearance, hemodialysis catheter; Catheter clearance, peritoneal dialysis catheter; Frostbite; Mechanical prosthetic valve or bioprosthetic valve thrombosis; Parapneumonic effusions, complicated and empyema; Peripheral arterial occlusion, acute; Pulmonary embolism, acute (hemodynamically stable, intermediate to high risk [submassive]); Pulmonary embolism associated with cardiac arrest.

The dosage and the duration of treatment should be as per the clinical judgment of the treating physician.

Alteplase is available in various dosage strengths:2mg, 50mg, 100mg

Alteplase is available in the form of dosage forms, such as Solution Reconstituted, Injection.

• Dose Adjustment in Kidney Patients:

There are no dosage adjustments provided in the manufacturer's labeling. Plasma clearance is rapid and mediated primarily by the liver; therefore, the degree of renal impairment is unlikely to influence the elimination of Alteplase.

Hemostatic defects due to severe renal disease may increase the risk for bleeding.

Hemodialysis: Dialyzable: Unknown, but unlikely

• Dose Adjustment in Hepatic Impairment Patient

There are no dosage adjustments provided in the manufacturer’s labeling. Plasma clearance is rapid and mediated primarily by the liver. Significant hepatic impairment and hemostatic defects due to severe hepatic disease may increase the risk for bleeding.

• Dose Adjustment in Pediatric Patients

Occluded IV catheters: Infants, Children, Adolescents: Intracatheter: Dose listed is per lumen; for multilumen catheters, treat one lumen at a time; do not infuse into patient; dose should always be aspirated out of catheter after dwell.

Central venous catheter:

• Patients <30 kg: Use a 1 mg/mL concentration; instill a volume equal to 110% of the internal lumen volume of the catheter; do not exceed 2 mg in 2 mL; may instill a second dose if catheter remains occluded after 2-hour dwell time.

• Patients ≥30 kg: 2 mg in 2 mL; may instill second dose if catheter remains occluded after 2-hour dwell time.

• Chest guidelines (Ref): Note: The most recent guidelines (2012) continue to recommend Alteplase as a treatment option but specific dosage recommendation is not provided (Ref).

• Central venous catheter: Note: Some institutions use lower doses (eg, 0.25 mg/0.5 mL) in infants 1 to <3 months.

• Patients ≤10 kg: 0.5 mg diluted in NS to a volume equal to the internal volume of the lumen; instill in lumen over 1 to 2 minutes; leave in lumen for 1 to 2 hours, then aspirate out of catheter, do not infuse into patient; flush catheter with NS.

• Patients >10 kg: 1 mg in 1 mL of NS; use a volume equal to the internal volume of the lumen; maximum: 2 mg in 2 mL per lumen; instill in each lumen over 1 to 2 minutes; leave in lumen for 1 to 2 hours; then aspirate out of catheter, do not infuse into patient; flush catheter with NS.

Subcutaneous port:

• Patients ≤10 kg: 0.5 mg diluted with NS to 3 mL.
• Patients >10 kg: 2 mg diluted with NS to 3 mL.

Systemic thrombosis

Standard dose infusion: optimal dose not established; most published papers consist of case reports; few prospective pediatric studies have been conducted; several studies have used the following doses : Infants, Children, and Adolescents: Chest 2012 and AHA 2013 recommendations: IV: Usual dose: 0.5 mg/kg/hour for 6 hours; range: 0.1 to 0.6 mg/kg/hour; some patients may require longer or shorter duration of therapy; higher doses may be associated with an increased incidence of serious bleeding .

Low-dose infusion:

Various “low-dose” regimens have been used: Infants, Children, and Adolescents:

AHA 2013 recommendations:

IV: 0.03 to 0.06 mg/kg/hour for 12 to 48 hours; maximum hourly dose: 2 mg/hour .

Additional reported regimens: IV:

Initial: 0.01 to 0.03 mg/kg/hour; usual effective range: 0.015 to 0.03 mg/kg/hour; duration of therapy based on clinical response; in this study of 17 pediatric patients (1.5 to 18 years) with acute and chronic thrombus, dosing was titrated to effect up to 0.06 mg/kg/hour in children and adolescents; final effective range: 0.007 to 0.06 mg/kg/hour; administration included systemic therapy as well as local infusions directly at site of thrombus (n=4); duration of therapy ranged from 4 to 96 hours. A similar dosing range has been reported in pediatric case reports.

Initial: 0.03 to 0.06 mg/kg/hour for 12 to 48 hours; doses were titrated as necessary up to 0.12 mg/kg/hour; dosing from a retrospective study of 23 patients (median age: 12 years, range: 6 months to 21.5 years) diagnosed with DVT; eight patients required a dose increase to 0.12 mg/kg/hour; overall response rate: 59%, with complete clot resolution in 18% and partial resolution in 41%.

Initial: 0.05 mg/kg/hour for 30 minutes, if no signs of bleeding, the rate increased to 0.1 mg/kg/hour; therapy used in 12 children with arterial or femoral vascular occlusions following cardiac catheterization.

Catheter-directed infusion: Children and Adolescents: Intra-arterial, IV (administered through catheter or via catheter with tip placed at anatomic site of clot): 0.025 mg/kg/hour or 0.5 to 2 mg/hour for 12 to 24 hours.

Parapneumonic effusion:

Infants >3 months, Children, and Adolescents: Intrapleural:

Fixed dose: 4 mg in 40 mL NS, first dose at time of chest tube placement with 1-hour dwell time, repeat every 24 hours for 3 days (total of 3 doses) .

Weight-directed: 0.1 mg/kg (maximum: 3 mg) in 10 to 30 mL NS, first dose after chest tube placement, 0.75- to 1-hour dwell time, repeat every 8 hours for 3 days (total of 9 doses)

Alteplase is approved for the treatment of Acute ischemic stroke.

Acute ischemic stroke: Limit foods high in saturated fat such as biscuits, cakes, pastries, pies, processed meats, commercial burgers, pizza, fried foods, potato chips, crisps and other savoury snacks. Limit foods that contain mostly saturated fats such as butter, cream, cooking margarine, coconut oil, and palm oil.

Alteplase may be contraindicated in the following.

• Bleeding disorder (at present or w/in 6 mth), severe stroke, haemorrhagic diathesis, intracranial and subarachnoid haemorrhage, aneurysm, history of CNS damage (i.e. neoplasm, spinal injury), severe uncontrolled HTN, bacterial endocarditis, pericarditis, acute pancreatitis, ulcerative GI disease, oesophageal varices, major surgery or significant trauma in the past 3 mth. Use of rigid catheters. Severe hepatic impairment, including hepatic failure, cirrhosis, portal HTN and active hepatitis.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows.

Concerns related to adverse effects:

• Bleeding: Internal bleeding (intracranial, retroperitoneal, gastrointestinal, genitourinary, respiratory) or external bleeding, especially at arterial and venous puncture, sites may occur (may be fatal). The total dose should not exceed 90 mg for acute ischemic stroke or 100 mg for acute myocardial infarction or pulmonary embolism. Doses ≥150 mg are associated with significantly increased risk of intracranial hemorrhage compared to doses ≤100 mg. Bleeding risk is low. Monitor all potential bleeding sites; if serious bleeding occurs, the infusion of alteplase and any other concurrent anticoagulants (eg, heparin) should be stopped and the patient should be treated appropriately.

• Cholesterol embolization: Has been reported rarely in patients treated with thrombolytic agents; may present with livedo reticularis, “purple toe” syndrome, acute renal failure, gangrenous digits, hypertension, pancreatitis, myocardial infarction, cerebral infarction, spinal cord infarction, retinal artery occlusion, bowel infarction, or rhabdomyolysis and can be fatal.

• Extravasation: Alteplase may be an irritant; avoid extravasation. Extravasation may result in inflammation or ecchymosis. If extravasation occurs, discontinue infusion at that IV site and apply local therapy.

• Hypersensitivity reactions: Hypersensitivity reactions (eg, anaphylaxis, urticaria, angioedema) have been reported; fatal outcome has been reported (rare). Although typically mild and transient, orolingual angioedema has occurred during and up to 2 hours after alteplase infusion in patients treated for acute ischemic stroke and acute myocardial infarction; the use of concomitant ACE inhibitors, female sex and strokes involving the insular and frontal cortex have been associated with an increased risk.

Avoid taking alcohol with Alteplase as it may result in side effects like headache, dizziness and faintness.

Alteplase should not be administered to breastfeeding Women.

Pregnancy Category C

Alteplase is embryocidal in rabbits when intravenously administered in doses of approximately two times (3 mg/kg) the human dose for AMI. No maternal or fetal toxicity was evident at 0.65 times (1 mg/kg) the human dose in pregnant rats and rabbits dosed during the period of organogenesis. There are no adequate and well-controlled studies in pregnant women.

Salt Substitutes: Those who are taking Alteplase should avoid sodium, calcium and magnesium-rich foods. The salts may reduce the blood-pressure lowering effect of Alteplase.

The adverse reactions related to molecule Alteplase can be categorized as

• Common Adverse effect: Bleeding, angioedema, anaphylaxis, and fever.

• Less Common Adverse effects: Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, loss of coordination, feeling unsteady, very stiff muscles, high fever, profuse sweating, or tremors.
• Rare Common Adverse effects: Chills, Confusion, Fainting, Fast heartbeat, Fever, Lightheadedness, Pain in the chest, groin, or legs, especially the calves, Pain, redness, or swelling in the arm or leg, Rapid, shallow breathing

The clinically relevant drug interactions of Alteplase is briefly summarized here.

Increased risk of haemorrhage w/ coumarin derivatives, oral anticoagulants, platelet aggregation inhibitors, and unfractionated heparin/LMWH. Increased risk of anaphylactoid reaction w/ ACE inhibitors. Concomitant use w/ IV glyceryl trinitrate may result in impaired thrombolysis.

Pediatric Use

Safety and efficacy in pediatric patients have been established as per FDA.

Symptoms: Reduction in blood coagulation components (e.g., fibrinogen), severe bleeding.

Management: Treat severe bleeding w/ infusion of fresh frozen plasma. Synthetic antifibrinolytics may be beneficial.

Pharmacodynamics:

Alteplase binds to fibrin and plasminogen. Alteplase specificity for fibrin is achieved thanks to its high affinity for lysine residues. Also, it can bind plasminogen via loop structures called kringles, stabilized by three disulphide linkages similar to the ones in plasminogen. The specificity of Alteplase for plasminogen bound to fibrin allows this drug to act in a clot- or fibrin-specific manner, leading to low concentrations of circulating plasmin and a lower risk of hemorrhagic transformation.

Pharmacokinetics:

• Absorption

Healthy volunteers with a baseline endogenous tissue plasminogen activator (t-PA) of 3.3 ng/ml had a 290-fold increase in baseline concentrations after receiving Alteplase at an infusion rate of 0.25 mg/kg for 30 min; with an infusion rate of 0.5 mg/kg, a 550-fold increase was observed.Acute myocardial infarction patients (n=12) given 10 mg of Alteplase in a 2-minute infusion reached a peak plasma concentration of 3310 ng/ml. This was followed by 50 mg of Alteplase in 1 h and 30 mg in 1.5 h, resulting in steady-state plasma levels of 2210 ng/ml and 930 ng/ml, respectively.

• Distribution:

The initial volume of distribution approximates plasma volume.The average volume of distribution of the central compartment goes from 3.9 to 4.3 L, and the volume of distribution at steady state goes from 7.2 to 12 L.

• Metabolism:

Alteplase is mainly metabolized by the liver. The carbohydrate and polypeptide domains of Alteplase interact with hepatic glycoprotein receptors, leading to receptor-mediated endocytosis. In vivo studies suggest that Alteplase follows zero-order kinetics, meaning that its metabolism is saturable at higher plasma concentrations.

• Excretion:

Elimination half-life: 4-5 min (initial); approx 40 min (terminal).

1. https://www.mims.com/india/drug/info/Alteplase ?type=full&mtype=generic

2. https://www.uptodate.com/contents/Alteplase-drug-information?search=Alteplase-drug-in&usage_type=panel&kp_tab=drug_general&source=search_result&selectedTitle=1~37&display_rank=1#F162889

3. https://go.drugbank.com/drugs/DB00590

4. https://www.rxlist.com/consumer_Alteplase _cardura/drugs-condition.htm

5. https://reference.medscape.com/drug/cardura-xl-Alteplase -342343