alteplase (recombinant alteplase, tissue plasminogen activator)
Activase, Cathflo Activase

Available forms
Available by prescription only
Injection: 50-mg (29 million IU), 100-mg (58 million IU) vials
Lyophilized powder for intracatheter instillation: 2 mg single-patient vials

Indications and dosages
 Lysis of thrombi obstructing coronary arteries in management of acute MI. 3-hour infusion.
Adults who weigh more than 65 kg (143 lb): 60 mg in first hour, with 6 to 10 mg I.V. bolus over first 1 to 2 minutes; then 20 mg/hour for an additional 2 hours. Total dose, 100 mg.
Adults who weigh 65 kg or less: 1.25 mg/kg given over 3 hours. Infuse 0.75 mg/kg during the first hour with an initial bolus of 0.045 to 0.075 mg/kg rapidly over 1 to 2 minutes. After the first hour, begin a maintenance infusion of 0.25 mg/kg for the remaining 2 hours.
Accelerated infusion
Adults who weigh more than 67 kg (148 lb): 15 mg I.V. push, 50 mg over 30 minutes, then 35 mg over 60 minutes.
Adults who weigh 67 kg or less: 15 mg I.V. push, 0.75 mg/kg over 30 minutes (not to exceed 50 mg), then 0.5 mg/kg over 60 minutes (not to exceed 35 mg).
 Prevention of reocclusion after thrombolysis for acute MI. Adults: 3.3 mcg/kg/min by I.V. infusion for 4 hours together with heparin therapy immediately after initial thrombolytic infusion.
 Pulmonary embolism. Adults: 100 mg by I.V. infusion over 2 hours. Start heparin therapy at the end of infusion. Or, 30 to 50 mg infused via the intrapulmonary artery over 11/2 or 2 hours, respectively, in conjunction with heparin therapy.
 Lysis of arterial occlusion in a peripheral vessel or bypass graft. ◇ Adults: 0.05 to 0.1 mg/ kg/hour infused via the intrapulmonary artery for 1 to 8 hours.
 Acute ischemic stroke. Adults: 0.9 mg/kg (maximum dose, 90 mg). Administer 10% of dose as an I.V. bolus over 1 minute; remaining 90% over 1 hour.
 Restoration of function to central venous access devices as assessed by the ability to withdraw blood (Cathflo Activase). Adults and children older than age 2: For patients weighing more than 66 lb (30 kg), instill 2 mg in 2 ml sterile water into catheter. For patients weighing 10 kg (22 lb) up to 30 kg (66 lb), instill 110% of the internal lumen volume of the catheter, not to exceed 2 mg. After 30 minutes of dwell time, assess catheter function by aspirating blood. If function is restored, aspirate 4 to 5 ml of blood to remove Cathflo Activase and residual clot, and gently irrigate the catheter with normal saline solution. If catheter function not restored after 120 minutes, instill a second dose.

Pharmacodynamics
Thrombolytic action: Alteplase is an enzyme that catalyzes the conversion of tissue plasminogen to plasmin in the presence of fibrin. This fibrin specificity produces local fibrinolysis in the area of recent clot formation, with limited systemic proteolysis. In patients with acute MI, this allows for reperfusion of ischemic cardiac muscle and improved left ventricular function with a decreased risk of heart failure after an MI.

Pharmacokinetics
Absorption: Administered I.V.
Distribution: Rapidly cleared from the plasma by the liver; 80% of dose is cleared within 10 minutes after infusion is discontinued.
Metabolism: Primarily hepatic.
Excretion: More than 85% of drug is excreted in urine; 5% in feces. Plasma half-life is less than 10 minutes.

Contraindications and precautions
Contraindicated in patients with history or evidence of intracranial hemorrhage, suspected subarachnoid hemorrhage, seizure at the onset of CVA, active internal bleeding, intracranial neoplasm, arteriovenous malformation, aneurysm, and severe uncontrolled hypertension (more than 185 mm Hg systolic or 110 mm Hg diastolic). Also contraindicated in patients with a history of CVA, recent (within 2 months) intraspinal or intracranial trauma or surgery, or bleeding diathesis (see package insert).
  Use cautiously in patients with recent (within 10 days) major surgery; pregnant patients; patients within the first 10 days postpartum; and patients with recent organ biopsy, trauma (including cardiopulmonary resuscitation), GI or GU bleeding, cerebrovascular disease, hypertension, a likelihood of left-sided heart thrombus, hemostatic defects (including those secondary to severe hepatic or renal disease), hepatic dysfunction, occluded AV cannula, severe neurologic deficit (NIH [National Institutes of Health] Stroke Scale above 22), signs of major early infarct on a computed tomography scan, mitral stenosis, atrial fibrillation, acute pericarditis or subacute bacterial endocarditis, septic thrombophlebitis, or diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions. Also use cautiously in those receiving anticoagulants and in patients age 75 and older.

Interactions
Drug-drug. Drugs that antagonize platelet function (abciximab, aspirin, dipyridamole): May increase risk of bleeding if given before, during, or after alteplase therapy. Use together cautiously.

Adverse reactions
CNS: cerebral hemorrhage, fever.
CV: hypotension, arrhythmias, edema.
GI: nausea, vomiting.
Hematologic: severe, spontaneous bleeding (cerebral, retroperitoneal, GU, GI).
Other: bleeding at puncture sites, hypersensitivity reactions (anaphylaxis).

Effects on lab test results
None reported.

Overdose and treatment
No information is available regarding accidental ingestion. Excessive I.V. dosage can lead to bleeding problems. Doses of 150 mg have been linked to a higher risk of intracranial bleeding.
 Discontinue infusion immediately if signs or symptoms of bleeding are observed.

Special considerations
• Altered results may be expected in coagulation and fibrinolytic tests. The use of aprotinin (150 to 200 units/ml) in the blood sample may attenuate this interference.
• Expect to begin alteplase infusions as soon as possible after onset of MI symptoms, such as angina or equivalent greater than 30 minutes’ duration; angina that’s unresponsive to nitroglycerin; or ECG evidence of MI.
• Administer drug within 3 hours after onset of CVA symptoms after exclusion of intracranial hemorrhage by CT scan or other diagnostic imaging methods capable of detecting presence of hemorrhage. Treatment should be performed only in facilities that can provide appropriate evaluation and management of intracranial hemorrhage.
• Prepare solution using supplied sterile water for injection. Don’t use bacteriostatic water for injection.
• Don’t mix other drugs with alteplase. Use 18G needle for preparing solution-aim water stream at lyophilized cake. Expect a slight foaming to occur. Don’t use if vacuum isn’t present.
• Drug may be further diluted with normal saline solution injection or D₅W to yield 0.5 mg/ml. Reconstituted or diluted solutions are stable for up to 8 hours at room temperature.
• Heparin is usually administered during or after alteplase as part of the treatment regimen for acute MI or pulmonary embolism. The use of anticoagulant or antiplatelet therapy for 24 hours is contraindicated when alteplase is used for acute ischemic stroke.
• Discontinue drug therapy for acute ischemic stroke in patients who haven’t recently used oral anticoagulants or heparin if pretreatment PT exceeds 15 seconds or if an elevated activated partial PT is identified.
• Staff should avoid I.M. injections, venipuncture, and arterial puncture during therapy. Use pressure dressings or ice packs on recent puncture sites to prevent bleeding. If arterial puncture is needed, select a site on the arm and apply pressure for 30 minutes afterward.
• Reconstitute Cathflo Activase with 2.2 ml sterile water, dissolve completely into a colorless to pale yellow solution that yields a concentration of 1 mg/ml. Solutions are stable for up to 8 hours at room temperature. Assess the cause of catheter dysfunction before using Cathflo Activase. Some conditions that occluded the catheter include: Catheter malposition, mechanical failure, constriction by a suture, and lipid deposits or drug precipitates within the catheter lumen. Do not attempt to suction because of the risk of damage to the vascular wall or collapse of soft-walled catheters.
• Do not use excessive pressure while instilling Cathflo Activase into the catheter, which could cause catheter rupture or expulsion of the clot into the circulation.
• Monitor patient for bleeding or hemorrhage.
• Monitor ECG for transient arrhythmias (sinus bradycardia, ventricular tachycardia, accelerated idioventricular rhythm, ventricular premature depolarizations) related to reperfusion after coronary thrombolysis. Antiarrhythmics should be available.
Pediatric patients
• Safety and efficacy of use in children haven’t been established, but the drug has been used investigationally in children with some success.
Geriatric patients
• Use cautiously in patients older than age 75 because they have an increased risk of adverse CV effects.

Patient education
• Teach patient signs and symptoms of internal bleeding and tell him to report these immediately.
• Tell patient to report adverse effects promptly.
• Advise patient about proper dental care to avoid excessive gum trauma resulting from vigorous brushing; drug increases chances of bleeding.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use