Activase

Name: Activase

If OVERDOSE is suspected

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Dosage Forms and Strengths

  • 50 mg lyophilized powder per single use vial with 50 mL SWFI USP for reconstitution
  • 100 mg lyophilized powder per single use vial with 100 mL SWFI USP for reconstitution

Activase Description

Activase is a tissue plasminogen activator produced by recombinant DNA technology. It is a sterile, purified glycoprotein of 527 amino acids. It is synthesized using the complementary DNA (cDNA) for natural human tissue-type plasminogen activator obtained from a human melanoma cell line. Activase is a sterile, white to off-white, lyophilized powder for intravenous administration after reconstitution with Sterile Water for Injection, USP.

Table 6 Quantitative Composition of the Lyophilized Product
100 mg Vial 50 mg Vial
Alteplase 100 mg (58 million IU) 50 mg (29 million IU)
L-Arginine 3.5 g 1.7 g
Phosphoric Acid 1 g 0.5 g
Polysorbate 80 10 mg 5 mg
Vacuum No Yes

Biological potency is determined by an in vitro clot lysis assay and is expressed in International Units (IU).

The reconstituted preparation results in a colorless to pale yellow transparent solution containing Activase 1 mg/mL at approximately pH 7.3. The osmolality of this solution is approximately 215 mOsm/kg.

Side Effects of Activase

Serious side effects have been reported with Activase. See the “Activase Precautions” section.

Common side effects of Activase include bleeding. 

This is not a complete list of Activase side effects. Ask your doctor or pharmacist for more information. Tell your doctor if you have any side effect that bothers you or does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088

Activase Interactions

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

  • anticoagulant (blood thinner) medications such as warfarin (Coumadin, Jantoven), heparin, enoxaparin (Lovenox), fondaparinux (Arixtra), rivaroxaban (Xarelto), and apixaban (Eliquis)
  • aspirin

This is not a complete list of Activase drug interactions. Ask your doctor or pharmacist for more information

Activase and Pregnancy

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Activase falls into category C. In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

Activase Dosage

The dose your doctor recommends may be be based on your weight.

The recommended dose/dose range of Activase (alteplase) for the treatment of myocardial infarction (heart attack) for patients weighing more than 67kg is 100mg and given in the following manner:

  • Accelerated infusion
    • 15mg bolus (one-time) dose
    • 50mg dose infused (given over) next 30 minutes
    • 35mg dose infused (given over) next 60 minutes
  • 3 hour infusion
    • 60mg (of which 6-10 mg given as a one-time dose) infused (given over) in the first hour
    • 20mg infused (given over) over the second hour
    • 20mg infused (given over) over the third hour

The recommended dose/dose range of Activase (alteplase) for the treatment of stroke is 0.9 mg/kg (not to exceed 90mg total dose) and is given in the following manner:

  • 10% of the total dose given as a bolus (one-time dose) over 1 minute
  • the remaining 90% is infused (given over) over 60 minutes

The recommended dose/dose range of Activase (alteplase) for the treatment of pulmonary embolism (blood clot in lung) is 100mg infused (given over) over 2 hours.

Other Requirements

Activase should be stored at room temperature not to exceed 30°C (86°F), or refrigerated (2°–8°C/36°–46°F). Protect Activase from excessive exposure to light.

  • Heart Attack
  • Stroke (Signs, Symptoms, Warning Signs)

What Is Activase?

Alteplase is a thrombolytic (THROM-bo-LIT-ik) drug, sometimes called a "clot-busting" drug. It helps your body produce a substance that dissolves unwanted blood clots.

Alteplase is used to treat a stroke caused by a blood clot or other obstruction in a blood vessel. Alteplase is also used to prevent death from a heart attack (acute myocardial infarction).

Alteplase is also used to treat a blood clot in the lung (pulmonary embolism).

Alteplase is also used to dissolve blood clots that have formed in or around a catheter placed inside a blood vessel. This improve the flow of medicines injected in through the catheter, or blood drawn out through the catheter.

Alteplase may also be used for purposes not listed in this medication guide.

If possible before you receive alteplase, tell your doctor if you have a brain tumor or aneurysm, high blood pressure, stomach bleeding, hemophilia or other bleeding disorder, or if you have recently had a head injury, brain or spinal surgery, or other major surgery or serious injury.

In an emergency situation it may not be possible to tell your caregivers about your health conditions. Make sure any doctor caring for you afterward knows you have received this medicine.

You should not be treated with alteplase if you are allergic to it, or if you have:

  • bleeding inside your brain;
  • active bleeding inside your body;
  • a recent history of medical trauma or injury;
  • stomach bleeding;
  • a bleeding or blood clotting disorder such as hemophilia;
  • severe or uncontrolled high blood pressure;
  • a brain tumor or aneurysm (dilated blood vessel);
  • recent major surgery;
  • a recent history of head injury or surgery on your brain or spinal cord within the past 3 months; or
  • a recent history of stroke (unless you are being treated for stroke).

If possible before you receive alteplase, tell your doctor if you have:

  • a past history of strokes;
  • a recent history of bleeding in your brain, stomach, intestines, or urinary tract;
  • high blood pressure;
  • heart problems;
  • an infection of the lining of your heart (also called bacterial endocarditis);
  • liver or kidney disease;
  • eye problems caused by diabetes;
  • severe bruising or infection around a vein where an IV was placed;
  • if you are pregnant or have recently had a baby;
  • if you have recently had an organ biopsy; or
  • if you have recently had a serious injury or major surgery.

In an emergency situation it may not be possible to tell your caregivers if you are pregnant or breast-feeding. Make sure any doctor caring for your pregnancy or your baby knows you have received this medicine.

For Healthcare Professionals

Applies to alteplase: injectable powder for injection, intravenous powder for injection

Hematologic

The incidence of major hemorrhagic events among heparinized patients with acute myocardial infarction who underwent cardiac catheterization in the Thrombolysis in Myocardial Infarction (TIMI) study significantly increased with age, averaging 8.7% and 24.7% for patients less than 65 years and 70 to 76 years old, respectively. These values agree with GISSI-2 data, where the overall incidence of bleeding associated with alteplase (the active ingredient contained in Activase) with and without heparin was 8.5% (0.5% major, 8.0% minor). Concomitant administration of heparin did not increase the incidence of stroke, although the incidence of major bleeding was greater in patients who received both thrombolytic (alteplase or streptokinase) and heparin therapy.

In one large study of 139 patients with acute thrombotic or embolic stroke, the incidence of hemorrhagic infarction averaged 20.2%. Parenchymal hematoma was observed in 10.6% of patients in this study, and neurological worsening accompanied by either hemorrhagic infarction or brain parenchymal hematoma was observed in 9.6% of patients. Limited data in which 100 mg of alteplase was given to 32 patients with documented middle cerebral artery and/or intracranial internal carotid artery occlusion reveal an incidence of hemorrhagic infarction without clinical deterioration in 28%, fatal parenchymal hemorrhage in 9%, and serious puncture site hemorrhage in 6% of patients.

In general, the overall incidence of alteplase-induced symptomatic intracerebral hemorrhage (ICH) in most studies has ranged between 3% and 7%. It appears that the overall risk of symptomatic ICH with the use of IV alteplase therapy is dependent on the expertise of the treating clinician. In one report, the risk of symptomatic ICH was 4% if protocol guidelines were strictly followed, but more than 10% when deviating from protocol guidelines. Other studies have confirmed these findings. The risk of ICH appears to be higher in elderly patients treated with thrombolytics for acute MI. An alternative reperfusion strategy (i.e., angioplasty) may be considered in this patient population.[Ref]

The hematologic side effect, bleeding, is the most common adverse event in all approved indications.

The incidence of bleeding among patients with acute myocardial infarction who received alteplase (often with aspirin and heparin) ranged from 8% to 77% (0.5% to 10% serious). Blood loss of greater than 250 mL occurred in up to 5% of patients, and typically affected the gastrointestinal tract (5%) or genitourinary tract (4%). Ecchymosis, epistaxis, gingival, or retroperitoneal bleeding occurred in up to 1% of patients.

The incidence of alteplase-associated intracranial hemorrhagic (ICH) in patients with acute myocardial infarction is dose-related and has averaged about 1%. Administration of 100 mg over 3 hours resulted in an incidence of stroke of 0.4%, at 100 mg over 90 minutes the rate was 0.7%, and at 150 mg over 90 minutes the rate of ICH was 1.3%. ICH in patients with acute ischemic stroke was significantly greater in patients receiving alteplase (15.4%) compared to placebo (6.4%). Symptomatic ICH (defined as sudden clinical worsening followed by subsequent CT verification of ICH) occurred in 8% (6.4% within 36 hours of receiving alteplase).

Stroke occurred in 1.2% to 1.6% of patients experiencing an AMI and receiving alteplase as a 3 hour infusion or an accelerated infusion, respectively.

Rare cases of atheroembolic events have been associated with the use of this drug and other lytic agents.

If bleeding occurs during therapy with alteplase and cannot be controlled by pressure, it is recommended that alteplase (and heparin, if applicable) should be discontinued immediately. Arterial punctures are of particular concern and an upper extremity accessible to manual compression is preferred. The usual precautions and procedures following arterial catheterization are extremely important. It is recommended that other invasive procedures be avoided or minimized. Non-compressible venous sites should be avoided.[Ref]

Cardiovascular

Cardiovascular-related side effects may occur more frequently in patient with an acute myocardial infarction (AMI) or pulmonary embolism. These events may be a sequelae of the disease and their relationship to the drug is not always clear. Reperfusion arrhythmias, including sinus bradycardia, accelerated idioventricular rhythm, premature ventricular depolarizations, or ventricular tachycardia commonly have occurred. Alteplase has been shown to significantly reduce the incidence of in-hospital mortality, left ventricular failure, postinfarction angina, reinfarction, and all ischemic events in patients with AMI.

Alteplase-associated cases of recurrent thrombosis or reinfarction have been reported. Rarely, reinfarction may be due to embolization of partially lysed thrombi. Reformation of thrombi may be due to elevated thrombin-antithrombin-III levels during alteplase (the active ingredient contained in Activase) therapy. Theoretically, adjunctive therapy with continuous heparin will significantly decrease the risk of an alteplase-induced hypercoagulable state.

Angioedema has also been reported (1% to 2%) during alteplase therapy in patients with acute ischemic stroke, particularly when alteplase was used in combination with an angiotensin-converting enzyme inhibitor. Orolingual angioedema has, in most cases, been mild, transient, and spontaneously reversible; however, it can be rapidly progressive requiring urgent intubation.

Recurrent hemopericardium, cardiac tamponade, massive hemorrhagic MI and death from cardiogenic shock have been associated with the use of some thrombolytic agents.

Rarely, cholesterol embolization syndrome presenting as peripheral cyanosis has been associated with alteplase therapy.[Ref]

The mortality rate among patients in the Thrombolysis in Myocardial Infarction (TIMI) study significantly increased with age, averaging 3.5% and 12% for patients less than 65 years and 70 to 76 years old, respectively. Risk factors for death were female gender, diabetes mellitus, extensive coronary artery disease, history of congestive heart failure, persistent chest pain after alteplase administration, low systolic blood pressure at presentation, and advanced age.[Ref]

Nervous system

A potentially life-threatening nervous system side effect, hemorrhagic stroke, has occurred in approximately 1% of patients with an acute myocardial infarction. Administration of 100 mg over 3 hours resulted in a 0.4% incidence of stroke, at 100 mg over 90 minutes the incidence was 0.7%, and at 150 mg over 90 minutes the rate of ICH was 1.3%. The incidence is significantly increased in patients with thrombotic stroke, with reports as high as 31% (4% to 10% experience worsening neurologic status). See "Hematologic" side effects. Rare cases of intracerebral hemorrhage associated with the use of t-PA in patients with cerebral amyloid angiopathy and cases of headache or subdural hematoma have been associated with alteplase (the active ingredient contained in Activase)

Recurrent intracerebral embolization following alteplase has been reported in a patient with dilated cardiomyopathy. Alteplase may promote lysis and embolization of detached intracranial thrombi.

Stroke has occurred in 1.2% to 1.6% of patients experiencing an AMI and receiving alteplase as a 3 hour infusion or an accelerated infusion, respectively.

Rare cases of atheroembolic events have been associated with the use of this drug and other lytic agents.[Ref]

A retrospective meta-analysis of patients with intracranial hemorrhage (ICH) who had received alteplase (n = 88) versus no alteplase (n = 148) revealed the following independent predictors for ICH (odds ratio): age over 65 years (2.2), body weight below 70 kg (2.1), and hypertension on admission (2.0). Furthermore, the probability of ICH increased with the number of risk factors present. Other studies have corroborated these data, with some finding a higher Killip classification and the occurrence of anterior myocardial infarction as additional risk factors. These data do not account for other possible risk factors, such as extensive peripheral vascular disease, diabetes, or the use of oral anticoagulants.[Ref]

Hypersensitivity

A 69-year-old beekeeper with acute myocardial infarction developed urticaria and gross facial, tongue, and neck edema within 25 minutes following administration of glyceryl trinitrate, nifedipine, aspirin, and alteplase (the active ingredient contained in Activase) Investigations revealed normal complement (qualitative and quantitative measurements), the absence of circulating immune complexes, normal levels of circulating IgE, and absence of t-PA antibodies by ELISA. Intradermal skin testing with each drug revealed no allergic response. This anaphylactoid reaction did not appear to be due to an antibody-antigen or direct chemical reaction. This patient had a history of atopy. The authors suggested that clinicians who administer alteplase to strongly atopic individuals consider the possibility of an anaphylactoid reaction and have resuscitative measures available.

A 51-year-old woman with systemic lupus erythematosus and deep vein thrombosis developed throat tightness, dyspnea and dysphagia within 24 hours after receiving alteplase therapy. Subconjunctival bullous edema of the left eye and angioedema of the tongue, face, neck and upper lip were also observed. Associated laboratory findings included markedly decreased C4 and C1 esterase inhibitor levels relative to baseline. The patient's angioedema resolved within six hours after discontinuation of alteplase and initiation of steroid and antihistamine therapy.

A separate report documented two cases of anaphylactic reactions following treatment of 105 consecutive patients receiving alteplase for the treatment of ischemic stroke.[Ref]

Hypersensitivity reactions have occurred in less than 0.02% of patients. A cause-and-effect relationship between anaphylaxis and alteplase has not been clearly established.[Ref]

Gastrointestinal

Gastrointestinal (GI) side effects generally have been limited to GI bleeding.[Ref]

Renal

Renal biopsy in a 76-year-old man with a history of angina, hypertension, and hypercholesterolemia who developed acute renal failure after alteplase (the active ingredient contained in Activase) therapy for an acute myocardial infarction revealed needle-shaped cholesterol crystals in small artery intima. There was mild focal segmental mesangial cell proliferation, tubular atrophy, and interstitial fibrosis. The patient required maintenance hemodialysis.[Ref]

Rare cases of cholesterol crystal embolization syndrome-associated renal failure have occurred during alteplase therapy.[Ref]

General

Bleeding has been the most frequent side effect noted with alteplase (the active ingredient contained in Activase) therapy. Arterial punctures are of particular concern and an upper extremity accessible to manual compression is preferred if arterial puncture is required. The usual precautions and procedures following arterial catheterization are extremely important. It is recommended that other invasive procedures be avoided or minimized. Non-compressible venous sites should be avoided.[Ref]

Hepatic

Hepatic side effects have been limited to rare (at least two cases) reports of hepatic cholesterol embolization syndrome.[Ref]

Local

Local inflammation and/or ecchymosis may occur with extravasation during alteplase (the active ingredient contained in Activase) infusion.[Ref]

Some side effects of Activase may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

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