|
Activase (alteplase) for injection, for intravenous
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use ACTIVASE safely and effectively. See full prescribing information for ACTIVASE.
Activase (alteplase) for injection, for intravenous use
Initial U.S. Approval: 1987
INDICATIONS AND USAGE
Activase is a tissue plasminogen activator (tPA) indicated for the treatment of
-
Acute Ischemic Stroke (AIS). (1.1)
-
Acute Myocardial Infarction (AMI) to reduce mortality and incidence of heart failure. (1.2)
Limitation of Use in AMI: the risk of stroke may be greater than the benefit in patients at low risk of death from cardiac causes. (1.2)
-
Acute Massive Pulmonary Embolism (PE) for lysis. (1.3)
DOSAGE AND ADMINISTRATION
-
Acute Ischemic Stroke: The recommended dose is 0.9 mg/kg (not to exceed 90 mg total dose) infused intravenously over 60 minutes with 10% of the total dose administered as an initial bolus over 1 minute. (2.1)
-
Acute Myocardial Infarction: The recommended total dose is based on patient weight, not to exceed 100 mg. (2.2)
-
Acute Massive Pulmonary Embolism: The recommended dose is 100 mg administered by IV infusion over 2 hours. (2.3)
-
Do not add other medications to infusions containing Activase. (2.5)
DOSAGE FORMS AND STRENGTHS
-
Lyophilized powder: 50 mg and 100 mg with Sterile Water for Injection USP for reconstitution at 1 mg per 1 mL. (3)
CONTRAINDICATIONS
General
-
Active internal bleeding. (4.1, 4.2)
-
Recent intracranial or intraspinal surgery or serious head trauma. (4.1, 4.2)
-
Intracranial conditions that may increase the risk of bleeding. (4.1, 4.2)
-
Bleeding diathesis. (4.1, 4.2)
-
Current severe uncontrolled hypertension. (4.1, 4.2)
Acute Ischemic Stroke
-
Current intracranial hemorrhage. (4.1)
-
Subarachnoid hemorrhage. (4.1)
Acute Myocardial Infarction or Pulmonary Embolism
-
History of recent stroke. (4.2)
WARNINGS AND PRECAUTIONS
-
Increases the risk of bleeding. Avoid intramuscular injections. Monitor for bleeding. If serious bleeding occurs, discontinue Activase. (5.1)
-
Monitor patients during and for several hours after infusion for orolingual angioedema. If angioedema develops, discontinue Activase. (5.2)
-
Cholesterol embolism has been reported rarely in patients treated with thrombolytic agents. (5.3)
-
Consider the risk of reembolization from the lysis of underlying deep venous thrombi in patients with pulmonary embolism. (5.4)
ADVERSE REACTIONS
The most frequently occurring adverse reaction ( > 5%) is bleeding. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
-
Anticoagulants and drugs that inhibit platelet function increase the risk of bleeding when administered with Activase therapy. (7)
-
Concomitant angiotensin-converting enzyme inhibitors may increase the risk of orolingual angioedema. (7)
USE IN SPECIFIC POPULATIONS
Pregnancy: Activase is embryocidal in rabbits. (8.1)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 2/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 Acute Ischemic Stroke
Activase is indicated for the treatment of acute ischemic stroke.
Exclude intracranial hemorrhage as the primary cause of stroke signs and symptoms prior to initiation of treatment [see Contraindications (4.1)]. Initiate treatment as soon as possible but within 3 hours after symptom onset.
1.2 Acute Myocardial Infarction
Activase is indicated for use in acute myocardial infarction (AMI) for the reduction of mortality and reduction of the incidence of heart failure.
Limitation of Use: The risk of stroke may outweigh the benefit produced by thrombolytic therapy in patients whose AMI puts them at low risk for death or heart failure.
1.3 Pulmonary Embolism
Activase is indicated for the lysis of acute massive pulmonary embolism, defined as:
-
Acute pulmonary emboli obstructing blood flow to a lobe or multiple lung segments.
-
Acute pulmonary emboli accompanied by unstable hemodynamics, e.g., failure to maintain blood pressure without supportive measures.
2 DOSAGE AND ADMINISTRATION
2.1 Acute Ischemic Stroke
Administer Activase as soon as possible but within 3 hours after onset of symptoms.
The recommended dose is 0.9 mg/kg (not to exceed 90 mg total dose), with 10% of the total dose administered as an initial intravenous bolus over 1 minute and the remainder infused over 60 minutes.
During and following Activase administration for the treatment of acute ischemic stroke, frequently monitor and control blood pressure.
In patients without recent use of oral anticoagulants or heparin, Activase treatment can be initiated prior to the availability of coagulation study results. Discontinue Activase if the pretreatment International Normalized Ratio (INR) is greater than 1.7 or the activated partial thromboplastin time (aPTT) is elevated [see Contraindications (4.1)].
2.2 Acute Myocardial Infarction
Administer Activase as soon as possible after the onset of symptoms.
The recommended total doses for acute myocardial infarction (AMI) is based on patient weight, not to exceed 100 mg, regardless of the selected administration regimen (accelerated or 3 hour, described below).
There are two Activase dose regimens (accelerated and 3-hour) for use in the management of AMI; there are no controlled studies to compare clinical outcomes with these regimens [see Clinical Studies (14.2)].
Accelerated Infusion
The recommended accelerated infusion dose consists of an IV bolus [see Dosage and Administration (2.5)] followed by an IV infusion as set forth in Table 1.
The safety and efficacy of accelerated infusion of Activase have only been investigated with concomitant administration of heparin and aspirin [see Clinical Studies (14.2)].
3-Hour Infusion
For patients weighing ≥ 65 kg, the recommended dose is 100 mg administered as 60 mg in the first hour (6-10 mg administered as a bolus), 20 mg over the second hour, and 20 mg over the third hour. For smaller patients (< 65 kg), a dose of 1.25 mg/kg administered over 3 hours may be used. Weight-based doses are shown in Table 2.
2.3 Pulmonary Embolism (PE)
The recommended dose is 100 mg administered by IV infusion over 2 hours.
Institute parenteral anticoagulation near the end of or immediately following the Activase infusion when the partial thromboplastin time or thrombin time returns to twice normal or less.
2.4 Preparation for Administration
Reconstitution
Use only the accompanying Sterile Water for Injection (SWFI), USP without preservatives. Do not use Bacteriostatic Water for Injection, USP.
Reconstitute using aseptic technique. Do not add other medication to solutions containing Activase. Reconstitute Activase no more than 8 hours before use, as it contains no antibacterial preservatives [see How Supplied/Storage and Handling (16.2)].
Slight foaming is not unusual; let stand undisturbed for several minutes to allow large bubbles to dissipate. Inspect parenteral drug products for particulate matter and discoloration prior to administration whenever solution and container permit.
Activase may be administered as reconstituted at 1 mg/mL or further diluted immediately before administration in an equal volume of 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP, to yield a concentration of 0.5 mg/mL, using either polyvinyl chloride bags or glass vials.
Avoid excessive agitation during dilution; mix by gently swirling and/or slow inversion.
50 mg Vials
-
-
DO NOT USE IF VACUUM IS NOT PRESENT.
-
-
Using a large bore needle (e.g., 18 gauge) and a syringe, reconstitute by adding the contents of the accompanying 50 mL vial of SWFI to the 50 mg vial of Activase, directing the SWFI stream into the lyophilized cake.
100 mg Vials
-
-
THE 100 mg VIALS DO NOT CONTAIN VACUUM.
-
-
Using the transfer device provided, reconstitute by adding the contents of the accompanying 100 mL vial of SWFI to the 100 mg vial of Activase.
-
Use aseptic technique.
-
Remove the protective flip-caps from one vial of Activase and one vial of SWFI.
-
Open the package containing the transfer device by peeling the paper label off the package.
-
Remove the protective cap from one end of the transfer device and keeping the vial of SWFI upright, insert the piercing pin vertically into the center of the stopper of the vial of SWFI.
-
Remove the protective cap from the other end of the transfer device. DO NOT INVERT THE VIAL OF SWFI.
-
Hold the vial of Activase upside down, position it so that the center of the stopper is directly over the exposed piercing pin of the transfer device, and push the vial of Activase down so that the piercing pin is inserted through the center of the Activase vial stopper.
-
Invert the two vials so that the vial of Activase is on the bottom (upright) and the vial of SWFI is upside-down, allowing the SWFI to flow down through the transfer device. Allow the entire contents of the vial of SWFI to flow into the Activase vial (approximately 0.5 cc of SWFI will remain in the diluent vial).
-
Remove the transfer device and the empty SWFI vial from the Activase vial and discard.
-
Swirl gently to dissolve the Activase powder. DO NOT SHAKE.
Preparation of Bolus Dose
-
Prepare the bolus dose in one of the following ways: Remove the appropriate volume from the vial of reconstituted (1 mg/mL) Activase using a syringe and needle. If this method is used with the 50 mg vials, the syringe should not be primed with air and the needle should be inserted into the Activase vial stopper. If the 100 mg vial is used, the needle should be inserted away from the puncture mark made by the transfer device.
-
Remove the appropriate volume from a port (second injection site) on the infusion line after the infusion set is primed.
-
Program an infusion pump to deliver the appropriate volume as a bolus at the initiation of the infusion
2.5 Administration
Following bolus dose, if indicated [see Dosage and Administration (2.1, 2.2)]:
-
50 mg vials - administer using either a polyvinyl chloride bag or glass vial and infusion set.
-
100 mg vials - remove from the vial any quantity of drug in excess of that specified for patient treatment [see Dosage and Administration (2.1, 2.2)]. Insert the spike end of an infusion set through the same puncture site created by the transfer device in the stopper of the vial of reconstituted Activase. Peel the clear plastic hanger from the vial label. Hang the Activase vial from the resulting loop.
Activase is for intravenous administration only. Extravasation of Activase infusion can cause ecchymosis or inflammation. If extravasation occurs, terminate the infusion at that IV site and apply local therapy.
Do not add any other medication to infusion solutions containing Activase.
3 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
4 CONTRAINDICATIONS
4.1 Acute Ischemic Stroke
Do not administer Activase to treat acute ischemic stroke in the following situations in which the risk of bleeding is greater than the potential benefit [see Warnings and Precautions (5.1)]:
-
Current intracranial hemorrhage
-
Subarachnoid hemorrhage
-
Active internal bleeding
-
Recent (within 3 months) intracranial or intraspinal surgery or serious head trauma
-
Presence of intracranial conditions that may increase the risk of bleeding (e.g., some neoplasms, arteriovenous malformations, or aneurysms)
-
Bleeding diathesis
-
Current severe uncontrolled hypertension.
4.2 Acute Myocardial Infarction or Pulmonary Embolism
Do not administer Activase for treatment of AMI or PE in the following situations in which the risk of bleeding is greater than the potential benefit [see Warnings and Precautions (5.1)]:
-
Active internal bleeding
-
History of recent stroke
-
Recent (within 3 months) intracranial or intraspinal surgery or serious head trauma
-
Presence of intracranial conditions that may increase the risk of bleeding (e.g. some neoplasms, arteriovenous malformations, or aneurysms)
-
Bleeding diathesis
-
Current severe uncontrolled hypertension.
5 WARNINGS AND PRECAUTIONS
5.1 Bleeding
Activase can cause internal bleeding (intracranial, retroperitoneal, gastrointestinal, genitourinary, respiratory) or external bleeding, especially at arterial and venous puncture sites. Avoid intramuscular injections and trauma to the patient while on Activase. Perform venipunctures carefully and only as required. To minimize bleeding from noncompressible sites, avoid internal jugular and subclavian venous punctures. If an arterial puncture is necessary during Activase infusion, use an upper extremity vessel that is accessible to manual compression, apply pressure for at least 30 minutes, and monitor the puncture site closely.
Because of the higher risk of intracranial hemorrhage in patients treated for acute ischemic stroke, limit treatment to facilities that can provide timely access to appropriate eva luation and management of intracranial hemorrhage.
Fatal cases of hemorrhage associated with traumatic intubation in patients administered Activase have been reported.
Aspirin and heparin have been administered concomitantly with and following infusions of Activase in the management of acute myocardial infarction and pulmonary embolism, but the concomitant administration of heparin and aspirin with and following infusions of Activase for the treatment of acute ischemic stroke during the first 24 hours after symptom onset has not been investigated. Because heparin, aspirin, or Activase may cause bleeding complications, carefully monitor for bleeding, especially at arterial puncture sites. Hemorrhage can occur 1 or more days after administration of Activase, while patients are still receiving anticoagulant therapy.
If serious bleeding occurs, terminate the Activase infusion.
In the following conditions, the risks of bleeding with Activase therapy for all approved indications are increased and should be weighed against the anticipated benefits:
-
Recent major surgery or procedure, (e.g., coronary artery bypass graft, obstetrical delivery, organ biopsy, previous puncture of noncompressible vessels)
-
Cerebrovascular disease
-
Recent intracranial hemorrhage
-
Recent gastrointestinal or genitourinary bleeding
-
Recent trauma
-
Hypertension: systolic BP above 175 mm Hg or diastolic BP above 110 mm Hg
-
High likelihood of left heart thrombus, e.g., mitral stenosis with atrial fibrillation
-
Acute pericarditis
-
Subacute bacterial endocarditis
-
Hemostatic defects including those secondary to severe hepatic or renal disease
-
Significant hepatic dysfunction
-
Pregnancy
-
Diabetic hemorrhagic retinopathy, or other hemorrhagic ophthalmic conditions
-
Septic thrombophlebitis or occluded AV cannula at seriously infected site
-
Advanced age [see Use in Specific Populations (8.5)]
-
Patients currently receiving anticoagulants (e.g., warfarin sodium)
-
Any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location.
5.2 Orolingual Angioedema
Orolingual angioedema has been observed during and up to 2 hours after Activase infusion in patients treated for acute ischemic stroke and acute myocardial infarction [see Adverse Reactions (6.1)]. In many cases, patients received concomitant angiotensin-converting enzyme inhibitors [see Drug Interactions (7)]. Monitor patients treated with Activase during and for several hours after infusion for orolingual angioedema. If angioedema develops, discontinue the Activase infusion and promptly institute appropriate therapy (e.g., antihistamines, intravenous corticosteroids, epinephrine).
5.3 Cholesterol Embolization
Cholesterol embolism has been reported rarely in patients treated with thrombolytic agents; the true incidence is unknown. Cholesterol embolism 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. It is associated with invasive vascular procedures (e.g., cardiac catheterization, angiography, vascular surgery) and/or anticoagulant therapy.
5.4 Reembolization of Deep Venous Thrombi during Treatment for Acute Massive Pulmonary Embolism
Activase has not been shown to treat adequately underlying deep vein thrombosis in patients with PE. Consider the possible risk of reembolization due to the lysis of underlying deep venous thrombi in this setting.
5.5 Coagulation Tests May Be Unreliable during Activase Therapy
Coagulation tests and measures of fibrinolytic activity may be unreliable during Activase therapy, unless specific precautions are taken to prevent in vitro artifacts. When present in blood at pharmacologic concentrations, Activase remains active under in vitro conditions, which can result in degradation of fibrinogen in blood samples removed for analysis.
6 ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in the other sections of the label:
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The most frequent adverse reaction associated with Activase in all approved indications is bleeding.
Bleeding
Acute Ischemic Stroke (AIS)
In clinical studies in patients with AIS (Studies 1 and 2) the incidence of intracranial hemorrhage, especially symptomatic intracranial hemorrhage, was higher in Activase-treated patients than in placebo patients. A dose-finding study of Activase suggested that doses greater than 0.9 mg/kg may be associated with an increased incidence of intracranial hemorrhage.
The incidence of all-cause 90-day mortality, intracranial hemorrhage, and new ischemic stroke following Activase treatment compared to placebo are presented in Table 3 as a combined safety analysis (n=624) for Studies 1 and 2. These data indicate a significant increase in intracranial hemorrhage following Activase treatment, particularly symptomatic intracranial hemorrhage within 36 hours. There was no increase in the incidences of 90-day mortality or severe disability in Activase-treated patients compared to placebo.
Bleeding events other than intracranial hemorrhage were noted in the studies of AIS and were consistent with the general safety profile of Activase. In Studies 1 and 2, the frequency of bleeding requiring red blood cell transfusions was 6.4% for Activase-treated patients compared to 3.8% for placebo (p = 0.19).
Although exploratory analyses of Studies 1 and 2 suggest that severe neurological deficit (National Institutes of Health Stroke Scale [NIHSS > 22]) at presentation was associated with an increased risk of intracranial hemorrhage, efficacy results suggest a reduced but still favorable clinical outcome for these patients.
Acute Myocardial Infarction (AMI)
For the 3-hour infusion regimen in the treatment of AMI, the incidence of significant internal bleeding (estimated as > 250 mL blood loss) has been reported in studies in over 800 patients (Table 4). These data do not include patients treated with the Activase accelerated infusion.
The incidence of intracranial hemorrhage in AMI patients treated with Activase is presented in Table 5.
A dose of 150 mg or greater should not be used in the treatment of AMI because it has been associated with an increase in intracranial bleeding.
Pulmonary Embolism (PE)
For acute massive pulmonary embolism, bleeding events were consistent with the general safety profile observed with Activase treatment of AMI patients receiving the 3-hour infusion regimen.
Allergic Reactions
Allergic-type reactions, e.g., anaphylactoid reaction, laryngeal edema, orolingual angioedema, rash, and urticaria have been reported. When such reactions occur, they usually respond to conventional therapy.
6.2 Post-Marketing Experience
The following adverse reactions have been identified during post-approval use of Activase. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions are frequent sequelae of the underlying disease, and the effect of Activase on the incidence of these events is unknown.
Acute Ischemic Stroke: Cerebral edema, cerebral herniation, seizure, new ischemic stroke. These events may be life threatening and may lead to death.
Acute Myocardial Infarction: Arrhythmias, AV block, cardiogenic shock, heart failure, cardiac arrest, recurrent ischemia, myocardial reinfarction, myocardial rupture, electromechanical dissociation, pericardial effusion, pericarditis, mitral regurgitation, cardiac tamponade, thromboembolism, pulmonary edema. These events may be life threatening and may lead to death. Nausea and/or vomiting, hypotension and fever have also been reported.
Pulmonary Embolism: Pulmonary reembolization, pulmonary edema, pleural effusion, thromboembolism, hypotension. These events may be life thre |
|
