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Review Use of Activase in acute massive PE >

Important Safety Information & Indication

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Indications
Activase® (alteplase) is indicated for the treatment of acute ischemic stroke (AIS). Exclude intracranial hemorrhage as the primary cause of stroke signs and symptoms prior to initiation of treatment. Initiate treatment as soon as possible but within 3 hours after symptom onset.

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.

Activase is indicated for the lysis of acute massive pulmonary embolism (PE), 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.

Contraindications
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: current intracranial hemorrhage (ICH); 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; bleeding diathesis; and current severe uncontrolled hypertension.

Do not administer Activase to treat acute myocardial infarction or pulmonary embolism in the following situations in which the risk of bleeding is greater than the potential benefit: 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; bleeding diathesis; and current severe uncontrolled hypertension.

Warnings and Precautions

Bleeding
Activase can cause significant, sometimes fatal, internal or external bleeding, especially at arterial and venous puncture sites. Avoid intramuscular injections and trauma to the patient. Fatal cases of hemorrhage associated with traumatic intubation in patients administered Activase have been reported. The concomitant administration of heparin and aspirin with and following infusions of Activase 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 are increased and should be weighed against the anticipated benefits: recent major surgery or procedure; cerebrovascular disease; recent intracranial hemorrhage; recent gastrointestinal or genitourinary bleeding; recent trauma; hypertension; high likelihood of left heart thrombus; 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; and patients currently receiving oral anticoagulants, or any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location.

Orolingual Angioedema
Orolingual angioedema has been observed during and up to 2 hours after infusion. In many cases, patients received concomitant angiotensin‑converting enzyme inhibitors. Monitor patients treated with Activase during and for several hours after Activase infusion for orolingual angioedema. If angioedema develops, discontinue the Activase infusion and promptly institute appropriate therapy.

Cholesterol Embolization
Cholesterol embolism, sometimes fatal, has been reported rarely in patients treated with thrombolytic agents; the true incidence is unknown. It is associated with invasive vascular procedures and/or anticoagulant therapy.

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.

Coagulation Tests May be Unreliable during Activase Therapy
Coagulation tests and/or measures of fibrinolytic activity may be unreliable during Activase therapy unless specific precautions are taken to prevent in vitro artifacts.

Adverse Reactions
The most frequent adverse reaction associated with Activase therapy is bleeding.

Although exploratory analyses of the AIS clinical studies 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.

Allergic‑type reactions, e.g., anaphylactoid reaction, laryngeal edema, orolingual angioedema, rash, and urticaria have been reported.

Please see full Prescribing Information for additional Important Safety Information.

References

1.

National Institute of Neurological Disorders and Stroke. Know stroke. Know the signs. Act in time. National Institute of Neurological Disorders and Stroke website. Last modified March 29, 2016. Accessed August 12, 2016. http://www.ninds.nih.gov/disorders/stroke/knowstroke.htm.

2.

Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44:870-947.

3.

Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scientific Rationale for the Inclusion and Exclusion Criteria for Intravenous Alteplase in Acute Ischemic Stroke: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2016;47(2):581-641.

4.

FDA Information on Medication Errors Involving Activase and TNKase. September 2015. Accessed August 9, 2016. http://www.fda.gov/downloads/ForHealthProfessionals/LearningActivities/UCM464193.pdf.

5.

Activase [Prescribing Information]. South San Francisco, CA: Genentech, Inc; January 2017.

6.

National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333:1581-1587.    

7.

FDA Access Summary basis of approval. Accessed August 14, 2017. https://www.accessdata.fda.gov/drugsatfda_docs/nda/96/altegen061896s.pdf.

8.

Rost N. Stroke Reperfusion Therapy: IV t-PA Administration. Massachusetts General Hospital: Stroke Services Web Site. Last updated: January 16, 2015. Accessed September 29, 2017. http://stopstroke.massgeneral.org/protocolThromIVAdmin.aspx

9.

Summers D, Leonard A, Wentworth D, et al. Comprehensive overview of nursing and interdisciplinary care of the acute ischemic stroke patient: a scientific statement from the American Heart Association. Stroke. 2009;40:2911-2944.

10.

American Association of Neurosicence Nurses (AANN) Reference Series for Clinical Practice. Guide to the Care of the Patient with Ischemic Stroke. 2004. Accessed August 9, 2016. http://www.pennstatehershey.org/c/document_library/get_file?folderId=115233&name=DLFE-2409.pdf.

11.

Tamm A, Siddiqui M, Shuaib A, et al. Impact of stroke care unit on patient outcomes in a community hospital. Stroke. 2014;45(1):211-216.

12.

CMS Quality Measurement Programs Characteristics. Centers for Medicare and Medicaid Services website. Published June 28, 2012. Accessed August 13, 2016. 2012. https://www.cms.gov/Medicare/Quality-Initiatives-Patient-Assessment-Instruments/QualityMeasures/Downloads/CMSQualityMeasurementProgramsCharacteristics.PDF.

13.

The Joint Commission, Stroke. Last updated June 17, 2016. Accessed August 1, 2016. https://www.jointcommission.org/stroke/.

14.

Busby L, Owada K, Dhungana S, et al. CODE FAST: a quality improvement initiative to reduce door-to-needle times. J Neurointerv Surg. 2016;8(7):661-664.

15.

Jauch EC, Cucchiara B, Adeoye O, et al. Part 11: adult stroke: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;122(18 Suppl 3):S818-S828.

16.

TARGET: STROKE PHASE II, Campaign Manual. 2014. Accessed August 2, 2016. http://www.strokeassociation.org/idc/groups/heart-public/@wcm/@gwtg/documents/downloadable/ucm_470730.pdf.

17.

Target: StrokeSM Phase II. 11 key best practice strategies. October 2014. Accessed March 30, 2015. http://www.strokeassociation.org/STROKEORG/Professionals/TargetStroke/Target-Stroke_UCM_314495_SubHomePage.jsp.

18.

Kalanithi L, Tai W, Conley J, Platchek T, Zulman D, Milstein A. Better health, less spending: delivery innovation for ischemic cerebrovascular disease. Stroke. 2014;45(10):3105-3111.

19.

American Hospital Association. October 2012. Accessed October 11, 2016. http://www.aha.org/research/reports/tw/12oct-tw-quality.pdf.

20.

Wood KE. Major pulmonary embolism: review of a pathophysiologic approach to the golden hour of hemodynamically significant pulmonary embolism. Chest. 2002;121:877-905.

21.

Tan KT, Oudkerk M, van Beek EJR. Deep Vein Thrombosis and Pulmonary Embolism. In: Hallet JW Jr, Mills JL, Earnshaw JJ, Reekers JA, Eds. Comprehensive Vascular and Endovascular Surgery. Philadelphia, PA: Elsevier Limited; 2003.

22.

Kearon C, Akl EA, Ornelas J, Blaivas A, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016 Feb;149(2):315-52.

23.

Fesmire FM, Brown MD, Espinosa JA, et al. Critical issues in the evaluation and management of adult patients presenting to the emergency department with suspected pulmonary embolism. Ann Emerg Med. 2011 Jun;57(6):628-652.e75.

24.

Skolarus LE, Meurer WJ, Shanmugasundaram K, et al. Marked regional variation in acute stroke treatment among Medicare beneficiaries. Stroke. 2015;46:1890-1896.

25.

ICD-10. Accessed August 14, 2017. https://www.cms.gov/Medicare/Coding/ICD10/.

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Follow these steps for reconstituting 50-mg vials.5

  • Reconstitute Activase immediately before administration, using only preservative free Sterile Water for Injection (SWFI), U.S. Pharmacopeia (USP).
  • A single 50-mg vial of Activase may be used to treat patients weighing up to 122 lbs (55.5 kg). Reconstitute Activase immediately before administration, using aseptic technique at all times.
  • Begin by assembling the 50-mg vial of Activase, the vial of SWFI USP, (included with the Activase package), a 50-mL syringe, a large-bore needle (eg, 18-gauge), and alcohol wipes. Also, prepare a polyvinyl chloride bag or glass vial along with an infusion set.
  • Reconstitution should be carried out by adding SWFI to the 50-mg vial of Activase powder.

Step 1: Remove the protective cap from the top of the Activase vial and the vial of SWFI. Swab the top of each vial with an alcohol wipe to reduce the risk of contamination.

Step 2: Using the large-bore needle and syringe, withdraw 50 mL of SWFI. Do not use Bacteriostatic Water for Injection, USP. Do not prime the syringe with air. Safely discard the diluent vial according to institutional procedures.

Step 3: Insert the syringe into the stopper on the 50-mg vial of Activase and inject the contents, directing the stream into the lyophilized cake. DO NOT USE IF VACUUM IS NOT PRESENT. Safely discard the needle and syringe according to institutional procedures.

Step 4: Mix the solution with a gentle swirl. DO NOT SHAKE. Slight foaming of the solution is normal. Let the solution stand undisturbed for several minutes to allow any large bubbles to dissipate. Visually inspect the Activase solution for particulate matter and discoloration before administration.

Comprehensive list of recommended diagnostic tests

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2013 AHA/ASA Guidelines recommend these immediate diagnostic tests for all patients with AIS2:

  • Non-contrast brain CT or brain magnetic resonance imaging (MRI)
  • Blood glucose
  • Oxygen saturation
  • Serum electrolytes/renal function testsa
  • Complete blood count, including platelet counta
  • Markers of cardiac ischemiaa
  • Prothrombin time (PT)/international normalized ratio (INR)a
  • Activated partial thromboplastin time (aPTT)a
  • Electrocardiograma

Additional diagnostic tests for selected patients with suspected AIS recommended by the 2013 AHA/ASA Guidelines2:

  • aPTT, INR, platelet count, ecarin clotting time (ECT), thromboplastin time (TT), or appropriate direct factor Xa activity assays if it is suspected the patient is taking direct thrombin inhibitors or direct factor Xa inhibitors
  • Hepatic function tests
  • Toxicology screen
  • Blood alcohol level
  • Pregnancy test
  • Arterial blood gas tests (if hypoxia is suspected)
  • Chest radiography (if lung disease is suspected)
  • Lumbar puncture (if subarachnoid hemorrhage is suspected and CT scan is negative for blood)
  • Electroencephalogram (if seizures are suspected)
     

a Although it is desirable to know the results of these tests before administering Activase, fibrinolytic therapy should not be delayed while awaiting results unless: 1) there is clinical suspicion of a bleeding abnormality or thrombocytopenia, 2) the patient has received heparin or warfarin, or 3) the patient has received other anticoagulants (direct thrombin inhibitors or direct factor Xa inhibitors).
AHA=American Heart Association; AIS=acute ischemic stroke; ASA=American Stroke Association; CT=computed tomography.

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