Tenecteplase

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Kit, Intravenous:

TNKase: 50 mg

Pharmacology

Mechanism of Action

Promotes initiation of fibrinolysis by binding to fibrin and converting plasminogen to plasmin. Tenecteplase is essentially alteplase with the exception of 3 point mutations and is more fibrin specific, more resistant to plasminogen activator inhibitor -1 (PAI-1), with a longer duration of action compared to alteplase. Produced by recombinant DNA technology using a mammalian cell line (Chinese hamster ovary cells).

Pharmacokinetics/Pharmacodynamics

Distribution

V_d is weight related and approximates plasma volume

Metabolism

Primarily hepatic

Excretion

Clearance: Plasma: 99 to 119 mL/minute

Half-Life Elimination

Biphasic: Initial: 20 to 24 minutes; Terminal: 90 to 130 minutes

Use: Labeled Indications

ST-elevation myocardial infarction: Management of ST-elevation myocardial infarction (STEMI) for the lysis of thrombi in the coronary vasculature to restore perfusion and reduce mortality.

Recommended criteria for treatment of STEMI (ACC/AHA [O’Gara 2013]): Ischemic symptoms within 12 hours of treatment or evidence of ongoing ischemia 12 to 24 hours after symptom onset with a large area of myocardium at risk or hemodynamic instability.

STEMI ECG definition: New ST-segment elevation at the J point in at least 2 contiguous leads of ≥2 mm (0.2 mV) in men or ≥1.5 mm (0.15 mV) in women in leads V₂ to V₃ and/or of ≥1 mm (0.1 mV) in other contiguous precordial leads or limb leads on ECG. New or presumably new left bundle branch block (LBBB) may interfere with ST-elevation analysis and should not be considered diagnostic in isolation.

At non-PCI-capable hospitals, the ACC/AHA recommends thrombolytic therapy administration when the anticipated first medical contact (FMC)-to-device time at a PCI-capable hospital is >120 minutes due to unavoidable delays.

Use: Off Label

Pulmonary embolism, acute (hemodynamically unstable/massive)yes

Based on the 2016 American College of Chest Physicians (ACCP) guidelines for antithrombotic therapy for VTE disease, thrombolytic therapy is suggested in patients with acute pulmonary embolism who are hemodynamically unstable defined as sustained hypotension (SBP <90 mm Hg for 15 minutes) or with signs/symptoms of shock and without a high bleeding risk.

Pulmonary embolism, acute (hemodynamically stable/submassive)yes

Based on the American College of Chest Physicians (ACCP) guidelines for antithrombotic therapy for VTE disease, thrombolytic therapy (eg, tenecteplase) may be considered on an individual basis in select patients with acute PE without hypotension after systemic anticoagulation has been initiated. In most patients, thrombolytic therapy is not warranted or recommended for acute PE without hypotension (systolic BP >90 mm Hg). However, in patients without hypotension who have severe symptoms or marked cardiopulmonary impairment and show signs of cardiopulmonary deterioration (eg, worsening symptoms, increasing heart rate, decreasing systolic BP, tissue hypoperfusion, worsening gas exchange, increasing cardiac biomarkers, right ventricular dysfunction), the risks vs benefits may be altered in favor of tenecteplase use.

Pulmonary embolism associated with cardiac arrestcyes

Several case reports suggest that the use of tenecteplase may be beneficial in the treatment of patients in cardiac arrest due to suspected pulmonary embolism (PE) Nobre 2015, Perrot 2010. A prospective multicenter observational clinical trial in patients with non-traumatic undifferentiated cardiac arrest failing to respond to advanced cardiac life support measures demonstrated improved rates of ROSC, increased short term survival and neurologically intact survival to hospital discharge when treated with tenecteplase Bozeman 2006. Subsequently, however, a double-blind, multicenter trial conducted in patients with witnessed out of hospital undifferentiated cardiac arrest (patients with suspected pulmonary embolism were administered open label tenecteplase) did not demonstrate improvement in any outcomes; number of confirmed pulmonary embolism cases were too small to determine benefit in this subpopulation Böttiger 2008. Additional randomized controlled trials are needed to further define the role of tenecteplase for cardiac arrest due to PE.

Based on the American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care, thrombolytics may be considered when PE is presumed or confirmed as the cause of cardiac arrest. Contraindications should be considered but can be overridden since this therapy is potentially lifesaving Lavonas 2015.

Contraindications

Treatment of STEMI: Active internal bleeding; history of cerebrovascular accident; recent (ie, within 2 months) intracranial/intraspinal surgery or trauma; intracranial neoplasm; arteriovenous malformation or aneurysm; bleeding diathesis; severe uncontrolled hypertension

Additional absolute contraindications (ACC/AHA [O’Gara 2013]): Ischemic stroke within 3 months; prior intracranial hemorrhage; active bleeding (excluding menses); suspected aortic dissection; significant closed head or facial trauma within 3 months

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to tenecteplase or any component of the formulation.

Treatment of PE (off-label): Structural intracranial disease, previous intracranial hemorrhage, ischemic stroke within 3 months, active bleeding, recent brain or spinal surgery, recent head trauma with fracture or brain injury, bleeding diathesis

Dosage and Administration

Dosing: Adult

Pulmonary embolism, acute (hemodynamically unstable/massive) (off-label use): IV: Administer dose as a single bolus over 5 to 10 seconds (Kline 2007; Melzer 2004):

<60 kg: 30 mg

≥60 to <70 kg: 35 mg

≥70 to <80 kg: 40 mg

≥80 to <90 kg: 45 mg

≥90 kg: 50 mg

Pulmonary embolism, acute (hemodynamically stable/submassive) (off-label use): Note: Not recommended for most patients with acute PE without hypotension; use only in select patients showing signs of clinical deterioration despite maintaining a systolic BP >90 mm Hg where benefits outweigh risks (Kearon 2012; Kearon 2016).

IV: Administer dose as a single bolus over 5 to 10 seconds (Kline 2007; Kline 2014; Melzer 2004; Meyer 2014):

<60 kg: 30 mg

≥60 to <70 kg: 35 mg

≥70 to <80 kg: 40 mg

≥80 to <90 kg: 45 mg

≥90 kg: 50 mg

Pulmonary embolism associated with cardiac arrest (off-label use): IV: Administer as a single bolus over 5 seconds (Böttiger 2008; Bozeman 2006):

<60 kg: 30 mg

≥60 to <70 kg: 35 mg

≥70 to <80 kg: 40 mg

≥80 to <90 kg: 45 mg

≥90 kg: 50 mg

STEMI: IV: The recommended total dose should not exceed 50 mg and is based on weight. Administer as a single bolus over 5 seconds:

<60 kg: 30 mg

≥60 to <70 kg: 35 mg

≥70 to <80 kg: 40 mg

≥80 to <90 kg: 45 mg

≥90 kg: 50 mg

Note: Thrombolytic should be administered within 30 minutes of hospital arrival. Generally, there is only a small trend for benefit of therapy after a delay of 12 to 24 hours from symptom onset, but thrombolysis may be considered for selected patients with ongoing ischemic pain and extensive ST elevation; however, primary PCI is preferred in these patients. Administer concurrent aspirin, clopidogrel, and anticoagulant therapy (ie, unfractionated heparin, enoxaparin, or fondaparinux) with tenecteplase (O’Gara 2013).

Dosing: Geriatric

Refer to adult dosing. Although dosage adjustments are not recommended, the elderly have a higher incidence of morbidity and mortality with the use of tenecteplase.

Reconstitution

Tenecteplase should be reconstituted using the supplied 10 mL syringe with TwinPak Dual Cannula Device and 10 mL sterile water for injection. Do not shake when reconstituting. Slight foaming is normal and will dissipate if left standing for several minutes. The reconstituted solution is 5 mg/mL. Any unused solution should be discarded. If reconstituted and not used immediately, store in refrigerator and use within 8 hours.

Administration

IV: Tenecteplase is incompatible with dextrose solutions. Dextrose-containing lines must be flushed with a saline solution before and after administration. Administer as a single IV bolus over 5 seconds. Avoid IM injections and nonessential handling of patient.

PE, acute (off-label use): Administer as an IV bolus over 5 to 10 seconds using a peripheral vein (Kearon 2012; Kearon 2016).

Storage

Store under refrigeration of 2°C to 8°C (36°F to 46°F) or at room temperature; do not exceed 30°C (86°F). If reconstituted and not used immediately, store in refrigerator and use within 8 hours.

Drug Interactions

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Thrombolytic Agents. Monitor therapy

Anticoagulants: Thrombolytic Agents may enhance the anticoagulant effect of Anticoagulants. Management: See full drug monograph for guidelines for the use of alteplase for acute ischemic stroke during treatment with oral anticoagulants. Monitor therapy

Aprotinin: May diminish the therapeutic effect of Thrombolytic Agents. Consider therapy modification

Dabigatran Etexilate: Thrombolytic Agents may enhance the anticoagulant effect of Dabigatran Etexilate. Management: Carefully monitor for bleeding. Dabigatran Canadian labeling recommends avoiding use with thrombolytic agents. Consider avoiding alteplase treatment of acute ischemic stroke in patients receiving dabigatran (see full drug monograph for details). Monitor therapy

Desirudin: Thrombolytic Agents may enhance the anticoagulant effect of Desirudin. Management: Discontinue treatment with thrombolytic agents prior to desirudin initiation. If concomitant use cannot be avoided, monitor patients receiving these combinations closely for clinical and laboratory evidence of excessive anticoagulation. Consider therapy modification

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Thrombolytic Agents. Bleeding may occur. Consider therapy modification

Limaprost: May enhance the adverse/toxic effect of Thrombolytic Agents. The risk for bleeding may be increased. Monitor therapy

Prostacyclin Analogues: Thrombolytic Agents may enhance the adverse/toxic effect of Prostacyclin Analogues. Specifically, the antiplatelet effects of prostacyclin analogues may lead to an increased risk of bleeding when combined with thrombolytic agents. Monitor therapy

Salicylates: May enhance the adverse/toxic effect of Thrombolytic Agents. An increased risk of bleeding may occur. Monitor therapy

Test Interactions

Altered results of coagulation and fibrinolytic activity tests

Adverse Reactions

>10%:

Hematologic & oncologic: Hemorrhage (ASSENT-2 trial: minor: 22%; major: 5%), hematoma (local: minor: 12%; major: 2%)

1% to 10%:

Cardiovascular: Cerebrovascular accident (2%)

Gastrointestinal: Gastrointestinal hemorrhage (minor: 2%; major: 1%)

Genitourinary: Genitourinary tract hemorrhage (minor: 4%; major: <1%)

Hematologic & oncologic: Local hemorrhage (catheter puncture site: minor: 4%; major: <1%)

Respiratory: Pharyngeal bleeding (minor: 3%), epistaxis (minor: 2%)

Frequency not defined:

Cardiovascular: Atrioventricular block, cardiac arrhythmia, cardiac failure, cardiac tamponade, cardiogenic shock, embolism, hypotension, ischemic heart disease (recurrent), mitral valve insufficiency (regurgitation), myocardial reinfarction, myocardial rupture, pericardial effusion, pericarditis, pulmonary edema, thrombosis

Gastrointestinal: Nausea, vomiting

Miscellaneous: Fever

<1%, postmarketing, and/or case reports: Anaphylaxis, angioedema, intracranial hemorrhage, laryngeal edema, respiratory tract hemorrhage, retroperitoneal hemorrhage, skin rash, thrombolytic drug-induced cholesterol embolism (clinical features may include acute renal failure, bowel infarction, cerebral infarction, gangrenous digits, hypertension, livedo reticularis, myocardial infarction, pancreatitis, “purple toe” syndrome, retinal artery occlusion, rhabdomyolysis, spinal cord infarction), urticaria

Warnings/Precautions

Concerns related to adverse effects:

• Arrhythmias: Coronary thrombolysis may result in reperfusion arrhythmias (eg, sinus bradycardia, accelerated idioventricular rhythm, ventricular premature depolarizations, ventricular tachycardia). Antiarrhythmic therapy should be available during therapy.
• Bleeding: Internal bleeding (intracranial, retroperitoneal, gastrointestinal, genitourinary, respiratory) or external bleeding (especially at arterial and venous puncture sites) may occur. Monitor all potential bleeding sites; if serious bleeding occurs, the infusion of tenecteplase and any other concurrent anticoagulants (eg, heparin) and antiplatelets should be stopped and the patient should be treated appropriately.
• Cholesterol embolization: Cholesterol embolization has been reported rarely in patients treated with thrombolytic agents; may present as 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.
• Hypersensitivity reactions: Hypersensitivity reactions (eg, anaphylaxis, urticaria, angioedema, laryngeal edema, rash) have been reported after administration. Monitor closely for hypersensitivity reactions during infusion and for several hours after; initiate appropriate therapy if symptoms of hypersensitivity occur.
• Thromboembolic events: Use may increase risk of thromboembolic events in patients with high probability of left heart thrombus (eg, patients with mitral stenosis or atrial fibrillation).

Disease-related concerns:

• Conditions that increase bleeding risk: For the following conditions, the risk of bleeding is higher with use of thrombolytics and should be weighed against the benefits of therapy:

• PE: Systolic BP >180 mm Hg or diastolic BP >110 mm Hg; recent bleeding (nonintracranial); recent surgery or invasive procedure; ischemic stroke >3 months previously; anticoagulated (eg, VKA therapy); traumatic CPR; pericarditis or pericardial fluid; diabetic retinopathy; age >75 years; low body weight (<60 kg); female; black (Kearon 2012; Kearon 2016); lumbar puncture within 10 days (ASRA [Horlocker 2012]).

• STEMI: History of chronic, severe, poorly controlled hypertension; significant hypertension on presentation (systolic BP >180 mm Hg or diastolic BP >110 mm Hg); history of prior ischemic stroke >3 months; dementia; traumatic or prolonged CPR (>10 minutes); major surgery (<3 weeks); recent internal bleeding (within 2 to 4 weeks); noncompressible vascular punctures; active peptic ulcer; oral anticoagulant therapy (ACC/AHA [O’Gara 2013]); lumbar puncture within 10 days (ASRA [Horlocker 2012]).

Concurrent drug therapy issues:

• Anticoagulants: Use with caution in patients receiving oral anticoagulants; increased risk of bleeding. Adjunctive use of parenteral anticoagulants (eg, enoxaparin, heparin, or fondaparinux) is recommended in STEMI patients to improve vessel patency and prevent reocclusion and may also contribute to bleeding; monitor for bleeding (ACC/AHA [O’Gara 2013]).
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Use with caution in patients with advanced age; increased risk of bleeding. The 30-day mortality in the ASSENT-2 trial of AMI patients was 2.5% for patients <65 years of age, 8.5% for patients 65 to 74 years, and 16.2% for patients ≥75 years. The intracranial hemorrhage rate was 0.4% for patients <65 years, 1.6% for patients 65 to 74 years, and 1.7% for patients ≥75 years. The risks and benefits of use should be weighed carefully in the elderly.
• Pregnancy: Use with caution in pregnancy; increased risk of bleeding.

Other warnings/precautions:

• Administration: Avoid intramuscular injections and nonessential handling of the patient for a few hours after administration. Venipunctures should be performed carefully and only when necessary. If arterial puncture is necessary, use an upper extremity vessel that can be manually compressed. Caution with readministration of tenecteplase.

Monitoring Parameters

CBC, aPTT, signs and symptoms of bleeding, ECG monitoring

Pregnancy

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies. The risk of bleeding may be increased in pregnant women. Administer to pregnant women only if the potential benefits justify the risk to the fetus.

Patient Education

What is this drug used for?

• It is used to treat a heart attack.

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums, abnormal vaginal bleeding, bruises without a reason or that get bigger; or any severe or persistent bleeding
• Severe cerebrovascular disease like change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or vision changes
• Confusion
• Abnormal heartbeat
• Slow heartbeat
• Blue/black/purple skin discoloration
• Change in amount of urine passed
• Severe headache
• Severe dizziness
• Severe dizziness
• Passing out
• Chest pain
• Vision changes
• Muscle pain
• Dark urine
• Severe abdominal pain
• Back pain
• Nausea
• Vomiting
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.