Alteplase

Dosage Forms

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

Solution Reconstituted, Injection [preservative free]:

Cathflo Activase: 2 mg (1 ea) [contains polysorbate 80]

Solution Reconstituted, Intravenous [preservative free]:

Activase: 50 mg (1 ea); 100 mg (1 ea) [contains polysorbate 80]

Pharmacology

Mechanism of Action

Initiates local fibrinolysis by binding to fibrin in a thrombus (clot) and converts entrapped plasminogen to plasmin

Pharmacokinetics/Pharmacodynamics

Distribution

V_d (initial): Approximates plasma volume

Excretion

Clearance (in patients with acute MI receiving accelerated regimen): Rapidly from circulating plasma (572 ± 132 mL/minute) (Tanswell 1992), primarily hepatic; >50% present in plasma is cleared within 5 minutes after the infusion is terminated, ~80% cleared within 10 minutes (Semba 2000)

Duration of Action

>50% present in plasma cleared ~5 minutes after infusion terminated, ~80% cleared within 10 minutes; fibrinolytic activity persists for up to 1 hour after infusion terminated (Semba 2000)

Half-Life Elimination

Initial: 5 minutes

Use: Labeled Indications

Activase:

Acute ischemic stroke: Treatment of acute ischemic stroke (AIS) as soon as possible but within 3 hours of symptom onset.

Pulmonary embolism: Management of acute massive pulmonary embolism (PE)

ST-elevation myocardial infarction: Management of ST-elevation myocardial infarction (STEMI) for the lysis of thrombi in coronary arteries.

Limitations of use: The risk of stroke may outweigh the benefit produced by thrombolytic therapy in patients whose acute myocardial infarction (MI) puts them at low risk for death or heart failure.

Recommended criteria for treatment:

STEMI (ACCF/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-V₃ and/or of ≥1 mm (0.1 mV) in other contiguous precordial leads or limb leads. 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 ACCF/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.

AIS: Onset of stroke symptoms within 3 hours of treatment

Pulmonary embolism (PE), acute (hemodynamically unstable/massive): Acute PE in patients with sustained hypotension (SBP <90 mm Hg for 15 minutes) or with signs/symptoms of shock and without a high bleeding risk (Kearon 2012; Kearon 2016).

Cathflo Activase: Restoration of function to central venous access device

Use: Off Label

Acute ischemic stroke presenting 3 to 4.5 hours after symptom onsetayes

Data from a multicenter, randomized, double-blind, placebo-controlled trial in patients with acute ischemic stroke (AIS) presenting during the time period of 3 to 4.5 hours after symptom onset who were treated with IV alteplase supports the use of alteplase for the treatment of patients presenting during this time period Hacke 2008.

Based on the 2013 American Heart Association/American Stroke Association (AHA/ASA) guidelines for the early management of patients with acute ischemic stroke, including the 2015 focused update of these guidelines, and the 2015 American College of Emergency Physicians clinical policy on the use of IV tissue plasminogen activator for the management of acute ischemic stroke in the emergency department, alteplase administered within 3 to 4.5 hours after symptom onset is effective and recommended for patients who present during this time period.

Acute ischemic stroke (intra-arterial use [off-label route])cyes

The optimal dose is not established. Initial data to support the use of intra-arterial thrombolysis evaluated the use of other thrombolytics (eg, urokinase) instead of alteplase. Data from two retrospective evaluations in which patients with acute ischemic stroke (AIS) received intra-arterial alteplase at various doses and regimens suggests that intra-arterial alteplase may be beneficial for patients with this condition Christoforidis 2012, Tountopoulou 2008. A prospective, randomized, controlled clinical trial in patients with AIS due to middle cerebral artery occlusion administered intra-arterial alteplase within 6 hours of symptom onset suggested benefit as compared to IV anticoagulation alone Poncyljusz 2007. More recently, data from a randomized clinical trial in the Netherlands in patients with AIS caused by a proximal intracranial arterial occlusion comparing endovascular treatment (ie, intra-arterial thrombolysis with urokinase or alteplase, mechanical treatment, or both) plus usual care to usual care alone suggests that the use of intra-arterial alteplase within 6 hours of symptom onset may be of benefit Berkhemer 2015. Additional trials are necessary to further define the role of intra-arterial alteplase in the treatment of patients with AIS.

Based on the 2015 American Heart Association/American Stroke Association (AHA/ASA) focused update of the 2013 guidelines for the early management of patients with AIS, endovascular therapy with stent retrievers is recommended over intra-arterial fibrinolysis. Initial treatment with intra-arterial fibrinolysis is beneficial for selected patients with major ischemic strokes (<6 hours' duration) caused by middle cerebral artery occlusion; however, the recommendation is derived from clinical trials that do not reflect current practice. The use of salvage technical adjuncts (eg, intra-arterial alteplase) may be reasonable if completed within 6 hours of symptom onset. In carefully selected patients with contraindications to the use of IV alteplase, the use of intra-arterial fibrinolysis initiated within 6 hours of stroke onset may be considered. Intra-arterial treatment requires the patient to be at an experienced stroke center with rapid access to cerebral angiography and qualified interventionalists.

Frostbitecyes

Data from a limited number of patients evaluated in retrospective and prospective studies and in one case series suggest alteplase may be beneficial in the treatment of patients with deep frostbite. Additional data may be necessary to further define the role of alteplase in the treatment of frostbite. According to Wilderness Medical Society practice guidelines for the prevention and treatment of frostbite, alteplase may be considered in patients with deep frostbite injury with potential significant morbidity (eg, extending proximally to the proximal interphalangeal joints of digits), without contraindications to use of alteplase and who present within 24 hours of injury. Alteplase use in the field setting is not recommended; administer treatment in a facility capable of intensive care monitoring.

Parapneumonic pleural effusions and empyemasb

Use of alteplase with or without dornase alfa in the treatment of complicated parapneumonic effusions or empyemas in adults has been evaluated in controlled and noncontrolled settings. Alteplase monotherapy has produced conflicting results in small trials and case series. In a large controlled trial, alteplase with dornase alfa demonstrated reductions in effusion volume, the need for surgical intervention, and hospital stay.

British Thoracic Society guidelines state that there is no indication for the routine use of intrapleural fibrinolytics in the management of pleural infection. However, fibrinolytics may be considered for use in patients with pleural infection refractory to traditional therapy and who are not candidates for surgery.

Peripheral arterial occlusioncyes

Clinical experience suggests the utility of alteplase in managing patients with peripheral arterial occlusion Semba 2000. Additional data may be necessary to further define the role of alteplase in the management of this condition.

Based on the American College of Cardiology/American Heart Association (ACC/AHA) 2005 guidelines for the management of patients with peripheral arterial disease, catheter-based thrombolysis is an effective and recommended treatment for patients with acute limb ischemia of <14 days' duration and may be considered for patients with acute limb ischemia of >14 days' duration.

Prosthetic mechanical valve thrombosiscyes

Data from a prospective, single-center, observational study demonstrated that a low-dose extended infusion of alteplase is effective in most cases of obstructive and nonobstructive prosthetic mechanical valve thrombosis with low rates of thromboembolic and bleeding complications Ozkan 2015. Other observational studies utilizing different dosing schemes have also been successful in this situation Ozkan 2013a, Ozkan 2013b, Roudaut 2003.

Based on the 2017 American Heart Association/American College of Cardiology (AHA/ACC) focused update of the 2014 guideline for the management of patients with valvular heart disease, and the 2012 American College of Chest Physicians (ACCP) guidelines for the management of antithrombotic therapy, a thrombolytic (eg, alteplase) is effective and recommended in select patients with prosthetic mechanical valve thrombosis.

Pulmonary embolism, acute (hemodynamically stable/submassive)byes

Data from a randomized double-blind study in patients with submassive pulmonary embolism (PE), defined as those with acute PE and pulmonary hypertension or right ventricular (RV) dysfunction but without arterial hypotension or shock, suggests alteplase can improve the clinical course of patients with this condition Konstantinides 2002. Additional trials may be necessary to further define the role of alteplase in the treatment of submassive PE.

Based on the American College of Chest Physicians (ACCP) guidelines for antithrombotic therapy for VTE disease, thrombolytic therapy (eg, alteplase) 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 alteplase use.

Pulmonary embolism associated with cardiac arrestcyes

Data from an early study in patients with undifferentiated out of hospital cardiac arrest suggest that the use of alteplase as a bolus may improve rates of return of spontaneous circulation (ROSC) and survival to hospital admission in these patients Bottiger 2001. However, a similar randomized, controlled study reported no difference in these endpoints Abu-Laban 2002. Several retrospective studies evaluating cardiac arrest due to presumed or confirmed PE consistently report improved rates of ROSC and survival with alteplase Er 2009, Janata 2003, Kurkciyan 2000, Lederer 2001, Sharifi 2016. The optimal dose for alteplase in the setting of cardiac arrest due to PE is not well established. Additional randomized controlled trials are needed to further define the role of alteplase specifically for cardiac arrest due to PE.

The 2010 American Heart Association (AHA) Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care and the 2015 AHA Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care recommend thrombolytics be considered when PE is presumed or confirmed as the cause of cardiac arrest. Contraindications should be considered but may be overridden because this therapy is potentially lifesaving.

Contraindications

Hypersensitivity to alteplase or any component of the formulation

Treatment of STEMI or PE: Active internal bleeding; history of recent stroke; recent (within 3 months [ACCF/AHA: Within 2 months]) intracranial or intraspinal surgery or serious head trauma; presence of intracranial conditions that may increase the risk of bleeding (eg, intracranial neoplasm, arteriovenous malformation, aneurysm); known bleeding diathesis; severe uncontrolled hypertension (ACCF/AHA: Unresponsive to emergency therapy)

Additional absolute contraindications (ACCF/AHA [O’Gara 2013]; Kearon 2012; Kearon 2016): Active bleeding (excluding menses); any prior intracranial hemorrhage; suspected aortic dissection; ischemic stroke within 3 months except when within 4.5 hours; significant closed head or facial trauma within 3 months with radiographic evidence of bony fracture or brain injury

Treatment of acute ischemic stroke(AIS): 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 (eg, intracranial neoplasm, arteriovenous malformation, aneurysm); known bleeding diathesis; severe uncontrolled hypertension

Additional contraindications (AHA/ASA [Jauch 2013]): History of intracranial hemorrhage; suspicion of subarachnoid hemorrhage; stroke within 3 months; arterial puncture at a noncompressible site in previous 7 days; uncontrolled hypertension at time of treatment (eg, >185 mm Hg systolic or >110 mm Hg diastolic); multilobar cerebral infarction (hypodensity >¹/₃ cerebral hemisphere); known bleeding diathesis including but not limited to current use of oral anticoagulants with an INR >1.7 (or PT >15 seconds), current use of direct thrombin inhibitors or direct factor Xa inhibitors with elevated sensitive laboratory tests (eg, aPTT, INR, ECT, TT, or appropriate factor Xa activity assays) (See “Note”), administration of heparin within 48 hours preceding the onset of stroke with an elevated aPTT greater than the upper limit of normal, or platelet count <100,000/mm³.

Note: The AHA/ASA 2013 guidelines do allow the use of alteplase in patients taking direct thrombin inhibitors (eg, dabigatran) or direct factor Xa inhibitors (eg, rivaroxaban) when sensitive laboratory tests (eg, aPTT, INR, ECT, TT, or appropriate direct factor Xa activity assays) are normal or the patient has not received a dose of these agents for >2 days (assuming normal renal function) (Jauch 2013). The AHA/ASA 2016 scientific statement states that alteplase is not recommended in patients who have received LMWH treatment doses within the previous 24 hours (AHA/ASA [Demaerschalk 2016]).

Additional exclusion criteria within clinical trials:

Presentation <3 hours after initial symptoms (NINDS, 1995): Time of symptom onset unknown, rapidly improving or minor symptoms, major surgery within 2 weeks, GI or urinary tract hemorrhage within 3 weeks, aggressive treatment required to lower blood pressure, glucose level <50 or >400 mg/dL, and lumbar puncture within 1 week.

Note: The AHA/ASA 2016 scientific statement recommends alteplase use in patients presenting <3 hours after initial symptoms with mild but disabling stroke symptoms in the opinion of the treating physician. Alteplase is also reasonable in patients presenting <3 hours after initial symptoms with moderate-to-severe ischemic stroke who demonstrate early improvement, but remain moderately impaired and potentially disabled in the examiner's judgment (AHA/ASA [Demaerschalk 2016]).

Presentation 3 to 4.5 hours after initial symptoms (AHA/ASA [Jauch 2013]; ECASS-III; Hacke 2008; Powers 2015): Age >80 years, time of symptom onset unknown, rapidly improving or minor symptoms, current use of oral anticoagulants regardless of INR, glucose level <50 or >400 mg/dL, aggressive intravenous treatment required to lower blood pressure, major surgery or severe trauma within 3 months, baseline National Institutes of Health Stroke Scale (NIHSS) score >25 [ie, severe stroke], and history of both stroke and diabetes.

Note: The AHA/ASA 2016 scientific statement has provided updated evidence on certain patients presenting in the 3 to 4.5 hour after initial symptoms window excluded in the aforementioned earlier guidelines, including: patients >80 years (alteplase use in the 3 to 4.5 hour window can be safe and as effective as in younger patients); patients taking warfarin with an INR <1.7 (alteplase use appears safe and may be beneficial); patients with a history of both stroke and diabetes (alteplase use may be as effective as treatment in the 0 to 3 hour window, and may be a reasonable option) (AHA/ASA [Demaerschalk 2016]).

Dosage and Administration

Dosing: Adult

Acute ischemic stroke: Activase: IV: Within 3 hours of the onset of symptom onset (labeled use) or within 3 to 4.5 hours of symptom onset (off-label use; AHA/ASA [Jauch 2013]; Hacke 2008; Powers 2015): Note: Perform non-contrast-enhanced CT or MRI prior to administration. Aspirin initiation is generally delayed ≥24 hours after administration of alteplase; use of antiplatelet agents (eg, aspirin) or therapeutic-dose anticoagulants (eg, heparin) within 24 hours of alteplase administration is not recommended (AHA/ASA [Jauch 2013; Powers 2018]).

Recommended total dose: 0.9 mg/kg (maximum total dose: 90 mg)

Patients <100 kg: Load with 0.09 mg/kg (10% of 0.9 mg/kg dose) as an IV bolus over 1 minute, followed by 0.81 mg/kg (90% of 0.9 mg/kg dose) as a continuous infusion over 60 minutes.

Patients ≥100 kg: Load with 9 mg (10% of 90 mg) as an IV bolus over 1 minute, followed by 81 mg (90% of 90 mg) as a continuous infusion over 60 minutes.

Acute peripheral arterial occlusion (off-label use): Intra-arterial:

Weight-based regimen: 0.001 to 0.02 mg/kg/hour (maximum dose: 2 mg/hour) (Semba 2000)

or

Fixed-dose regimen: 0.12 to 2 mg/hour (Semba 2000)

Note: The ACC/AHA guidelines state that thrombolysis is an effective and beneficial therapy for those with acute limb ischemia (Rutherford categories I and IIa) of <14 days' duration (Hirsch 2006). The optimal dosage and concentration has not been established; a number of intra-arterial delivery techniques are employed with continuous infusion being the most common (Ouriel 2004). The Advisory Panel to the Society for Cardiovascular and Interventional Radiology on Thrombolytic Therapy recommends dosing of ≤2 mg/hour and concomitant administration of subtherapeutic heparin (aPTT 1.25 to 1.5 × baseline) (Semba 2000). Duration of alteplase infusion dependent upon size and location of the thrombus; typically between 6 to 48 hours (Disini 2008).

Central venous catheter clearance: Cathflo Activase (1 mg/mL): Intracatheter:

Patients <30 kg: 110% of the internal lumen volume of the catheter, not to exceed 2 mg/2 mL; retain in catheter for 0.5 to 2 hours; may instill a second dose if catheter remains occluded.

Patients ≥30 kg: 2 mg/2 mL; retain in catheter for 0.5 to 2 hours; may instill a second dose if catheter remains occluded.

Frostbite (off-label use): Note: For use in patients with deep frostbite injury with potential significant morbidity (eg, extending proximally to the proximal interphalangeal joints of digits), without contraindications to the use of alteplase, who present within 24 hours of injury. Use of alteplase in the field is not recommended; administer treatment in a facility capable of intensive-care monitoring (WMS [McIntosh 2014]). Additional data may be necessary to further define the role of alteplase in the treatment of frostbite.

Intra-arterial: 2 to 4 mg bolus followed by a continuous intra-arterial infusion of 0.5 to 1 mg/hour (total dose if bilateral extremity involvement) via femoral or brachial artery; administer with continuous infusion heparin via an intra-arterial catheter. Discontinue alteplase if fibrinogen levels decrease to <150 mg/dL, if reperfusion is complete (as evidenced by angiography), or after a period of 48 hours whether or not reperfusion is achieved (Bruen 2007; Ibrahim 2015).

Parapneumonic effusions and empyema (off-label use): Note: Some clinicians suggest consideration of fibrinolytic use in patients in whom treatment with at least 24 hours of chest tube drainage has failed and who are poor surgical candidates (Hamblin 2010). Different regimens exist with variations in chest tube sizes, number of doses, patient positions (still vs rotation), and clamping/dwell durations (Thommi 2007; Thommi 2012).

Intrapleural: 10 mg twice daily for a total of 3 days; each alteplase dose should be followed >2 hours later by an intrapleural dornase alfa dose (with a 1-hour dwell time for each drug) (Rahman 2011). Data from a single-center study suggest that concurrent administration of alteplase and dornase alfa (with a 2-hour dwell time) is safe and effective (Majid 2016).

Prosthetic mechanical valve thrombosis (off-label use): Note: Fibrinolysis may be considered for right-sided (any size thrombus) or small left-sided (thrombus area <0.8 cm²) prosthetic mechanical valve thrombosis or large left-sided (thrombus area ≥0.8 cm²) prosthetic mechanical valve thrombus if contraindications to surgery exist. When choosing between fibrinolysis or surgery for the treatment of prosthetic mechanical valve thrombosis, patient and hospital-specific factors must be considered (ie, surgical expertise, surgical risk, contraindications to fibrinolysis, presence of left atrial thrombus, concomitant coronary disease, NYHA heart failure function class, other valvular disease, patient choice) (AHA/ACC [Nishimura 2017]).

IV: Wait for INR to be <2.5 before starting alteplase infusion. Administer 1 mg/hour continuous infusion for 25 hours (25 mg total); may repeat this dose up to 8 times if there is not adequate resolution of thrombus based on echocardiographic assessment (maximum total dose: 200 mg); administer a 6-hour infusion of heparin titrated to aPTT of 1.5 to 2.5 times the control between alteplase doses; aPTT should be <50 seconds prior to starting the next dose of alteplase (if necessary) and heparin should not be given during alteplase infusions (Ozkan 2015). Higher dose and/or more rapid administration regimens have been described; however, low-dose extended infusions tend to have fewer thromboembolic and bleeding complications without compromising efficacy (Ozkan 2013a; Ozkan 2013b; Roudaut 2003).

Note: After successful administration of alteplase, heparin infusion should be introduced until warfarin achieves therapeutic INR (aortic: 3.0 to 4.0; mitral: 3.5 to 4.5) (Bonow 2008). The 2012 ACCP guidelines for antithrombotic therapy make no recommendation regarding INR range after prosthetic valve thrombosis.

Pulmonary embolism (PE), acute (hemodynamically stable/submassive) (off-label use): IV: Activase: 100 mg as an infusion over 2 hours. Institute or resume parenteral anticoagulation near the end of or immediately following the alteplase infusion when the partial thromboplastin time or thrombin time returns to twice normal or less. 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 (ACCP [Kearon 2012]; ACCP [Kearon 2016]; Konstantinides 2002).

Pulmonary embolism (PE), acute (hemodynamically unstable/massive):

IV: Activase: 100 mg as an infusion over 2 hours. Institute or resume parenteral anticoagulation near the end of or immediately following the alteplase infusion when the partial thromboplastin time or thrombin time returns to twice normal or less.

Catheter-directed thrombolysis (off-label): 24 mg administered either as 1 mg/hour for 24 hours via a unilateral catheter or as 1 mg/hour/catheter for 12 hours via bilateral catheters (Piazza 2015). Note: Due to insufficient evidence, catheter directed thrombolysis (CDT) is not recommended for acute PE unless there is access to the expertise and resources necessary to perform CDT; intravenous administration of a systemic thrombolytic is preferred (ACCP [Kearon 2012]; ACCP [Kearon 2016]; Wang 2015).

Pulmonary embolism (PE) associated with cardiac arrest (off-label use): Activase: IV, Intraosseous (if IV access cannot be obtained): 50 mg bolus over 2 minutes; repeat a second 50 mg bolus 15 minutes later if return of spontaneous circulation (ROSC) is not achieved. Early administration is recommended when PE is presumed or confirmed. Systemic anticoagulation (eg, unfractionated heparin) should be administered with or shortly after administration of alteplase (AHA [Lavonas 2015]; Logan 2014). Note: When administered via intraosseous catheter, monitor for extravasation and subcutaneous bleeding at the intraosseous catheter insertion site (Landy 2012; Logan 2014).

ST-elevation MI (STEMI): Activase: IV: Note: Manufacturer's labeling recommends 3-hour infusion regimen; however, accelerated regimen preferred by the ACC/AHA (ACC/AHA [O'Gara 2013]).

Accelerated regimen (weight-based):

Patients >67 kg: Total dose: 100 mg over 1.5 hours; administered as a 15 mg IV bolus over 1 to 2 minutes followed by infusions of 50 mg over 30 minutes, then 35 mg over 1 hour. Maximum total dose: 100 mg

Patients ≤67 kg: Infuse 15 mg IV bolus over 1 to 2 minutes followed by infusions of 0.75 mg/kg (not to exceed 50 mg) over 30 minutes then 0.5 mg/kg (not to exceed 35 mg) over 1 hour. Maximum total dose: 100 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, fondaparinux) with alteplase (ACC/AHA [O'Gara 2013]).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Occluded IV catheters: Infants, Children, Adolescents: Intracatheter: Dose listed is per lumen; for multilumen catheters, treat one lumen at a time; do not infuse into patient; dose should always be aspirated out of catheter after dwell.

Manufacturer's labeling: Cathflo Activase: Central venous catheter:

Patients <30 kg: Use a 1 mg/mL concentration; instill a volume equal to 110% of the internal lumen volume of the catheter; do not exceed 2 mg in 2 mL; may instill a second dose if catheter remains occluded after 2-hour dwell time

Patients ≥30 kg: 2 mg in 2 mL; may instill second dose if catheter remains occluded after 2-hour dwell time

Chest guidelines (Monagle 2008): Note: The most recent guidelines (2012) continue to recommend alteplase as a treatment option but specific dosage recommendation is not provided (Monagle 2012)

Central venous catheter: Note: Some institutions use lower doses (eg, 0.25 mg/0.5 mL) in infants 1 to <3 months

Patients ≤10 kg: 0.5 mg diluted in NS to a volume equal to the internal volume of the lumen; instill in lumen over 1 to 2 minutes; leave in lumen for 1 to 2 hours, then aspirate out of catheter, do not infuse into patient; flush catheter with NS.

Patients >10 kg: 1 mg in 1 mL of NS; use a volume equal to the internal volume of the lumen; maximum: 2 mg in 2 mL per lumen; instill in each lumen over 1 to 2 minutes; leave in lumen for 1 to 2 hours; then aspirate out of catheter, do not infuse into patient; flush catheter with NS

SubQ port:

Patients ≤10 kg: 0.5 mg diluted with NS to 3 mL

Patients >10 kg: 2 mg diluted with NS to 3 mL

Systemic thrombosis: Note: Dose must be titrated to effect. No pediatric studies have compared local to systemic thrombolytic therapy; therefore, there is no evidence to suggest that local infusions are superior. The pediatric patients' small vessel size may increase the chance of local damage to blood vessels and formation of a new thrombus; however, local infusion may be appropriate for catheter-related thromboses if the catheter is already in place (Monagle 2012).

Standard dose infusion: Limited data available; optimal dose not established; most published papers consist of case reports; few prospective pediatric studies have been conducted; several studies have used the following doses (Levy 1991; Weiner 1998): Infants, Children, and Adolescents: Chest 2012 and AHA 2013 recommendations: IV: Usual dose: 0.5 mg/kg/hour for 6 hours; range: 0.1 to 0.6 mg/kg/hour; some patients may require longer or shorter duration of therapy; higher doses may be associated with an increased incidence of serious bleeding (Giglia 2013; Monagle 2008; Monagle 2012).

Low-dose infusion: Limited data available. Various “low-dose” regimens have been used: Infants, Children, and Adolescents:

AHA 2013 recommendations: IV: 0.03 to 0.06 mg/kg/hour for 12 to 48 hours; maximum hourly dose: 2 mg/hour (Giglia 2013)

Additional reported regimens: IV:

Wang 2003: Initial: 0.01 to 0.03 mg/kg/hour; usual effective range: 0.015 to 0.03 mg/kg/hour; duration of therapy based on clinical response; in this study of 17 pediatric patients (1.5 to 18 years) with acute and chronic thrombus, dosing was titrated to effect up to 0.06 mg/kg/hour in children and adolescents; final effective range: 0.007 to 0.06 mg/kg/hour; administration included systemic therapy as well as local infusions directly at site of thrombus (n=4); duration of therapy ranged from 4 to 96 hours. A similar dosing range has been reported in pediatric case reports (Doyle 1992).

Leary 2010: Initial: 0.03 to 0.06 mg/kg/hour for 12 to 48 hours; doses were titrated as necessary up to 0.12 mg/kg/hour; dosing from a retrospective study of 23 patients (median age: 12 years, range: 6 months to 21.5 years) diagnosed with DVT; eight patients required a dose increase to 0.12 mg/kg/hour; overall response rate: 59%, with complete clot resolution in 18% and partial resolution in 41%

Bratincsák 2013: Initial: 0.05 mg/kg/hour for 30 minutes, if no signs of bleeding, rate increased to 0.1 mg/kg/hour; therapy used in 12 children with arterial or femoral vascular occlusions following cardiac catheterization

Catheter-directed infusion: Limited data available: Children and Adolescents: Intra-arterial, IV (administered through catheter or via catheter with tip placed at anatomic site of clot): 0.025 mg/kg/hour or 0.5 to 2 mg/hour for 12 to 24 hours (Giglia 2013)

Parapneumonic effusion: Limited data available: Infants >3 months, Children, and Adolescents: Intrapleural:

Fixed dose: 4 mg in 40 mL NS, first dose at time of chest tube placement with 1-hour dwell time, repeat every 24 hours for 3 days (total of 3 doses) (Bradley 2011; St. Peter 2009)

Weight-directed: 0.1 mg/kg (maximum: 3 mg) in 10 to 30 mL NS, first dose after chest tube placement, 0.75- to 1-hour dwell time, repeat every 8 hours for 3 days (total of 9 doses) (Bradley 2011; Hawkins 2004)

Reconstitution

Activase:

50 mg vial: Use accompanying diluent (50 mL vial of sterile water for injection); let stand undisturbed for several minutes to allow large bubbles to dissipate; mix by gentle swirling and/or slow inversion; do not shake. Vacuum is present in 50 mg vial. Final concentration: 1 mg/mL.

100 mg vial: Use transfer set with accompanying diluent (100 mL vial of sterile water for injection); let stand undisturbed for several minutes to allow large bubbles to dissipate; mix by gentle swirling; do not shake. No vacuum is present in 100 mg vial. Final concentration: 1 mg/mL.

Activase: ST-elevation MI: Accelerated infusion: Bolus dose may be prepared by one of three methods:

1) Removal of 15 mL reconstituted (1 mg/mL) solution from vial

2) Removal of 15 mL from a port on the infusion line after priming

3) Programming an infusion pump to deliver a 15 mL bolus at the initiation of infusion

Activase: Acute ischemic stroke: Bolus dose (10% of total dose) may be prepared by one of three methods:

1) Removal of the appropriate volume from reconstituted solution (1 mg/mL)

2) Removal of the appropriate volume from a port on the infusion line after priming

3) Programming an infusion pump to deliver the appropriate volume at the initiation of infusion

Cathflo Activase: Add 2.2 mL sterile water for injection to vial; let the vial stand undisturbed to allow large bubbles to dissipate. Mix by gently swirling until completely dissolved (complete dissolution should occur within 3 minutes); do not shake. Final concentration: 1 mg/mL.

Administration

IV: Activase:

ST-elevation MI or acute ischemic stroke: Administer bolus dose (prepared by one of three methods) over 1 minute followed by an infusion.

Infusion: Remaining dose for STEMI or AIS may be administered as follows: Any quantity of drug not to be administered to the patient must be removed from vial(s) prior to administration of remaining dose.

50 mg vial: Either PVC bag or glass vial and infusion set

100 mg vial: Insert spike end of the infusion set through the same puncture site created by transfer device and infuse from vial.

If further dilution is desired, may be diluted in equal volume of 0.9% sodium chloride or D5W to yield a final concentration of 0.5 mg/mL.

PE, acute:

Hemodynamically unstable/massive PE or hemodynamically stable/submassive PE (off-label use): Administer as an IV infusion using a peripheral vein (ACCP [Kearon 2012]; ACCP [Kearon 2016]).

PE associated with cardiac arrest (off-label use): During cardiopulmonary resuscitation, administer as a rapid IV bolus over 2 minutes (AHA [Lavonas 2015]; Böttiger 2001). When IV access cannot be established, some experts have suggested administration via intraosseous catheter; must monitor for extravasation and subcutaneous bleeding at the intraosseous catheter insertion site (Landy 2012; Logan 2014).

Intracatheter: Cathflo Activase: Instill dose into occluded catheter. Do not force solution into catheter. After a 30-minute dwell time, assess catheter function by attempting to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood to remove Cathflo Activase and residual clots. Gently irrigate the catheter with NS. If catheter remains nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell time: 120 minutes) and reassess function. If catheter function is not restored, a second dose may be instilled.

Intrapleural: Parapneumonic pleural effusions and empyemas (off-label use): Adults: For sequential administration of alteplase and dornase alfa, dilute each dose in 30 mL sterile water. Instill dose into chest tube and clamp drain. Although the optimum dwell time has not been determined, clinical trials more often have used either a 45-minute (Hawkins 2004) or 1-hour (Rahman 2011; St. Peter 2009) dwell time; after dwell period, release clamp and connect chest tube to continuous suction. For concurrent administration of alteplase and dornase alfa, using separate syringes, dilute each dose in 50 mL of normal saline. Instill each dose into chest tube, one immediately after the other, followed by a 60 mL normal saline flush. Clamp drain; after 2-hour dwell time, release clamp (Majid 2016).

Storage

Activase: Store intact vials at room temperature (not to exceed 30°C [86°F]), or under refrigeration at 2°C to 8°C (36°F to 46°F); protect from light. Store reconstituted solution at 2°C to 30°C (36°F to 86°F) and use within 8 hours. Discard any unused solution

Cathflo Activase: Store intact vials at 2°C to 8°C (36°F to 46°F); protect from light. Store reconstituted solution at 2°C to 30°C (36°F to 86°F) and use within 8 hours. Discard any unused solution.

Solutions of 0.5 mg/mL, 1 mg/mL, and 2 mg/mL in SWI retained ≥94% of fibrinolytic activity at 48 hours when stored at 2°C in plastic syringes; these solutions retained ≥90% of fibrinolytic activity when stored in plastic syringes at -25°C or -70°C for 7 or 14 days, thawed at room temperature and then stored at 2°C for 48 hours (Davis 2000). Solutions of 1 mg/mL in SWI were stable for 22 weeks in plastic syringes when stored at -30°C and for ∼1 month in glass vials when stored at -20°C; bioactivity remained unchanged for 6 months in propylene containers when stored at -20°C and for 2 weeks in glass vials when stored at -70°C (Generali 2001).

Drug Interactions

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

Angiotensin-Converting Enzyme Inhibitors: May enhance the adverse/toxic effect of Alteplase. Specifically, the risk for angioedema may be increased. 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

Nitroglycerin: May decrease the serum concentration of Alteplase. 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%: Cardiovascular: Intracranial hemorrhage (CVA: Within 90 days: 15%, within 36 hours: 6%; AMI: <1%)

1% to 10%:

Cerebrovascular accident (new ischemic stroke in CVA: 6%)

Dermatologic: Ecchymosis (AMI: 1%)

Gastrointestinal: Gastrointestinal hemorrhage (AMI: 5%)

Genitourinary: Genitourinary tract hemorrhage (AMI: 4%)

Frequency not defined:

Hematologic & oncologic: Arterial embolism, major hemorrhage, pulmonary embolism

Infection: Sepsis

1%, postmarketing, and/or case reports: Anaphylaxis, angioedema, atrioventricular block, atrioventricular dissociation, cardiac arrhythmia, cardiac failure, cardiac tamponade, cardiogenic shock, cerebral edema, cerebral herniation, deep vein thrombosis, embolism, epistaxis, fever, gingival hemorrhage, hypersensitivity reaction, hypotension, ischemia (recurrent), laryngeal edema, mitral valve insufficiency, myocardial reinfarction, myocardial rupture, nausea, pericardial effusion, pericarditis, pleural effusion, pulmonary edema, retroperitoneal hemorrhage, seizure, skin rash, thromboembolism, urticaria, vomiting

Warnings/Precautions

Concerns related to adverse effects:

• Arrhythmias: Coronary thrombolysis may result in reperfusion arrhythmias (eg, accelerated idioventricular rhythm) (Miller 1986).
• Bleeding: Internal bleeding (intracranial, retroperitoneal, gastrointestinal, genitourinary, respiratory) or external bleeding, especially at arterial and venous puncture, sites may occur (may be fatal). The total dose should not exceed 90 mg for acute ischemic stroke or 100 mg for acute myocardial infarction or pulmonary embolism. Doses ≥150 mg associated with significantly increased risk of intracranial hemorrhage compared to doses ≤100 mg. Bleeding risk is low. Monitor all potential bleeding sites; if serious bleeding occurs, the infusion of alteplase and any other concurrent anticoagulants (eg, heparin) should be stopped and the patient should be treated appropriately.
• Cholesterol embolization: Has been reported rarely in patients treated with thrombolytic agents; 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.
• Hypersensitivity reactions: Hypersensitivity reactions (eg, anaphylaxis, urticaria, angioedema) have been reported; fatal outcome has been reported (rare). Although typically mild and transient, orolingual angioedema has occurred during and up to 2 hours after alteplase infusion in patients treated for acute ischemic stroke and acute myocardial infarction; the use of concomitant ACE inhibitors, female sex and strokes involving the insular and frontal cortex have been associated with an increased risk (Foster-Goldman 2013; Lin 2014; Pinho 2016). Monitor closely for hypersensitivity reactions during infusion and for several hours after; if signs of hypersensitivity occur or angioedema develops, discontinue the infusion and promptly institute appropriate therapy.
• 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 of age; low body weight (<60 kg); female; black race (Kearon 2012; Kearon 2016); lumbar puncture within 10 days (ASRA [Horlocker 2012]).

• ST-elevation myocardial infarction (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 (ACCF/AHA [O’Gara 2013]); lumbar puncture within 10 days (ASRA [Horlocker 2012])

• End-stage renal disease: In the treatment of acute ischemic stroke (AIS), according to the AHA/ASA 2016 scientific statement, alteplase use is recommended in patients with end-stage renal disease on hemodialysis who have a normal aPTT (very limited populations evaluated). Patients with an elevated aPTT may have an increased risk for hemorrhagic complications (AHA/ASA [Demaerschalk 2016]).
• STEMI: Appropriate use: Follow standard management for STEMI while infusing alteplase.
• Stroke: Appropriate use: Patients who present within 3 hours of stroke symptom onset should be treated with alteplase unless contraindications exist. A longer time window (3 to 4.5 hours after symptom onset) has been shown to be safe and efficacious for select individuals who meet ECASS III criteria (AHA/ASA [Demaerschalk 2016]; AHA/ASA [Jauch 2013]; Hacke 2008; Powers 2015).

Concurrent drug therapy issues:

• Anticoagulants: Use with caution in patients receiving oral anticoagulants; increased risk of bleeding. According to the AHA/ASA 2013 guidelines, in the treatment of AIS within 3 hours of symptom onset, the current use of oral anticoagulants producing an INR >1.7, direct thrombin inhibitors, or direct factor Xa inhibitors with elevated sensitive laboratory test are contraindications. However, alteplase may be administered to patients with AIS having received direct thrombin inhibitors (eg, dabigatran) or direct factor Xa inhibitors (eg, rivaroxaban) when sensitive laboratory tests (eg, aPTT, INR, platelet count, ECT, TT, or appropriate direct factor Xa activity assays) are normal or the patient has not received a dose of these agents for >2 days (assuming normal renal function). When treating AIS 3 to 4.5 hours after symptom onset, the use of alteplase should be avoided with current use of any oral anticoagulant regardless of INR (AHA/ASA [Jauch 2013]). However, according to the AHA/ASA 2016 scientific statement, when treating AIS 3 to 4.5 hours after symptom onset, the use of alteplase appears safe and may be beneficial for patients taking warfarin with an INR <1.7 (AHA/AHA [Demaerschalk 2016]). In the treatment of STEMI, adjunctive use of parenteral anticoagulants (eg, enoxaparin, heparin, or fondaparinux) is recommended to improve vessel patency and prevent reocclusion and may also contribute to bleeding; monitor for bleeding (ACCF/AHA [O’Gara 2013]).
• Aspirin: In the treatment of acute ischemic stroke, avoid aspirin for 24 hours following administration of alteplase; administration within 24 hours increases the risk of hemorrhagic transformation. According to the AHA/ASA 2016 scientific statement, alteplase is recommended for patients taking antiplatelet drug monotherapy or antiplatelet combination therapy (eg, aspirin and clopidogrel) before stroke on the basis that the benefit outweighs a possible small increased risk of symptomatic intracerebral hemorrhage (sICH) (AHA/AHA [Demaerschalk 2016]).
• Heparin or low molecular weight heparin: Concurrent heparin anticoagulation may contribute to bleeding. In the treatment of AIS, concurrent use of anticoagulants was not permitted during the initial 24 hours of the <3 hour window trial (NINDS 1995). The AHA/ASA does not recommend initiation of anticoagulant therapy within 24 hours of treatment with alteplase (AHA/ASA [Jauch 2013]). Initiation of SubQ heparin (≤10,000 units) or equivalent doses of low molecular weight heparin for prevention of DVT during the first 24 hours of the 3 to 4.5 hour window trial was permitted and did not increase the incidence of intracerebral hemorrhage (Hacke 2008). Alteplase use is not recommended for acute ischemic stroke in patients who have received a treatment dose of LMWH within the previous 24 hours (AHA/ASA [Demaerschalk 2016]). For acute PE, withhold heparin during the 2-hour infusion period.

Special populations:

• Elderly: Use with caution in patients with advanced age (eg, >75 years of age); increased risk of bleeding. In the treatment of pulmonary embolism, >75 years of age is considered a relative contraindication (Kearon 2012; Kearon 2016). In the treatment of acute ischemic stroke (within 3 to 4.5 hours after symptom onset), alteplase use in patients >80 years of age is considered an exclusion criteria (AHA/ASA [Jauch 2013]; Hacke 2008). However, according to the AHA/ASA 2016 scientific statement, alteplase use in patients >80 years of age with acute ischemic stroke presenting within 3 to 4.5 hours after symptom onset is safe and can be as effective as in younger patients (AHA/ASA [Demaerschalk 2016]).
• Pregnancy: Use with caution in pregnancy; increased risk of bleeding.

Dosage form specific issues:

• Cathflo Activase: When used to restore catheter function, use Cathflo cautiously in those patients with known or suspected catheter infections. Evaluate catheter for other causes of dysfunction before use. Avoid excessive pressure when instilling into catheter.
• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.

Other warnings/precautions:

• Administration: Intramuscular injections and nonessential handling of the patient should be avoided. Venipunctures should be performed carefully and only when necessary. Avoid internal jugular and subclavian venous punctures. If arterial puncture is necessary, use an upper extremity vessel that can be manually compressed.
• Appropriate use: Alteplase has not been shown to adequately treat underlying deep vein thrombosis in patients with PE. Consider the possible risk of re-embolization due to the lysis of underlying deep venous thrombi in this setting.

Monitoring Parameters

Acute ischemic stroke (AIS): Baseline: Neurologic examination, head CT (without contrast), blood pressure, CBC, aPTT, PT/INR, glucose. During and after initiation: In addition to monitoring for bleeding complications, the 2013 AHA/ASA guidelines for the early management of AIS recommends the following:

Perform neurological assessments every 15 minutes during infusion and every 30 minutes thereafter for the next 6 hours, then hourly until 24 hours after treatment.

If severe headache, acute hypertension, nausea, or vomiting occurs, discontinue the infusion and obtain emergency CT scan.

Measure BP every 15 minutes for the first 2 hours of initiation then every 30 minutes for the next 6 hours, then hourly until 24 hours after initiation of alteplase. Increase frequency if a systolic BP is ≥180 mm Hg or if a diastolic BP is ≥105 mm Hg; administer antihypertensive medications to maintain BP at or below these levels.

Obtain a follow-up CT scan at 24 hours before starting anticoagulants or antiplatelet agents.

Central venous catheter clearance: Assess catheter function by attempting to aspirate blood.

Pulmonary embolism: Monitor BP and HR continually and for at least 24 hours after administration; assess invasive catheters hourly for bleeding (Smithburger 2013).

ST-elevation MI: Baseline: Blood pressure, serum cardiac biomarkers, CBC, PT/INR, aPTT. During and after initiation: Assess for evidence of cardiac reperfusion through resolution of chest pain, resolution of baseline ECG changes, preserved left ventricular function, cardiac enzyme washout phenomenon, and/or the appearance of reperfusion arrhythmias; assess for bleeding potential through clinical evidence of GI bleeding, hematuria, gingival bleeding, fibrinogen levels, fibrinogen degradation products, PT and aPTT.

Pregnancy

Pregnancy Considerations

The risk of bleeding may be increased in pregnant women. Outcome information is available following alteplase use in pregnancy (Hirano 2013; Leonhardt 2006; Li 2012; Özkan 2013). Currently, most guidelines consider pregnancy to be a relative contraindication for its use (ACCF/AHA [O’Gara 2013]; AHA/ASA [Jauch 2013]; Kearon 2012; Kearon 2016; O'Connor 2010). Alteplase should not be withheld from pregnant women in life-threatening situations but should be avoided when safer alternatives are available (Bates 2012; Leonhardt 2006; Li 2012).

Patient Education

What is this drug used for?

• It is used to clear blood clots out of catheters.
• It is used to treat blood clots that have caused certain health problems like some types of heart attacks or strokes.
• It may be given to you for other reasons. Talk with the doctor.

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.
• DVT like edema, warmth, numbness, change in color, or pain in the extremities.
• Severe cerebrovascular disease like change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes.
• Blue/black/purple skin discoloration
• Change in amount of urine passed
• Chest pain
• Severe dizziness
• Passing out
• Severe headache
• Vision changes
• Muscle pain
• Severe abdominal pain
• Dark urine
• Back pain
• Nausea
• Vomiting
• Catheter site pain or irritation
• 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.