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  • CLASSES

    Fibrinolytics

    DEA CLASS

    Rx

    DESCRIPTION

    Recombinant form of the human tissue plasminogen activator (rt-PA); used for acute ischemic stroke, acute PE, or acute coronary arterial thromboembolism associated with evolving transmural MI; also used for the restoration of function to central venous access devices.

    COMMON BRAND NAMES

    Activase, Cathflo Activase

    HOW SUPPLIED

    Activase/Cathflo Activase Intravenous Inj Pwd F/Sol: 2.2mg, 50mg, 100mg

    DOSAGE & INDICATIONS

    For the treatment of acute myocardial infarction with ST-elevation (STEMI) due to coronary artery thrombosis.
    NOTE: A dose of 150 mg of alteplase is no longer recommended due to an increased incidence of intracranial bleeding.
    NOTE: Randomized controlled trials have demonstrated beneficial outcomes when fibrinolytic therapy is administered as early as possible after onset of STEMI symptoms (e.g., prehospital fibrinolysis or within 30 minutes of hospital arrival). When indicated for patients with acute myocardial infarction and ST-elevation (STEMI), fibrinolytic therapy may be administered within 12 hours following the onset of symptoms. It is reasonable to administer fibrinolytic therapy within 24 hours of the onset of STEMI symptoms in patients who have continuing ischemic symptoms and ST elevation greater than 0.1 mV in at least 2 contiguous precordial leads or at least 2 adjacent limb leads.
    NOTE: See heparin monograph for suggested dosing regimens during thrombolysis for acute myocardial infarction.
    Accelerated intravenous infusion.
    Intravenous dosage
    Adults > = 67 kg

    100 mg total dosage administered as a 15 mg IV bolus, followed by 50 mg IV infused over 30 minutes, and then 35 mg IV infused over the next 60 minutes.

    Adults < 67 kg

    15 mg IV bolus, followed by 0.75 mg/kg IV (not to exceed 50 mg) infused over 30 minutes, and then 0.5 mg/kg IV (not to exceed 35 mg) over the next 60 minutes.

    Geriatric

    See adult dosage. In elderly patients, the benefits of therapy should be carefully weighed against the risk of increased adverse events, including bleeding.

    Three (3) hour intravenous infusion.
    Intravenous dosage
    Adults >= 65 kg

    A total of 100 mg IV infused over 3 hours. During the first hour, 60 mg is administered over one hour, as a 6—10 mg IV bolus administered over 1—2 minutes then the remaining 50—54 mg, given by IV infusion over the remainder of the hour. During the second and third hours, 20 mg is given by continuous IV infusion (20 mg/hour).

    Adults < 65 kg

    A total of 1.25 mg/kg IV infused over 3 hours. During the first hour, 60% of the total dose is administered over one hour, by first injecting 6 to 10% of the dose by IV bolus over 1—2 minutes, then the remaining 50—54% of the dose by IV infusion over the remainder of the hour. During the second hour, 20% of the dose is administered by continuous IV infusion. During the third hour, 20% of the dose is administered by continuous IV infusion.

    Geriatric

    See adult dosage. In elderly patients, the benefits of therapy should be carefully weighed against the risk of increased adverse events, including bleeding.

    Reduced dose alteplase in combination with abciximab and very low dose heparin†.
    NOTE: See abciximab monograph for other fibrinolytic combinations (GUSTO V and SPEED trials) which included low dose reteplase plus abciximab therapy for acute MI.
    Intravenous dosage
    Adults

    15 mg IV bolus, followed by 35 mg IV over 60 minutes in combination with standard abciximab regimen (0.25 mg/kg IV bolus followed by a 12 hour IV continuous infusion of abciximab 0.125 mcg/kg/min) and very low dose heparin (30 units/kg IV bolus then 4 units/kg/hour continuous IV infusion) resulted in TIMI grade III flow rates of 72% and 77% at 60 and 90 minutes, respectively. These rate are significantly higher than those seen with alteplase alone (43% and 62%, respectively). The rate of major hemorrhage following this combination was 1%.

    Geriatric

    See adult dosage. In elderly patients, the benefits of therapy should be carefully weighed against the risk of increased adverse events, including bleeding.

    For the intracoronary treatment of acute coronary artery thrombosis (i.e., abrupt closure) in the setting of percutaneous coronary intervention (PCI)†, in combination with repeat balloon dilation.
    NOTE: The relative efficacy of alteplase compared with other treatment strategies has not been systematically evaluated.
    Intracoronary (IC), followed by Intravenous (IV) dosage
    Adults

    In one study of 27 patients, alteplase 20 mg IC was infused over 5 minutes, followed by 50 mg IV over the next 60 minutes. Although 82% of patients achieved initial angiographic success, 12 of these patients developed reocclusion on follow-up angiography. In a second study, 204 patients received a mean dose of 31 mg IC (range 10—100 mg) infused over 10—20 minutes; however, only 11/204 received alteplase for abrupt closure. In the entire study population, TIMI flow grade increased from 1.2 to 2.3 and TIMI thrombus grade decreased from 3.2 to 1.6.

    For the treatment of acute pulmonary embolism.
    Intravenous dosage
    Adults

    100 mg by IV infusion over 2 hours. Heparin in conjunction with alteplase has been recommended, provided that the activated partial thromboplastin time (aPTT) or thrombin time is not higher than twice the control value near the end or directly following the alteplase infusion.

    Infants†, Children†, and Adolescents†

    0.5 mg/kg/hour IV for 6 hours is a commonly used regimen; doses of 0.01 to 3.75 mg/kg/hour for 1 to 192 hours have been reported. Heparin therapy either during or immediately following thrombolytic therapy has been recommended; the loading dose may be omitted. Increased bleeding complications have been reported in pediatric patients receiving higher doses; therefore, some authors recommend initiating therapy at the lower end of the dosage range and increasing the dose only if necessary for adequate lysis.

    Neonates†

    0.1 to 0.3 mg/kg/hour IV for 6 to 48 hours has been recommended. Regimens reported in small case series and case reports of neonates (n = 94) have included loading doses up to 0.75 mg/kg IV over 10 to 60 minutes followed by infusions of 0.02 to 1 mg/kg/hour IV for 0.5 to 264 hours. Although the overall outcome in these reports was 94% patency restoration (68% to 79% complete clot dissolution and 14% to 26% partial clot dissolution), the number of patients in each report was too small and the regimens too varied to draw definitive conclusions regarding the appropriate dose. Heparin therapy either during or immediately following thrombolytic therapy has been recommended; the loading dose may be omitted. Increased bleeding complications have been reported in pediatric patients receiving higher doses; therefore, some authors recommend initiating therapy at the lower end of the dosage range and increasing the dose only if necessary for adequate lysis.

    For the treatment of acute ischemic stroke.
    Within 3 hours of the onset of stroke symptoms.
    Intravenous dosage
    Adults

    0.9 mg/kg IV (not to exceed 90 mg); give 10% of the total dose as an IV bolus over 1 minute, then give the remaining 90% as an IV infusion over 60 minutes. Initiate therapy as soon as possible but within 3 hours of onset of stroke symptoms.

    For acute ischemic stroke in pediatric patients†.
    Intravenous dosage
    Adolescents† and Children†

    NOTE: There is significant variability in the management of pediatric stroke and practice standards for the use of thrombolysis have not been established. The 2004 ACCP clinical guidelines do not recommend the use of thrombolytic therapy for the treatment of acute ischemic stroke in children. However, the use of 0.9 mg/kg total dose administered via IV infusion, with 10% of the dose administered as an initial IV loading dose over 1 minute and the remainder administered over 60 minutes has been described in 3 individual case reports. The patients described were 12, 13, and 16 years old. Following alteplase administration, all 3 patients had significant neurological improvement with no reports of significant bleeding.

    Neonates†

    The 2004 ACCP clinical guidelines do not recommend the use of anticoagulants and/or thrombolytics for the treatment of noncardioembolic acute ischemic stroke in neonates. For neonates with cardioembolic acute ischemic stroke, anticoagulation for 3 months with either unfractionated heparin or a low molecular weight heparin is recommended.

    For reestablishing patency of an occluded IV catheter.
    Intracatheter instillation dosage (Cathflo Alteplase)
    Adults

    Instill 2 mg/2 mL into the dysfunctional catheter for 2 hours. If catheter function is not restored 2 hours after the first dose, a second dose may be instilled. Efficacy and safety information for doses more than 2 mg/dose or total doses more than 4 mg is not available. Dwell times of 0.5 to 4 hours have been recommended. For multiple lumens, treat one lumen at a time. For subcutaneous ports, a dose of 2 mg diluted in 3 mL 0.9% NaCl Injection has been recommended. Doses of 1 to 2 mg injected into the lumen(s) of central venous catheters or PICC lines, allowed to dwell for 15 minutes to 4 hours, then removed by aspiration, have been reported effective in establishing patency.

    Children and Adolescents weighing 30 kg or more

    Instill 2 mg/2 ml into the dysfunctional catheter for 2 hours. If catheter function is not restored 2 hours after the first dose, a second dose may be instilled. Efficacy and safety information for doses more than 2 mg/dose or total doses more than 4 mg is not available. Dwell times of 0.5 to 4 hours have been recommended. For multiple lumens, treat one lumen at a time. For subcutaneous ports, a dose of 2 mg diluted in 3 ml 0.9% NaCl Injection has been recommended.

    Children weighing 10 to 29 kg

    Instill 110% of the internal lumen volume of the catheter with alteplase 1 mg/mL, not to exceed 2 mg/2 mL. If catheter function is not restored 2 hours after the first dose, a second dose may be instilled. Efficacy and safety information for doses more than 2 mg/dose or total doses more than 4 mg is not available. Dwell times of 0.5 to 4 hours have been recommended. For multiple lumens, treat one lumen at a time. For subcutaneous ports, a dose of 2 mg diluted in 3 mL 0.9% NaCl Injection has been recommended.

    Neonates, Infants, and Children weighing less than 10 kg

    Instill 110% of the internal lumen volume of the catheter with alteplase 1 mg/mL, not to exceed 2 mg/2 mL. If catheter function is not restored 2 hours after the first dose, a second dose may be instilled. Efficacy and safety information for doses more than 2 mg/dose or total doses more than 4 mg is not available. A solution of 0.5 to 1 mg diluted in 2 mL 0.9% NaCl Injection sufficient to fill the occluded catheter has also been used. Dwell times of 0.5 to 4 hours have been recommended. For multiple lumens, treat one lumen at a time. For subcutaneous ports, 0.5 mg diluted in 3 mL 0.9% NaCl Injection has been recommended.

    For the treatment of deep venous thrombosis (DVT)† using local administration of thrombolytics including catheter-directed thrombolysis (CDT) and intra-clot administration.
    NOTE: Clinical practice guidelines recommend anticoagulant therapy alone over catheter-directed thrombolysis (CDT) in patients with acute proximal DVT; however, guidelines do state that patients who are most likely to benefit from CDT are those with iliofemoral DVT, symptoms for less than 14 days, good functional status, life expectancy of more than 1 year, and a low risk of bleeding.
    Catheter-directed thrombolysis dosage
    Adults

    Various dosages and administration techniques have been studied. In one study of patients with acute iliofemoral DVT, 0.1 mg/kg/hr (maximum of 20 mg per 24 hours for up to 96 hours) administered via catheter-directed thrombolysis (CDT) plus anticoagulation had a significantly higher rate of venous patency at 6 months and a lower incidence of post-thrombotic syndrome at 24 months vs. anticoagulation alone. Bleeding was reported more often in the alteplase group, with 8 cases described as major and/or clinically relevant. Another study gave 10 mg bolus via CDT followed by 1 to 2 mg/hr via CDT and found long-term benefit with open veins without reflux in 82% of patients after 6 years. Once daily intra-clot administration of alteplase (4 mg for upper extremity DVT and 10 mg for lower extremity DVT) showed restoration of vein patency in 79% of upper extremity clots antegrade flow restoration in 97% of lower extremity clots.

    For the treatment of peripheral arterial thromboembolism†.
    Intra-arterial dosage
    Adults

    Various doses and administration times have been studied; the lowest effective dose has not been determined. Common doses used in combination with heparin include 0.5 to 2.5 mg/hr. Weight-based dosing of 0.05 to 0.1 mg/kg/hr for up to 12 hours (max of 100 mg) also has been studied. In clinical trials, alteplase was administered by catheter-directed intra-arterial administration. Administration time varied but typically continued until complete lysis was achieved or for up to 12 hours. Clinical practice guidelines recommend immediate systemic anticoagulation with unfractionated heparin in patients with acute limb ischemia due to arterial emboli or thrombosis. Guidelines also recommend reperfusion with surgery over intra-arterial thrombolysis.

    For intravascular catheter occlusion prophylaxis†.
    Intracatheter instillation dosage (Cathflo Alteplase)†
    Adults

    1 mg or 2 mg alteplase instilled in each catheter lumen at the end of hemodialysis sessions has been studied; one study used 2 mg alteplase after each dialysis session and the other used 1 mg alteplase in only one of three dialysis sessions each week, with heparin instilled after the other two sessions. ] Based on these limited data compared to heparin, alteplase appears to be more effective in maintaining catheter flow (blood flow), did not result in more bleeding events, and may reduce bacteremia.

    For the management of pleural effusion† or pleural empyema†.
    Intrapleural dosage
    Infants, Children, and Adolescents

    4 mg in 30 to 50 mL 0.9% Sodium Chloride Injection intrapleurally via chest tube and left to dwell for 1 hour as a single dose or as multiple doses 24 hours apart. Clinical practice guidelines suggest tube thoracostomy with or without subsequent fibrinolytic instillation should be attempted as the initial treatment of an empyema in pediatric patients.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    The maximum dosage is dependent on indication for therapy.

    Geriatric

    The maximum dosage is dependent on indication for therapy.

    Adolescents

    Safety and efficacy have not been established for systemic thrombolysis; various regimens have been used. For occluded catheters, instill no more than 4 mg/catheter.

    Children

    Safety and efficacy have not been established for systemic thrombolysis; various regimens have been used. For occluded catheters, instill no more than 4 mg/catheter.

    Infants

    Safety and efficacy have not been established for systemic thrombolysis; various regimens have been used. For occluded catheters, instill no more than 4 mg/catheter.

    Neonates

    Safety and efficacy have not been established for systemic thrombolysis; various regimens have been used. For occluded catheters, instill no more than 4 mg/catheter.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. The risks of alteplase therapy may be increased in patients with significant hepatic impairment and should be weighed against the anticipated benefits.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Alteplase is administered intravenously as a bolus injection or infusion.
    Intravenous dosage reconstitution :
    50 mg vials: Vials contain a vacuum; do not use if vacuum is not present. Using a large bore needle (e.g., 18 gauge) and a syringe add the Sterile Water for Injection supplied by the manufacturer to the vial containing alteplase to make a solution containing 1 mg/mL. Be sure to direct the stream of water into the lyophilized cake. Slight foaming upon reconstitution may occur; standing undisturbed for several minutes is sufficient to allow dissipation of any large bubbles. The reconstituted product is a colorless to pale yellow transparent solution.
    100 mg vials: Vials do not contain vacuum. Keeping the vial of Sterile Water for Injection upright, insert the piercing pin of the transfer device (provided by the manufacturer) vertically into the center of the stopper. Remove the protective cap from a vial of alteplase and hold it upside-down over the piercing pin of the transfer device. Push the vial down so that the piercing pin is inserted through the center of the vial stopper. Invert the two vials so that the vial of alteplase is on the bottom and allow the entire amount of water to flow into the alteplase vials (about 0.5 mL will remain in the Sterile Water for Injection vial). This will take about 2 minutes. The concentration of alteplase solution is 1 mg/mL. Separate the alteplase vial from the transfer device and gently swirl to dissolve the powder. DO NOT SHAKE.
    Dilution:
    The reconstituted solution may be administered as the 1 mg/mL solution or alternatively, the reconstituted solution may be further diluted with an equal volume of 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a concentration of 0.5 mg/mL. Polyvinyl chloride bags or glass vials are acceptable for dilution. Following dilution, the solution is stable for up to 8 hours at room temperature.
    Preparation of bolus dose :
    The bolus dose may be prepared in one of three ways:
    Remove the appropriate indication-specific volume from the reconstituted vial using a syringe and needle. If this method is used with 50 mg vials, the syringe should not be primed with air and the needle should be inserted into the 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 indication-specific 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 indication-specific volume as a bolus (1 mg/mL) at the initiation of the infusion.
    Intravenous infusion :
    For the 50-mg vial: Administer using a polyvinyl chloride bag or glass vial and infusion set.
    For the 100-mg vial: Remove from the vial the amount of drug that is not needed for the indication-specific dose for the patient. 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 alteplase. Hang the reconstituted vial of alteplase from the plastic molded capping attached to the bottom of the vial.
    Length of infusion depends upon indication.

    Other Injectable Administration

    Central Venous Catheter Instillation Administration
    Alteplase (Cathflo Activase) is instilled into the occluded lumen of a central venous catheter.
    Consider other reasons for catheter dysfunction, such as catheter malposition, mechanical failure, constriction by a suture, and lipid deposits or drug precipitates within the lumen, prior to treatment with alteplase.
    Avoid vigorous suction during attempts to determine catheter occlusion to prevent damage to the vascular wall or collapse of soft-walled catheters.
    Avoid excessive pressure when alteplase is instilled into the catheter. Such force could cause rupture of the catheter or expulsion of the clot into the circulation.
     
    Reconstitution (Cathflo Activase)
    Aseptically withdraw 2.2 mL Sterile Water for Injection. Do not use Bacteriostatic Water for Injection.
    Inject the 2.2 mL of Sterile Water for Injection into the vial, directing the diluent stream into the powder. Slight foaming is not unusual; let the vial stand undisturbed to allow large bubbles to dissipate.
    Mix gently by swirling until the contents completely dissolve. Complete dissolution should occur within 3 minutes. DO NOT SHAKE. The reconstituted product results in a colorless to pale yellow clear solution containing 1 mg/mL alteplase at a pH of about 7.3.
    The reconstituted product contains no antibacterial preservatives and should be reconstituted immediately prior to use. The solution may be used for intracatheter instillation within 8 hours following reconstitution when stored at 2—30 degrees C (36—86 degrees F).
    No other medication should be added to solutions containing alteplase.
     
    Preparation of cryopreserved bolus injections:
    NOTE: Alteplase is not approved by the FDA to be prepared as cryopreserved bolus injections.
    In vitro data support that cryopreserved alteplase solutions maintain bioactivity in propylene syringes for 6 months and in glass vials for 2 weeks. Using aseptic technique, dilute alteplase to a concentration of 1 mg/mL.
    For propylene syringes: Withdraw 1 mL into polypropylene syringes and cryopreserve at -20 degrees C. Aliquots retain bioactivity for 6 months.
    For glass vials: Withdraw 2 mL into glass vials and cryopreserve at -70 degrees C for 2 weeks; then, thaw and maintain at 22—24 degrees C for 24 hours; then, store at -70 degrees C for up to 19 days.
     
    Intracatheter instillation (Cathflo Activase):
    Inspect the product prior to administration for foreign matter and discoloration.
    Withdraw 2 mL (2 mg) of solution from the reconstituted vial.
    Instill the appropriate dose into the occluded catheter.
    After 30 minutes of dwell time, assess catheter function by attempting to aspirate blood.
    If the catheter is not functional after 30 minutes, allow the solution to remain for an additional 90 minutes (120 minutes of total dwell time) and assess catheter function by attempting to aspirate blood and catheter contents.
    If catheter function is not restored after 120 minutes, a second dose may be instilled. Following instillation of second dose, check catheter function 30 minutes and, if needed, 120 minutes following second instillation.
    If catheter function is restored, aspirate 4—5 mL of blood in patients weighing >= 10 kg or 3 mL in patients weighing < 10 kg to remove alteplase and residual clot. Gently irrigate the catheter with 0.9% Sodium Chloride Injection.
    Discard any unused solution.

    STORAGE

    Activase:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store unreconstituted product below 86 degrees F
    Cathflo Activase:
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Alteplase should not be used in patients with a hypersensitivity to alteplase or any component of the formulation.

    Atrial fibrillation, hypertension

    Weigh the risks of bleeding against the benefits of use in patients with mitral valve stenosis or atrial fibrillation; alteplase may increase the risk of bleeding in these conditions where there is a high likelihood of left heart thrombosis. Alteplase is contraindicated in patients with severe uncontrolled hypertension. Bleeding risk is increased with systolic blood pressure above 175 mmHg or diastolic blood pressure above 110 mmHg. Clinical practice guidelines for acute ischemic stroke exclude patients from alteplase use if systolic blood pressure is more than 185 mmHg or diastolic blood pressure is more than 110 mmHg. In patients with acute ischemic stroke with uncontrolled hypertension who are otherwise eligible for alteplase therapy, increase the frequency of blood pressure monitoring if systolic blood pressure is more than 180 mmHg or diastolic blood pressure is more than 105 mmHg. Administer antihypertensive medications to maintain blood pressure at or below these values. Ensure that the blood pressure is stabilized at a lower level before beginning treatment with alteplase, and maintain blood pressure below 180/105 mmHg for the first 24 hours after alteplase administration.

    Aneurysm, anticoagulant therapy, arteriovenous malformation, bleeding, brain tumor, coagulopathy, coronary artery bypass graft surgery (CABG), diabetic retinopathy, endocarditis, GI bleeding, head trauma, intracranial bleeding, intracranial mass, mitral stenosis, organ biopsy, peptic ulcer disease, pericarditis, seizures, stroke, surgery, thrombocytopenia, trauma, venipuncture

    Due to an increased risk for bleeding, alteplase is contraindicated in patients being treated for acute myocardial infarction or pulmonary embolism with the following concomitant conditions: severe uncontrolled hypertension, aneurysm or arteriovenous malformation; known coagulopathy or bleeding diathesis; active internal bleeding; brain tumor; recent (within the last 3 months) intracranial or intraspinal surgery or serious head trauma; intracranial mass; or history of cerebrovascular accident (stroke). In patients being treated for ischemic stroke, alteplase is contraindicated in patients with the following concomitant conditions: intracranial or intraspinal surgery, or serious head trauma within the last 3 months; evidence of current intracranial bleeding or suspicion of subarachnoid hemorrhage on pretreatment evaluation; uncontrolled hypertension; active internal bleeding; intracranial neoplasm, arteriovenous malformation or aneurysm; bleeding diathesis including, but not limited to, current use of oral anticoagulants or an INR >1.7 or PT>15 seconds, administration of heparin within 48 hours preceding the onset of stroke and an elevated aPTT at presentation, or thrombocytopenia (platelet count < 100,000/mm3). Patients who present with seizures at onset of stroke with postictal residual neurological impairments, history of intracranial hemorrhage, or those who have had a recent or previous stroke are also at increased risk of bleeding when alteplase is used for acute ischemic stroke. NOTE: Alteplase is indicated for the treatment of acute ischemic stroke, for improving neurological recovery and reducing the incidence of disability; treatment should ONLY be initiated within 3 hours after the onset of stroke symptoms, and after exclusion of intracranial hemorrhage by a cranial computerized tomography (CT) scan or other diagnostic imaging method sensitive for the presence of hemorrhage. There is an increased risk of intracranial hemorrhage in patients with severe neurological deficit (e.g., NIHSS > 22) at presentation. The risks of alteplase therapy may be increased in patients with major early infarct signs on CT (e.g., substantial edema, mass effect, or midline shift). The treatment of patients with minor neurological deficit or with rapidly improving symptoms is not recommended as the safety and efficacy in these patients has not been evaluated. In the following relative contraindications, the risk of thrombolytic therapy may be increased and should be weighed against the anticipated benefits. Thrombolytics should not be used in patients whom have recently (within the past 10 days) undergone or experienced GI bleeding (e.g., peptic ulcer disease) or genitourinary bleeding, major surgery (e.g., coronary artery bypass graft surgery (CABG)), delivering a baby, organ biopsy, trauma (including cardiopulmonary resuscitation), or venipuncture of a noncompressible vessel. Thrombolytics should not be used in patients with acute pericarditis, diabetic retinopathy (or other hemorrhagic ophthalmic conditions), infectious endocarditis, mitral stenosis with atrial fibrillation, or other conditions with a high risk of left heart thrombus. Thrombolytic therapy should also be used with extreme caution in other conditions that can be exacerbated as a result of bleeding or in which bleeding could be hazardous or difficult to control due to its location. Thrombolytics should be used with caution in patients who have recently received glycoprotein IIb/IIIa inhibitors or anticoagulant therapy (e.g., warfarin) due to the potential for enhanced risk of bleeding. The use of alteplase for occluded central venous catheters has not been studied in patients known to be at risk for bleeding events that may be associated with use of thrombolytics. Exercise caution in patients with active internal bleeding or other risk factors for bleeding within 48 hours of use.

    Hepatic disease, renal disease, renal failure

    Use systemic thrombolytics with caution in patients with hemostatic defects due to severe hepatic disease or renal disease associated with renal failure or in any patient with significant hepatic dysfunction; the bleeding risk of alteplase may be increased and should be weighed against the anticipated benefits.

    Intramuscular injections

    Avoid intramuscular injections and nonessential handling in patients receiving systemic thrombolytic therapy with alteplase. Systemic alteplase can cause significant, sometimes fatal, internal or external bleeding, especially at arterial and venous puncture sites. Perform venipunctures carefully and only when necessary. If an arterial puncture is necessary, use an upper extremity vessel accessible to manual compression, apply pressure for at least 30 minutes, and monitor the puncture site closely for evidence of bleeding.

    Infection, thrombophlebitis

    Alteplase for the management of occluded catheters should be used with caution in the presence of known or suspected infection in the catheter. Systemic infection can occur if thrombolytics are administered into an occluded IV or AV cannula that is proximal to an infection site or in the presence of septic thrombophlebitis, as the local infection can be released to the systemic circulation.

    Geriatric

    In exploratory, multivariate analyses, age more than 77 years was among baseline characteristics associated with an increased risk for intracranial hemorrhage. Efficacy results suggest a reduced but still favorable outcome in geriatric patients treated with alteplase for acute ischemic stroke. Although clinical practice guidelines recommend expanded use of alteplase at 3 to 4.5 hours after stroke onset, patients older than 80 years are not eligible for alteplase use in the expanded time window. This age group was excluded from acute ischemic stroke clinical trials evaluating the expanded alteplase use window.

    Labor, obstetric delivery, pregnancy

    Alteplase is classified as FDA pregnancy risk category C. It is unknown whether alteplase crosses the placenta. Alteplase has been shown to have an embryocidal effect in rabbits when administered systemically in doses of approximately two times (3 mg/kg) the human dose for acute myocardial infarction. No maternal or fetal toxicity was evident at 0.65 times (1 mg/kg) the human dose in pregnant rats and rabbits dosed during the period of organogenesis. There are no adequate and well-controlled studies in pregnant women. Thrombolytics should be given to pregnant women only if the potential benefits justify the potential risks. Labor and obstetric delivery are considered risk factors for bleeding with alteplase therapy.

    Breast-feeding

    According to the manufacturer, it is unknown whether alteplase is excreted into breast milk, and alteplase should be used with caution if it is given to a woman who is breast-feeding. However, based on the drug's large molecular weight and short half-life, experts state that clinically significant amounts of drug are not expected to be found in breast milk. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants, neonates

    The safety and effectiveness of alteplase have not been established in adolescents, children, infants, or neonates for indications involving the treatment of systemic thromboembolic events (e.g., myocardial infarction). Alteplase is approved for the management of occluded catheters in children and infants.[ In the Cathflo Activase Pediatric Study (CAPS), 310 patients between the ages of 2 weeks and 17 years with a weight distribution of 2.2—107 kg were treated for central venous catheter occlusion (see Dosage). Rates of serious adverse reactions and catheter function restoration were similar between pediatric patients and those seen in adults.

    ADVERSE REACTIONS

    Severe

    intracranial bleeding / Delayed / 0.4-15.4
    GI bleeding / Delayed / 5.0-5.0
    stroke / Early / 1.2-1.6
    retroperitoneal bleeding / Delayed / 0-1.0
    thrombosis / Delayed / 0-1.0
    ventricular tachycardia / Early / Incidence not known
    bradycardia / Rapid / Incidence not known
    cholesterol microembolization / Early / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    laryngeal edema / Rapid / Incidence not known
    coma / Early / Incidence not known
    cerebral edema / Early / Incidence not known
    seizures / Delayed / Incidence not known
    thromboembolism / Delayed / Incidence not known
    AV block / Early / Incidence not known
    cardiac tamponade / Delayed / Incidence not known
    pericardial effusion / Delayed / Incidence not known
    cardiac arrest / Early / Incidence not known
    heart failure / Delayed / Incidence not known
    pericarditis / Delayed / Incidence not known
    pulmonary edema / Early / Incidence not known
    pleural effusion / Delayed / Incidence not known

    Moderate

    bleeding / Early / 10.0
    premature ventricular contractions (PVCs) / Early / Incidence not known
    hypertension / Early / Incidence not known
    livedo reticularis / Delayed / Incidence not known
    hypotension / Rapid / Incidence not known

    Mild

    ecchymosis / Delayed / 1.0-1.0
    epistaxis / Delayed / 0-1.0
    infection / Delayed / 0-1.0
    fever / Early / Incidence not known
    nausea / Early / Incidence not known
    vomiting / Early / Incidence not known
    rash (unspecified) / Early / Incidence not known
    urticaria / Rapid / Incidence not known

    DRUG INTERACTIONS

    Abciximab: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
    Alpha interferons: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Altretamine: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Aminocaproic Acid: (Severe) The actions of aminocaproic acid can antagonize the actions of thrombolytic agents. Although antifibrinolytic agents can be beneficial in the treatment of thrombolytic-induced hemorrhage, the safety of concomitant administration of these agents has not been confirmed.
    Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
    Anagrelide: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
    Antimetabolites: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Antithrombin III: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants.
    Antithymocyte Globulin: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antithymocyte globulin.
    Apixaban: (Severe) Due to the increased bleeding risk, avoid concurrent use of apixaban with thrombolytic agents.
    Aprotinin: (Severe) Aprotinin interferes with fibrinolysis by inhibiting the actions of kallikrein and plasmin, and it could inhibit fibrinolysis by thrombolytic agents. Although antifibrinolytic agents can be beneficial in the treatment of thrombolytic-induced hemorrhage, the safety of concomitant administration of these agents has not been confirmed.
    Argatroban: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents with thrombin inhibitors.
    Arsenic Trioxide: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Aspirin, ASA: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
    Aspirin, ASA; Carisoprodol: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
    Aspirin, ASA; Dipyridamole: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution. (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
    Aspirin, ASA; Omeprazole: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
    Aspirin, ASA; Oxycodone: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
    Aspirin, ASA; Pravastatin: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
    Betrixaban: (Major) Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if betrixaban and thrombolytic agents are used concomitantly. Coadministration of betrixaban and thrombolytic agents may increase the risk of bleeding.
    Bevacizumab: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Bexarotene: (Moderate) Patients with thrombocytopenia are at increased risk of bleeding complications. An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Bismuth Subsalicylate: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
    Bivalirudin: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents with thrombin inhibitors.
    Chlorambucil: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Choline Salicylate; Magnesium Salicylate: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
    Chondroitin; Glucosamine: (Moderate) Increased effects from concomitant anticoagulant drugs including increased bruising or blood in the stool have been reported in patients taking methylsulfonylmethane, MSM. Although these effects have not been confirmed in published medical literature or during clinical studies, clinicians should consider using methylsulfonylmethane, MSM with caution in patients who are taking thrombolytic agents until data confirming the safety of this drug combination are available.
    Cilostazol: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
    Clofarabine: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Clopidogrel: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
    Cod Liver Oil: (Major) Cod liver oil should be used only with caution and with frequent monitoring in patients on concurrent thrombolytic agents. Theoretically, the risk of bleeding may be increased. (Moderate) Fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents.
    Dabigatran: (Major) Based on the pharmacology of dabigatran, other oral anticoagulants and thrombolytic agents could cause additive risk of bleeding when given concurrently with dabigatran.
    Dalteparin: (Moderate) An additive risk of bleeding may be seen in patients receiving dalteparin in combination with other agents known to increase the risk of bleeding such thrombolytic agents. Monitor clinical and laboratory response closely during concurrent use.
    Danaparoid: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants.
    Danazol: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with thrombolytic agents.
    Defibrotide: (Severe) Coadministration of defibrotide with fibrinolytics (thrombolytic agents) is contraindicated. The pharmacodynamic activity and risk of hemorrhage with fibrinolytics are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue systemic fibrinolytic therapy (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the fibrinolytic have abated.
    Denileukin Diftitox: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Desirudin: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents with thrombin inhibitors.
    Desvenlafaxine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving thrombolytic agents. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Dipyridamole: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
    Drotrecogin Alfa: (Major) Patients receiving thrombolytic agents are at increased risk of bleeding during drotrecogin alfa therapy.
    Duloxetine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving thrombolytic agents. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Edoxaban: (Major) Coadministration of edoxaban and thrombolytic agents should be avoided due to an increased risk of bleeding during concurrent use. Occasionally, short-term coadministration may be necessary in patients transitioning to and from edoxaban. Long-term coadminstration is not recommended. Promptly evaluate any signs or symptoms of blood loss in patients on concomitant therapy.
    Enoxaparin: (Moderate) An additive risk of bleeding may be seen in patients receiving enoxaparin in combination with other agents known to increase the risk of bleeding such as thrombolytic agents (e.g. alteplase, reteplase, streptokinase). Monitor clinical and laboratory response closely during concurrent use.
    Eptifibatide: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
    Estramustine: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) Fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents.
    Folate analogs: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytics.
    Fondaparinux: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants.
    Garlic, Allium sativum: (Moderate) Since garlic produces clinically-significant antiplatelet effects, it should be used cautiously in patients receiving thrombolytic agents.
    Ginger, Zingiber officinale: (Moderate) Since ginger inhibits thromboxane synthetase, a platelet aggregation inducer, and is a prostacyclin agonist, use with caution during times when bleeding is a concern. This includes patients receiving thrombolytic agents, however, no clinical data are available.
    Ginkgo, Ginkgo biloba: (Major) Ginkgo biloba should be used cautiously in patients taking thrombolytic agents. Ginkgo can produce clinically-significant antiplatelet effects; a compound found in Ginkgo biloba, ginkgolide-B, may act as a selective antagonist of platelet activating factor (PAF). Although a review of Ginkgo biloba in 1992 stated that no known drug interactions exist, spontaneous hyphema has been reported in an elderly male who began taking ginkgo while stabilized on daily aspirin. After ginkgo was stopped, no further bleeding was noted despite continuing the aspirin therapy. Other clinical data exist that describe spontaneous subdural hematomas associated with chronic Ginkgo biloba ingestion.
    Green Tea: (Moderate) Green tea has demonstrated antiplatelet and fibrinolytic actions in animals. It is possible that the use of green tea may increase the risk of bleeding if coadministered with thrombolytic agents. Caution and careful monitoring of clinical and/or laboratory parameters are warranted if green tea and thrombolytics are coadministered.
    Heparin: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
    Ibritumomab Tiuxetan: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Icosapent ethyl: (Moderate) Icosapent ethyl is an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA). Because omega-3 fatty acids inhibit platelet aggregation, caution is advised when icosapent ethyl is used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 36 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant icosapent ethyl therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Ifosfamide: (Moderate) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytic agents.
    Intravenous Lipid Emulsions: (Moderate) Fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents.
    Lepirudin: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents with thrombin inhibitors.
    Levomilnacipran: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SNRI.
    Lomustine, CCNU: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Magnesium Salicylate: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
    Methoxsalen: (Minor) Agents that decrease clotting, such as thrombolytic agents, could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Methylsulfonylmethane, MSM: (Moderate) Increased effects from concomitant anticoagulant drugs including increased bruising or blood in the stool have been reported in patients taking methylsulfonylmethane, MSM. Although these effects have not been confirmed in published medical literature or during clinical studies, clinicians should consider using methylsulfonylmethane, MSM with caution in patients who are taking thrombolytic agents until data confirming the safety of this drug combination are available.
    Milnacipran: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SNRI.
    Nitroglycerin: (Major) Two separate studies have shown that concomitant administration of IV nitroglycerin can compromise the therapeutic efficacy of alteplase. In one study, reperfusion occurred in 91% of patients receiving alteplase without nitroglycerin while only 44% of patients receiving alteplase with nitroglycerin were reperfused, however this was an uncontrolled study. In another controlled study, patients who did not receive concomitant IV nitroglycerin reperfused faster, more often, and had fewer reocclusions. It appears that when combined in vitro, nitroglycerin enhances the degradation of alteplase. Nitroglycerin may enhance the hepatic clearance of alteplase since alteplase plasma concentrations are lower in patients receiving concomitant nitroglycerin.
    Nonsteroidal antiinflammatory drugs: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
    Pegaspargase: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Pentosan: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants.
    Photosensitizing agents: (Moderate) Agents that decrease clotting, such as thrombolytic agents, could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Platelet Inhibitors: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
    Prasugrel: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
    Protein C Concentrate, Human: (Major) The concomitant use of protein C concentrate and alteplase, tPA may further increase the risk of bleeding from tPA. In clinical trials, several episodes of bleeding were reported. Concurrent anticoagulant medication may have been responsible for these bleeding episodes.
    Prothrombin Complex Concentrate, Human: (Major) The concomitant use of protein C concentrate and alteplase, tPA may further increase the risk of bleeding from tPA. In clinical trials, several episodes of bleeding were reported. Concurrent anticoagulant medication may have been responsible for these bleeding episodes.
    Rivaroxaban: (Major) Due to the increased bleeding risk, avoid concurrent use of rivaroxaban with thrombolytic agents; the safety of concomitant use has not been studied.
    Salicylates: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
    Salsalate: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
    Selective serotonin reuptake inhibitors: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
    Sodium Hyaluronate, Hyaluronic Acid: (Moderate) Increased bruising or bleeding at the injection site may occur when using hyaluronate sodium with thrombolytic agents, especially if used within the 3 weeks prior to the procedure.
    Sulfinpyrazone: (Moderate) Agents that may effect hemostasis including sulfinpyrazone, can increase the likelihood of hemorrhage if administered during or immediately before therapy with thrombolytic agents.
    Taxanes: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Thrombin Inhibitors: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents with thrombin inhibitors.
    Ticagrelor: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
    Ticlopidine: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
    Tinzaparin: (Moderate) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants.
    Tirofiban: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
    Tranexamic Acid: (Severe) Antifibrinolytic agents, including tranexamic acid, can antagonize the actions of thrombolytic agents. Although antifibrinolytic agents can be beneficial in the treatment of thrombolytic-induced hemorrhage, the safety of concomitant administration of these agents has not been confirmed.
    Trazodone: (Moderate) Platelet aggregation may be impaired by trazodone due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with trazodone.
    Tretinoin, ATRA: (Moderate) Patients with thrombocytopenia are at increased risk of bleeding complications. An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Venlafaxine: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered concurrently with venlafaxine.
    Vilazodone: (Moderate) Platelet aggregation may be impaired by vilazodone due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with vilazodone.
    Vorapaxar: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
    Vorinostat: (Moderate) Due to the thrombocytopenic effects of vorinostat, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytic agents.
    Vortioxetine: (Moderate) Platelet aggregation may be impaired by vortioxetine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving thrombolytic agents. Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymosis to life-threatening hemorrhages. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with vortioxetine and instructed to promptly report any bleeding events to the practitioner.
    Warfarin: (Severe) Based on the pharmacology of warfarin, other thrombolytic agents could cause additive risk of bleeding when given concurrently with warfarin. Pre-treatment with oral anticoagulants is reported to be an independent risk factor for intracranial hemorrhage in thrombolytic-treated patients. Prothrombin times stabilized during administration of both agents will change slightly when heparin is discontinued.

    PREGNANCY AND LACTATION

    Pregnancy

    Alteplase is classified as FDA pregnancy risk category C. It is unknown whether alteplase crosses the placenta. Alteplase has been shown to have an embryocidal effect in rabbits when administered systemically in doses of approximately two times (3 mg/kg) the human dose for acute myocardial infarction. No maternal or fetal toxicity was evident at 0.65 times (1 mg/kg) the human dose in pregnant rats and rabbits dosed during the period of organogenesis. There are no adequate and well-controlled studies in pregnant women. Thrombolytics should be given to pregnant women only if the potential benefits justify the potential risks. Labor and obstetric delivery are considered risk factors for bleeding with alteplase therapy.

    MECHANISM OF ACTION

    Alteplase exerts its action on the endogenous fibrinolytic system to convert plasminogen to plasmin by directly hydrolyzing the arginine-valine bond in plasminogen. Plasmin degrades fibrin and fibrinogen as well as the procoagulant factors V and VIII. Unlike streptokinase or urokinase, most of the activity of alteplase is dependent on the presence of fibrin. Minimal amounts of plasminogen are converted to plasmin in the absence of fibrin. Upon binding to fibrin, the one-chain form of t-PA is converted to the two-chain form. Both forms have similar fibrinolytic and plasminogen-activating potential; however, the one-chain t-PA is considerably less active in the absence of fibrin. Alteplase that is bound to fibrin acquires a high affinity for plasminogen, which is responsible for an increased activity at the fibrin surface compared to the circulation.

    PHARMACOKINETICS

    Alteplase (t-PA) is administered by IV infusion. The distribution of this agent has not been described; the initial volume of distribution approximates plasma volume. It is unknown whether alteplase crosses the placenta or is excreted into breast milk. Hepatic clearance is the predominant route of metabolism. More than 50% of the drug is cleared following discontinuation of IV infusion and 80% is cleared within 10 minutes. Limited studies in patients with myocardial infarction and patients with thromboembolic disease indicate that the terminal half-life of alteplase is approximately 45 and 30 minutes, respectively. Alteplase has been shown to be primarily excreted in the urine (80%).