PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Vascular Occlusion Management Fibrinolytics

    DEA CLASS

    Rx

    DESCRIPTION

    Intravenous recombinant plasminogen activator
    Used for acute STEMI to reduce the risk of death and heart failure
    More potent and rapid-acting than alteplase

    COMMON BRAND NAMES

    Retavase, Retavase Half-Kit

    HOW SUPPLIED

    Retavase/Retavase Half-Kit Intravenous Inj Pwd F/Sol: 10U

    DOSAGE & INDICATIONS

    For the treatment of acute myocardial infarction, STEMI to reduce the risk of death and heart failure.
    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).[31689] 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.[31689] [32417] 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.[31689]
    Intravenous dosage
    Adults

    10 units IV over 2 minutes followed by a second dose of 10 units IV 30 minutes after first dose.[46914]

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

    0.125 to 0.5 units/hour IA with heparin 400 to 800 units has been studied in a dose finding trial. Thrombolytic success was not statistically different between doses and ranged from 84 to 87%. The mean infusion time was significantly prolonged in the 0.125 units/hour compared to the higher doses (42 hours vs. 29 hours). Higher doses were reported in a retrospective review comparing the bleeding rates of alteplase and reteplase. Patients received reteplase 0.25 to 2 units/hour (mean dose 0.61 units/hour) IA in combination with heparin 30 to 1200 units/hour (mean dose 183 units/hour). In this trial, reteplase was associated with a higher thrombolytic success rate and less significant bleeding rate.

    For reestablishing patency of an occluded IV catheter† or occluded arteriovenous (AV) cannula† (e.g., fistula).
    Intracatheter dosage
    Adults

    0.4 units instilled into the catheter lumen and allowed to dwell for at least 30 minutes has been studied. Additional doses of 0.4 units have been used and dwell times have exceeded 30 minutes. Higher doses (up to 3 units/lumen) have been studied, but lower doses appear to be just as effective.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    20 units IV.

    Geriatric

    20 units IV.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

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

    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

    Reteplase potency is expressed in units using a reference standard, which is specific for reteplase and is not comparable with units used for other thrombolytic agents.
     
    Reconstitution
    Reconstitute immediately prior to administration.
    Reconstitute only with Sterile Water for Injection provided.
    Connect the sterile prefilled syringe to the reconstitution spike and firmly insert the spike into the vial of reteplase.
    Connect the syringe plunger to the sterile 10 mL prefilled syringe by screwing the plunger into the rubber stopper.
    Transfer the 10 mL of Sterile Water for Injection through the reconstitution spike into the vial or reteplase.
    With the reconstitution spike and empty prefilled syringe still attached to the vial, swirl the vial gently to dissolve the reteplase. Do not shake. The resulting solution concentration is 1 unit/mL and delivers 10 units of reteplase.
    Slight foaming upon reconstitution may occur; allow the vial to stand undisturbed for several minutes to dissipate any large bubbles.
    Disconnect the empty prefilled syringe from the reconstitution spike.
    Connect the graduated syringe to the reconstitution spike that is still attached to the vial. Withdraw 10 mL of the reteplase solution into the graduated syringe, and detach the graduated syringe from the reconstitution spike.[46914]
     
    Intravenous injection
    Do not administer reteplase through an IV line containing heparin.
    Administer IV over 2 minutes. Administer the second dose 30 minutes after the first dose.[46914]

    STORAGE

    Retavase:
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Store between 36 to 77 degrees F
    - Store in carton until time of use
    Retavase Half-Kit:
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Store between 36 to 77 degrees F
    - Store in carton until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Hypertension

    Reteplase is contraindicated in severe uncontrolled hypertension.[46914]

    Aneurysm, arteriovenous malformation, bleeding, brain tumor, coagulopathy, head trauma, intracranial mass, stroke, surgery

    Reteplase is contraindicated in patients with active internal bleeding, recent cerebrovascular accident (stroke), intracranial or intraspinal surgery or serious head trauma within the last 3 months, intracranial conditions that increase the risk of bleeding (e.g., brain tumor or intracranial mass, arteriovenous malformation, aneurysm), and coagulopathy or bleeding diathesis. Reteplase can cause significant and sometimes fatal bleeding. Bleeding from recent puncture sites or other recent trauma may occur. Discontinue concomitant anticoagulant therapy if serious bleeding, uncontrollable by local pressure, occurs. Withhold the second reteplase dose if serious bleeding occurs before it is administered.[46914]

    Intramuscular injections, venipuncture

    Avoid intramuscular injections in patients receiving reteplase. Minimize venipuncture. Avoid puncturing noncompressible veins (e.g., internal jugular, subclavian). If an arterial puncture is necessary, use an upper extremity vessel that is accessible to manual compression, apply pressure for at least 30 minutes, and monitor the puncture site closely. Reteplase can cause significant and sometimes fatal bleeding. Bleeding from recent puncture sites or other recent trauma may occur. Discontinue concomitant anticoagulant therapy if serious bleeding, uncontrollable by local pressure, occurs. Withhold the second reteplase dose if serious bleeding occurs before it is administered.[46914]

    Laboratory test interference

    Reteplase may cause laboratory test interference. Coagulation tests and measures of fibrinolytic activity are unreliable during reteplase therapy unless specific precautions are taken to prevent in vitro artifacts. Reteplase remains active under in vitro conditions, which can result in degradation of fibrinogen in blood samples.[46914]

    Labor, obstetric delivery, pregnancy

    Limited published data with reteplase use in human pregnancy are insufficient to inform a drug-associated risk of adverse developmental outcomes. In animal reproduction studies, reteplase administration to pregnant rabbits at doses 3 times the human dose resulted in genital tract hemorrhage, leading to abortions in mid-gestation. However, there was no evidence of fetal anomalies in rats at doses up to 15 times the human dose. The most common complication of thrombolytic therapy is bleeding, and pregnancy, labor, or obstetric delivery may increase this risk.[46914]

    Breast-feeding

    There is no data on the presence of reteplase in human milk, the effects on the breast-fed infant, or the effects on milk production. Reteplase has not been studied in breast-feeding mothers.[46914]

    ADVERSE REACTIONS

    Severe

    GI bleeding / Delayed / 1.8-9.0
    anaphylactoid reactions / Rapid / 0-1.0
    intracranial bleeding / Delayed / 0.8-0.8
    cholesterol microembolization / Early / Incidence not known
    purple-toe syndrome / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known

    Moderate

    bleeding / Early / 21.1-21.1
    anemia / Delayed / 0.9-2.6
    livedo reticularis / Delayed / Incidence not known
    hypertension / Early / Incidence not known
    edema / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    erythema / Early / Incidence not known

    Mild

    pruritus / Rapid / Incidence not known
    rash / Early / 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; Aspirin: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
    Acetaminophen; Aspirin; Diphenhydramine: (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: (Contraindicated) 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.
    Antithrombin III: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants.
    Apixaban: (Contraindicated) Due to the increased bleeding risk, avoid concurrent use of apixaban with thrombolytic agents.
    Aprotinin: (Contraindicated) 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: (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; Caffeine; Orphenadrine: (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; Citric Acid; Sodium Bicarbonate: (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.
    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.
    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.
    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: (Contraindicated) 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: (Major) Whenever possible, discontinue agents which may enhance the risk of hemorrhage, including thrombolytic agents, before initiation of enoxaparin therapy. If coadministration is essential, conduct close clinical and laboratory monitoring.
    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. Avoid concurrent use of herbs which interact with thrombolytic agents when possible. If Garlic supplements are taken, monitor appropriate parameters to attain proper clinical endpoints.
    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: (Moderate) Monitor for signs or symptoms of bleeding with coadministration of ginkgo biloba and thrombolytic agents as an increased bleeding risk may occur. Although data are mixed, ginkgo biloba is reported to inhibit platelet aggregation and several case reports describe bleeding complications with ginkgo biloba, with or without concomitant drug therapy.
    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: (Major) During and after therapy, avoid the concomitant use of Yttrium (Y)-90 ibrutumomab tiuxetan with drugs that interfere with coagulation such as thrombolytic agents; the risk of bleeding may be increased. If coadministration with thrombolytic agents is necessary, monitor platelet counts more frequently for evidence of thrombocytopenia.
    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.
    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.
    Methenamine; Sodium 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.
    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.
    Pentosan: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants.
    Photosensitizing agents (topical): (Minor) 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.
    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.
    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.
    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: (Contraindicated) 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.
    Verteporfin: (Moderate) Use caution if coadministration of verteporfin with thrombolytic agents is necessary due to the risk of decreased verteporfin efficacy. Verteporfin is a light-activated drug. Once activated, local damage to neovascular endothelium results in a release of procoagulant and vasoactive factors resulting in platelet aggregation, fibrin clot formation, and vasoconstriction. Concomitant use of drugs that decrease clotting like thrombolytic agents could decrease the efficacy of verteporfin therapy.
    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: (Contraindicated) 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

    There is no data on the presence of reteplase in human milk, the effects on the breast-fed infant, or the effects on milk production. Reteplase has not been studied in breast-feeding mothers.[46914]

    MECHANISM OF ACTION

    Reteplase is a "fibrin-selective" thrombolytic agent. The activation of plasminogen by reteplase is stimulated in the presence of fibrin and is mediated by the kringle-2 domain. Reteplase exerts its action on the endogenous fibrinolytic system by cleaving the arginine-valine bond in plasminogen to convert plasminogen to plasmin. Plasmin degrades fibrin and fibrinogen as well as the coagulation factors V and VIII. Unlike streptokinase or urokinase, most of the activity of reteplase is dependent on the presence of fibrin. Minimal amounts of plasminogen are converted to plasmin in the absence of fibrin.
     
    In the presence of perfused clots, reteplase acts differently than tissue plasminogen activator (t-PA). Reteplase penetrates the clots and activates plasminogen inside the clot, while t-PA binds tightly to the fibrin matrix and accumulates on the surface of the clot. This difference is possibly due to the lower affinity of reteplase for fibrin compared to t-PA. Pharmacodynamic differences and pharmacokinetic differences between reteplase and t-PA may account for the higher initial clot lysis rates reported with reteplase.

    PHARMACOKINETICS

    Reteplase is administered intravenously. Based on measurements of thrombolytic activity, reteplase is cleared from plasma at a rate of 250 to 450 mL/minute with an effective half-life of 13 to 16 minutes. Reteplase is primarily cleared by the liver and kidney.[46914]
     
    The majority of patients (64%) treated for myocardial infarction had a decrease in fibrinogen concentrations to below 100 mg/dL within 2 hours of reteplase administration during a controlled trial. The mean fibrinogen concentration returned to baseline by 48 hours.[46914]
     
    Affected cytochrome P450 isoenzymes and drug transporters: none