Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous [preservative free]:
Generic: 250 mg/50 mL in NaCl 0.9% (50 mL); 500 mg/100 mL in NaCl 0.9% (100 mL)
Solution Reconstituted, Intravenous:
Angiomax: 250 mg (1 ea)
Generic: 250 mg (1 ea)
Solution Reconstituted, Intravenous [preservative free]:
Generic: 250 mg (1 ea)
Pharmacology
Mechanism of Action
Bivalirudin acts as a specific and reversible direct thrombin inhibitor; it binds to the catalytic and anionic exosite of both circulating and clot-bound thrombin. Catalytic binding site occupation functionally inhibits coagulant effects by preventing thrombin-mediated cleavage of fibrinogen to fibrin monomers, and activation of factors V, VIII, and XIII. Shows linear dose- and concentration-dependent prolongation of ACT, aPTT, PT, and TT.
Pharmacokinetics/Pharmacodynamics
Metabolism
Proteolytic cleavage
Excretion
Urine (20%), glomerular filtration, tubular secretion, and tubular reabsorption
Onset of Action
Immediate
Duration of Action
Coagulation times return to baseline ~1 hour following discontinuation of infusion
Half-Life Elimination
Normal renal function and mild renal impairment: 25 minutes
Moderate renal impairment: 34 minutes
Severe renal impairment: 57 minutes
Dialysis: 3.5 hours
Protein Binding
Plasma: Does not bind other than thrombin
Use in Specific Populations
Special Populations: Renal Function Impairment
Clearance is reduced by 21% in moderate and severe renal impairment and by 70% in dialysis patients.
Use: Labeled Indications
Percutaneous coronary intervention: Anticoagulant for use in patients undergoing percutaneous coronary intervention (PCI) including patients with heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia/thrombosis syndrome (HIT/TS)
Use: Off Label
Cardiac Surgery (with heparin-induced thrombocytopenia/thrombosis syndrome)byes
Data from 2 clinical trials in patients undergoing both on- and off-pump cardiac surgery support the use of bivalirudin in these patients Dyke 2007, Koster 2007. Additional trials may be necessary to further define the role of bivalirudin in this setting.
Based on the American College of Chest Physicians (ACCP) guidelines and the American Society of Hematology (ASH) guidelines, bivalirudin is effective and recommended for use in patients with heparin-induced thrombocytopenia/thrombosis syndrome (HIT/TS) undergoing cardiac surgery.
Heparin-induced thrombocytopenia, complicated by thrombosiscyes
Data from a retrospective cohort study evaluating the safety, efficacy, and dosing requirements in patients with a diagnosis or history of HIT and another retrospective study evaluating the efficacy, safety, and associated costs of available direct thrombin inhibitors (including bivalirudin) in patients with HIT or presumed HIT suggest that bivalirudin may be beneficial in the treatment of this condition Dang 2006, Kiser 2008.
Based on the ACCP guidelines and the ASH guidelines, bivalirudin is an effective and recommended treatment option for use in patients with HIT complicated by thrombosis.
Contraindications
Hypersensitivity (eg, anaphylaxis) to bivalirudin or any component of the formulation; active major bleeding.
Canadian labeling: Additional contraindications (not in US labeling): Major blood clotting disorders; acute gastric or duodenal ulcer; cerebral hemorrhage; severe cerebrospinal trauma; bacterial endocarditis; severe uncontrolled hypertension; diabetic or hemorrhagic retinopathy; proximal use of spinal/epidural anesthesia
Dosage and Administration
Dosing: Adult
Cardiac surgery in patients with acute or subacute heparin-induced thrombocytopenia, urgent surgery required (off-label use) (Linkins 2012): IV: Intraoperative:
Off-pump: Initial bolus: 0.75 mg/kg, followed by continuous infusion 1.75 mg/kg/hour to maintain ACT >300 seconds (Dyke 2007). If patient needs to go on-pump, some have recommended an additional 0.25 mg/kg bolus and increasing the infusion rate to 2.5 mg/kg/hour (Angiomax Canadian product labeling 2016).
On-pump:Initial bolus: 1 mg/kg, followed by continuous infusion 2.5 mg/kg/hour; 50 mg bolus added to priming solution of cardiopulmonary bypass (CPB) circuit. Additional boluses of 0.1 to 0.5 mg/kg may be given to maintain ACT >2.5 times baseline ACT. Discontinue infusion 10 to 15 minutes prior to weaning from CPB (Salter 2016). Note: Special maneuvers needed to prevent stasis and consequent clotting within CPB circuit during or after surgery (Koster 2007). After completion of CPB, provision to allow recirculation of the circuit may be done by administering 50 mg into the circuit followed by a continuous infusion of 50 mg/hour into the bypass circuit; continue infusion until it is evident the patient will not require an urgent return to CPB. If separation from circuit does not occur within 20 minutes of stopping infusion, redose patient with 0.5 mg/kg and restart infusion at 2.5 mg/kg/hour (Salter 2016).
Heparin-induced thrombocytopenia (HIT) (off-label use): IV: Initial dose: 0.15 to 0.2 mg/kg/hour; adjust to aPTT 1.5 to 2.5 times baseline value (ACCP [Linkins 2012]; ASH [Cuker 2018]). Note: The ACCP recommends overlapping administration of warfarin for a minimum of 5 days until INR is within target range; recheck INR after effect of bivalirudin has dissipated (ACCP [Linkins 2012]).
Ischemic heart disease, percutaneous coronary intervention: Note: Includes patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) (eg, ST-elevation myocardial infarction [STEMI] or a non-ST-elevation acute coronary syndrome [NSTE-ACS]) or when PCI is chosen for stable ischemic heart disease. If unfractionated heparin (UFH) is initiated then switched to bivalirudin prior to PCI, wait 30 minutes before initiating bivalirudin (ACC/AHA [Amsterdam 2014]; ACC/AHA [O’Gara 2013]; ACCF/AHA/SCAI [Levine 2011]; Lincoff 2004; Stone 2006; Stone 2008)
IV:
If initiating bivalirudin during PCI: Initial: 0.75 mg/kg bolus immediately prior to procedure, followed immediately by 1.75 mg/kg/hour for the duration of procedure. During the procedure, may determine ACT 5 minutes after bolus dose and administer an additional bolus of 0.3 mg/kg if necessary. After the procedure, may continue the infusion at 1.75 mg/kg/hour for up to 4 hours if needed (ACC/AHA [Amsterdam 2014]; ACC/AHA [O’Gara 2013]; ACCF/AHA/SCAI [Levine 2011]; Cutlip 2018; Lincoff 2018).
If initiating bivalirudin prior to PCI or diagnostic angiography for non-STE ACS (off-label): IV: Initial: Administer an initial 0.1 mg/kg bolus, followed by 0.25 mg/kg/hour; continue until diagnostic angiography or PCI. If PCI is determined to be necessary, give an additional bolus of 0.5 mg/kg and increase infusion rate to 1.75 mg/kg/hour during PCI (ACC/AHA [Amsterdam 2014]; Stone 2006).
Note: Use in addition to oral antiplatelet agents (eg, aspirin and a P2Y12 inhibitor [eg, clopidogrel, prasugrel, ticagrelor]). If clinically indicated, a glycoprotein (GP) IIb/IIIa inhibitor (eg, abciximab, eptifibatide, tirofiban) may be administered in combination with parenteral anticoagulation (eg, bivalirudin) during PCI. However, GP IIb/IIIa inhibitor use may be associated with more bleeding complications (ACCF/AHA/SCAI [Levine 2011]; Stone 2006; Stone 2008). Some experts prefer heparin alone over bivalirudin due to decreased cost and similar outcomes although bivalirudin is still a reasonable option (Cutlip 2018; Lincoff 2018).
Dosing: Geriatric
Refer to adult dosing. No dosage adjustment is needed in elderly patients with normal renal function. Puncture site hemorrhage and catheterization site hemorrhage were seen in more patients ≥65 years of age than in patients <65 years of age.
Reconstitution
Vials: Reconstitute each 250 mg vial with 5 mL SWFI. Gently swirl to dissolve. Must further dilute bivalirudin prior to infusion; withdraw and discard 5 mL from a D5W or NS infusion bag and add reconstituted bivalirudin to the infusion bag (50 mL infusion bag to make 5 mg/mL solution).
Premixed frozen solution: Thaw at room temperature (25°C [77°F]) or under refrigeration (5°C [41°F]). Do not thaw in microwave or by bath immersion.
Administration
For IV administration only after reconstitution and dilution.
Storage
Vials: Store unopened vials at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Following reconstitution, store vials at 2°C to 8°C (36°F to 46°F) for up to 24 hours. Do not freeze. Final dilutions of 5 mg/mL, in D5W or NS, are stable at room temperature for up to 24 hours.
Premixed frozen solution: Store at or below -20°C (-4°F). Thawed solution is stable for 24 hours at room temperature (25°C [77°F]) or for 14 days under refrigeration (5°C [41°F]); do not refreeze.
Drug Interactions
Acalabrutinib: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Apixaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of apixaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Avoid combination
Bromperidol: May enhance the adverse/toxic effect of Anticoagulants. Monitor therapy
Caplacizumab: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Collagenase (Systemic): Anticoagulants may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Monitor therapy
Dabigatran Etexilate: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of dabigatran etexilate with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Avoid combination
Dasatinib: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Deferasirox: Anticoagulants may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy
Deoxycholic Acid: Anticoagulants may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Monitor therapy
Desirudin: Anticoagulants may enhance the anticoagulant effect of Desirudin. Consider therapy modification
Edoxaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of edoxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Management: Some limited combined use may be indicated during periods of transition from one anticoagulant to another. See the full edoxaban drug monograph for specific recommendations on switching anticoagulant treatment. Avoid combination
Estrogen Derivatives: May diminish the anticoagulant effect of Anticoagulants. More specifically, the potential prothrombotic effects of some estrogens and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of estrogens against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Exceptions: Tibolone. Consider therapy modification
Fat Emulsion (Fish Oil Based): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Hemin: May enhance the anticoagulant effect of Anticoagulants. Avoid combination
Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Management: Avoid such combinations when possible. If used concomitantly, increase diligence in monitoring for adverse effects (eg, bleeding, bruising, altered mental status due to CNS bleeds). Consider therapy modification
Ibritumomab Tiuxetan: Anticoagulants may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to an increased risk of bleeding. Monitor therapy
Ibrutinib: May enhance the adverse/toxic effect of Anticoagulants. Monitor therapy
Inotersen: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Limaprost: May enhance the adverse/toxic effect of Anticoagulants. The risk for bleeding may be increased. Monitor therapy
MiFEPRIStone: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the risk of bleeding may be increased. Avoid combination
Nintedanib: Anticoagulants may enhance the adverse/toxic effect of Nintedanib. Specifically, the risk for bleeding may be increased. Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Obinutuzumab: Anticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Monitor therapy
Omacetaxine: Anticoagulants may enhance the adverse/toxic effect of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Management: Avoid concurrent use of anticoagulants with omacetaxine in patients with a platelet count of less than 50,000/uL. Avoid combination
Omega-3 Fatty Acids: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Oritavancin: May diminish the therapeutic effect of Anticoagulants. Specifically, oritavancin may artificially increase the results of laboratory tests commonly used to monitor anticoagulant effectiveness, which could lead to incorrect decisions to decrease anticoagulant doses. Monitor therapy
Pentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Progestins: May diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of progestins against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Consider therapy modification
Prostacyclin Analogues: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the antiplatelet effects of these agents may lead to an increased risk of bleeding with the combination. Monitor therapy
Rivaroxaban: Anticoagulants may enhance the anticoagulant effect of Rivaroxaban. Refer to separate drug interaction content and to full drug monograph content regarding use of rivaroxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Avoid combination
Salicylates: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Sugammadex: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Sulodexide: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Telavancin: May diminish the therapeutic effect of Anticoagulants. Specifically, telavancin may artificially increase the results of laboratory tests commonly used to monitor anticoagulant effectiveness, which could lead to incorrect decisions to decrease anticoagulant doses. Monitor therapy
Thrombolytic Agents: May enhance the anticoagulant effect of Anticoagulants. Management: See full drug monograph for guidelines for the use of alteplase for acute ischemic stroke during treatment with oral anticoagulants. Monitor therapy
Tibolone: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Tipranavir: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Urokinase: May enhance the anticoagulant effect of Anticoagulants. Avoid combination
Vitamin E (Systemic): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Vitamin K Antagonists (eg, warfarin): Anticoagulants may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy
Vorapaxar: May enhance the adverse/toxic effect of Anticoagulants. More specifically, this combination is expected to increase the risk of bleeding. Avoid combination
Zanubrutinib: May enhance the adverse/toxic effect of Anticoagulants. Monitor therapy
Test Interactions
PT/INR levels may become elevated in the absence of warfarin. If warfarin is initiated, initial PT/INR goals while on bivalirudin may require modification.
Adverse Reactions
As with all anticoagulants, bleeding is the major adverse effect of bivalirudin. Hemorrhage may occur at virtually any site. Risk is dependent on multiple variables, including the intensity of anticoagulation, concurrent use of a glycoprotein IIb/IIIa inhibitor, and patient susceptibility. Additional adverse effects are often related to idiosyncratic reactions, and the frequency is difficult to estimate. Adverse reactions reported were generally less than those seen with heparin.
>10%:
Cardiovascular: Hypotension (≤12%)
Central nervous system: Pain (≤15%), headache (≤12%)
Gastrointestinal: Nausea (≤15%)
Hematologic & oncologic: Minor hemorrhage (Protocol defined: 14%; heparin 26%; TIMI defined: 1%; heparin 3% [Lincoff, 2003])
Neuromuscular & skeletal: Back pain (9% to 42%)
1% to 10%:
Cardiovascular: Hypertension (6%), bradycardia (5%), angina pectoris (≤5%), thrombosis (1%; <4 hours, in patients with STEMI undergoing primary PCI)
Central nervous system: Insomnia (7%), anxiety (6%), nervousness (5%)
Gastrointestinal: Vomiting (≤6%), abdominal pain (5%), dyspepsia (5%)
Genitourinary: Pelvic pain (6%), urinary retention (4%)
Hematologic & oncologic: Major hemorrhage (Protocol defined: 2% to 4%; heparin 4% to 9%; TIMI defined: 0.6%; heparin 0.9%; transfusion required: 1% to 2%; heparin 2% to 6% [Lincoff, 2003])
Local: Pain at injection site (≤8%)
Miscellaneous: Fever (5%)
<1%, postmarketing, and/or case reports: Cardiac tamponade, cerebral ischemia, confusion, facial paralysis, hemorrhage, hypersensitivity reaction (including anaphylaxis), increased INR, increased susceptibility to infection, intracranial hemorrhage, oliguria, pulmonary edema, pulmonary hemorrhage, renal failure, retroperitoneal hemorrhage, sepsis, syncope, thrombocytopenia, vascular disease, venous thrombosis (during PCI, including intracoronary brachytherapy), ventricular fibrillation
Warnings/Precautions
Concerns related to adverse effects:
- Acute stent thrombosis: In patients with STEMI undergoing PCI, acute stent thrombosis (some fatal) occurring within 4 hours of the procedure was observed at a greater frequency as compared to those treated with heparin. Patients should remain for at least 24 hours in a facility capable of managing ischemic complications; monitor for signs and symptoms consistent with myocardial ischemia.
- Bleeding: The most common complication is bleeding. Certain patients are at increased risk of bleeding; risk factors include bacterial endocarditis; congenital or acquired bleeding disorders; recent puncture of large vessels or organ biopsy; recent CVA, stroke, intracerebral surgery, or other neuraxial procedure; severe uncontrolled hypertension; renal impairment; recent major surgery; recent major bleeding (intracranial, GI, intraocular, or pulmonary). Monitor for signs and symptoms of bleeding.
- Thrombus formation: Increased risk of intracoronary thrombus formation (some fatal, as reported by the manufacturer) has been reported with use in gamma brachytherapy even with the use of higher doses as compared to doses used for beta radiation (Kuchulakanti 2005). If used during brachytherapy, maintain meticulous catheter technique with frequent aspiration and flushing while minimizing conditions of stasis within the catheter or vessels.
Disease-related concerns:
- Renal impairment: Use with caution in patients with renal impairment; dosage reduction required.
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Monitoring Parameters
ACT (5 minutes after bolus dose); signs/symptoms of bleeding
Pregnancy
Pregnancy Considerations
Bivalirudin is used in conjunction with aspirin, which may lead to maternal or fetal adverse effects, especially during the third trimester. Use of parenteral direct thrombin inhibitors in pregnancy should be limited to those women who have severe allergic reactions to heparin, including heparin-induced thrombocytopenia, and who cannot receive danaparoid (Guyatt 2012).
Patient Education
What is this drug used for?
- It is used to thin the blood during certain heart blood vessel procedures.
- It may be given to you for other reasons. Talk with the doctor.
Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:
- Signs of bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding.
- Severe cerebrovascular disease like change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes.
- Severe dizziness
- Passing out
- Severe loss of strength and energy
- Crash or fall that hit head
- Severe headache
- Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.
Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.
Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.
