(bye VAL i roo din)
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous:
Angiomax: 250 mg (1 ea)
Generic: 250 mg (1 ea)
Brand Names: U.S.
- Anticoagulant, Direct Thrombin Inhibitor
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.
Urine (20%), proteolytic cleavage
Onset of Action
Duration of Action
Coagulation times return to baseline ~1 hour following discontinuation of infusion
Normal renal function (CrCl ≥90 mL/minute): 25 minutes
Severe renal impairment (CrCl 10 to 29 mL/minute): 57 minutes
Dialysis-dependent patients (off dialysis): 3.5 hours
Plasma: Does not bind other than thrombin
Special Populations: Renal Function Impairment
Clearance is reduced about 20% in moderate to severe renal function impairment and about 80% in dialysis-dependent patients.
Use: Labeled Indications
Percutaneous coronary intervention: Anticoagulant used in conjunction with aspirin with provisional glycoprotein IIb/IIIa inhibitor as described in the REPLACE-2 trial in patients undergoing percutaneous coronary intervention (PCI) (see Note); used in conjunction with aspirin for patients undergoing PCI with (or at risk of) heparin-induced thrombocytopenia (HIT) / thrombosis syndrome (HITTS). Note: Patients requiring immediate catheter-based reperfusion for STEMI were excluded from the REPLACE-2 trial (Lincoff 2004).
Percutaneous transluminal coronary angioplasty: Anticoagulant used in conjunction with aspirin for patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA).
Limitations of use: Safety and effectiveness have not been established in patients with acute coronary syndromes who are not undergoing PTCA or PCI.
Hypersensitivity 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
Note: If clinically indicated, provisional glycoprotein (GP) IIb/IIIa inhibition (eg, abciximab, eptifibatide, tirofiban) may be concomitantly administered during percutaneous coronary intervention (PCI). In addition to aspirin, concomitant administration of clopidogrel, prasugrel, or ticagrelor is also recommended for patients undergoing PCI (ACCF/AHA/SCAI [Levine 2011]).
Non-ST-elevation ACS (moderate-high risk) undergoing early invasive strategy (off-label use):
If initiating bivalirudin during PCI: 0.75 mg/kg bolus prior to procedure, followed by 1.75 mg/kg/hour; Note: If patient received unfractionated heparin (UFH) prior to procedure, wait 30 minutes before initiating bivalirudin (ACC/AHA [Amsterdam 2014]).
If initiating bivalirudin prior to PCI or diagnostic angiography: Administer an initial 0.1 mg/kg bolus, followed by 0.25 mg/kg/hour; continue until diagnostic angiography or PCI. Once 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 [Amersterdam 2014])
PTCA/PCI with or without HIT/HITTS: IV: 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. If continued anticoagulation is needed after the initial 4-hour postprocedure infusion, the infusion may be continued at 0.2 mg/kg/hour for up to an additional 20 hours.
STEMI undergoing primary PCI (US off-label use): IV: Initial: 0.75 mg/kg bolus, followed by 1.75 mg/kg/hour for the duration of procedure (ACCF/AHA [O'Gara 2013]; Stone 2008). Consider continuation of the infusion at 1.75 mg/kg/hour for up to 4 hours to mitigate risk of stent thrombosis. If the infusion is continued and an additional infusion is clinically necessary, may continue the infusion at a reduced dose of 0.2 mg/kg/hour for up to 20 hours. Of note, a single-center, open-label, randomized controlled trial comparing heparin to bivalirudin in patients with STEMI undergoing primary PCI (mostly with a radial approach) demonstrated that heparin reduces the incidence of major adverse cardiovascular events with no increase in bleeding as compared to bivalirudin (Shahzad 2014).
If patient received unfractionated heparin (UFH) prior to procedure and bivalirudin is the desired anticoagulant: Discontinue heparin if infusing; without measurement of ACT, may initiate bivalirudin ≥30 minutes after the last UFH bolus but before PCI occurs (Stone 2008). Switching patients from UFH to bivalirudin has been shown to be safe compared to continuing with UFH and as needed glycoprotein IIb/IIIa inhibition; median time from prerandomization UFH bolus to bivalirudin administration within the HORIZONS-AMI trial was 64 ± 61 minutes (Dangas 2011).
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 (Linkins 2012). Note: Although the use of bivalirudin is not a currently recommended treatment for HIT due to insufficient evidence, the American College of Chest Physicians recommends overlapping administration of warfarin for a minimum of 5 days until INR is within target range; recheck INR after the non-heparin anticoagulant effect has dissipated (Linkins 2012).
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.
Dosing: Renal Impairment
Initial bolus dose remains unchanged. Infusion dose should be reduced based on degree of renal impairment. Monitor activated coagulation time (ACT) or aPTT depending on indication.
For use in PCI:
CrCl ≥30 mL/minute: No dosage adjustment necessary.
CrCl <30 mL/minute: Decrease infusion rate to 1 mg/kg/hour
Dialysis-dependent patients (off dialysis during administration): Decrease infusion rate to 0.25 mg/kg/hour
Hemodialysis: Approximately 25% removed during hemodialysis
For use in HIT (off-label use): The following dose ranges have been observed in small retrospective observational studies (Kiser 2006; Kiser 2008; Tsu 2011). Of note, critically-ill patients comprised a significant proportion of patients in these observational studies. The following dose recommendations are based on the mean dose achieving aPTT goal within these studies; overlaps may exist; Note: The Cockcroft-Gault equation was used in all studies to define creatinine clearance:
CrCl >60 mL/minute: 0.13 mg/kg/hour
CrCl 30 to 60 mL/minute: 0.08 to 0.1 mg/kg/hour
CrCl <30 mL/minute: 0.04 to 0.05 mg/kg/hour
Intermittent hemodialysis (IHD): 0.07 mg/kg/hour (Tsu 2011)
CRRT (eg, CVVH or CVVHDF): 0.03 to 0.07 mg/kg/hour (Kiser 2006; Tsu 2011)
Sustained low-efficiency daily diafiltration (SLEDD): 0.09 mg/kg/hour (Tsu 2011)
Dosing: Hepatic Impairment
No dosage adjustment necessary (Seybert 2006). In patients treated for HIT (off-label use), patients with hepatic impairment required slightly lower doses compared to previous reports for patients with normal hepatic function; however, the lower doses may have been required due to critical illness instead of hepatic impairment (Kiser 2006).
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 or 500 mL infusion bag to make 0.5 mg/mL solution).
For IV administration only.
See Trissel’s IV Compatibility Database
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 0.5 mg/mL or 5 mg/mL, in D5W or NS, are stable at room temperature for up to 24 hours.
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
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
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. Consider therapy modification
Ibritumomab: Anticoagulants may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to an increased risk of bleeding. Monitor therapy
Ibrutinib: May enhance the adverse/toxic 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: 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
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
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
Tositumomab and Iodine I 131 Tositumomab: Anticoagulants may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse effects may be increased. 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
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.
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.
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% (Limited to important or life-threatening): Cardiac tamponade, cerebral ischemia, confusion, facial paralysis, hemorrhage (fatal), 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
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.
• Renal impairment: Use with caution in patients with renal impairment; dosage reduction required.
Depends upon indication for use of bivalirudin: ACT or aPTT
Pregnancy Risk Factor
Adverse events have not been observed in animal reproduction studies. 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).
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience nausea, back pain, or pain. Have patient report immediately to prescriber signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; 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), signs of severe cerebrovascular disease (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, crash or fall that hit head, or severe headache (HCAHPS).
• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
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- Drug class: thrombin inhibitors
Other brands: Angiomax