Cardiac surgery (alternative to heparin) ( off-label use):
Note: Consider for use in patients with heparin allergy (eg, allergy to pork containing products) or heparin-induced thrombocytopenia (ACCP [Linkins 2012]; ASH [Cuker 2018]).
IV: Intraoperative:
Off-pump:
Initial bolus: 0.75 mg/kg followed by continuous infusion (Dyke 2007).
Maintenance continuous infusion: 1.75 mg/kg/hour to maintain ACT >300 seconds (Dyke 2007).
Note: 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 to 1.25 mg/kg followed by continuous infusion; add 50 mg bolus to priming solution of cardiopulmonary bypass (CPB) circuit (Dyke 2006; Koster 2007; Salter 2016).
Maintenance continuous infusion: 2.5 mg/kg/hour to maintain ACT >2.5 times baseline; if ACT is subtherapeutic may administer an additional bolus of 0.1 to 0.5 mg/kg and increase infusion by 0.25 mg/kg/hour. Discontinue infusion 10 to 15 minutes prior to weaning from CPB (Dyke 2006; Koster 2007; Salter 2016). Note: Special maneuvers are needed to prevent stasis and clotting within the CPB circuit during and after surgery. When weaning from CPB, may keep blood recirculating through the circuit and administer 50 mg into the CPB circuit followed by a continuous infusion of 50 mg/hour into the CPB 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 (Koster 2007; 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]).
Transitioning from bivalirudin to an oral anticoagulant:
Transitioning from bivalirudin to warfarin: Start warfarin and continue bivalirudin until INR is within therapeutic range; overlap bivalirudin with warfarin until INR is ≥2 for at least 2 measurements taken ~24 hours apart and for a minimum of 5 days; recheck INR after effect of bivalirudin has dissipated (ACCP [Ageno 2012]); ACCP [Linkins 2012]); Dager 2018).
Transitioning from bivalirudin to a direct-acting oral anticoagulant: Start direct-acting oral anticoagulant when bivalirudin infusion is stopped (consult local protocol if the aPTT is above the target range) (Dager 2018).
Ischemic heart disease, percutaneous coronary intervention:
Note: Includes patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome or when PCI is chosen for stable ischemic heart disease. Use in combination with an appropriate antithrombotic regimen. If unfractionated heparin is initiated then switched to bivalirudin prior to PCI, wait 30 minutes before starting 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, measure ACT ~5 minutes after initial 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 (ACC/AHA [Amsterdam 2014]; ACC/AHA [O’Gara 2013]; ACCF/AHA/SCAI [Levine 2011]).
If initiating bivalirudin prior to PCI or diagnostic angiography (off-label): Initial: 0.1 mg/kg bolus, followed by 0.25 mg/kg/hour; continue until diagnostic angiography or PCI. If PCI is necessary, give an additional bolus of 0.5 mg/kg and increase infusion to 1.75 mg/kg/hour during PCI (ACC/AHA [Amsterdam 2014]; Stone 2006).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Percutaneous coronary intervention: IV: Note: CrCl may be estimated using the Cockcroft-Gault equation (Washam 2015; manufacturer’s labeling). Recommendations are only applicable if initiating bivalirudin during percutaneous coronary intervention.
Bolus: No dosage adjustment necessary.
Continuous infusion:
CrCl ≥30 mL/minute: 1.75 mg/kg/hour.
CrCl <30 mL/minute: 1 mg/kg/hour.
Hemodialysis, intermittent (thrice weekly): Dialyzable (25%): 0.25 mg/kg/hour.
Heparin-induced thrombocytopenia (off-label use):
IV: Note: Initial continuous infusion doses based on estimated CrCl using Cockcroft Gault. Dosing is derived from the results of retrospective, observational data from single-center studies. For higher targets or urgent need to more rapidly achieve therapeutic levels, it may be appropriate to choose a starting dose at the higher end of the recommended ranges. Refer to institution-specific protocols for titration.
CrCl >60 mL/minute: No dosage adjustment necessary; however, based on observational data, a range of 0.13 to 0.16 mg/kg/hour may achieve a target aPTT of 1.5 to 2.5 times patient baseline or normal range (Kiser 2008; Runyan 2011; Tsu 2011; Wisler 2012).
CrCl 30 to 60 mL/minute: Initial: 0.08 to 0.12 mg/kg/hour; titrate to achieve target aPTT of 1.5 to 2.5 times patient baseline or normal range (Kiser 2008; Runyan 2011; Tsu 2011; Wisler 2012).
CrCl <30 mL/minute: Initial: 0.04 to 0.07 mg/kg/hour; titrate to achieve target aPTT of 1.5 to 2.5 times patient baseline or normal range (Kiser 2008; Runyan 2011; Tsu 2011; Wisler 2012).
Hemodialysis, intermittent (thrice weekly): Dialyzable (25% over 4 hours): Initial: 0.04 to 0.08 mg/kg/hour; titrate to achieve target aPTT of 1.5 to 2.5 times patient baseline or normal range (Runyan 2011; Tsu 2011; Wisler 2012).
CRRT: Note: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations assume high-flux dialyzers and flow rates of ~1,500 to 3,000 mL/hour, unless otherwise noted. Close monitoring of response and adverse reactions due to drug accumulation is important.
CVVH/CVVHD/CVVHDF: IV: Initial: 0.03 to 0.07 mg/kg/hour; titrate to achieve target aPTT of 1.5 to 2.5 times patient baseline or normal range (Chanas 2019; Kiser 2006; Runyan 2011; Tsu 2011).
Prolonged intermittent renal replacement therapy (eg, sustained low-efficiency diafiltration): Note: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Close monitoring of response and adverse reactions due to drug accumulation is important.
Prolonged intermittent renal replacement therapy (6- to 8-hour session, 6 days per week): IV: Initial: 0.09 mg/kg/hour; titrate to achieve target aPTT of 1.5 to 2.5 times patient baseline or normal range (Tsu 2011).
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).
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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution, Intravenous [preservative free]:
Bivalirudin RTU: 250 mg/50 mL (50 mL) [contains polyethylene glycol]
Generic: 250 mg/50 mL in NaCl 0.9% (50 mL [DSC]); 500 mg/100 mL in NaCl 0.9% (100 mL [DSC])
Solution Reconstituted, Intravenous:
Angiomax: 250 mg (1 ea [DSC])
Generic: 250 mg (1 ea)
Solution Reconstituted, Intravenous [preservative free]:
Angiomax: 250 mg (1 ea)
Generic: 250 mg (1 ea)
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous:
Generic: 250 mg/50 mL (50 mL)
Solution Reconstituted, Intravenous:
Angiomax: 250 mg (1 ea)
Generic: 250 mg (1 ea)
IV: For IV administration only. After initial bolus dose (when recommended), administer as a continuous infusion; refer to indication-specific infusion rates in dosing for detailed recommendations.
IV infusion: 250 mg in 50 mL (concentration: 5 mg/mL) of D5W or NS
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)
Cardiac surgery (alternative to heparin); Heparin-induced thrombocytopenia, complicated by thrombosis
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs which have a heightened risk of causing significant patient harm when used in error.
The Joint Commission (TJC) requires healthcare organizations that provide anticoagulant therapy to have approved protocols and evidence-based practice guidelines in place to reduce the risk of anticoagulant-associated patient harm. Patients receiving anticoagulants should receive individualized care through a defined process that includes medication selection, dosing (including adjustments for age, renal function, or liver function), drug-drug interactions, drug-food interactions, other applicable risk factors, monitoring, patient and family education, proper administration, reversal of anticoagulation, management of bleeding events, and perioperative management. This does not apply to routine short-term use of anticoagulants for prevention of venous thromboembolism during procedures or hospitalizations (NPSG.03.05.01).
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
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
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
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.
None known.
Acalabrutinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Alemtuzumab: May enhance the anticoagulant effect of Anticoagulants. Risk C: 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. Risk X: Avoid combination
Bromperidol: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy
Caplacizumab: May enhance the anticoagulant effect of Anticoagulants. Risk C: 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. Risk C: 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. Risk X: Avoid combination
Dasatinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: 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. Risk C: 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. Risk C: Monitor therapy
Desirudin: Anticoagulants may enhance the anticoagulant effect of Desirudin. Management: Discontinue treatment with other anticoagulants prior to desirudin initiation. If concomitant use cannot be avoided, monitor patients receiving these combinations closely for clinical and laboratory evidence of excessive anticoagulation. Risk D: 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. Risk X: Avoid combination
Hemin: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination
Herbal Products with Anticoagulant/Antiplatelet Effects (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Risk C: Monitor therapy
Ibritumomab Tiuxetan: Anticoagulants may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to an increased risk of bleeding. Risk C: Monitor therapy
Ibrutinib: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy
Icosapent Ethyl: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Inotersen: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Kanamycin: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Limaprost: May enhance the adverse/toxic effect of Anticoagulants. The risk for bleeding may be increased. Risk C: Monitor therapy
Lipid Emulsion (Fish Oil Based): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Mesoglycan: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
MiFEPRIStone: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the risk of bleeding may be increased. Risk X: Avoid combination
Nintedanib: Anticoagulants may enhance the adverse/toxic effect of Nintedanib. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (Topical): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Obinutuzumab: Anticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Risk C: 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. Risk X: Avoid combination
Omega-3 Fatty Acids: May enhance the anticoagulant effect of Anticoagulants. Risk C: 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. Risk C: Monitor therapy
Pentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
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. Risk C: 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. Risk X: Avoid combination
Salicylates: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Sugammadex: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Sulodexide: May enhance the anticoagulant effect of Anticoagulants. Risk C: 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. Risk C: 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. Risk C: Monitor therapy
Tibolone: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Tipranavir: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Urokinase: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination
Vitamin E (Systemic): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Anticoagulants may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Vorapaxar: May enhance the adverse/toxic effect of Anticoagulants. More specifically, this combination is expected to increase the risk of bleeding. Risk X: Avoid combination
Zanubrutinib: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy
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).
It is not known if bivalirudin is present in breast milk. The manufacturer recommends that caution be exercised when administering bivalirudin to breastfeeding women.
According to the manufacturer, the decision to continue or discontinue breastfeeding during therapy should take into account the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.
ACT; aPTT; PT/INR; signs/symptoms of bleeding.
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.
Onset of action: Immediate
Duration: Coagulation times return to baseline ~1 hour following discontinuation of infusion
Protein binding, plasma: Does not bind other than thrombin
Metabolism: Proteolytic cleavage
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
Excretion: Urine (20%), glomerular filtration, tubular secretion, and tubular reabsorption
Renal function impairment: Clearance is reduced by 21% in moderate and severe renal impairment and by 70% in dialysis patients.
Solution (reconstituted) (Angiomax Intravenous)
250 mg (per each): $1,170.00
Solution (reconstituted) (Bivalirudin Trifluoroacetate Intravenous)
250 mg (per each): $120.00 - $1,137.27
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