Bivalirudin: Pediatric drug information

For additional information see "Bivalirudin: Drug information" and "Bivalirudin: Patient drug information"

For abbreviations, symbols, and age group definitions show table

Brand Names: US

Angiomax;
Bivalirudin RTU [DSC]

Brand Names: Canada

Angiomax

Therapeutic Category

Anticoagulant;
Anticoagulant, Direct Thrombin Inhibitor

Dosing: Neonatal

Dosage guidance:

Clinical considerations: Bivalirudin is an alternative treatment option to heparin; reserve for use in patients with heparin resistance or evidence of significant thrombosis while on heparin (Ref). Use in heparin-induced thrombocytopenia (HIT) has been described in adult and pediatric patients; however, dosing recommendations are limited (Ref). Measure baseline aPTT and kidney function prior to initiation.

Anticoagulation, mechanical circulatory support

Anticoagulation, mechanical circulatory support:

Extracorporeal membrane oxygenation [ECMO]/extracorporeal life support [ECLS] (Ref): Very limited data available:

Note: Determine patient's kidney function prior to initiating therapy; dosage adjustment recommended in cases of kidney impairment (CrCl ≤60 mL/minute/1.73 m²); goal aPTT range determined by risk of bleeding and thrombosis and postoperative phase of care.

Neonates:

Initial dose: Continuous IV infusion: 0.15 to 0.3 mg/kg/hour; reported initial range: 0.05 to 0.3 mg/kg/hour. Note: Some experts recommend a lower initial dose of 0.2 mg/kg/hour in patients with open sternotomy. Measure aPTT 2 to 4 hours after initiation and titrate to achieve goal aPTT.

Dose adjustment: Continuous IV infusion: One published approach to dose adjustment presented in the table; refer to institutional protocols.

**Bivalirudin ECMO/ECLS in Neonates: Dose Adjustments to Achieve Target aPTT**
aPTT	Bivalirudin titration	Time to repeat aPTT^a
^a Consider more frequent aPTT monitoring based on clinical scenario.
Adapted from Seelhammer 2021.
>20 seconds below goal range	Increase infusion rate by 20%	2 hours
10 to 20 seconds below goal range	Increase infusion rate by 10%	2 hours
Within goal range	No change	12 hours; decrease frequency based on clinical scenario
10 to 20 seconds above goal range	Decrease infusion rate by 10%	2 hours
>20 seconds above goal range	Hold for 1 hour then decrease infusion rate by 20%	2 hours

Ventricular assist device (VAD) (Ref): Very limited data available:

Note: Dosing based on a consensus protocol; determine patient's kidney function prior to initiating therapy; dosage adjustment recommended in cases of kidney impairment (GFR ≤60 mL/minute/1.73 m²); goal aPTT range determined by risk of bleeding and thrombosis and postoperative phase of care.

Neonates:

Initial dose: Continuous IV infusion: 0.3 mg/kg/hour. Measure aPTT 2 hours after initiation; use caution when titrating after first aPTT and adjust as follows:

**Bivalirudin VAD in Neonates: First Dose Adjustment After Initiation**
aPTT	Bivalirudin titration	Time to repeat aPTT
Adapted from ACTION 2023.
1 to 1.5 × baseline	No change	2 to 3 hours
>2 to 3 × baseline	Decrease infusion rate by 50%	2 to 3 hours

Maintenance dose: Continuous IV infusion: After first aPTT measurement and adjustment, measure aPTT in 2 to 3 hours and adjust as follows:

**Bivalirudin VAD in Neonates: Maintenance Dose Adjustments to Achieve Target aPTT**
aPTT	Bivalirudin titration	Time to repeat aPTT^a
^a Consider more frequent anti-factor Xa monitoring based on clinical scenario. ^b Round dose up to closest second decimal (hundredth place). ^c Recommendation in patient with normal kidney function; dose adjustment required for all levels of kidney impairment; see recommendations for mild to moderate and severe kidney impairment. Adapted from ACTION 2023.
≥15 to 30 seconds below target range	Increase infusion rate by 25%^b	2 to 3 hours
5 to <15 seconds below target range	Increase infusion rate by 15%^b	2 to 3 hours
Within goal range	No change	2 to 3 hours; decrease frequency based on clinical scenario
5 to <15 seconds above target range	Decrease infusion rate by 15%^b	2 to 3 hours
≥15 to 30 seconds above target range	Decrease infusion rate by 25%^b	2 to 3 hours
>3 × baseline or ~120 seconds	Hold infusion for 15 minutes then decrease infusion rate by 30%^b,c	2 to 3 hours

Anticoagulation, interventional cardiac catheterization/percutaneous coronary interventional procedures

Anticoagulation, interventional cardiac catheterization/percutaneous coronary interventional procedures: Very limited data available:

Note: Determine patient's kidney function prior to initiating therapy; dosage adjustment recommended in cases of kidney impairment (GFR <30 mL/minute/1.73 m²) (Ref).

Neonates weighing ≥2.5 kg: IV bolus (prior to catheterization): 0.75 mg/kg once followed by continuous IV infusion of 1.75 mg/kg/hour, titrated to goal activated clotting time (ACT) (Ref).

Thrombosis, treatment

Thrombosis (not associated with mechanical circulatory support), treatment: Very limited data available:

Note: Goal aPTT range determined by risk of bleeding. Dosing based on 2 retrospective reviews that included 8 neonates (Ref).

Neonates: GA >35 weeks:

Bolus dose (optional): IV: Reported range: 0.125 to 0.25 mg/kg once; Note: A higher dose of 0.5 mg/kg was reported in one patient.

Continuous IV infusion: Initial: 0.05 to 0.25 mg/kg/hour; titrate to achieve target aPTT; reported average dose range: 0.06 to 0.31 mg/kg/hour; maximum reported dose: 0.4 mg/kg/hour.

Dosing: Altered kidney function: Neonatal:

ECMO/ECLS:

Baseline kidney impairment:

Initial dosing (Ref): Based on an initial dose of 0.15 mg/kg/hour:

CrCl >60 mL/minute/1.73 m²: No dosage adjustment necessary.

CrCl 30 to 60 mL/minute/1.73 m²: Continuous IV infusion: Initial: Decrease initial dose to 0.1 mg/kg/hour.

CrCl 10 to 29 mL/minute/1.73 m²: Continuous IV infusion: Initial: Decrease initial dose to 0.07 mg/kg/hour.

CrCl <10 mL/minute/1.73 m²: Continuous IV infusion: Initial: Decrease initial dose to 0.02 mg/kg/hour.

Continuous renal replacement therapy (CRRT): Continuous IV infusion: Initial: Decrease initial dose to 0.04 mg/kg/hour.

VAD:

Baseline kidney impairment: Note: Measure baseline aPTT prior to initiation (Ref):

Initial dosing (Ref):

Mild to moderate impairment (GFR 30 to 60 mL/minute/1.73 m²): Continuous IV infusion: Initial: Decrease initial dose to 0.2 mg/kg/hour; measure aPTT 2 hours after initiation and titrate cautiously with first aPTT measurement; see "Bivalirudin VAD in Neonates: First Dose Adjustment After Initiation" table and "Bivalirudin VAD in Neonates: Maintenance Dosage Adjustments to Achieve Target aPTT" table for details.

Severe impairment (GFR <30 mL/minute/1.73 m²): Continuous IV infusion: Initial: Decrease initial dose to 0.1 mg/kg/hour; measure aPTT 2 hours after initiation and titrate cautiously with first aPTT measurement; see "Bivalirudin VAD in Neonates: First Dose Adjustment After Initiation" table and "Bivalirudin VAD in Neonates: Maintenance Dosage Adjustments to Achieve Target aPTT" table for details.

Kidney impairment during therapy (Ref):

Dosage adjustments for aPTT >3 times baseline or ~120 seconds:

Mild to moderate impairment (GFR 30 to 60 mL/minute/1.73 m²): Continuous IV infusion: Hold infusion for 45 minutes then decrease infusion rate by 40%.

Severe impairment (GFR <30 mL/minute/1.73 m²): Continuous IV infusion: Hold infusion for 2 hours then recheck aPTT before restarting.

Anticoagulation, interventional cardiac catheterization/percutaneous coronary interventional procedures:

Baseline kidney impairment:

Neonates weighing ≥2.5 kg: GFR <30 mL/minute/1.73 m²: Continuous IV infusion: Decrease initial dose to 1 mg/kg/hour, titrate to goal ACT (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Pediatric

Dosage guidance:

Anticoagulation, mechanical circulatory support

Anticoagulation, mechanical circulatory support:

Cardiopulmonary bypass (CPB) (Ref): Very limited data available:

Children:

CPB circuit prime: IV: 50 mg once added to pump prime.

Bolus: Initial: IV bolus: 1 mg/kg followed by continuous IV infusion at 2.5 mg/kg/hour; check activated clotting time (ACT) in 5 minutes; if ACT <480 seconds, repeat IV bolus of 0.25 mg/kg and increase continuous IV infusion by 1.25 mg/kg/hour; titrate to goal ACT >480 seconds. Dosing based on one prospective, randomized controlled trial (n=24) in which the mean IV bolus dose required was 1.7 ± 0.2 mg/kg and the mean continuous IV infusion required was 3 ± 0.7 mg/kg/hour.

Extracorporeal membrane oxygenation [ECMO]/extracorporeal life support [ECLS] (Ref): Limited data available:

Infants, Children, and Adolescents:

Initial dose: Continuous IV infusion: Initial: 0.15 to 0.3 mg/kg/hour; reported initial range: 0.05 to 0.3 mg/kg/hour. Note: Some experts recommend a lower initial dose of 0.2 mg/kg/hour in patients with open sternotomy. Measure aPTT 2 to 4 hours after initiation and titrate to achieve goal aPTT.

Dose adjustment: Continuous IV infusion: One published approach to dose adjustment presented in the table; refer to institutional protocols.

**Bivalirudin ECMO/ECLS in Infants, Children, and Adolescents: Dose Adjustments to Achieve Target aPTT**
aPTT	Bivalirudin titration	Time to repeat aPTT^a
^a Consider more frequent aPTT monitoring based on clinical scenario.
Adapted from Seelhammer 2021.
>20 seconds below goal range	Increase infusion rate by 20%	2 hours
10 to 20 seconds below goal range	Increase infusion rate by 10%	2 hours
Within goal range	No change	12 hours; decrease frequency based on clinical scenario
10 to 20 seconds above goal range	Decrease infusion rate by 10%	2 hours
>20 seconds above goal range	Hold for 1 hour then decrease infusion rate by 20%	2 hours

Ventricular assist device (VAD) (Ref): Very limited data available:

Infants, Children, and Adolescents:

Initial dose: Continuous IV infusion: Initial: 0.3 mg/kg/hour. Measure aPTT 2 hours after initiation; use caution when titrating after first aPTT and adjust as follows:

**Bivalirudin VAD in Infants, Children, and Adolescents: First Dose Adjustment After Initiation**
aPTT	Bivalirudin titration	Time to repeat aPTT
Adapted from ACTION 2023.
1 to 1.5 × baseline	No adjustment	2 to 3 hours
>2 to 3 × baseline	Decrease infusion rate by 50%	2 to 3 hours

Maintenance dose: Continuous IV infusion: After first aPTT measurement and adjustment, measure aPTT in 2 to 3 hours and adjust as follows:

**Bivalirudin VAD in Infants, Children, and Adolescents: Maintenance Dose Adjustments to Achieve Target aPTT**
aPTT	Bivalirudin titration	Time to repeat aPTT^a
^a Consider more frequent anti-factor Xa monitoring based on clinical scenario. ^b Round dose up to closest second decimal (hundredth place). ^c Recommendation in patient with normal kidney function; dose adjustment required for all levels of kidney impairment; see recommendations for mild to moderate and severe kidney impairment. Adapted from ACTION 2023.
≥15 to 30 seconds below target range	Increase infusion rate by 25%^b	2 to 3 hours
5 to <15 seconds below target range	Increase infusion rate by 15%^b	2 to 3 hours
Within goal range	No change	2 to 3 hours; decrease frequency based on clinical scenario
5 to <15 seconds above target range	Decrease infusion rate by 15%^b	2 to 3 hours
≥15 to 30 seconds above target range	Decrease infusion rate by 25%^b	2 to 3 hours
>3 × baseline or ~120 seconds	Hold infusion for 15 minutes then decrease infusion by 30%^b,c	2 to 3 hours

Anticoagulation, interventional cardiac catheterization/percutaneous coronary interventional procedures

Anticoagulation, interventional cardiac catheterization/percutaneous coronary interventional procedures: Very limited data available:

Note: Determine patient's kidney function prior to initiating therapy; dosage adjustment recommended in cases of kidney impairment (CrCl <30 mL/minute/1.73 m²) (Ref).

Infants weighing ≥2.5 kg, Children, and Adolescents: IV bolus (prior to catheterization): 0.75 mg/kg once followed by continuous IV infusion of 1.75 mg/kg/hour, titrated to goal ACT. Note: A lower bolus dose of 0.5 mg/kg and maintenance dose of 0.25 mg/kg/hour have also been reported in an infant (Ref).

Thrombosis, treatment

Thrombosis (not associated with mechanical circulatory support), treatment: Very limited data available:

Note: Goal aPTT range determined by risk of bleeding. Dosing based on one retrospective review and one prospective, open-label pilot study (n=20) (Ref).

Infants, Children, and Adolescents:

Bolus dose (optional): IV: Usual initial range: 0.05 to 0.25 mg/kg once; doses up to 0.5 mg/kg have been described.

Continuous IV infusion: Initial: 0.05 to 0.25 mg/kg/hour; titrate to achieve target aPTT; reported average dose range: 0.05 to 0.21 mg/kg/hour; reported maximum dose: 0.3 mg/kg/hour. Higher doses (0.5 and 0.625 mg/kg/hour) were reported; however, significant hematuria occurred in both patients.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

Anticoagulation, extracorporeal membrane oxygenation [ECMO]/extracorporeal life support [ECLS]:

Baseline kidney impairment: Based on an initial dose of 0.15 mg/kg/hour:

Initial dosing (Ref):

Infants, Children, and Adolescents:

CrCl >60 mL/minute/1.73 m²: No dosage adjustment necessary.

CrCl 30 to 60 mL/minute/1.73 m²: Continuous IV infusion: Initial: Decrease initial dose to 0.1 mg/kg/hour.

CrCl 10 to 29 mL/minute/1.73 m²: Continuous IV infusion: Initial: Decrease initial dose to 0.07 mg/kg/hour.

CrCl <10 mL/minute/1.73 m²: Continuous IV infusion: Initial: Decrease initial dose to 0.02 mg/kg/hour.

Continuous renal replacement therapy (CRRT): Continuous IV infusion: Initial: Decrease initial dose to 0.04 mg/kg/hour.

Anticoagulation, ventricular assist device (VAD):

Baseline kidney impairment:

Infants, Children, and Adolescents:

Initial dosing: Note: Measure baseline aPTT prior to initiation (Ref):

Mild to moderate impairment (CrCl 30 to 60 mL/minute/1.73 m²): Continuous IV infusion: Initial: Decrease initial dose to 0.2 mg/kg/hour; measure aPTT 2 hours after initiation and titrate cautiously with first aPTT measurement; see "Bivalirudin VAD in Infants, Children, and Adolescents: First Dose Adjustment After Initiation" table and "Bivalirudin VAD in Infants, Children, and Adolescents: Maintenance Dosage Adjustments to Achieve Target aPTT" table for details.

Severe impairment (CrCl <30 mL/minute/1.73 m²): Continuous IV infusion: Initial: Decrease initial dose to 0.1 mg/kg/hour; measure aPTT 2 hours after initiation and titrate cautiously with first aPTT measurement; see "Bivalirudin VAD in Infants, Children, and Adolescents: First Dose Adjustment After Initiation" table and "Bivalirudin VAD in Infants, Children, and Adolescents: Maintenance Dosage Adjustments to Achieve Target aPTT" table for details.

Kidney impairment during therapy (Ref):

Infants, Children, and Adolescents:

Dosage adjustments for aPTT >3 times baseline or ~120 seconds:

Mild to moderate impairment (GFR 30 to 60 mL/minute/1.73 m²): Continuous IV infusion: Hold infusion for 45 minutes then decrease infusion rate by 40%.

Severe impairment (GFR <30 mL/minute/1.73 m²): Continuous IV infusion: Hold infusion for 2 hours then recheck aPTT before restarting.

Anticoagulation, interventional cardiac catheterization/percutaneous coronary interventional procedures:

Baseline kidney impairment:

Infants weighing ≥2.5 kg, Children, and Adolescents:

GFR <30 mL/minute/1.73 m²: Continuous IV infusion: Decrease initial dose to 1 mg/kg/hour, titrated to goal activated clotting time (ACT) (Ref).

Dosing: Hepatic Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling. In adults, no dosage adjustment necessary (Ref).

Dosing: Adult

(For additional information see "Bivalirudin: Drug information")

Cardiac surgery

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 (Ref).

IV: Intraoperative:

Off-pump:

Initial bolus: 0.75 mg/kg followed by continuous infusion (Ref).

Maintenance continuous infusion: 1.75 mg/kg/hour to maintain ACT >300 seconds (Ref).

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 (Ref).

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 (Ref).

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 (Ref). 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 (Ref).

Heparin-induced thrombocytopenia

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 (Ref).

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 (Ref).

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) (Ref).

Ischemic heart disease, percutaneous coronary intervention

Ischemic heart disease, percutaneous coronary intervention (alternative agent):

Note: Includes patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome or when PCI is chosen for stable ischemic heart disease. Consider for use as an alternative to heparin. Use in combination with an appropriate antithrombotic regimen. If unfractionated heparin is initiated then switched to bivalirudin prior to PCI, discontinue unfractionated heparin and wait 30 minutes before starting bivalirudin (Ref).

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. After the procedure, may continue the infusion at 1.75 mg/kg/hour for up to 4 hours (Ref).

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 (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

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 (Ref). 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 (Ref).

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 (Ref).

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 (Ref).

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 (Ref).

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 (Ref).

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 (Ref).

Dosing: Hepatic Impairment: Adult

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 (Ref).

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.

1% to 10%:

Cardiovascular: Thrombosis (acute stent thrombosis [<4 hours] in patients with STEMI undergoing primary PCI: 1%)

Hematologic & oncologic: Hemorrhage (including intracranial hemorrhage, major hemorrhage, and retroperitoneal hemorrhage: 4%)

<1%: Immunologic: Antibody development

Frequency not defined:

Hematologic & oncologic: Major hemorrhage, retroperitoneal hemorrhage

Nervous system: Intracranial hemorrhage

Postmarketing:

Cardiovascular: Cardiac tamponade, coronary thrombosis (during PCI, including intracoronary brachytherapy)

Hematologic & oncologic: Increased INR, pulmonary hemorrhage

Hypersensitivity: Anaphylaxis, hypersensitivity reaction

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

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.

Dosage Forms: US

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 [DSC]) [contains polyethylene glycol (macrogol)]

Generic: 250 mg/50 mL (50 mL)

Solution Reconstituted, Intravenous:

Generic: 250 mg (1 ea)

Solution Reconstituted, Intravenous [preservative free]:

Angiomax: 250 mg (1 ea)

Generic: 250 mg (1 ea)

Generic Equivalent Available: US

Yes

Pricing: US

Solution (Bivalirudin Trifluoroacetate Intravenous)

250 mg/50 mL (per mL): $1.72

Solution (reconstituted) (Angiomax Intravenous)

250 mg (per each): $1,170.00

Solution (reconstituted) (Bivalirudin Trifluoroacetate Intravenous)

250 mg (per each): $72.00 - $1,137.27

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Dosage Forms: Canada

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)

Administration: Pediatric

Parenteral: IV administration only. Vials (lyophilized powder) must be reconstituted and further diluted prior to administration; premixed frozen IV solution (5 mg/mL) is available. After initial bolus dose (when recommended), administer as a continuous IV infusion via an infusion device.

Administration: Adult

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.

Storage/Stability

Solution reconstituted, IV: 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.

Solution, IV: Store unopened vials at 2°C to 8°C (36°F to 46°F); may be stored at 20°C to 25°C (68°F to 77°F) for up to 72 hours. Avoid excess heat.

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.

Use

Anticoagulant used in patients undergoing percutaneous coronary intervention (PCI), including those with heparin-induced thrombocytopenia (HIT)/thrombosis syndrome (HITTS) (FDA approved in adults); has also been used as an anticoagulant in mechanical circulatory support (eg, extracorporeal membrane oxygenation, ventricular assist devices) and in the treatment of thrombosis (not associated with mechanical circulatory support).

Medication Safety Issues

High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (direct thrombin inhibitor) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care, Community/Ambulatory Care, and Long-Term Care Settings).

National Patient Safety Goals:

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).

Metabolism/Transport Effects

None known.

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program

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

Alteplase: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination

Anacaulase: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Anagrelide: 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. Management: Avoid coadministration of caplacizumab with antiplatelets if possible. If coadministration is required, monitor closely for signs and symptoms of bleeding. Interrupt use of caplacizumab if clinically significant bleeding occurs. Risk D: Consider therapy modification

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

Defibrotide: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination

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

Lecanemab: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the risk of hemorrhage may be increased. 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 (Ophthalmic): 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

Pirtobrutinib: 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

Protein C Concentrate (Human): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Reteplase: May enhance the anticoagulant effect of Anticoagulants. 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

Streptokinase: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination

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

Tenecteplase: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination

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. Management: Consider avoiding this combination due to an increased risk of hemorrhage. If anticoagulants are coadministered with urokinase, monitor patients closely for signs and symptoms of bleeding. Risk D: Consider therapy modification

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

Volanesorsen: May enhance the anticoagulant effect of Anticoagulants. 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

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).

Monitoring Parameters

Obtain baseline PT/INR, aPTT, kidney function tests, and CBC with differential prior to start of therapy. Check aPTT 2 to 4 hours after start of therapy and with any dosage adjustment. Monitor hemoglobin, hematocrit, platelets, and signs and symptoms of bleeding. Monitor kidney function tests as clinically indicated.

Note: Activated clotting time may also be used in clinical settings where aPTT is not utilized (eg, cardiac catheterization lab, operating room).

Thromboelastography (TEG) R-Time of 12 to 30 minutes has been reported as a modality for monitoring response to bivalirudin in extracorporeal life support (Ranucci 2011) and may be valuable in the setting of decreased sensitivity of aPTT monitoring (ie, significant inflammation, hyperfibrinogenemia, elevated factor VIII levels).

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 (Adult Data Unless Noted)

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:

Neonates, Infants, Children, and Adolescents: GFR ≥30 mL/minute: 15 to 18 minutes (Forbes 2011).

Adults:

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.

Pharmacokinetics: Additional Considerations (Adult Data Unless Noted)

Altered kidney function: Clearance is reduced by 21% in moderate and severe renal impairment and by 70% in dialysis patients.

Brand Names: International

International Brand Names by Country

For country code abbreviations (show table)

(AR) Argentina: Amuprux;
(AT) Austria: Angiox | Bivalirudin accord;
(AU) Australia: Angiomax | Apo bivalirudin;
(BE) Belgium: Bivalirudin accord;
(CN) China: Tai jia ning;
(CO) Colombia: Angiomax;
(DE) Germany: Angiox | Bivalirudin accord | Bivalirudin cipla;
(EE) Estonia: Bivacard;
(ES) Spain: Angiox | Bivalirudina accord | Bivalirudina sala;
(FI) Finland: Angiox | Bivalirudin accord | Bivalirudin Reig Jofre;
(FR) France: Angiox | Bivalirudine Accord;
(GB) United Kingdom: Angiox | Bivalirudin Reig Jofre;
(GR) Greece: Angiox;
(HU) Hungary: Angiox;
(IE) Ireland: Angiox;
(IN) India: Bivacard | Bivacs | Bivaflo | Bivamax | Bivasave | Bivastat | Flopace | Nubimax;
(IT) Italy: Bivalirudina accord;
(LT) Lithuania: Angiox;
(LV) Latvia: Angiox;
(NL) Netherlands: Angiox | Bivalirudine Accord;
(NO) Norway: Angiox;
(NZ) New Zealand: Angiomax;
(PE) Peru: Angiomax;
(PL) Poland: Biwalirudyna accord;
(PR) Puerto Rico: Angiomax;
(PT) Portugal: Angiox | Bivalirudin accord;
(QA) Qatar: Bivasave;
(RO) Romania: Angiox;
(RU) Russian Federation: Angiox | Bivalirudin j;
(SE) Sweden: Angiox | Bivalirudin accord | Bivalirudin Reig Jofre;
(SI) Slovenia: Angiox | Bivalirudin accord;
(TR) Turkey: Bivacard

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Topic 144295 Version 14.0

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Bivalirudin: Pediatric drug information