Bivalirudin (Monograph)

Brand name: Angiomax
Drug class: Direct Thrombin Inhibitors
Chemical name: d-Phenylalanyl-l-prolyl-l-arginyl-l-prolylglycylglycylglycylglycyl-l-asparaginylglycyl-l-α-aspartyl-l-phenylalanyl-l-α-glutamyl-l-α-glutamyl-l-isoleucyl-l-prolyl-l-α-glutamyl-l-α-glutamyl-l-tyrosyl-l-leucine
CAS number: 128270-60-0

Medically reviewed by Drugs.com on Dec 5, 2024. Written by ASHP.

Introduction

Anticoagulant; synthetic analog of hirudin that acts as a direct thrombin inhibitor.

Uses for Bivalirudin

Percutaneous Coronary Intervention

Used as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI), including those with heparin-induced thrombocytopenia (HIT) or heparin-induced thrombocytopenia and thrombosis syndrome (HITTS).

Parenteral anticoagulant is recommended in all patients undergoing PCI to prevent thrombus formation during the procedure. Bivalirudin (with or without prior unfractionated heparin) is recommended by the American College of Cardiology Foundation (ACCF), the American Heart Association (AHA), and the Society for Cardiovascular Angiography and Interventions (SCAI) as an appropriate choice of anticoagulant for this use. In the subset of patients with acute HIT who require PCI, experts generally suggest the use of bivalirudin or argatroban. Factors such as availability, cost, experience with the drug, and anticoagulation monitoring capabilities may influence choice of drug.

Bivalirudin has been studied only in patients receiving concomitant aspirin.

Studies have shown that bivalirudin is associated with similar rates of ischemic events but substantially reduced rates of bleeding compared with heparin (LMWH or unfractionated heparin). However, benefit with respect to bleeding may be reduced with routine use of a GPIIb/IIIa inhibitor or concurrent use of P2Y12 inhibitors.

Non-ST-Segment-Elevation Acute Coronary Syndrome

Has been used as an initial anticoagulant in patients with non-ST-segment-elevation acute coronary syndrome (NSTE-ACS)^{† [off-label]} who are being managed with an early invasive strategy. In this setting, bivalirudin is continued until the time of diagnostic angiography or PCI.

Cardiac Surgery in Patients with HIT

Also has been used for anticoagulation during cardiovascular surgery in patients with HIT^{† [off-label]}.

Prevention of Thrombosis During Renal Replacement Therapy

Has been used as an anticoagulant to prevent thrombosis of dialysis circuitry during renal replacement therapy in patients with acute HIT^{† [off-label]}.

Acute HIT/HITTS

Has been used for treatment of acute HIT or HITTS^{† [off-label]}.

In patients with acute HIT/HITTS, all forms of heparin (e.g., unfractionated heparin, LMWH) should be discontinued and a nonheparin anticoagulant initiated. The American College of Chest Physicians (ACCP) and American Society of Hematology (ASH) suggest bivalirudin as one of several nonheparin anticoagulants that can be used in these patients. Consider drug- and patient-specific factors when choosing an agent.

Bivalirudin Dosage and Administration

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by direct IV injection followed by IV infusion. Do not administer IM.

Commercially available as a lyophilized powder that must be reconstituted and diluted prior to administration. Also available in 5 mg/mL ready-to-use formulations (e.g., bivalirudin ready-to-use [RTU] injection, bivalirudin in 0.9% sodium chloride injection).

Bivalirudin Powder for Injection

Reconstitute vial containing 250 mg of lyophilized bivalirudin with 5 mL of sterile water for injection (swirl gently) to provide a solution containing 50 mg/mL.

Further dilute to a total volume of 50 mL in 5% dextrose or 0.9% sodium chloride injection to provide a final solution for administration containing 5 mg/mL.

Discard any unused reconstituted solution.

Bivalirudin RTU Injection

Remove RTU injection vials from refrigerator immediately before use. Discard any unused portions.

Bivalirudin in 0.9% Sodium Chloride Injection

Thaw commercially available frozen premixed injection at room temperature (25°C) or in refrigerator (5°C); do not thaw by immersion in a water bath or by exposure to microwave radiation. A precipitate may have formed in the frozen injection, but should dissolve with little or no agitation after reaching room temperature. Discard thawed injection if an insoluble precipitate is present or if container seals or outlet ports are not intact or leaks are found.

Dosage

Available as bivalirudin trifluoroacetate; dosage expressed in terms of bivalirudin.

Adults

Percutaneous Coronary Intervention

IV

0.75 mg/kg by direct IV injection immediately before PCI, followed by 1.75 mg/kg per hour by continuous IV infusion for the duration of the procedure. Assess activated clotting time (ACT) 5 minutes after initial loading dose and administer an additional direct IV dose of 0.3 mg/kg if needed.

Consider continuing infusion for up to 4 hours after PCI in patients with ST-segment-elevation myocardial infarction (STEMI).

In patients with non-ST-segment-elevation acute coronary syndrome (NSTE-ACS) who have received prior treatment with unfractionated heparin, American Heart Association (AHA)/American College of Cardiology (ACC) recommends waiting 30 minutes and then administering the 0.75-mg/kg IV loading dose of bivalirudin followed by continuous IV infusion of bivalirudin at 1.75 mg/kg per hour.

In patients with NSTE-ACS already receiving bivalirudin for initial anticoagulation, AHA/ACC recommends an additional 0.5-mg/kg loading dose of bivalirudin followed by continuous IV infusion of 1.75 mg/kg per hour during PCI.

Bivalirudin has only been studied in combination with aspirin in this setting.

Initial Anticoagulation in Patients with NSTE-ACS† [off-label]

IV

For initial anticoagulation in patients with NSTE-ACS being managed with an early invasive strategy, a loading dose of 0.1 mg/kg, followed by continuous IV infusion of 0.25 mg/kg per hour until diagnostic angiography or PCI has been recommended.

Aspirin and a P2Y12 inhibitor are also recommended in this setting.

If PCI is performed while the patient is on bivalirudin, administer an additional loading dose of 0.5 mg/kg and increase continuous IV infusion to 1.75 mg/kg per hour during PCI.

Cardiac Surgery in Patients with HIT†

IV

During “off-pump” cardiac surgery (i.e., without cardiopulmonary bypass), 0.75 mg/kg by direct IV injection, followed by 1.75 mg/kg per hour by continuous IV infusion to maintain an ACT >300 seconds has been used.

During cardiopulmonary bypass, initially, 1 mg/kg by direct IV injection followed by 2.5 mg/kg per hour by continuous IV infusion has been used; if needed, additional direct IV doses of 0.1–0.5 mg/kg have been given to maintain a 2.5-fold or greater prolongation of the baseline ACT. In addition, 50 mg of bivalirudin is added to the recirculating priming fluid of the cardiopulmonary bypass circuit.

Prevention of Thrombosis During Renal Replacement Therapy†

IV

A treatment protocol with initial dose and dosage adjustments based on aPTT, risk of bleeding, and risk of thrombosis has been used. According to this protocol, an initial continuous IV infusion of 0.02 mg/kg per hour is given; dosage is then adjusted based on aPTT. In patients at high risk of bleeding, a target aPTT of 1.5–2.5 times the normal value is used; in patients at high risk of clotting or active HITTS, a target aPTT of 2–2.5 times the normal value is used.

Treatment of Acute HIT/HITTS†

IV

If bivalirudin is used for the treatment of HIT/HITTS, a continuous IV infusion of 0.15 mg/kg per hour adjusted to aPTT 1.5–2.5 times baseline has been used.

No initial bolus dose is needed.

Consider reduced infusion rate for renal or hepatic impairment.

Special Populations

Renal Impairment

Manufacturers state that reduction of the initial loading dose not necessary in patients with renal impairment undergoing PCI. Closely monitor ACT in patients with renal impairment. Reduce infusion rate to 1 mg/kg per hour in patients with severe renal impairment (Cl_cr <30 mL/minute). In dialysis-dependent patients, reduce off-dialysis infusion rate to 0.25 mg/kg per hour.

Hepatic Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Cautions for Bivalirudin

Contraindications

• Active major bleeding.

• Known hypersensitivity to bivalirudin or any ingredient in the formulation.

Warnings/Precautions

Warnings

Bleeding

Risk of bleeding, sometimes fatal. Unexplained decreases in hematocrit, hemoglobin, or BP may indicate hemorrhage.

Discontinue if severe hemorrhage occurs. Use with caution in patients with an increased risk of hemorrhage.

Acute Stent Thrombosis

Higher rate of acute stent thrombosis reported with bivalirudin than heparin in patients with STEMI undergoing primary PCI. Monitor patients closely in an appropriate healthcare setting for ≥24 hours after PCI.

Thrombotic Risk with Brachytherapy Procedures

Increased risk of potentially fatal thrombosis during vascular brachytherapy procedures; use caution. Assess catheter function frequently by attempting to aspirate blood, and ensure patency by repeated flushing. Minimize conditions promoting stasis within the catheter or circulatory system.

Immunogenicity

Positive bivalirudin antibody tests reported rarely; however, not associated with allergic or anaphylactic reactions.

Specific Populations

Pregnancy

No adequate and well-controlled studies in pregnancy; animal studies do not suggest fetal harm at therapeutic doses. Consider potential risks and benefits to the mother and the fetus.

Lactation

Not known whether bivalirudin is distributed into milk or has any effects on milk production or the breast-fed infant. Consider potential risks and benefits to the mother and infant.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

Potential for greater risk of bleeding complications relative to younger adults.

Renal Impairment

Clearance is reduced; dosage reduction may be necessary

Common Adverse Effects

Bleeding.

Drug Interactions

Specific Drugs

Bivalirudin Pharmacokinetics

Absorption

Onset

Immediate anticoagulant effect.

Duration

Effects are dose- and concentration-dependent and reversible; thrombin slowly cleaves the bivalirudin-Arg₃-Pro₄ bond, which results in recovery of the thrombin active site function. Coagulation times return to normal approximately 1 hour after cessation of infusion.

Distribution

Extent

Not known whether the drug is distributed into human milk.

Plasma Protein Binding

Does not bind to plasma proteins (other than thrombin) or to RBCs.

Elimination

Metabolism

Cleared from the plasma by a combination of renal mechanisms and intracellular proteolysis.

Elimination Route

Approximately 20% of unchanged bivalirudin is cleared renally, and the remainder presumably undergoes intracellular proteolysis.

Half-life

22 minutes.

Special Populations

In patients with mild renal impairment (GFR of 60–89 mL/minute), clearance and half-life are similar to patients with normal renal function.

In patients with moderate renal impairment (GFR of 30–59 mL/minute), half-life is 34 minutes.

In patients with severe renal impairment (GFR of 10–29 mL/minute), half-life is 57 minutes.

In dialysis-dependent patients, off-dialysis half-life is 3.5 hours.

Total body clearance reduced by about 20% in patients with moderate to severe renal impairment and by 80% in dialysis-dependent patients.

Approximately 25% of drug removed by hemodialysis.

Stability

Storage

Parenteral

Powder for Injection

20–25°C (may be exposed to 15–30°C).

Reconstituted solution (50 mg/mL) may be stored at 2–8°C for up to 24 hours; do not freeze.

Diluted IV solutions (0.5–5 mg/mL) are stable at room temperature for up to 24 hours; do not freeze.

Ready-to-Use Injection

2–8°C (may be exposed to 20–25°C); do not expose to excessive heat.

Premixed (frozen) solution in 0.9% Sodium Chloride

-20°C or below.

Thaw at room temperature or in refrigerator; do not microwave or use water bath.

Thawed solutions are stable for 24 hours at room temperature (25°C) or 14 days under refrigeration (5°C); do not refreeze after thawing.

Compatibility

Parenteral

Solution Compatibility1

Drug CompatibilityHID

Actions

• Anticoagulant; synthetic analog of the polypeptide found in the saliva of the medicinal leech (Hirudo medicinalis).

• Specific and reversible direct thrombin inhibitor that binds to circulating and clot-bound thrombin.

• Inhibition of thrombin prevents various steps in the coagulation process (e.g., activation of factors V, VIII, and XIII; conversion of fibrinogen to fibrin; platelet activation and aggregation).

• Prolongs activated clotting time (ACT), aPTT, thrombin time (TT), and PT.

Advice to Patients

• Importance of patients reporting any signs of bleeding (e.g., bruising, petechiae, hematuria) to clinicians immediately.

• Importance of patients informing clinicians of history of bleeding disorders or impaired renal function.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of patients informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant diseases.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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