Bivalirudin

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
Brands: Angiomax

Introduction

Anticoagulant; synthetic peptide analog of hirudin, an anticoagulant polypeptide found in the saliva of the medicinal leech (Hirudo medicinalis).^{1 2 3 4 5 6}

Uses for Bivalirudin

Acute Ischemic Complications of PCI

Used with aspirin to reduce the risk of acute ischemic complications (e.g., death, MI, need for urgent revascularization procedures) in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA).^{5 6 7 28}

Used with aspirin and “provisional” treatment with a platelet glycoprotein GP IIb/IIIa-receptor inhibitor in patients undergoing PCI; in clinical studies, patients who received provisional treatment included those with prolonged ischemia, decreased perfusion (TIMI grade 0–2 flow) or slow reflow, dissection with decreased perfusion, new or suspected thrombus, persistent residual stenosis, distal embolization, unplanned or suboptimal stent placement, side branch closure, abrupt closure, or other clinical instability.^{8 9 14 28 994}

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Use of a parenteral anticoagulant is recommended in patients undergoing PCI to prevent thrombus formation during the procedure.⁹⁹⁴ Bivalirudin (with or without prior heparin [referring throughout this monograph to unfractionated heparin] treatment) is recommended by the American College of Cardiology Foundation (ACCF), the AHA, and the Society for Cardiovascular Angiography and Interventions (SCAI) as an appropriate choice of anticoagulant for use during PCI.⁹⁹⁴

Current evidence suggests that bivalirudin may be associated with a lower risk of bleeding than heparin plus a GP IIb/IIIa-receptor inhibitor; however, this benefit is reduced when a GP IIb/IIIa-receptor inhibitor is used concomitantly.⁹⁹⁴ Therefore, a strategy of provisional use of a GP IIb/IIIa-receptor inhibitor has become widely accepted in patients receiving bivalirudin during PCI.⁹⁹⁴

Safety and efficacy not established in patients with acute coronary syndromes who are not undergoing PTCA or PCI.¹

Heparin-induced Thrombocytopenia in Patients Undergoing PCI

Used with aspirin in patients undergoing PCI who have, or are at risk for, heparin-induced thrombocytopenia (HIT) or heparin-induced thrombocytopenia and thrombosis syndrome (HITTS).^{1 994 1006}

Experts recommend use of bivalirudin or argatroban as a substitute for heparin or low molecular weight heparin therapy in patients with HIT undergoing PCI.^{994 1006}

Heparin-induced Thrombocytopenia in Patients Undergoing Cardiac Surgery

Also used as a substitute for heparin in patients with acute HIT who require urgent cardiac surgery† (e.g., CABG).^{24 1006}

ACCP suggests the use of bivalirudin over other nonheparin anticoagulants in such patients.¹⁰⁰⁶

Bivalirudin Dosage and Administration

General

• Manufacturer states that bivalirudin is intended for use concomitantly with aspirin 300–325 mg daily.¹ According to some experts, a lower dose of aspirin (e.g., 81–325 mg) may be administered prior to PCI in patients who are already receiving daily aspirin therapy.⁹⁹⁴

Administration

IV Administration

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

Administer by direct IV injection followed by IV infusion.¹ Do not administer IM.¹

Reconstitution

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.¹

Discard any unused reconstituted solution.¹

Dilution

Dilute reconstituted solution in 50 mL of 5% dextrose or 0.9% sodium chloride injection to a final concentration of 5 mg/mL for direct IV injection and infusion.¹

For low-rate infusion, further dilute the 5-mg/mL solution in 500 mL of 5% dextrose or 0.9% sodium chloride injection to a final concentration of 0.5 mg/mL.^{1 7}

Dosage

Adults

Acute Ischemic Complications of PCI

IV

0.75 mg/kg (5-mg/mL solution) by direct IV injection immediately before PCI, followed by 1.75 mg/kg per hour (5-mg/mL solution) by continuous IV infusion for the duration of the procedure.¹ Obtain an activated clotting time (ACT) (as measured by a Hemochron device) 5 minutes after initial loading dose and administer an additional direct IV dose of 0.3 mg/kg if needed (e.g., if the ACT is <225 seconds).^{1 8}

May continue infusion for up to 4 hours after the procedure if necessary.¹ If needed, administer an additional IV infusion (0.5-mg/mL solution) at 0.2 mg/kg per hour for up to 20 hours.¹

Consider administration of a GP IIb/IIIa-receptor inhibitor if procedural complications occur (“provisional use”).²⁸ (See Acute Ischemic Complications of Percutaneous Coronary Intervention under Uses.)

HIT in Patients Undergoing PCI

IV

0.75 mg/kg (5-mg/mL solution) by direct IV injection immediately before PCI, followed by 1.75 mg/kg per hour (5-mg/mL solution) by continuous IV infusion for the duration of the procedure.¹

May continue infusion for up to 4 hours after the procedure if necessary.¹ If needed, administer an additional IV infusion (0.5-mg/mL solution) at 0.2 mg/kg per hour for up to 20 hours.¹

HIT in Patients Undergoing Cardiac Surgery†

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.²⁶

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;²⁴ 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.²⁴ In addition, 50 mg of bivalirudin is added to the recirculating priming fluid of the cardiopulmonary bypass circuit.²⁴

Special Populations

Renal Impairment

Reduction of the initial loading dose not necessary in patients with moderate to severe renal impairment.^{1 7} Closely monitor ACT in patients with renal impairment.¹ Reduce infusion rate to 1 mg/kg per hour in patients with severe renal impairment (Cl_cr <30 mL/minute).¹ In dialysis-dependent patients, reduce off-dialysis infusion rate to 0.25 mg/kg per hour.¹

Cautions for Bivalirudin

Contraindications

• Active major bleeding.¹

• Known hypersensitivity to bivalirudin or any ingredient in the formulation.¹

Warnings/Precautions

Warnings

Hematologic Effects

Possible bleeding, especially at site of arterial puncture.^{1 7} Unexplained decreases in hematocrit, hemoglobin, or BP may indicate hemorrhage.¹

Discontinue if severe hemorrhage occurs.¹ Use with caution in patients with an increased risk of hemorrhage.^{1 7}

Increased risk of potentially fatal thrombosis during vascular brachytherapy procedures; use caution.¹ Assess catheter function frequently by attempting to aspirate blood, and ensure patency by repeated flushing.¹ Minimize conditions promoting stasis within the catheter or circulatory system.¹

Sensitivity Reactions

Hypersensitivity

Positive bivalirudin antibody tests found rarely in clinical studies; however, no allergic or anaphylactic reactions reported.^{1 7}

General Precautions

Factors Increasing Risk of Hemorrhage

Increased risk of major bleeding events with concomitant heparin, warfarin, thrombolytic, or GP IIb/IIIa-receptor inhibitor therapy in clinical trials.¹ (See Common Adverse Effects and see Specific Drugs under Interactions.) No experience with concomitant administration of plasma expanders such as dextran.¹

Use with caution in patients with disease states associated with increased risk of hemorrhage.¹

Brachytherapy Procedures

Use with caution during vascular brachytherapy procedures because of an increased risk of potentially fatal thrombosis.¹

Patients with HIT Undergoing Cardiac Surgery

Possible formation of clots due to degradation of bivalirudin in areas of blood stasis; special maneuvers needed to avoid stasis within the cardiopulmonary bypass circuit during and after cardiac surgery.^{24 1006}

Specific Populations

Pregnancy

Category B.¹

Lactation

Not known whether bivalirudin is distributed into milk.¹ Use with caution.¹

Pediatric Use

Safety and efficacy not established in pediatric patients.¹

Geriatric Use

No substantial differences in safety or efficacy relative to younger adults.^{1 7}

Renal Impairment

Dosage reduction recommended in patients with moderate to severe renal impairment.¹ (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Major hemorrhagic events less frequent with bivalirudin with or without provisional GP IIb/IIIa-receptor inhibitor therapy (2.3%) compared with unfractionated heparin and routine GP IIb/IIIa-receptor inhibitor therapy (4%).¹

Nonhemorrhagic effects in patients with unstable angina undergoing PTCA: Back pain,¹ pain (unspecified),¹ nausea,¹ headache,¹ hypotension,¹ injection site pain,¹ insomnia,¹ hypertension,¹ vomiting,¹ pelvic pain,¹ anxiety,¹ bradycardia,¹ dyspepsia,¹ abdominal pain,¹ fever,¹ nervousness,¹ urinary retention.¹

Nonhemorrhagic effects in patients undergoing PCI and receiving provisional therapy with a GP IIb/IIIa-receptor inhibitor: Back pain, angina pectoris,¹ pain (unspecified),¹ hypotension,¹ nausea,¹ injection site pain,¹ headache,¹ chest pain.¹

Interactions for Bivalirudin

Specific Drugs

Drug	Interaction	Comments
Aspirin	Increased risk of hemorrhage13
GP IIb/IIIa-receptor inhibitors	Increased risk of hemorrhage1
Heparin	Increased risk of hemorrhage1
Heparin, low molecular weight	No apparent pharmacodynamic interaction13	Limited data; safety and efficacy of combination therapy not established13
Plasma-volume expanders (e.g., dextran)	No experience with concomitant therapy1
Thrombolytic agents	Increased risk of hemorrhage1
Ticlopidine	No apparent pharmacodynamic interaction13	Limited data; safety and efficacy of combination therapy not established13
Warfarin	Increased risk of hemorrhage1

Bivalirudin Pharmacokinetics

Absorption

Onset

Immediate anticoagulant effect.¹

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.^{1 3 4} Coagulation times return to normal approximately 1–2 hours after cessation of infusion.^{1 7}

Distribution

Extent

Not known whether the drug is distributed into human milk.¹

Plasma Protein Binding

Does not bind to plasma proteins (other than thrombin).¹

Elimination

Metabolism

Cleared from the plasma by a combination of renal mechanisms and intracellular proteolysis.^{1 27}

Elimination Route

Approximately 20% of unchanged bivalirudin is cleared renally, and the remainder presumably undergoes intracellular proteolysis.²⁷

Half-life

22 minutes.¹

Special Populations

In patients with mild renal impairment (GFR of 60–89 mL/minute), half-life is 25 minutes.¹

In patients with moderate renal impairment (GFR of 30–59 mL/minute), half-life is 34 minutes.¹

In patients with severe renal impairment (GFR of 10–29 mL/minute), half-life is 57 minutes.¹

In dialysis-dependent patients, off-dialysis half-life is 3.5 hours.¹

Total body clearance reduced by about 20% in patients with moderate to severe renal impairment and by 80% in dialysis-dependent patients.¹

Approximately 25% of drug removed by hemodialysis.¹

Stability

Storage

Parenteral

Powder for Injection

20–25°C (may be exposed to 15–30°C).¹

Reconstituted solution (50 mg/mL) may be stored at 2–8°C for up to 24 hours.¹

Diluted IV solutions (0.5–5 mg/mL) are stable at room temperature for up to 24 hours.¹

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility¹

Compatible
Dextrose 5% in water
Sodium chloride 0.9%

Drug Compatibility^HID

Y-Site CompatibilityHID

Compatible
Abciximab
Alfentanil HCl
Amikacin sulfate
Aminophylline
Ampicillin sodium
Ampicillin sodium-sulbactam sodium
Azithromycin
Aztreonam
Bretylium tosylate
Bumetanide
Butorphanol tartrate
Calcium gluconate
Cefazolin sodium
Cefepime HCl
Cefotaxime sodium
Cefoxitin sodium
Ceftazidime
Ceftizoxime sodium
Ceftriaxone sodium
Cefuroxime sodium
Cimetidine HCl
Ciprofloxacin
Clindamycin phosphate
Co-trimoxazole
Dexamethasone sodium phosphate
Digoxin
Diltiazem HCl
Diphenhydramine HCl
Dobutamine HCl
Dopamine HCl
Doxycycline hyclate
Droperidol
Enalaprilat
Ephedrine sulfate
Epinephrine HCl
Epoprostenol sodium
Eptifibatide
Erythromycin lactobionate
Esmolol HCl
Famotidine
Fentanyl citrate
Fluconazole
Furosemide
Gentamicin sulfate
Haloperidol lactate
Heparin sodium
Hydrocortisone sodium succinate
Hydromorphone HCl
Isoproterenol HCl
Labetalol HCl
Levofloxacin
Lidocaine HCl
Lorazepam
Magnesium sulfate
Mannitol
Meperidine HCl
Methylprednisolone sodium succinate
Metoclopramide HCl
Metronidazole
Midazolam HCl
Milrinone lactate
Morphine sulfate
Nalbuphine HCl
Nitroglycerin
Norepinephrine bitartrate
Phenylephrine HCl
Piperacillin sodium-tazobactam
Potassium chloride
Procainamide HCl
Promethazine HCL
Ranitidine HCl
Sodium bicarbonate
Sodium nitroprusside
Sufentanil citrate
Theophylline
Thiopental sodium
Ticarcillin disodium-clavulanate potassium
Tirofiban HCl
Tobramycin sulfate
Verapamil HCl
Warfarin sodium
Incompatible
Alteplase
Amiodarone HCl
Amphotericin B
Chlorpromazine HCl
Diazepam
Prochlorperazine edisylate
Reteplase
Vancomycin HCl

Actions

• Specific and reversible direct thrombin inhibitor that binds to circulating and clot-bound thrombin.^{1 2 3 4}

• 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).^{1 2 3 4}

• Prolongs activated clotting time (ACT), aPTT, thrombin time (TT), and PT.^{1 7}

Advice to Patients

• Importance of patients reporting any signs of bleeding (e.g., bruising, petechiae, hematuria) to clinicians immediately.¹

• Importance of patients informing clinicians of history of bleeding disorders or impaired renal function.¹

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

• Importance of patients informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant diseases.¹

• Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

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

Bivalirudin

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for IV infusion	250 mg	Angiomax	Medicines Company