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Angiomax

Generic Name: 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

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 Angiomax

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

Angiomax 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 (Clcr <30 mL/minute).1 In dialysis-dependent patients, reduce off-dialysis infusion rate to 0.25 mg/kg per hour.1

Cautions for Angiomax

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 Angiomax

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

Angiomax 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 CompatibilityHID
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

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 15, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. The Medicines Company. Angiomax (bivalirudin) for injection prescribing information. Cambridge, MA; 2005 Dec 6.

2. Haines ST, Bussey HI. Thrombosis and the pharmacology of antithrombotic agents. Ann Pharmacother. 1995; 29:892-905. [IDIS 353388] [PubMed 8547739]

3. Stringer KA, Lindenfeld J. Hirudins: antithrombin anticoagulants. Ann Pharmacother. 1992; 26:1535-40. [IDIS 306624] [PubMed 1482812]

4. Bates SM, Weitz JI. Direct thrombin inhibitors for treatment of arterial thrombosis: potential differences between bivalirudin and hirudin. Am J Cardiol. 1998; 82:12-8P.

5. Bittl JA, Strony J, Brinker JA et al for the Hirulog Angioplasty Study investigators. Treatment with bivalirudin (hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina. N Engl J Med. 1995; 333:764-9. [IDIS 353197] [PubMed 7643883]

6. Bittl JA, Feit F for Hirulog Angioplasty Study investigators. A randomized comparison of bivalirudin and heparin in patients undergoing coronary angioplasty for postinfarction angina. Am J Cardiol. 1998; 82:43-9P. [PubMed 9671007]

7. The Medicines Company, Cambridge, MA: Personal communication.

8. Lincoff AM, Bittl JA, Harrington RA et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA. 2003; 289:853-63. [IDIS 493155] [PubMed 12588269]

9. Saw J, Lincoff M, DeSmet W et al. Lack of clopidogrel pretreatment effect on the relative efficacy of bivalirudin with provisional glycoprotein IIb/IIIa blockade compared to heparin with routine glycoprotein IIb/IIIa blockade: a REPLACE-2 substudy. J Am Coll Cardiol. 2004; 44:1194-9. [IDIS 524399] [PubMed 15364319]

13. The Medicines Company. Angiomax (bivalirudin) for injection prescribing information. Cambridge, MA; 2002 Jun 18.

14. Lincoff, AM, Kleiman NS, Kereiakes DJ et al. Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary revascularization: REPLACE-2 randomized trial. JAMA. 2004; 292:696-703.

16. Lansky AJ, Hochman JS, Ward PA et al. Percutaneous coronary intervention and adjunctive pharmacotherapy in women: a statement for healthcare professionals from the American Heart Association. Circulation. 2005; 111:940-5. [PubMed 15687113]

20. Antman EM, Hand M, Armstrong PW et al. 2007 focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction. J Am Coll Cardiol. 2008; 51:210-47. [PubMed 18191746]

24. Koster A, Dyke CM, Aldea G et al. Bivalirudin during cardiopulmonary bypass in patients with previous or acute heparin-induced thrombocytopenia and heparin antibodies: results of the CHOOSE-ON trial. Ann Thorac Surg. 2007; 83:572-7. [PubMed 17257990]

25. Lewis SZ (American College of Chest Physicians, Northbrook, IL): Personal communication. 2011 Mar 15.

26. Dyke CM, Aldea G, Koster A et al. Off-pump coronary artery bypass with bivalirudin for patients with heparin-induced thrombocytopenia or antiplatelet factor four/heparin antibodies. Ann Thorac Surg. 2007; 84:836-40. [PubMed 17720385]

27. Robson R, White H, Aylward P et al. Bivalirudin pharmacokinetics and pharmacodynamics: effect of renal function, dose, and gender. Clin Pharmacol Ther. 2002; 71:433-39. [PubMed 12087346]

28. The Medicines Company. Angiomax (bivalirudin) for injection prescribing information. Parsippany, NJ; 2010 Jun.

991. Anderson JL, Adams CD, Antman EM et al. 2011 ACCF/AHA Focused Update Incorporated Into the ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011; 123:e426-579.

994. Levine GN, Bates ER, Blankenship JC et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol. 2011; 58:e44-122. [PubMed 22070834]

1006. Linkins LA, Dans AL, Moores LK et al. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 Suppl):e495S-530S.

HID. Trissel LA. Handbook on injectable drugs. 14th ed; Bethesda, MD: American Society of Health-System Pharmacists; 2007:207-13.

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