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Bivalirudin

Pronunciation

(bye VAL i roo din)

Index Terms

  • Hirulog

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous:

Angiomax: 250 mg (1 ea)

Generic: 250 mg (1 ea)

Brand Names: U.S.

  • Angiomax

Pharmacologic Category

  • Anticoagulant
  • Anticoagulant, Direct Thrombin Inhibitor

Pharmacology

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.

Distribution

0.2 L/kg

Metabolism

Blood proteases

Excretion

Urine (20%), proteolytic cleavage

Onset of Action

Immediate

Duration of Action

Coagulation times return to baseline ~1 hour following discontinuation of infusion

Half-Life Elimination

Normal renal function (CrCl ≥90 mL/minute): 25 minutes

Severe renal impairment (CrCl 10 to 29 mL/minute): 57 minutes

Dialysis-dependent patients (off dialysis): 3.5 hours

Protein Binding

Plasma: Does not bind other than thrombin

Special Populations: Renal Function Impairment

Clearance is reduced about 20% in moderate to severe renal function impairment and about 80% in dialysis-dependent patients.

Use: Labeled Indications

Anticoagulant used in conjunction with aspirin for patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA) or percutaneous coronary intervention (PCI) with provisional glycoprotein IIb/IIIa inhibitor; anticoagulant used in conjunction with aspirin for patients undergoing PCI with (or at risk of) heparin-induced thrombocytopenia (HIT) / thrombosis syndrome (HITTS)

Canadian labeling: Additional uses (not in U.S. labeling): In conjunction with aspirin for treatment of patients with ST-elevation myocardial infarction (STEMI) undergoing primary PCI; anticoagulant with or without aspirin in patients undergoing cardiac surgery with (or at risk of) heparin-induced thrombocytopenia (HIT) / thrombosis syndrome (HITTS)

Use: Unlabeled

Heparin-induced thrombocytopenia (HIT); ST-elevation myocardial infarction (STEMI) undergoing primary PCI

Contraindications

Hypersensitivity to bivalirudin or any component of the formulation; active major bleeding

Canadian labeling: Additional contraindications (not in U.S. labeling): Major blood clotting disorders; acute gastric or duodenal ulcer; cerebral hemorrhage; severe cerebro-spinal trauma; bacterial endocarditis; severe uncontrolled hypertension; diabetic or hemorrhagic retinopathy; proximal use of spinal/epidural anesthesia

Dosing: Adult

Note:If clinically indicated, provisional glycoprotein (GP) IIb/IIIa inhibition (eg, abciximab, eptifibatide, tirofiban) may be concomitantly administered during percutaneous coronary intervention (PCI). In addition to aspirin, concomitant administration of clopidogrel, prasugrel, or ticagrelor is also recommended for patients undergoing PCI (ACCF/AHA/SCAI [Levine, 2011]).

PTCA/PCI with or without HIT/HITTS: IV: Initial: 0.75 mg/kg bolus immediately prior to procedure, followed by 1.75 mg/kg/hour for the duration of procedure and up to 4 hours postprocedure if needed (according to the manufacturer); may determine ACT 5 minutes after bolus dose; may administer additional bolus of 0.3 mg/kg if necessary. If continued anticoagulation is needed after the initial 4-hour postprocedure infusion, the infusion may be continued at 0.2 mg/kg/hour for up to an additional 20 hours (U.S. labeling) or 0.25 mg/kg/hour for 4 to 12 hours post procedure (Canadian labeling).

Unstable angina/non-ST-elevation myocardial infarction (UA/NSTEMI) (moderate-high risk) undergoing early invasive strategy: IV:

During PCI: 0.75 mg/kg bolus prior to procedure, followed by 1.75 mg/kg/hour (ACCF/AHA [Anderson, 2013]).

Prior to PCI (U.S. off-label dose): Alternatively, may administer an initial 0.1 mg/kg bolus prior to diagnostic angiography, followed by 0.25 mg/kg/hour. Once PCI is determined to be necessary, give an additional bolus of 0.5 mg/kg and increase infusion rate to 1.75 mg/kg/hour; may discontinue at end of procedure or continue for up to 4 hours postprocedure if necessary (Stone, 2006). If after angiography, cardiac surgery is deemed necessary, discontinue bivalirudin 3 hours prior to surgery and dose with unfractionated heparin per institutional practice. If medical management is the decided treatment approach, may either discontinue bivalirudin or continue at 0.25 mg/kg/hour for up to 72 hours (ACCF/AHA [Anderson, 2013]).

Canadian labeling: Initial: 0.1 mg/kg bolus, followed by 0.25 mg/kg/hour for up to 72 hours if patient is medically managed. If PCI is determined to be necessary, give an additional bolus of 0.5 mg/kg and increase infusion rate to 1.75 mg/kg/hour; may resume infusion at 0.25 mg/kg/hour for 4-12 hours following PCI if necessary. If coronary artery bypass graft (CABG) surgery is deemed necessary, discontinue bivalirudin infusion 1 hour prior to CABG (on-pump) surgery and dose with unfractionated heparin or continue infusion until time of CABG (off-pump) surgery then give 0.5 mg/kg bolus and increase infusion rate to 1.75 mg/kg/hour until end of surgery.

STEMI undergoing primary PCI (U.S. off-label use): IV: Initial: 0.75 mg/kg bolus, followed by 1.75 mg/kg/hour for the duration of procedure; may continue postprocedure at a reduced dose if clinically indicated (ACCF/AHA [O'Gara, 2013]; Stone, 2008). In STEMI patients who are at a high risk of bleeding, it is reasonable to use bivalirudin monotherapy in preference to the combination of unfractionated heparin and a GP IIb/IIIa receptor antagonist (ACCF/AHA [O'Gara 2013]). Of note, a single-center, open-label, randomized controlled trial comparing heparin to bivalirudin in patients with STEMI undergoing primary PCI (mostly with a radial approach) demonstrated that heparin reduces the incidence of major adverse cardiovascular events with no increase in bleeding as compared to bivalirudin (Shahzad, 2014).

If patient received unfractionated heparin (UFH) prior to procedure and bivalirudin is the desired anticoagulant: Discontinue heparin if infusing; without measurement of ACT, may initiate bivalirudin ≥30 minutes after the last UFH bolus but before PCI occurs (Stone, 2008). Switching patients from UFH to bivalirudin has been shown to be safe compared to continuing with UFH and as needed glycoprotein IIb/IIIa inhibition; median time from prerandomization UFH bolus to bivalirudin administration within the HORIZONS-AMI trial was 64 ± 61 minutes (Dangas, 2011).

Canadian labeling: Initial: 0.1 mg/kg bolus, followed by 0.25 mg/kg/hour for up to 72 hours if patient is medically managed. If PCI is determined to be necessary, give an additional bolus of 0.5 mg/kg and increase infusion rate to 1.75 mg/kg/hour; may resume infusion at 0.25 mg/kg/hour for 4-12 hours following PCI if necessary. If coronary artery bypass graft (CABG) surgery is deemed necessary, discontinue bivalirudin infusion 1 hour prior to CABG (on-pump) surgery and dose with unfractionated heparin or continue infusion until time of CABG (off-pump) surgery then give 0.5 mg/kg bolus and increase infusion rate to 1.75 mg/kg/hour until end of surgery.

Cardiac surgery in patients with acute or subacute heparin-induced thrombocytopenia, urgent surgery required: U.S. off-label use (Linkins, 2012): IV: Intraoperative:

Off-pump: Initial bolus: 0.75 mg/kg, followed by continuous infusion 1.75 mg/kg/hour to maintain ACT >300 seconds (Dyke, 2007). If patient needs to go on-pump, Canadian labeling recommends an additional 0.25 mg/kg bolus and increasing the infusion rate to 2.5 mg/kg/hour.

On-pump: Initial bolus: 1 mg/kg, followed by continuous infusion 2.5 mg/kg/hour; 50 mg bolus added to priming solution of cardiopulmonary bypass (CPB) circuit. Additional boluses of 0.1-0.5 mg/kg may be given to maintain ACT >2.5 times baseline ACT. Note: Special maneuvers needed to prevent stasis and consequent clotting within CPB circuit during or after surgery (Koster, 2007). Per Canadian labeling, after completion of CPB, provision to allow recirculation of the circuit may be done by administering 50 mg into the circuit followed by a continuous infusion of 50 mg/hour into the circuit.

Canadian labeling: Pre -and post-cardiac surgery administration: Initial bolus: 0.1 mg/kg, followed by continuous infusion 0.2 mg/kg/hour for up to 48 hours prior to surgery or for up to 14 days after surgery; maintain aPTT 1.5-2.5 times baseline aPTT.

Heparin-induced thrombocytopenia (HIT) (off-label use): IV: Initial dose: 0.15-0.2 mg/kg/hour; adjust to aPTT 1.5-2.5 times baseline value (Linkins, 2012). Note: Although the use of bivalirudin is not a currently recommended treatment for HIT due to insufficient evidence, the American College of Chest Physicians recommends overlapping administration of warfarin for a minimum of 5 days until INR is within target range; recheck INR after the non-heparin anticoagulant effect has dissipated (Linkins, 2012).

Dosing: Geriatric

Refer to adult dosing. No dosage adjustment is needed in elderly patients with normal renal function. Puncture site hemorrhage and catheterization site hemorrhage were seen in more patients ≥65 years of age than in patients <65 years of age.

Dosing: Renal Impairment

Infusion dose should be reduced based on degree of renal impairment. Initial bolus dose remains unchanged. Monitor activated coagulation time (ACT) or aPTT depending on indication.

For use in PCI:

U.S. labeling:

CrCl ≥30 mL/minute: No adjustment required.

CrCl 10-29 mL/minute: Decrease infusion rate to 1 mg/kg/hour

Dialysis-dependent patients (off dialysis during administration): Decrease infusion rate to 0.25 mg/kg/hour

Hemodialysis: Approximately 25% removed during hemodialysis

Canadian labeling: Note: Check ACT following dose alterations at 5 and 45 minutes in renally impaired patients. If ACT ≤250 seconds give additional bolus 0.3 mg/kg and double infusion rate to maintain ACT ~350 seconds; if ACT 250-300 seconds give additional bolus 0.3 mg/kg to maintain ACT ~350 seconds.

CrCl ≥30 mL/minute: No adjustment required.

CrCl 10-29 mL/minute: Decrease infusion rate to 1 mg/kg/hour

Dialysis-dependent patients (off dialysis during administration): Decrease infusion rate to 0.25 mg/kg/hour

For use in cardiac surgery:

Canadian labeling:

CrCl ≥30 mL/minute: No adjustment required; monitor ACT.

CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling; has not been studied; monitor ACT.

For use in HIT: There are no dosage adjustments provided in the manufacturer’s labeling for this population; however, the following dose ranges have been observed in small retrospective observational studies (Kiser 2006; Kiser, 2008; Tsu, 2011). Of note, critically-ill patients comprised a significant proportion of patients in these observational studies. The following dose recommendations are based on the mean dose achieving aPTT goal within these studies; overlaps may exist; Note: The Cockcroft-Gault equation was used in all studies to define creatinine clearance:

CrCl >60 mL/minute: 0.13 mg/kg/hour

CrCl 30-60 mL/minute: 0.08-0.1 mg/kg/hour

CrCl <30 mL/minute: 0.04-0.05 mg/kg/hour

Intermittent hemodialysis (IHD): 0.07 mg/kg/hour (Tsu, 2011)

CRRT (eg, CVVH or CVVHDF): 0.03-0.07 mg/kg/hour (Kiser, 2006; Tsu, 2011)

Sustained low-efficiency daily diafiltration (SLEDD): 0.09 mg/kg/hour (Tsu, 2011)

Dosing: Hepatic Impairment

No dosage adjustment necessary.

Reconstitution

Reconstitute each 250 mg with 5 mL SWFI. Gently swirl to dissolve. Further dilution in D5W or NS (50 mL to make 5 mg/mL solution or 500 mL to make 0.5 mg/mL solution) is required prior to infusion.

Administration

For IV administration only.

Compatibility

Stable in D5W, NS, SWFI

Y-site administration: Incompatible: Alteplase, amiodarone, amphotericin B, chlorpromazine, diazepam, prochlorperazine, reteplase, vancomycin.

Compatibility in syringe: Incompatible with ceftriaxone.

Storage

Store unopened vials at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C. Following reconstitution, vials should be stored at 2°C to 8°C for up to 24 hours. Do not freeze. Final dilutions of 0.5 mg/mL or 5 mg/mL are stable at room temperature for up to 24 hours.

Drug Interactions

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Apixaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to Lexi-Drugs full drug monograph content regarding use of apixaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Avoid combination

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. Monitor therapy

Dabigatran Etexilate: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to Lexi-Drugs full drug monograph content regarding use of dabigatran etexilate with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Avoid combination

Dasatinib: May enhance the anticoagulant effect of Anticoagulants. 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. Monitor therapy

Deoxycholic Acid: Anticoagulants may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Monitor therapy

Desirudin: Anticoagulants may enhance the anticoagulant effect of Desirudin. Consider therapy modification

Edoxaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to Lexi-Drugs 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. Avoid combination

Estrogen Derivatives: May diminish the anticoagulant effect of Anticoagulants. More specifically, the potential prothrombotic effects of some estrogens and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of estrogens against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Exceptions: Tibolone. Consider therapy modification

Hemin: May enhance the anticoagulant effect of Anticoagulants. Avoid combination

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Consider therapy modification

Ibritumomab: Anticoagulants may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to an increased risk of bleeding. Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Anticoagulants. Monitor therapy

Limaprost: May enhance the adverse/toxic effect of Anticoagulants. The risk for bleeding may be increased. Monitor therapy

Nintedanib: Anticoagulants may enhance the adverse/toxic effect of Nintedanib. Specifically, the risk for bleeding may be increased. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Obinutuzumab: Anticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. 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. Avoid combination

Omega-3 Fatty Acids: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Pentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Progestins: May diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of progestins against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Consider therapy modification

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. Monitor therapy

Rivaroxaban: Anticoagulants may enhance the anticoagulant effect of Rivaroxaban. Refer to separate drug interaction content and to Lexi-Drugs full drug monograph content regarding use of rivaroxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Avoid combination

Salicylates: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Sugammadex: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Thrombolytic Agents: May enhance the anticoagulant effect of Anticoagulants. Management: See full drug monograph for guidelines for the use of alteplase for acute ischemic stroke during treatment with oral anticoagulants. Monitor therapy

Tibolone: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Tipranavir: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Tositumomab and Iodine I 131 Tositumomab: Anticoagulants may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse effects may be increased. Monitor therapy

Urokinase: May enhance the anticoagulant effect of Anticoagulants. Avoid combination

Vitamin E: May enhance the anticoagulant effect of Anticoagulants. Vitamin E may also increase the overall risk for bleeding. Monitor therapy

Vitamin E (Oral): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Anticoagulants may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Vorapaxar: May enhance the adverse/toxic effect of Anticoagulants. More specifically, this combination is expected to increase the risk of bleeding. Avoid combination

Test Interactions

PT/INR levels may become elevated in the absence of warfarin. If warfarin is initiated, initial PT/INR goals while on bivalirudin may require modification.

Adverse Reactions

As with all anticoagulants, bleeding is the major adverse effect of bivalirudin. Hemorrhage may occur at virtually any site. Risk is dependent on multiple variables, including the intensity of anticoagulation, concurrent use of a glycoprotein IIb/IIIa inhibitor, and patient susceptibility. Additional adverse effects are often related to idiosyncratic reactions, and the frequency is difficult to estimate. Adverse reactions reported were generally less than those seen with heparin.

>10%:

Cardiovascular: Hypotension (≤12%)

Central nervous system: Pain (≤15%), headache (≤12%)

Gastrointestinal: Nausea (≤15%)

Hematologic & oncologic: Minor hemorrhage (Protocol defined: 14%; heparin 26%; TIMI defined: 1%; heparin 3% [Lincoff, 2003])

Neuromuscular & skeletal: Back pain (9% to 42%)

1% to 10%:

Cardiovascular: Hypertension (6%), bradycardia (5%), angina pectoris (≤5%), thrombosis (1%; <4 hours, in patients with STEMI undergoing primary PCI)

Central nervous system: Insomnia (7%), anxiety (6%), nervousness (5%)

Gastrointestinal: Vomiting (≤6%), abdominal pain (5%), dyspepsia (5%)

Genitourinary: Pelvic pain (6%), urinary retention (4%)

Hematologic & oncologic: Major hemorrhage (Protocol defined: 2% to 4%; heparin 4% to 9%; TIMI defined: 0.6%; heparin 0.9%; transfusion required: 1% to 2%; heparin 2% to 6% [Lincoff, 2003])

Local: Pain at injection site (≤8%)

Miscellaneous: Fever (5%)

<1% (Limited to important or life-threatening): Cardiac tamponade, cerebral ischemia, confusion, facial paralysis, hemorrhage (fatal), hypersensitivity reaction (including anaphylaxis), increased INR, increased susceptibility to infection, intracranial hemorrhage, oliguria, pulmonary edema, pulmonary hemorrhage, renal failure, retroperitoneal hemorrhage, sepsis, syncope, thrombocytopenia, vascular disease, venous thrombosis (during PCI, including intracoronary brachytherapy), ventricular fibrillation

Warnings/Precautions

Concerns related to adverse effects:

• 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 thrombus formation (some fatal) has been reported with use in gamma brachytherapy.

Disease-related concerns:

• Angina/ACS: Safety and efficacy have not been established in patients with unstable angina or acute coronary syndromes who are not undergoing PTCA or PCI.

• Renal impairment: Use with caution in patients with renal impairment; dosage reduction required.

Other warnings/precautions:

• Intramuscular administration: Not for intramuscular (IM) use.

Monitoring Parameters

Depends upon indication for use of bivalirudin: ACT or aPTT

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies. 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).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, back pain, or pain. Have patient report immediately to prescriber signs of bleeding (vomiting blood or vomit that looks like coffee grounds, coughing up blood, blood in the urine, black, red, or tarry stools, bleeding from the gums, abnormal vaginal bleeding, bruises without a reason or that get bigger, or any bleeding that is very bad or that will not stop), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), severe dizziness, passing out, crash or fall that hit head, or severe headache (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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