Bivalirudin (Systemic)

VA CLASSIFICATION
Primary: BL119

Commonly used brand name(s): Angiomax.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Anticoagulant—

Indications

Accepted

Angina pectoris, unstable (treatment)—Bivalirudin is indicated for use as an anticoagulant^{02} in patients with unstable angina who are undergoing percutaneous transluminal coronary angioplasty (PTCA). Intended for use with aspirin.^{01}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    2180 daltons^{01}


pH
    Reconstituted solution: 5 to 6 .^{01}

Mechanism of action/Effect:

A highly specific inhibitor of the thrombogenic activity of thrombin; specifically binds to both circulating and clot bound thrombin.^{01}

Protein binding:

With the exception of thrombin, bivalirudin does not bind to plasma proteins.^{01}

Biotransformation:

Cleared from plasma by proteolytic cleavage.^{01}

Half-life:

Normal renal function (glomerular filtration rate [GFR] ³ 90 mL per minute [mL/minute])—25 minutes.^{01}

Mild renal function impairment (GFR 60 to 90 mL/minute)—22 minutes.^{01}

Moderate renal function impairment (GFR 30 to 59 mL/minute)—34 minutes.^{01}

Severe renal function impairment (GFR 10 to 29 mL per minute)—57 minutes.^{01}

Dialysis-dependent patients (off-dialysis)—3.5 hours.^{01}

Onset of action:

Immediately following intravenous administration.^{01}

Duration of action:

Approximately 1 hour.^{01}

Elimination:
    Renal; related to glomerular filtration rate (GFR).^{01}


In dialysis—
        Hemodialyzable; approximately 25% cleared by hemodialysis.^{01}



Precautions to Consider

Carcinogenicity

Long-term studies in animals have not been done.^{01}

Mutagenicity

Bivalirudin was not found to be genotoxic in the Ames test, Chinese hamster ovary cell forward gene mutation test, human lymphocyte chromosomal aberration test, the rat hepatocyte unscheduled DNA synthesis (UDS) assay, and the rat micronucleus assay.^{01}

Pregnancy/Reproduction
Fertility—
Adequate and well controlled studies in humans have not been done. Studies in rats given subcutaneous doses up to 150 mg per kg of body weight (mg/kg) per day (1.6 times the maximum recommended human dose on a body surface area basis [mg/m ²]) showed no effect on fertility and general reproductive performance.^{01}

Pregnancy—
Adequate and well-controlled studies in humans have not been done. Teratogenicity studies in rats given subcutaneous doses up to 150 mg/kg per day (1.6 times the maximum recommended human dose based on body surface area) and rabbits given subcutaneous doses up to 150 mg/kg per day (3.2 times the maximum recommended human dose based on body surface area) revealed no evidence of harm to the fetus that was attributable to bivalirudin.^{01}

Bivalirudin is intended for use with aspirin. Because of possible adverse effects on the neonate and the potential for increased maternal bleeding, especially during the third trimester, bivalirudin and aspirin should be used together during pregnancy only if clearly needed.^{01}

FDA Pregnancy Category B.^{01}

Breast-feeding

It is not known whether bivalirudin is distributed into human breast milk.^{01}

Pediatrics

No information is available on the relationship of age to the effects of bivalirudin in the pediatric population. Safety and efficacy in pediatric patients have not been established.^{01}


Geriatrics


Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of bivalirudin in the elderly.^{02}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Drug interaction studies have been conducted with the adenosine diphosphate (ADP) antagonist, ticlopidine, and the glycoprotein IIb/IIa inhibitor, abciximab, and with low molecular weight heparin. Data is limited, but the results do not suggest any pharmacodynamic interactions. ^{01}

» Heparin^{01} or
» Warfarin^{01} or
» Thrombolytic agents^{01}    (concurrent use with bivalirudin may increase the risk of major bleeding^{01})


Platelet inhibitors, excluding aspirin^{01}    (safety and efficacy of concurrent use of bivalirudin with platelet inhibitors other than aspirin have not been established^{01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Active major bleeding^{01}
» Hypersensitivity to bivalirudin or its components^{01}
Risk-benefit should be considered when the following medical problems exist
» Conditions associated with a possible increased risk of bleeding^{01}    (caution is recommended^{01})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Activated clotting time (ACT)^{01}    (periodic monitoring recommended in patients with renal function impairment^{01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Bradycardia ( slow or irregular heartbeat ; light-headedness ; dizziness or fainting ; unusual tiredness )^{01}
    
hypertension (blurred vision; dizziness severe or continuing ; dull nervousness ; headache; pounding in the ears; slow or fast heartbeat )^{01}
    
hypotension (blurred vision; confusion ; dizziness; faintness; light-headedness when getting up from a lying or sitting position; sudden sweating; unusual tiredness or weakness)^{01}

Incidence less frequent
    
Hemorrhage, major ^{01}

Note: During clinical trials, major hemorrhage was defined as clincally overt bleeding with a decrease in hemoglobin ³ 3 grams per dL or leading to a transfusion of 2 or more units of blood, intracranial bleeding, or retroperitoneal bleeding.^{01}


Incidence rare
    
Cerebral ischemia ^{01}
    
facial paralysis ^{01}
    
fever ^{01}
    
infection ^{01}
    
lung edema ^{01}
    
oliguria ^{01}
    
renal failure ^{01}
    
sepsis ^{01}
    
vascular anomaly ^{01}
    
ventricular fibrillation ^{01}



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Abdominal pain ^{01}
    
anxiety ^{01}
    
back pain ^{01}
    
dyspepsia (acid or sour stomach ; belching ; heartburn ; indigestion ; stomach discomfort upset or pain)^{01}
    
headache ^{01}
    
injection site pain ^{01}
    
insomnia ( sleeplessness ; trouble sleeping; unable to sleep)^{01}
    
nausea ^{01}
    
nervousness ^{01}
    
pain ^{01}
    
pelvic pain ^{01}
    
urinary retention (painful or difficult urination)^{01}
    
vomiting ^{01}

Incidence rare
    
Confusion ^{01}





Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Treatment of overdose
There is no known antidote to bivalirudin. Bivalirudin is hemodialyzable. Discontinuation leads to a gradual reduction in the anticoagulant effects due to metabolism of the drug.^{01}

In the case of overdosage, bivalirudin should be stopped immediately and the patient should be carefully monitored for any signs of bleeding.^{01}



General Dosing Information
Bivalirudin is not intended for intramuscular administration. Although most bleeding occurs at the site of arterial puncture, hemorrhage can occur at any site. An unexplained fall in blood pressure or hematocrit, or any unexplained symptom, should lead to serious consideration of a hemorrhagic event and cessation of bivalirudin administration.^{01}

Bivalirudin should be administered via an intravenous line just prior to percutaneous transluminal coronary angioplasty (PTCA) and should be used in conjunction with 300 to 325 mg of aspirin per day.^{01}


Parenteral Dosage Forms

BIVALIRUDIN FOR INJECTION

Usual Adult Dose
Anticoagulant
Intravenous, direct, initially 1 mg per kg of body weight followed by a four-hour intravenous infusion at a rate of 2.5 mg per kg of body weight per hour. After completion of the initial four-hour infusion, if needed, an additional infusion may be initiated at a rate of 0.2 mg per kg of body weight per hour and may be continued for up to twenty hours.^{01}

Note: The dose of the intravenous infusion should be reduced by 20% in patients with moderate renal function impairment (glomerular filtration rate [GFR] 30 to 59 mL per minute), by 60% in patients with severe renal function impairment (GFR 10 to 29 mL per minute), and by 90% in dialysis-dependent patients.^{01}
For more detailed infusion-rate guidelines, consult the manufacturer's labeling.


^{01}
Usual Pediatric Dose
Safety and efficacy have not been established.^{01}
{01}
Usual Geriatric Dose
See Usual adult dose.
^{01}
Size(s) usually available:
U.S.—


250 mg per vial (Rx) [Angiomax ( mannitol 125 mg) (sodium hydroxide)]^{01}

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F).^{01} Protect the reconstituted and diluted solutions from freezing.^{01}

Preparation of dosage form:
Initial intravenous infusion—To each 250-mg vial add 5 mL of Sterile Water for Injection, USP. Gently swirl until all material is dissolved. Each reconstituted vial should be further diluted in 50 mL of 5% dextrose injection or 0.9% sodium chloride injection to yield a final concentration of 5 mg per mL^{01}.

Low rate intravenous infusion (used after the initial intravenous infusion)—Reconstitute the 250-mg vial with 5 mL of Sterile Water for Injection, USP. Gently swirl until all material is dissolved. Each reconstituted vial should be further diluted in 500 mL of 5% dextrose injection or 0.9% sodium chloride injection to yield a final concentration of 0.5 mg per mL. ^{01}

Stability:
The reconstituted solution is stable for up to 24 hours when stored at a temperature between 2 and 8 °C (36 and 46 °F).^{01} The diluted solution is stable for up to 24 hours when stored at room temperature.^{01}

Incompatibilities:
Glass bottles and polyvinyl chloride bags and administration sets have not been found to be incompatible with bivalirudin.^{01}

It is recommended that bivalirudin, after reconstitution or dilution, be administered by itself through a separate line without mixing with other medications.^{01}

Additional information:
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.^{01}

Reconstituted material will be a clear to slightly opalescent, colorless to slightly yellow solution.^{01}

Developed: 01/29/2001
Revised: 04/20/2001

References

1. Product Information: Angiomax ™, bivalirudin. ICS, Louisville, KY, (PI revised 12/2000) reviewed 01/2001.
   

2. Manufacturer comment, 03/16/2001.