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Argatroban

Pronunciation

Pronunciation

(ar GA troh ban)

Dosage Forms

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

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Solution, Intravenous:

Generic: 125 mg/125 mL (125 mL); 250 mg/250 mL (250 mL); 250 mg/2.5 mL (2.5 mL)

Solution, Intravenous [preservative free]:

Generic: 50 mg/50 mL (50 mL); 250 mg/2.5 mL (2.5 mL)

Pharmacologic Category

  • Anticoagulant
  • Anticoagulant, Direct Thrombin Inhibitor

Pharmacology

A direct, highly-selective thrombin inhibitor. Reversibly binds to the active thrombin site of free and clot-associated thrombin. Inhibits fibrin formation; activation of coagulation factors V, VIII, and XIII; activation of protein C; and platelet aggregation.

Distribution

174 mL/kg

Metabolism

Hepatic via hydroxylation and aromatization (major route). Metabolism via CYP3A4/5 (minor route) to four known metabolites. Unchanged argatroban is the major plasma component. Plasma concentration of metabolite M1 is 0% to 20% of the parent drug and is three- to fivefold weaker.

Excretion

Feces (65%; 14% unchanged); urine (22%; 16% unchanged); low quantities of metabolites M2-4 in urine

Clearance:

Pediatric patients (seriously ill): 0.16 L/kg/hour; 50% lower than healthy adults

Pediatric patients (seriously ill with elevated bilirubin due to hepatic impairment or cardiac complications; n=4): 0.03 L/kg/hour; 80% lower than pediatric patients with normal bilirubin

Adult: 0.31 L/kg/hour (5.1 mL/kg/minute); hepatic impairment: 1.9 mL/kg/minute

Onset of Action

Immediate

Time to Peak

Steady-state: 1-3 hours

Half-Life Elimination

39-51 minutes; Hepatic impairment: ≤181 minutes

Protein Binding

Albumin: 20%; alpha1-acid glycoprotein: 35%

Use: Labeled Indications

Heparin-induced thrombocytopenia: Prophylaxis or treatment of thrombosis in adult patients with heparin-induced thrombocytopenia (HIT)

Percutaneous coronary intervention: As an anticoagulant for percutaneous coronary intervention (PCI) in adult patients who have or are at risk of developing HIT

Use: Unlabeled

To maintain extracorporeal circuit patency (prefilter administration) of continuous renal replacement therapy (CRRT) in critically-ill patients with HIT

Contraindications

Hypersensitivity to argatroban or any component of the formulation; major bleeding

Dosage

IV:

Children: Heparin-induced thrombocytopenia (HIT) (dosing based on limited data from critically-ill patients):

Initial dose: 0.75 mcg/kg/minute

Maintenance dose: Patient may not be at steady-state but measure aPTT after 2 hours; adjust dose until the steady-state aPTT is 1.5 to 3 times the initial baseline value, not exceeding 100 seconds; dosage may be adjusted in increments of 0.1 to 0.25 mcg/kg/minute. Note: Frequent dosage adjustments may be required to maintain desired anticoagulant activity.

Adults:

Heparin-induced thrombocytopenia (HIT):

Initial dose: 2 mcg/kg/minute

Obesity: Pharmacokinetics and pharmacodynamics have not been evaluated prospectively in obese patients; however, retrospective data suggest using actual body weight to dose and that adjustment of initial dose is unnecessary in obesity (BMI up to 51 kg/m2) (Rice, 2007).

Maintenance dose: Patient may not be at steady-state but measure aPTT after 2 hours; adjust dose until the steady-state aPTT is 1.5 to 3 times the initial baseline value, not exceeding 100 seconds; dosage should not exceed 10 mcg/kg/minute

Note: Critically-ill patients with normal hepatic function have become excessively anticoagulated with FDA-approved or lower starting doses of argatroban. Doses between 0.15 to 1.3 mcg/kg/minute were required to maintain aPTTs in the target range (Reichert, 2003). In a prospective observational study of critically-ill patients with multiple organ dysfunction (MODS) and suspected or proven HIT, an initial infusion dose of 0.2 mcg/kg/minute was found to be sufficient and safe in this population (Beiderlinden, 2007). Consider reducing starting dose to 0.2 mcg/kg/minute in critically-ill patients with MODS defined as a minimum number of two organ failures. Another report of a cardiac patient with anasarca secondary to acute renal failure had a reduction in argatroban clearance similar to patients with hepatic dysfunction. Reduced clearance may have been due to reduced liver perfusion (de Denus, 2003). The American College of Chest Physicians has recommended an initial infusion rate of 0.5 to 1.2 mcg/kg/minute for patients with heart failure, MODS, severe anasarca, or postcardiac surgery (Linkins, 2012).

Conversion to oral anticoagulant: Because there may be a combined effect on the INR when argatroban is combined with warfarin, loading doses of warfarin should not be used. Warfarin therapy should be started at the expected daily dose.

Patients receiving ≤2 mcg/kg/minute of argatroban: Argatroban therapy can be stopped when the INR is >4 on combined warfarin and argatroban therapy; repeat INR measurement in 4 to 6 hours; if INR is below therapeutic level, argatroban therapy may be restarted. Repeat procedure daily until desired INR on warfarin alone is obtained.

Patients receiving >2 mcg/kg/minute of argatroban: In order to predict the INR on warfarin alone, reduce dose of argatroban to 2 mcg/kg/minute; measure INR for argatroban and warfarin 4 to 6 hours after dose reduction; argatroban therapy can be stopped when the INR on warfarin and argatroban combined therapy is >4. Repeat INR measurement in 4 to 6 hours; if INR is below therapeutic level, argatroban therapy may be restarted. Repeat procedure daily until desired INR on warfarin alone is obtained.

Note: The American College of Chest Physicians suggests monitoring chromogenic factor X assay when transitioning from argatroban to warfarin (Garcia, 2012) or overlapping administration of warfarin for a minimum of 5 days until INR is within target range; recheck INR after anticoagulant effect of argatroban has dissipated (Guyatt, 2012). Factor X levels <45% have been associated with INR values >2 after the effects of argatroban have been eliminated (Arpino, 2005).

Prefilter administration for continuous renal replacement therapy (CRRT) in critically-ill patients with HIT (off-label use; Link, 2009): 0.1 to 1.5 mcg/kg/minute. Note: Loading dose of 100 mcg/kg was administered during clinical trial; however, this may be unnecessary.

Percutaneous coronary intervention (PCI):

Initial: Begin infusion of 25 mcg/kg/minute and administer bolus dose of 350 mcg/kg (over 3 to 5 minutes). ACT should be checked 5 to 10 minutes after bolus infusion; proceed with procedure if ACT >300 seconds.

Obesity: Pharmacokinetics and pharmacodynamics have not been evaluated prospectively in obese patients; however, retrospective data suggest using actual body weight to dose and that adjustment of initial dose is unnecessary in obesity (BMI up to 51 kg/m2) (Hursting, 2008).

Following initial bolus:

ACT <300 seconds: Give an additional 150 mcg/kg bolus, and increase infusion rate to 30 mcg/kg/minute (recheck ACT in 5 to 10 minutes)

ACT >450 seconds: Decrease infusion rate to 15 mcg/kg/minute (recheck ACT in 5 to 10 minutes)

Once a therapeutic ACT (300 to 450 seconds) is achieved, infusion should be continued at this dose for the duration of the procedure.

If dissection, impending abrupt closure, thrombus formation during PCI, or inability to achieve ACT >300 seconds: An additional bolus of 150 mcg/kg, followed by an increase in infusion rate to 40 mcg/kg/minute may be administered.

Note: Post-PCI anticoagulation, if required, may be achieved by continuing infusion at a reduced dose of 2 mcg/kg/minute with close monitoring of aPTT; adjust infusion rate as needed.

Elderly: No initial dose adjustment is necessary for elderly patients with normal liver function

Dosage adjustment in renal impairment: Removal during hemodialysis and continuous venovenous hemofiltration is clinically insignificant (Tang, 2005). No dosage adjustment necessary.

Dosage adjustment in hepatic impairment: Decreased clearance and increased elimination half-life are seen with hepatic impairment; dose reduction and careful titration are required.

Children: Initial dose: 0.2 mcg/kg/minute; adjust dose in increments of ≤0.05 mcg/kg/minute

Adults: Per manufacturer labeling, the initial dose for moderate-to-severe hepatic impairment (Child-Pugh classes B and C) is 0.5 mcg/kg/minute; monitor aPTT closely and adjust dose as necessary. However, patients with severe hepatic impairment (Child-Pugh class C) may require further reduction of the initial dose. One case report describes a dose of 0.05 mcg/kg/minute required to maintain a stable, therapeutic aPTT in a patient with severe hepatic impairment (Yarbrough, 2012). Note: During PCI, avoid use in patients with elevations of ALT/AST (≥3 times ULN); the use of argatroban in these patients has not been evaluated.

Reconstitution

Vials for injection, 2.5 mL (100 mg/mL) concentrate: Prior to administration, each vial must be diluted to a final concentration of 1 mg/mL. Solution may be mixed with sodium chloride 0.9% injection, dextrose 5% injection, or lactated Ringer's injection. Do not mix with other medications prior to dilution. To prepare solution for IV administration, dilute each 250 mg vial with 250 mL of diluent or dilute 500 mg per 500 mL of diluent. Mix by repeated inversion for 1 minute. A slight but brief haziness may occur upon mixing; use of diluent at room temperature is recommended.

Premixed vials (50 mL or 125 mL) and single-use bags for infusion (1 mg/mL): No further dilution is required.

Administration

The 2.5 mL (100 mg/mL) concentrated vial must be diluted to 1 mg/mL prior to administration. The premixed 50 mL or 125 mL vials and 250 mL bag (1 mg/mL) require no further dilution. The premixed 1 mg/mL vial may be inverted for use with an infusion set.

Administer bolus dose over 3 to 5 minutes through a large bore intravenous line.

Compatibility

Stable in D5W, LR, NS

Storage

Vials for injection, 2.5 mL (100 mg/mL) concentrate: Prior to use, store vial in original carton at 25°C (77°F); excursions permitted to 15ºC to 30º C (59ºF to 86°F). Do not freeze. Retain in the original carton to protect from light. The diluted, prepared solution is stable for 24 hours at 20°C to 25°C (68°F to 77°F) in ambient indoor light. Do not expose to direct sunlight. Prepared solutions that are protected from light and kept at 20°C to 25°C (68°F to 77°F) or under refrigeration at 2°C to 8°C (36°F to 46°F) are stable for up to 96 hours.

Premixed vials (50 mL or 125 mL) and single-use bags for infusion (1 mg/mL): Store at 20°C to 25°C (68°F to 77°F). Do not freeze. Protect from light.

Drug Interactions

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

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

Apixaban: May enhance the anticoagulant effect of Anticoagulants. 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. 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

Edoxaban: May enhance the anticoagulant effect of Anticoagulants. 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. 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

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

Argatroban may elevate PT/INR levels in the absence of warfarin. If warfarin is started, initial PT/INR goals while on argatroban may require modification. The American College of Chest Physicians suggests monitoring chromogenic factor X assay when transitioning from argatroban to warfarin (Garcia, 2012) or overlapping administration of warfarin for a minimum of 5 days until INR is within target range; recheck INR after anticoagulant effect of argatroban has dissipated (Guyatt, 2012). Factor Xa levels <45% have been associated with INR values >2 after the effects of argatroban have been eliminated (Arpino, 2005).

Adverse Reactions

As with all anticoagulants, bleeding is the major adverse effect of argatroban. Hemorrhage may occur at virtually any site. Risk is dependent on multiple variables, including the intensity of anticoagulation and patient susceptibility.

>10%:

Cardiovascular: Chest pain (PCI related: <1% to 15%), hypotension (7% to 11%)

Genitourinary: Genitourinary tract hemorrhage (including hematuria; major: <1%; minor: 2% to 12%)

1% to 10%:

Cardiovascular: Vasodilation (1% to 10%), cardiac arrest (6%), bradycardia (5%), ventricular tachycardia (5%), myocardial infarction (PCI: 4%), angina pectoris (2%), coronary occlusion (2%), ischemic heart disease (2%), thrombosis (<1% to 2%)

Central nervous system: Headache (5%), pain (5%), intracranial hemorrhage (1% to 4%)

Dermatologic: Dermatological reaction (bullous eruption, rash; 1% to <10%)

Gastrointestinal: Nausea (5% to 7%), diarrhea (6%), vomiting (4% to 6%), abdominal pain (3% to 4%), gastrointestinal hemorrhage (major: <1% to 3%; minor: 3%)

Hematologic & oncologic: Decreased hematocrit (minor: ≤10%; major: <1%), decreased hemoglobin (minor: ≤10%; major: <1%; ≥2g/dl), groin bleeding (5%), brachial bleeding (2%), minor hemorrhage (CABG related: 2%)

Neuromuscular & skeletal: Back pain (PCI related: 8%)

Respiratory: Dyspnea (10%), cough (3% to 10%), hemoptysis (minor: ≤1% to 3%)

Miscellaneous: Fever (<1% to 7%)

<1% (Limited to important or life-threatening): Aortic valve stenosis, bleeding at injection site (or access site; minor), hypersensitivity reaction, local hemorrhage (limb and below-the-knee stump), pulmonary edema, retroperitoneal bleeding

Warnings/Precautions

Concerns related to adverse effects:

• Bleeding: The most common complication is bleeding and can occur at any site in the body. Use with extreme caution in disease states and other circumstances in which there is an increased danger of bleeding (eg, hematologic conditions associated with increased bleeding tendencies such as congenital or acquired bleeding disorders and GI lesions such as ulcerations; recent puncture of large vessels or organ biopsy; spinal anesthesia or immediately following lumbar puncture; recent CVA, stroke, intracerebral surgery, or other neuraxial procedure; severe hypertension; renal impairment; recent major surgery; recent major bleeding (intracranial, GI, intraocular, or pulmonary). Monitor for signs and symptoms of bleeding.

• Hypersensitivity: Airway, skin, and generalized hypersensitivity reactions have been reported.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment; may require >4 hours to achieve full reversal of argatroban's anticoagulant effect following treatment. Avoid use during PCI in patients with clinically significant hepatic disease or elevations of ALT/AST (≥3 times ULN); use in these patients has not been evaluated.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Critically-ill patients: Use with caution in critically-ill patients; reduced clearance may require dosage reduction.

• Pediatric: Limited pharmacokinetic and dosing information is available following use in critically-ill children with heparin-induced thrombocytopenia (HIT).

Monitoring Parameters

Monitor hemoglobin, hematocrit, signs and symptoms of bleeding.

HIT: Obtain baseline aPTT prior to start of therapy. Patient may not be at steady-state but check aPTT 2 hours after start of therapy to adjust dose, keeping the steady-state aPTT 1.5 to 3 times the initial baseline value (not exceeding 100 seconds).

PCI: Monitor ACT before dosing, 5 to 10 minutes after bolus dosing, and after any change in infusion rate and at the end of the procedure. Additional ACT assessments should be made every 20 to 30 minutes during extended PCI procedures.

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies. Information related to argatroban in pregnancy is limited. 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 diarrhea, nausea, back pain, headache, or injection site hemorrhaging (mild). Have patient report immediately to prescriber signs of hemorrhaging, severe dizziness, syncope, angina, arrhythmia, strength differences from one side to another, difficulty speaking or thinking, change in balance, blurred vision, considerable headache, groin or pelvic pain or edema, dyspnea, or flushing (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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