Argatroban

Argatroban is injected into a vein through an IV. You will receive this injection in a clinic or hospital setting. Argatroban is sometimes given together with aspirin.

If you are receiving this injection during an angioplasty procedure, the medicine will be given throughout the entire procedure and for up to 24 hours after the procedure.

Argatroban is given around the clock until your blood coagulates properly. Your doctor will test your blood often to determine how long to treat you with argatroban.

To be sure this medicine is helping your condition and is not causing harmful effects, your blood will need to be tested often. Visit your doctor regularly.

Because argatroban keeps your blood from coagulating (clotting) to prevent unwanted blood clots, it can also make it easier for you to bleed, even from a minor injury. Contact your doctor or seek emergency medical attention if you have bleeding that will not stop.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Since argatroban is given by a healthcare professional, you are not likely to miss a dose.

>10%

GI bleeding (14%)

Hematuria (12%)

1-10%

Chest pain (1-15%)

Hemoglobin and hematocrit decrease (10%)

Hypotension (7-10%)

Dyspnea (8%)

Fever (7%)

Sepsis (6%)

Cardiac arrest (6%)

Diarrhea (6%)

Nausea (5%)

Groin hemorrhage (5%)

Pain (5%)

Urinary tract infection (5%)

Ventricular tachycardia (5%)

Bradyarrhythmia (4.5%)

Infection (4%)

Vomiting (2.6-4%)

Intracranial hemorrhage (1-4%)

Myocardial infarction (3.5%)

Hemoptysis (3%)

Nephrotoxicity (3%)

Cough (3%)

Atrial fibrillation (3%)

Brachial hemorrhage (2%)

Major GI hemorrhage (1-2%)

Angina (1.8%)

Coronary arterial hemorrhage (1.8%)

Coronary artery thrombosis (1.8%)

Frequency Not Defined

Minor hematuria

Pulmonary edema

Argatroban is an anticoagulant (thrombin inhibitor) that helps prevent the formation of blood clots.

Argatroban is used to treat or prevent blood clots in people who have thrombocytopenia (low levels of platelets in the blood) caused by using heparin. Argatroban is sometimes used in people who are undergoing a procedure called angioplasty (to open blocked arteries).

Argatroban may also be used for purposes not listed in this medication guide.

Anticoagulant; synthetic piperidinecarboxylic acid derivative of l-arginine.1 2 3 6

Absorption

Onset

Immediate anticoagulant effect.1 Steady-state anticoagulant effect achieved 1–3 hours after start of infusion.1 3 6 9

Duration

The aPTT generally returns to normal within 2–4 hours following discontinuance of infusion.1 3

Special Populations

In patients with hepatic impairment, reversal of anticoagulant effect may take >4 hours.1

Distribution

Extent

Mainly in extracellular fluid as evidenced by apparent steady-state volume of distribution of 174 mL/kg.1 21 Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

54% (20% to albumin and 34% to α1-acid glycoprotein).1

Elimination

Metabolism

Mainly hepatic hydroxylation and aromatization.1 CYP isoenzymes 3A4/5 catalyze the formation of metabolites in vitro; CYP3A4/5-mediated metabolism not an important elimination pathway in vivo.1

Elimination Route

Excreted primarily in feces (65%), presumably through biliary secretion.1 Also eliminated in urine (22%).1 Partially removed by hemodialysis.1

Half-life

Terminal half-life 39–51 minutes.1 2

Special Populations

Hepatic impairment associated with decreased clearance and increased elimination half-life (to 1.9 mL/kg per minute and 181 minutes, respectively, in patients with Child-Pugh score >6).1 21 Clearance is decreased fourfold in patients with HIT and moderate hepatic impairment.1 3 (See Hepatic Impairment under Cautions.)

No appreciable effects of gender on the pharmacokinetics or pharmacodynamics of argatroban.1

In seriously ill pediatric patients, clearance was reduced by 50%.1 9 Clearance was reduced approximately 80% in pediatric patients with elevated bilirubin concentrations.1 9

Preparation for Intravenous Administration

Argatroban Injection must be diluted 100-fold prior to infusion. Argatroban Injection should not be mixed with other drugs prior to dilution.

Argatroban Injection should be diluted in 0.9% Sodium Chloride Injection, 5% Dextrose Injection, or Lactated Ringer's Injection to a final concentration of 1 mg/mL. The contents of each 2.5-mL vial should be diluted 100-fold by mixing with 250 mL of diluent. Use 250 mg (2.5 mL) per 250 mL of diluent or 500 mg (5 mL) per 500 mL of diluent.

The constituted solution must be mixed by repeated inversion of the diluent bag for 1 minute. Upon preparation, the solution may show slight but brief haziness due to the formation of microprecipitates that rapidly dissolve upon mixing. Use of diluent at room temperature is recommended. Colder temperatures can slow down the rate of dissolution of precipitates. The final solution must be clear before use. The pH of the intravenous solution prepared as recommended is 3.2 to 7.5. Solutions prepared as recommended are stable at controlled room temperature, 20°C to 25°C (68°F to 77°F) (see USP) in ambient indoor light for 24 hours; therefore, light-resistant measures such as foil protection for intravenous lines are unnecessary. Solutions are physically and chemically stable for up to 96 hours when protected from light and stored at controlled room temperature, 20°C to 25°C (68°F to 77°F) (see USP), or at refrigerated conditions, 5°C ± 3°C (41°F ± 5°F). Prepared solutions should not be exposed to direct sunlight. No significant potency losses have been noted following simulated delivery of the solution through intravenous tubing.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Dosing in Patients with Heparin-Induced Thrombocytopenia

Initial Dosage:

Before administering Argatroban, discontinue heparin therapy and obtain a baseline activated partial thromboplastin time (aPTT). The recommended initial dose of Argatroban for adult patients without hepatic impairment is 2 mcg/kg/min, administered as a continuous infusion (see Table 1).

Monitoring Therapy:

For use in HIT, therapy with Argatroban Injection is monitored using the aPTT with a target range of 1.5 to 3 times the initial baseline value (not to exceed 100 seconds). Tests of anticoagulant effects (including the aPTT) typically attain steady-state levels within 1 to 3 hours following initiation of Argatroban Injection. Check the aPTT 2 hours after initiation of therapy and after any dose change to confirm that the patient has attained the desired therapeutic range.

Dosage Adjustment:

After the initiation of Argatroban Injection, adjust the dose (not to exceed 10 mcg/kg/min) as necessary to obtain a steady-state aPTT in the target range [see Clinical Studies (14.1)].

Dosing in Patients Undergoing Percutaneous Coronary Interventions

Initial Dosage:

Initiate an infusion of Argatroban Injection at 25 mcg/kg/min and administer a bolus of 350 mcg/kg via a large bore intravenous line over 3 to 5 minutes (see Table 2). Check an activated clotting time (ACT) 5 to 10 minutes after the bolus dose is completed. The PCI procedure may proceed if the ACT is greater than 300 seconds.

Dosage Adjustment:

If the ACT is less than 300 seconds, an additional intravenous bolus dose of 150 mcg/kg should be administered, the infusion dose increased to 30 mcg/kg/min, and the ACT checked 5 to 10 minutes later (see Table 3).

If the ACT is greater than 450 seconds, decrease the infusion rate to 15 mcg/kg/min, and check the ACT 5 to 10 minutes later (Table 3).

Continue titrating the dose until a therapeutic ACT (between 300 and 450 seconds) has been achieved; continue the same infusion rate for the duration of the PCI procedure.

In case of dissection, impending abrupt closure, thrombus formation during the procedure, or inability to achieve or maintain an ACT over 300 seconds, additional bolus doses of 150 mcg/kg may be administered and the infusion dose increased to 40 mcg/kg/min. Check the ACT after each additional bolus or change in the rate of infusion.

Monitoring Therapy:

For use in PCI, therapy with Argatroban Injection is monitored using ACT. Obtain ACTs before dosing, 5 to 10 minutes after bolus dosing, following adjustments in the infusion rate, and at the end of the PCI procedure.

Obtain additional ACTs every 20 to 30 minutes during a prolonged procedure.

Continued Anticoagulation after PCI:

If a patient requires anticoagulation after the procedure, Argatroban Injection may be continued, but at a rate of 2 mcg/kg/min and adjusted as needed to maintain the aPTT in the desired range [see Dosage and Administration (2.1)].

Dosing in Patients With Hepatic Impairment

Initial Dosage:

For adult patients with HIT and moderate or severe hepatic impairment (based on Child-Pugh classification), an initial dose of 0.5 mcg/kg/min is recommended, based on the approximately 4-fold decrease in Argatroban clearance relative to those with normal hepatic function. Monitor the aPTT closely, and adjust the dosage as clinically indicated.

Monitoring Therapy:

Achievement of steady state aPTT levels may take longer and require more dose adjustments in patients with hepatic impairment compared to patients with normal hepatic function.

For patients with hepatic impairment undergoing PCI and who have HIT or are at risk for HIT, carefully titrate Argatroban until the desired level of anticoagulation is achieved. Use of Argatroban in PCI patients with clinically significant hepatic disease or AST/ALT levels ≥ 3 times the upper limit of normal should be avoided [see Warnings and Precautions (5.2)].

Conversion to Oral Anticoagulant Therapy

Initiating Oral Anticoagulant Therapy:

When converting patients from Argatroban to oral anticoagulant therapy, consider the potential for combined effects on INR with co-administration of Argatroban and warfarin. A loading dose of warfarin should not be used. Initiate therapy using the expected daily dose of warfarin. To avoid prothrombotic effects and to ensure continuous anticoagulation when initiating warfarin, it is suggested that Argatroban and warfarin therapy be overlapped. There are insufficient data available to recommend the duration of the overlap.

Co-Administration of Warfarin and Argatroban Injection at Doses up to 2 mcg/kg/min:

Measure INR daily while Argatroban Injection and warfarin are co-administered. In general, with doses of Argatroban Injection up to 2 mcg/kg/min, Argatroban Injection can be discontinued when the INR is > 4 on combined therapy. After Argatroban Injection is discontinued, repeat the INR measurement in 4 to 6 hours. If the repeat INR is below the desired therapeutic range, resume the infusion of Argatroban Injection and repeat the procedure daily until the desired therapeutic range on warfarin alone is reached.

Co-Administration of Warfarin and Argatroban Injection at Doses Greater than 2 mcg/kg/min:

For doses of Argatroban greater than 2 mcg/kg/min, the relationship of INR between warfarin alone to the INR on warfarin plus Argatroban is less predictable. In this case, in order to predict the INR on warfarin alone, temporarily reduce the dose of Argatroban Injection to a dose of 2 mcg/kg/min. Repeat the INR on Argatroban Injection and warfarin 4 to 6 hours after reduction of the Argatroban Injection dose and follow the process outlined above for administering Argatroban Injection at doses up to 2 mcg/kg/min.

Argatroban is contraindicated in

Heparin-Induced Thrombocytopenia

The safety and efficacy of Argatroban were evaluated in a historically controlled efficacy and safety study (Study 1) and a follow-on efficacy and safety study (Study 2). These studies were comparable with regard to study design, study objectives, dosing regimens as well as study outline, conduct, and monitoring.

In these studies, 568 adult patients were treated with Argatroban and 193 adult patients made up the historical control group. Patients had a clinical diagnosis of heparin-induced thrombocytopenia, either without thrombosis (HIT) or with thrombosis (HITTS [heparin-induced thrombocytopenia and thrombosis syndrome]) and were males or non-pregnant females between the age of 18 and 80 years old. HIT/HITTS was defined by a fall in platelet count to less than 100,000/µL or a 50% decrease in platelets after the initiation of heparin therapy with no apparent explanation other than HIT. Patients with HITTS also had an arterial or venous thrombosis documented by appropriate imaging techniques or supported by clinical evidence such as acute myocardial infarction, stroke, pulmonary embolism, or other clinical indications of vascular occlusion. Patients who had documented histories of positive heparin-dependent antibody tests without current thrombocytopenia or heparin challenge (e.g., patients with latent disease) were also included if they required anticoagulation.

These studies did not include patients with documented unexplained aPTT >200% of control at baseline, documented coagulation disorder or bleeding diathesis unrelated to HIT, a lumbar puncture within the past 7 days or a history of previous aneurysm, hemorrhagic stroke, or a thrombotic stroke within the past 6 months unrelated to HIT.

The initial dose of Argatroban was 2 mcg/kg/min. Two hours after the start of the Argatroban infusion, an aPTT level was obtained and dose adjustments were made (up to a maximum of 10 mcg/kg/min) to achieve a steady- state aPTT value that was 1.5 to 3.0 times the baseline value, not to exceed 100 seconds. Overall the mean aPTT level for HIT and HITTS patients during the Argatroban infusion increased from baseline values of 34 and 38 seconds, respectively, to 62.5 and 64.5 seconds, respectively.

The primary efficacy analysis was based on a comparison of event rates for a composite endpoint that included death (all causes), amputation (all causes) or new thrombosis during the treatment and follow-up period (study days 0 to 37). Secondary analyses included evaluation of the event rates for the components of the composite endpoint as well as time-to-event analyses.

In Study 1, a total of 304 patients were enrolled as follows: active HIT (n=129), active HITTS (n=144), or latent disease (n=31). Among the 193 historical controls, 139 (72%) had active HIT, 46 (24%) had active HITTS, and 8 (4%) had latent disease. Within each group, those with active HIT and those with latent disease were analyzed together. Positive laboratory confirmation of HIT/HITTS by the heparin-induced platelet aggregation test or serotonin release assay was demonstrated in 174 of 304 (57%) Argatroban-treated patients (i.e., in 80 with HIT or latent disease and 94 with HITTS) and in 149 of 193 (77%) historical controls (i.e., in 119 with HIT or latent disease and 30 with HITTS). The test results for the remainder of the patients and controls were either negative or not determined.

There was a significant improvement in the composite outcome in patients with HIT and HITTS treated with Argatroban versus those in the historical control group (see Table 9). The components of the composite endpoint are shown in Table 9.

Time-to-event analyses showed significant improvements in the time-to-first event in patients with HIT or HITTS treated with Argatroban versus those in the historical control group. The between-group differences in the proportion of patients who remained free of death, amputation, or new thrombosis were statistically significant in favor of Argatroban by these analyses.

A time-to-event analysis for the composite endpoint is shown in Figure 3 for patients with HIT and Figure 4 for patients with HITTS.

In Study 2, a total of 264 patients were enrolled as follows: HIT (n=125) or HITTS (n=139). There was a significant improvement in the composite efficacy outcome for Argatroban-treated patients, versus the same historical control group from Study 1, among patients having HIT (25.6% vs. 38.8%), patients having HITTS (41.0% vs. 56.5%), and patients having either HIT or HITTS (33.7% vs. 43.0%). Time-to-event analyses showed significant improvements in the time-to-first event in patients with HIT or HITTS treated with Argatroban versus those in the historical control group. The between-group differences in the proportion of patients who remained free of death, amputation, or new thrombosis were statistically significant in favor of Argatroban.

Anticoagulant Effect:

In Study 1, the mean (± SE) dose of Argatroban administered was 2.0 ± 0.1 mcg/kg/min in the HIT arm and 1.9 ± 0.1 mcg/kg/min in the HITTS arm. Seventy-six percent of patients with HIT and 81% of patients with HITTS achieved a target aPTT at least 1.5-fold greater than the baseline aPTT at the first assessment occurring on average at 4.6 hours (HIT) and 3.9 hours (HITTS) following initiation of Argatroban therapy.

No enhancement of aPTT response was observed in subjects receiving repeated administration of Argatroban.

Platelet Count Recovery:

In Study 1, 53% of patients with HIT and 58% of patients with HITTS, had a recovery of platelet count by Day 3. Platelet Count Recovery was defined as an increase in platelet count to >100,000/µL or to at least 1.5-fold greater than the baseline count (platelet count at study initiation) by Day 3 of the study.

Percutaneous Coronary Interventions (PCI) Patients with or at Risk for HIT

In 3 similarly designed trials, Argatroban was administered to 91 patients with current or previous clinical diagnosis of HIT or heparin-dependent antibodies, who underwent a total of 112 percutaneous coronary interventions (PCIs) including percutaneous transluminal coronary angioplasty (PTCA), coronary stent placement, or atherectomy. Among the 91 patients undergoing their first PCI with Argatroban, notable ongoing or recent medical history included myocardial infarction (n = 35), unstable angina (n = 23), and chronic angina (n = 34). There were 33 females and 58 males. The average age was 67.6 years (median 70.7, range 44 to 86), and the average weight was 82.5 kg (median 81.0 kg, range 49 to 141).

Twenty-one of the 91 patients had a repeat PCI using Argatroban an average of 150 days after their initial PCI. Seven of 91 patients received glycoprotein IIb/IIIa inhibitors. Safety and efficacy were assessed against historical control populations who had been anticoagulated with heparin.

All patients received oral aspirin (325 mg) 2 to 24 hours prior to the interventional procedure. After venous or arterial sheaths were in place, anticoagulation was initiated with a bolus of Argatroban of 350 mcg/kg via a large-bore intravenous line or through the venous sheath over 3 to 5 minutes. Simultaneously, a maintenance infusion of 25 mcg/kg/min was initiated to achieve a therapeutic ACT of 300 to 450 seconds. If necessary to achieve this therapeutic range, the maintenance infusion dose was titrated (15 to 40 mcg/kg/min) and/or an additional bolus dose of 150 mcg/kg could be given. Each patient's ACT was checked 5 to 10 minutes following the bolus dose. The ACT was checked as clinically indicated. Arterial and venous sheaths were removed no sooner than 2 hours after discontinuation of Argatroban and when the ACT was less than 160 seconds.

If a patient required anticoagulation after the procedure, Argatroban could be continued, but at a lower infusion dose between 2.5 and 5 mcg/kg/min. An aPTT was drawn 2 hours after this dose reduction and the dose of Argatroban then was adjusted as clinically indicated (not to exceed 10 mcg/kg/min), to reach an aPTT between 1.5 and 3 times baseline value (not to exceed 100 seconds).

In 92 of the 112 interventions (82%), the patient received the initial bolus of 350 mcg/kg and an initial infusion dose of 25 mcg/kg/min. The majority of patients did not require additional bolus dosing during the PCI procedure. The mean value for the initial ACT measurement after the start of dosing for all interventions was 379 sec (median 338 sec; 5th percentile-95th percentile 238 to 675 sec). The mean ACT value per intervention over all measurements taken during the procedure was 416 sec (median 390 sec; 5th percentile-95th percentile 261 to 698 sec). About 65% of patients had ACTs within the recommended range of 300 to 450 seconds throughout the procedure. The investigators did not achieve anticoagulation within the recommended range in about 23% of patients. However, in this small sample, patients with ACTs below 300 seconds did not have more coronary thrombotic events, and patients with ACTs over 450 seconds did not have higher bleeding rates.

Acute procedural success was defined as lack of death, emergent coronary artery bypass graft (CABG), or Q- wave myocardial infarction. Acute procedural success was reported in 98.2% of patients who underwent PCIs with Argatroban anticoagulation compared with 94.3% of historical control patients anticoagulated with heparin (p = NS). Among the 112 interventions, 2 patients had emergency CABGs, 3 had repeat PTCAs, 4 had non-Q‑ wave myocardial infarctions, 3 had myocardial ischemia, 1 had an abrupt closure, and 1 had an impending closure (some patients may have experienced more than 1 event). No patients died.

NDC 0007-4407-01

Argatroban

INJECTION

250 mg / 2.5 mL

Each mL contains 100 mg Argatroban

Rx only

For I.V. Infusion Only

Dilute Prior to Use

Each 2.5 mL contains 250 mg Argatroban, 750 mg D-sorbitol and 1000 mg dehydrated alcohol. Contains no preservative.

Store at 25oC (77oF); excursions permitted to 15o – 30oC (59o – 86oF). DO NOT FREEZE.

Manufactured, Distributed and Marketed by GlaxoSmithKline

Research Triangle Park, NC 27709

Made in Japan

10000000106981 Rev. 6/12

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.

Heparin-induced thrombocytopenia (HIT) (dosing based on limited data from critically-ill patients): Infants, Children, and Adolescents ≤16 years: Continuous IV infusion:

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.

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. Once combined INR on warfarin and argatroban is >4, stop argatroban. 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.