Argatroban

Argatroban is a direct thrombin inhibitor indicated: For prophylaxis or treatment of thrombosis in adult patients with heparin-induced thrombocytopenia (HIT) As an anticoagulant in adult patients with or at risk for HIT undergoing percutaneous coronary intervention (PCI)

1.1Heparin-Induced Thrombocytopenia Argatroban Injection

is indicated for prophylaxis or treatment of thrombosis in adult patients with heparin-induced thrombocytopenia (HIT).

1.2Percutaneous Coronary Intervention Argatroban Injection

is indicated as an anticoagulant in adult patients with or at risk for HIT undergoing percutaneous coronary intervention (PCI).

Argatroban Injection 50 mg/50 mL (1 mg/mL) is ready for intravenous infusion. Dilution is not required. Heparin-Induced Thrombocytopenia The dose for heparin-induced thrombocytopenia without hepatic impairment is 2 mcg/kg/min administered as a continuous infusion. Percutaneous Coronary Intervention The dose for patients with or at risk for heparin-induced thrombocytopenia undergoing percutaneous coronary intervention is started at 25 mcg/kg/min and a bolus of 350 mcg/kg administered via a large bore intravenous line over 3 to 5 minutes.

2.1Preparation for Intravenous Administration Dilution

is not required for Argatroban Injection 50 mg/50 mL (1 mg/mL). Argatroban Injection 50 mg/50 mL (1 mg/mL) Each 50 mL glass vial contains 50 mg argatroban (1 mg/mL); and, as supplied, is ready for intravenous infusion. Dilution is not required. Argatroban Injection is a clear, colorless to pale yellow solution.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if solution is cloudy, contains precipitates, or if the flip top cap is not intact. Vial may be inverted for use with a medical infusion set.

2.2Dosing 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 . Table 1: Recommended Doses and Infusion Rates for 2 mcg/kg/min Dose of Argatroban for Patients With HIT with or without thrombosis and Without Hepatic Impairment (1 mg/mL Final Concentration) Body Weight (kg) Dose (mcg/min) Infusion Rate (mL/hr) 50 100 6 60 120 7 70 140 8 80 160 10 90 180 11 100 200 12 110 220 13 120 240 14 130 260 16 140 280 17 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 .

2.3Dosing in Patients Undergoing Percutaneous Coronary

Intervention 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 . 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 . 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 . 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. Table 2: Recommended Starting and Maintenance Doses (Within the Target ACT Range) of Argatroban Injection in Patients Undergoing PCI Without Hepatic Impairment (1 mg/mL Final Concentration) Body Weight (kg) Starting Bolus Dose (350 mcg/kg) Starting and Maintenance Continuous Infusion Dosing For ACT 300-450 seconds 25 mcg/kg/min Bolus Dose (mcg) Bolus Volume (mL) Continuous Infusion Dose (mcg/min) Continuous Infusion Rate (mL/hr) NOTE: 1 mg = 1,000 mcg; 1 kg = 2.2 lbs 50 17,500 18 1,250 75 60 21,000 21 1,500 90 70 24,500 25 1,750 105 80 28,000 28 2,000 120 90 31,500 32 2,250 135 100 35,000 35 2,500 150 110 38,500 39 2,750 165 120 42,000 42 3,000 180 130 45,500 46 3,250 195 140 49,000 49 3,500 210 Table 3: Recommended Dose Adjustments of Argatroban Injection for Patients Outside of ACT Target Range Undergoing PCI Without Hepatic Impairment (1 mg/mL Final Concentration) Body Weight (kg) If ACT Less than 300 seconds Dosage Adjustment Additional intravenous bolus dose of 150 mcg/kg should be administered if ACT less than 300 seconds. 30 mcg/kg/min If ACT Greater than 450 seconds Dosage Adjustment No bolus dose is given if ACT greater than 450 seconds 15 mcg/kg/min Additional Bolus Dose (mcg) Bolus Volume (mL) Continuous Infusion Dose (mcg/min) Continuous Infusion Rate (mL/hr) Continuous Infusion Dose (mcg/min) Continuous Infusion Rate (mL/hr) NOTE: 1 mg = 1,000 mcg; 1 kg = 2.2 lbs 50 7,500 8 1,500 90 750 45 60 9,000 9 1,800 108 900 54 70 10,500 11 2,100 126 1,050 63 80 12,000 12 2,400 144 1,200 72 90 13,500 14 2,700 162 1,350 81 100 15,000 15 3,000 180 1,500 90 110 16,500 17 3,300 198 1,650 99 120 18,000 18 3,600 216 1,800 108 130 19,500 20 3,900 234 1,950 117 140 21,000 21 4,200 252 2,100 126 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 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 .

2.4Dosing 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 .

2.5Conversion 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.

Hemorrhage can occur. Unexplained fall in hematocrit or blood pressure may indicate hemorrhage. Hepatic impairment: Adjust starting dose and titrate carefully in patients with HIT who have moderate or severe hepatic impairment. Avoid use in PCI in patients with clinically significant hepatic impairment.

5.1Risk of Hemorrhage Hemorrhage

can occur at any site in the body in patients receiving argatroban. Unexplained fall in hematocrit or blood pressure may indicate hemorrhage. Intracranial and retroperitoneal hemorrhage have been reported. The risk of hemorrhage with argatroban may be increased in severe hypertension; immediately following lumbar puncture, spinal anesthesia, major surgery (especially involving the brain, spinal cord, or eye), hematologic conditions associated with increased bleeding tendencies such as congenital or acquired bleeding disorders, and gastrointestinal lesions such as ulcerations.

Concomitant use of argatroban with antiplatelet agents, thrombolytics, and other anticoagulants may increase the risk of bleeding.

5.2Use in Hepatic Impairment When

administering argatroban to patients with hepatic impairment, start with a lower dose and carefully titrate until the desired level of anticoagulation is achieved. Achievement of steady state aPTT levels may take longer and require more argatroban dose adjustments in patients with hepatic impairment compared to patients with normal hepatic function . Also, upon cessation of argatroban infusion in the hepatically impaired patient, full reversal of anticoagulant effects may require longer than 4 hours due to decreased clearance and increased elimination half-life of argatroban . Avoid the use of high doses of argatroban in patients undergoing PCI who have clinically significant hepatic disease or AST/ALT levels ≥ 3 times the upper limit of normal.

5.3Laboratory Tests Anticoagulation

effects associated with argatroban infusion at doses up to 40 mcg/kg/min correlate with increases of the aPTT. Although other global clot-based tests including prothrombin time (PT), the International Normalized Ratio (INR), and thrombin time (TT) are affected by argatroban, the therapeutic ranges for these tests have not been identified for argatroban therapy. In clinical trials in PCI, the ACT was used for monitoring argatroban anticoagulant activity during the procedure. The concomitant use of argatroban and warfarin results in prolongation of the PT and INR beyond that produced by warfarin alone .

Argatroban is contraindicated in: Patients with major bleeding, Patients with a history of hypersensitivity to argatroban. Airway, skin, and generalized hypersensitivity reactions have been reported Major bleeding History of hypersensitivity to this product

8.1Pregnancy Risk Summary Limited

data from published literature and postmarketing reports do not suggest an association between argatroban and adverse fetal developmental outcomes. There are risks to the mother associated with untreated thrombosis in pregnancy and a risk of hemorrhage in the mother and fetus associated with use of anticoagulants . In animal reproduction studies, there was no evidence of adverse developmental outcomes with intravenous administration of argatroban during organogenesis in rats and rabbits at doses up to 0.3- and 0.2-times, respectively, the maximum recommended human dose (MHRD) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnancy confers an increased risk for thromboembolism that is higher for women with underlying thromboembolic disease and certain high risk pregnancy conditions. Published data describe that women with a previous history of venous thrombosis are at high risk for recurrence during pregnancy.

Fetal/Neonatal Adverse Reactions Use of anticoagulants, including argatroban, may increase the risk of bleeding in the fetus and neonate. Monitor neonates for bleeding . Labor or Delivery All patients receiving anticoagulants, including pregnant women, are at risk for bleeding. Pregnant women receiving argatroban should be carefully monitored for evidence of excessive bleeding or unexpected changes in coagulation parameters . Data Animal Data Developmental studies performed in rats with argatroban at intravenous doses up to 27 mg/kg/day (0.3 times the maximum recommended human dose, based on body surface area) and in rabbits at intravenous doses up to 10.8 mg/kg/day (0.2 times the maximum recommended human dose, based on body surface area) have revealed no evidence of harm to the fetus.

The following adverse reaction is also discussed in other sections of the labeling: Risk of Hemorrhage . HIT patients: The most common (> 5%) adverse reactions were dyspnea, hypotension, fever, diarrhea, sepsis, and cardiac arrest. PCI patients: The most common (> 5%) adverse reactions were chest pain, hypotension, back pain, nausea, vomiting and headache. To report SUSPECTED ADVERSE REACTIONS, contact Mullan Pharmaceutical Inc. at 1-800- 673-9839 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical Trials Experience Adverse Reactions

in Patients with HIT (With or Without Thrombosis) Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following safety information is based on all 568 patients treated with argatroban in Study 1 and Study 2. The safety profile of the patients from these studies is compared with that of 193 historical controls in which the adverse reactions were collected retrospectively.

Adverse reactions are separated into hemorrhagic and non-hemorrhagic reactions. Major bleeding was defined as bleeding that was overt and associated with a hemoglobin decrease ≥ 2 g/dL, that led to a transfusion of ≥ 2 units, or that was intracranial, retroperitoneal, or into a major prosthetic joint. Minor bleeding was overt bleeding that did not meet the criteria for major bleeding.

Table 4 gives an overview of the most frequently observed hemorrhagic reactions, presented separately by major and minor bleeding, sorted by decreasing occurrence among argatroban-treated patients with HIT (with or without thrombosis). Table 4: Major and Minor Hemorrhagic Adverse Reactions in Patients With HIT with or without thrombosis DIC = disseminated intravascular coagulation. BKA = below the knee amputation.

Major Hemorrhagic Reactions Patients may have experienced more than 1 adverse reaction. Argatroban-treated Patients (Study 1 and Study 2) (n = 568) % Historical Control The historical control group consisted of patients with a clinical diagnosis of HIT (with or without thrombosis) that were considered eligible by an independent medical panel. (n = 193) % Overall bleeding 5.3

6.7Gastrointestinal

2.3

1.6Genitourinary and

hematuria 0.9

0.5Decrease in

hemoglobin and hematocrit 0.7 0 Multisystem hemorrhage and DIC 0.5 1 Limb and BKA stump 0.5 0 Intracranial hemorrhage 0 One patient experienced intracranial hemorrhage 4 days after discontinuation of argatroban and following therapy with urokinase and oral anticoagulation.

0.5Minor Hemorrhagic Reactions Argatroban-treated Patients

(Study 1 and Study 2) (n = 568) % Historical Control (n = 193) % Gastrointestinal 14.4

18.1Genitourinary and

hematuria 11.6

0.8Decrease in

hemoglobin and hematocrit 10.4 0 Groin 5.4

3.1Hemoptysis

2.9

0.8Brachial

2.4

0.8Table

5 gives an overview of the most frequently observed non-hemorrhagic reactions sorted by decreasing frequency of occurrence (≥ 2%) among argatroban-treated HIT/HITTS patients. Table 5: Non-hemorrhagic Adverse Reactions in Patients Patients may have experienced more than 1 adverse reaction. With HIT With or without thrombosis Argatroban-treated Patients (Study 1 and Study 2) (n = 568) % Historical Control The historical control group consisted of patients with a clinical diagnosis of HIT (with or without thrombosis) that were considered eligible by an independent medical panel. (n = 193) % Dyspnea 8.1

8.8Hypotension

7.2

2.6Fever

6.9

2.1Diarrhea

6.2

1.6Sepsis

6.0

12.4Cardiac

arrest 5.8

3.1Nausea

4.8

0.5Ventricular

tachycardia 4.8

3.1Pain

4.6

3.1Urinary

tract infection 4.6

5.2Vomiting

4.2 0 Infection 3.7

3.6Pneumonia

3.3

9.3Atrial

fibrillation 3.0

11.4Coughing

2.8

1.6Abnormal

renal function 2.8

4.7Abdominal

pain 2.6

1.6Cerebrovascular

disorder 2.3

4.1Adverse Reactions in Patients with or at Risk for

HIT Undergoing PCI The following safety information is based on 91 patients initially treated with argatroban and 21 patients subsequently re-exposed to argatroban for a total of 112 PCIs with argatroban anticoagulation. Adverse reactions are separated into hemorrhagic (Table 6) and non-hemorrhagic (Table 7) reactions. Major bleeding was defined as bleeding that was overt and associated with a hemoglobin decrease ≥ 5 g/dL, that led to a transfusion of ≥ 2 units, or that was intracranial, retroperitoneal, or into a major prosthetic joint.

The rate of major bleeding events in patients treated with argatroban in the PCI trials was 1.8%. Table 6: Major and Minor Hemorrhagic Adverse Reactions in Patients With HIT Undergoing PCI Major Hemorrhagic Reactions Patients may have experienced more than 1 adverse reaction. Argatroban-treated Patients (n = 112) 91 patients who underwent 112 interventions. CABG = coronary artery bypass graft. % Retroperitoneal

0.9Gastrointestinal

0.9Intracranial

0 Minor Hemorrhagic Reactions Argatroban-treated Patients (n = 112) % Groin (bleeding or hematoma)

3.6Gastrointestinal

(includes hematemesis)

2.6Genitourinary

(includes hematuria)

1.8Decrease in

hemoglobin and/or hematocrit

1.8CABG

(coronary arteries)

1.8Access

site

0.9Hemoptysis

0.9Other

0.9Table

7 gives an overview of the most frequently observed non-hemorrhagic adverse reactions (> 2%), sorted by decreasing frequency of occurrence among argatroban-treated PCI patients. Table 7: Non-hemorrhagic Adverse Reactions Patients may have experienced more than 1 adverse reaction. in Patients With HIT Undergoing PCI Argatroban Procedures (n = 112) 91 patients who underwent 112 interventions. % Chest pain

15.2Hypotension

10.7Back

pain

8.0Nausea

7.1Vomiting

6.3Headache

5.4Bradycardia

4.5Abdominal

pain

3.6Fever

3.6Myocardial

infarction

3.6There

were 22 serious adverse reactions in 17 PCI patients (19.6% in 112 interventions). Table 8 lists the serious adverse reactions occurring in argatroban-treated patients with or at risk for HIT undergoing PCI. Table 8: Serious Adverse Reactions in Patients With HIT Undergoing PCI Individual reactions may also have been reported elsewhere . Coded Term Argatroban Procedures 91 patients underwent 112 procedures. Some patients may have experienced more than 1 reaction. (n = 112) Myocardial infarction 4 (3.5%) Angina pectoris 2 (1.8%) Coronary thrombosis 2 (1.8%) Myocardial ischemia 2 (1.8%) Occlusion coronary 2 (1.8%) Chest pain 1 (0.9%) Fever 1 (0.9%) Retroperitoneal hemorrhage 1 (0.9%) Aortic stenosis 1 (0.9%) Arterial thrombosis 1 (0.9%) Gastrointestinal hemorrhage 1 (0.9%) Gastrointestinal disorder (GERD) 1 (0.9%) Cerebrovascular disorder 1 (0.9%) Lung edema 1 (0.9%) Vascular disorder 1 (0.9%) Intracranial Bleeding in Other Populations Increased risks for intracranial bleeding have been observed in investigational studies of argatroban for other uses.

In a study of patients with acute myocardial infarction receiving both argatroban and thrombolytic therapy (streptokinase or tissue plasminogen activator), the overall frequency of intracranial bleeding was 1% (8 out of 810 patients). Intracranial bleeding was not observed in 317 subjects or patients who did not receive concomitant thrombolysis . The safety and effectiveness of argatroban for cardiac indications other than PCI in patients with HIT have not been established. Intracranial bleeding was also observed in a prospective, placebo-controlled study of argatroban in patients who had onset of acute stroke within 12 hours of study entry.

Symptomatic intracranial hemorrhage was reported in 5 of 117 patients (4.3%) who received argatroban at 1 to 3 mcg/kg/min and in none of the 54 patients who received placebo. Asymptomatic intracranial hemorrhage occurred in 5 (4.3%) and 2 (3.7%) of the patients, respectively. Allergic Reactions One hundred fifty-six allergic reactions or suspected allergic reactions were observed in 1,127 individuals who were treated with argatroban in clinical pharmacology studies or for various clinical indications.

About 95% (148/156) of these reactions occurred in patients who concomitantly received thrombolytic therapy (e.g., streptokinase) or contrast media. Allergic reactions or suspected allergic reactions in populations other than patients with HIT (with or without thrombosis) include (in descending order of frequency): Airway reactions (coughing, dyspnea): 10% or more Skin reactions (rash, bullous eruption): 1 to <10% General reactions (vasodilation): 1 to 10% Limited data are available on the potential formation of drug-related antibodies. Plasma from 12 healthy volunteers treated with argatroban over 6 days showed no evidence of neutralizing antibodies.

No loss of anticoagulant activity was noted with repeated administration of argatroban to more than 40 patients.

6.2Postmarketing Experience The

following adverse reactions have been identified during post approval use of argatroban. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Anaphylaxis