Argatroban

1 INDICATIONS AND USAGE Argatroban is a direct thrombin inhibitor indicated: For prophylaxis or treatment of thrombosis in adult patients with heparin-induced thrombocytopenia (HIT) ( 1.1 ) As an anticoagulant in adult patients with or at risk for HIT undergoing percutaneous coronary intervention (PCI) ( 1.2 ) 1.1 Heparin-Induced Thrombocytopenia Argatroban Injection is indicated for prophylaxis or treatment of thrombosis in adult patients with heparin-induced thrombocytopenia (HIT). 1.2 Percutaneous Coronary Intervention Argatroban Injection is indicated as an anticoagulant in adult patients with or at risk for HIT undergoing percutaneous coronary intervention (PCI).

2 DOSAGE AND ADMINISTRATION Argatroban 125 mg in 125 mL aqueous sodium chloride solution (1 mg/mL) is intended for administration to adult patients ( 2.1 ) Discontinue all parenteral anticoagulants before administering Argatroban Injection ( 2.1 ) Adjust dosing in patients with HIT who have moderate or severe hepatic impairment ( 2.3 ) Heparin-Induced Thrombocytopenia ( 2.1 ) The dose for heparin-induced thrombocytopenia without hepatic impairment is 2 mcg/kg/min administered as a continuous infusion ( 2.1 ) Discontinue heparin therapy and obtain a baseline aPTT before administering Argatroban ( 2.1 ) After the initial dose of Argatroban, the dose can be adjusted as clinically indicated ( 2.1 ) Percutaneous Coronary Intervention ( 2.2 ) 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 ( 2.2 ) Activated clotting time (ACT) should be checked 5 to 10 minutes after the bolus dose is completed. The procedure may proceed if the ACT is greater than 300 seconds ( 2.2 ) Monitoring therapy and dosage adjustments recommendations should be followed ( 2.2 ) See special dosing recommendations for hepatic and renal impaired patients ( 2.3 ) 2.1 Intravenous Administration Each 125 mL glass vial contains 125 mg of 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 the solution is cloudy, contains precipitates, or if the flip-off seal is not intact. 2.2 Dosing in Patients with Heparin-Induced Thrombocytopenia Initial Dosage Before administering argatroban, discontinue heparin therapy and obtain a baseline 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 ). Table 1. Recommended Doses and Infusion Rates for 2 mcg/kg/min Dose of Argatroban for Patients With HIT 1 and Without Hepatic Impairment (1 mg/mL 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 1. With or without thrombosis 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 )] . 2.3 Dosing 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 (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 2 ). 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 ). Con …

3 DOSAGE FORMS AND STRENGTHS Argatroban Injection is supplied in a single-dose vial containing 125 mg argatroban in 125 mL aqueous sodium chloride solution (1 mg/mL). The solution is ready for intravenous infusion. Injection: 125 mg per 125 mL (1 mg per mL) single-dose vial ( 3 )

4 CONTRAINDICATIONS Argatroban is contraindicated in: • Patients with major bleeding, [see Warnings and Precautions ( 5.1 )] • Patients with a history of hypersensitivity to argatroban. Airway, skin, and generalized hypersensitivity reactions have been reported [see Adverse Reactions ( 6.1 )] . Major bleeding ( 4 ) History of hypersensitivity to this product ( 4 )

6 ADVERSE REACTIONS The following adverse reaction is also discussed in other sections of the labeling: • Risk of Hemorrhage [see Warnings and Precautions ( 5.1 )] . HIT patients: The most common (> 5%) adverse reactions were dyspnea, hypotension, fever, diarrhea, sepsis, and cardiac arrest ( 6.1 ) PCI patients: The most common (> 5%) adverse reactions were chest pain, hypotension, back pain, nausea, vomiting and headache ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gland Pharma at 866-770-7144 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical 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 events, 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 1 Major Hemorrhagic Reactions 2 Argatroban- Treated Patients (Study 1 and Study 2) (n = 568) % Historical Control 3 (n = 193) % Overall bleeding 5.3 6.7 Gastrointestinal 2.3 1.6 Genitourinary and hematuria 0.9 0.5 Decrease in hemoglobin and hematocrit 0.7 0 Multisystem hemorrhage and DIC 0.5 1 Limb and BKA stump 0.5 0 Intracranial hemorrhage 0 4 0.5 Minor Hemorrhagic Reactions 2 Gastrointestinal 14.4 18.1 Genitourinary and hematuria 11.6 0.8 Decrease in hemoglobin and hematocrit 10.4 0 Groin 5.4 3.1 Hemoptysis 2.9 0.8 Brachial 2.4 0.8 1. with or without thrombosis 2. Patients may have experienced more than 1 adverse reaction. 3. 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. 4. One patient experienced intracranial hemorrhage 4 days after discontinuation of argatroban and following therapy with urokinase and oral anticoagulation. DIC = disseminated intravascular coagulation.BKA = below-the-knee amputation. Table 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 1 With HIT 2 Argatroban-Treated Patients (Study 1 and Study 2) (n = 568) % Historical Control 3 (n = 193) % Dyspnea 8.1 8.8 Hypotension 7.2 2.6 Fever 6.9 2.1 Diarrhea 6.2 1.6 Sepsis 6.0 12.4 Cardiac arrest 5.8 3.1 Nausea 4.8 0.5 Ventricular tachycardia 4.8 3.1 Pain 4.6 3.1 Urinary tract infection 4.6 5.2 Vomiting 4.2 0 Infection 3.7 3.6 Pneumonia 3.3 9.3 Atrial fibrillation 3.0 11.4 Coughing 2.8 1.6 Abnormal renal function 2.8 4.7 Abdominal pain 2.6 1.6 Cerebrovascular disorder 2.3 4.1 1. Patients may have experienced more than 1 adverse reaction. 2. with or without thrombosis 3. 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. Adverse Reactions in Patients with or at Risk for HIT Patie …

7 DRUG INTERACTIONS Heparin: Allow sufficient time for heparin’s effect on aPTT to decrease before initiating Argatroban Injection therapy ( 7.1 ) Warfarin: Concomitant use results in increased prolongation of PT and INR ( 7.2 ) Thrombolytic agents or glycoprotein IIb/IIIa antagonists: Safety and effectiveness of concomitant use with argatroban have not been established ( 7.4 , 7.5 ) 7.1 Heparin If argatroban is to be initiated after cessation of heparin therapy, allow sufficient time for heparin’s effect on the aPTT to decrease prior to initiation of argatroban therapy. 7.2 Oral Anticoagulant Agents Pharmacokinetic drug-drug interactions between argatroban and warfarin (7.5 mg single oral dose) have not been demonstrated. However, the concomitant use of argatroban and warfarin (5 to 7.5 mg initial oral dose, followed by 2.5 to 6 mg/day orally for 6 to 10 days) results in prolongation of the prothrombin time (PT) and International Normalized Ratio (INR) [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.2 )] . 7.3 Aspirin/Acetaminophen No drug-drug interactions have been demonstrated between argatroban and concomitantly administered aspirin or acetaminophen [see Clinical Pharmacology ( 12.3 )] . 7.4 Thrombolytic Agents The safety and effectiveness of argatroban with thrombolytic agents have not been established [see Adverse Reactions ( 6.1 )] . 7.5 Glycoprotein IIb/IIIa Antagonists The safety and effectiveness of argatroban with glycoprotein IIb/IIIa antagonists have not been established.

8 USE IN SPECIFIC POPULATIONS Lactation: Discontinue nursing or drug, taking into account the importance of the drug to the mother ( 8.2 ) Pediatric Use: Safety and effectiveness have not been established ( 8.4 ) 8.1 Pregnancy Risk Summary Limited data from published literature and postmarketing reports do not suggest an association between argatroban and adverse fetal 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 the use of anticoagulants ( see Clinical Considerations ). 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) ( see Data ). 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% to 4% and 15% to 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 [see Warnings and Precautions ( 5.1 , 5.3 )]. 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 [see Warnings and Precautions ( 5.1 , 5.3 )]. 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. 8.2 Lactation There are no data on the presence of argatroban in human milk, or its effects on milk production. Argatroban is detected in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s need for Argatroban and any potential adverse effects on the breastfed child from Argatroban or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients. Argatroban was studied among 18 seriously ill pediatric patients who required an alternative to heparin anticoagulation. Most patients were diagnosed with HIT or suspected HIT. Age ranges of patients were 100 seconds for seriously ill pediatric patients with HIT/HITTS who require an alternative to heparin suggested the following: • For patients with normal hepatic function, a starting infusion rate of 0.75 mcg/kg/min may have comparable aPTT responses as a starting dose of 2 mcg/kg/min in healthy adults. Additionally, based on an evaluation of aPTT every two hours, increasing the dosage by 0.1 to 0.25 mcg/kg/min could achieve additional aPTT responses. • For patients with hepatic impairment a starting infusion rate of 0.2 mcg/kg/min with increasing dosing by increments of 0.05 mcg/kg/min may have comparable argatroban exposure as expected with adult doses. The safety and effectiveness of argatroban with the above dosing have not been adequately assessed in pediatric patients and the safety and effectiveness …

12.1 Mechanism of Action Argatroban is a direct thrombin inhibitor that reversibly binds to the thrombin active site. Argatroban does not require the co-factor antithrombin III for antithrombotic activity. Argatroban exerts its anticoagulant effects by inhibiting thrombin-catalyzed or -induced reactions, including fibrin formation; activation of coagulation factors V, VIII, and XIII; activation of protein C; and platelet aggregation. Argatroban inhibits thrombin with an inhibition constant (Ki) of 0.04 μM. At therapeutic concentrations, argatroban has little or no effect on related serine proteases (trypsin, factor Xa, plasmin, and kallikrein). Argatroban is capable of inhibiting the action of both free and clot-associated thrombin.

11 DESCRIPTION Argatroban is a synthetic direct thrombin inhibitor and the chemical name is 1-[5- [(aminoiminomethyl)amino]-1-oxo-2-[[(1,2,3,4-tetrahydro-3-methyl-8- quinolinyl)sulfonyl] amino]pentyl]-4-methyl-2-piperidinecarboxylic acid, monohydrate. Argatroban has 4 asymmetric carbons. One of the asymmetric carbons has an R configuration (stereoisomer Type I) and an S configuration (stereoisomer Type II). Argatroban consists of a mixture of R and S stereoisomers at a ratio of approximately 65:35. The molecular formula of argatroban is C 23 H 36 N 6 O 5 S•H 2 O. Its molecular weight is 526.66 g/mol. The structural formula is: Argatroban Injection is a sterile, non-pyrogenic, clear, colorless to pale yellow isotonic solution. It is supplied in a single-dose clear glass vial containing 125 mg of argatroban in 125 mL sodium chloride solution. Each mL contains 1 mg argatroban, 9 mg sodium chloride, USP, 3 mg sorbitol, NF in water for injection, USP. The pH of the solution is between 3.2 to 7.5. argatroban-structure

10 OVERDOSAGE Excessive anticoagulation, with or without bleeding, may be controlled by discontinuing argatroban or by decreasing the argatroban dose. In clinical studies, anticoagulation parameters generally returned from therapeutic levels to baseline within 2 to 4 hours after discontinuation of the drug. Reversal of anticoagulant effect may take longer in patients with hepatic impairment. No specific antidote to argatroban is available; if life-threatening bleeding occurs and excessive plasma levels of argatroban are suspected, discontinue argatroban immediately and measure aPTT and other coagulation parameters. When argatroban was administered as a continuous infusion (2 mcg/kg/min) prior to and during a 4-hour hemodialysis session, approximately 20% of argatroban was cleared through dialysis. Single intravenous doses of argatroban at 200, 124, 150, and 200 mg/kg were lethal to mice, rats, rabbits, and dogs, respectively. The symptoms of acute toxicity were loss of righting reflex, tremors, clonic convulsions, paralysis of hind limbs, and coma.

16 HOW SUPPLIED/STORAGE AND HANDLING Argatroban Injection is supplied as a single-dose vial containing 125 mg argatroban in 125 mL of 0.9% aqueous sodium chloride solution (1 mg/mL). The vial is sealed with a gray rubber stopper and a red aluminum flip-off seal. NDC 68083-141-02 one package containing two vials of Argatroban Injection (each vial contains 125 mg of argatroban). Vial may be inverted for use with a medical infusion set. Storage Store the vials in original cartons at 20o to 25oC (68o to 77°F) [see USP Controlled Room Temperature]. Do not freeze. Retain in the original carton to protect from light. If the solution is cloudy, or if an insoluble precipitate is noted, the vial should be discarded.