Argatroban

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

1.2 Percutaneous Coronary Intervention Argatroban in Sodium Chloride Injection is indicated as an anticoagulant in adult patients with or at risk for HIT undergoing percutaneous coronary intervention (PCI).

Injection: 50 mg per 50 mL (1mg per mL) a single–dose vial. The solution is ready for intravenous infusion. Injection: 50 mg per 50 mL (1 mg per mL) single-dose vial ( 3 )

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 )

Risk of hemorrhage: Hemorrhage at any site can occur (unexplained fall in hematocrit or blood pressure or other unexplained symptom may indicate hemorrhage). Use with caution in patients at risk, including those receiving antiplatelet agents, thrombolytics, or other anticoagulants ( 5.1 ) Use in 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 ( 5.2 )

5.1 Risk of Hemorrhage Hemorrhage can occur at any site in the body in patients receiving argatroban [ see Adverse Reactions (6.1) ]. An unexplained fall in hematocrit or hemoglobin or a fall in blood pressure should lead to consideration of a hemorrhagic event. Argatroban in Sodium Chloride Injection should be used with extreme caution in disease states and other circumstances in which there is an increased danger of hemorrhage. These include 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.

5.2 Use in Hepatic Impairment When administering Argatroban in Sodium Chloride Injection 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 [see Use in Specific Populations (8.6) ]. 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 [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ]. Avoid the use of high doses of Argatroban in Sodium Chloride Injection in patients undergoing PCI who have clinically significant hepatic disease or AST/ALT levels ≥3 times the upper limit of normal.

5.3 Laboratory Tests Anticoagulation effects associated with argatroban infusion at doses up to 40 mcg/kg/min correlate with increases of the activated partial thromboplastin time (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 activated clotting time (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 [see Dosage and Administration (2.5) and Clinical Pharmacology (12.2) ] .

The following clinically significant adverse reactions are described elsewhere in 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 Accord Healthcare Inc. at 1-866-941-7875 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse event 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. Adverse Reactions in Patients with HIT (With or Without Thrombosis) 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). *with or without thrombosis a) Patients may have experienced more than 1 adverse reaction. b) One patient experienced intracranial hemorrhage 4 days after discontinuation of argatroban and following therapy with urokinase and oral anticoagulation. c) 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. DIC = disseminated intravascular coagulation. BKA = below-the-knee amputation Table 4. Major and Minor Hemorrhagic Adverse Reactions in Patients With HIT* Argatroban-treated Patients (Study 1 and Study 2) (n = 568) % Historical Control c (n = 193) % Major Hemorrhagic Reactions a 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 b

0.5 Minor Hemorrhagic Reactions a 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 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. a) Patients may have experienced more than 1 adverse reaction. b) with or without thrombosis c) 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. Table 5. Non-hemorrhagic Adverse Reactions in Patients a With HIT b Argatroban-treated Patients (Study 1 and Study 2) (n = 568) % Historical Control c (n = 193) % Dyspnea 8.1

8.8 Hypotension 7.2

2.6 Fever 6.9

2.1 Diarrhea 6.2

1.6 Sepsis 6

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

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 Adverse Reactions in Patients with or at Risk for HIT Patients 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 transfusion of ≥2 units, or that was intracranial, retroperitoneal, or into a major prosthetic joint. The rate of major bleeding reactions in patients treated with argatroban in the PCI trials was 1.8%. a) Patients may have experienced more than 1 adverse reaction. b) 91 patients who underwent 112 interventions. CABG = coronary artery bypass graft Table 6. Major and Minor Hemorrhagic Adverse Reactions in Patients With HIT Undergoing PCI Major Hemorrhagic Reactions a Argatroban-treated Patients (n = 112) b % Retroperitoneal

0.9 Gastrointestinal

0.9 Intracranial 0 Minor Hemorrhagic Reactions a Groin (bleeding or hematoma)

3.6 Gastrointestinal (includes hematemesis)

2.6 Genitourinary (includes hematuria)

1.8 Decrease in hemoglobin and/or hematocrit 1.8 CABG (coronary arteries)

1.8 Access site

0.9 Hemoptysis

0.9 Other

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

15.2 Hypotension

10.7 Back pain 8 Nausea

7.1 Vomiting

6.3 Headache

5.4 Bradycardia

4.5 Abdominal pain

3.6 Fever

3.6 Myocardial infarction

3.6 There 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. a) Individual reactions may also have been reported elsewhere (see Table 6 and Table 7 ). b) 91 patients underwent 112 procedures. Some patients may have experienced more than 1 reaction. Table 8. Serious Adverse Reaction in Patients With HIT Undergoing PCI a Adverse Reaction Argatroban Procedures b (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 disorder 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 [see Drug Interactions (7.4) ] . 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. […]

Heparin: Allow sufficient time for heparin's effect on aPTT to decrease before initiating Argatroban in Sodium Chloride 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.

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 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 (during gestation Days 7 to 17) 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 (during gestation Days 6 to 18) 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 Risk Summary There are no data on the presence of argatroban in human milk, or its effects on milk production. Argatroban is present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Argatroban in Sodium Chloride Injection and any potential adverse effects on the breastfed infant from Argatroban or from the underlying maternal condition. Data Argatroban is detected in rat milk.

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 <6 months, n = 8; six months to <8 years, n = 6; 8 to 16 years, n = 4. All patients had serious underlying conditions and were receiving multiple concomitant medications. Thirteen patients received argatroban solely as a continuous infusion (no bolus dose). Dosing was initiated in the majority of these 13 patients at 1 mcg/kg/min and subsequently titrated as needed to achieve and maintain an aPTT of 1.5 to 3 times the baseline value. Most patients required multiple dose adjustments to maintain anticoagulation parameters within the desired range. During the 30-day study period, thrombotic events occurred during argatroban administration to two patients: one patient experienced an intracranial hemorrhage after 4 days of argatroban therapy in the setting of sepsis and thrombocytopenia and another patient experienced an intracranial hemorrhage after receiving argatroban for greater than 14 days. The study findings did not establish the safe and effective use of argatroban in pediatric patients and the dosing of 1 mcg/kg/min was not supported by the pharmacometric data described below. Pediatric Pharmacokinetics (PK) and Pharmacodynamics (PD) PK parameters of argatroban were characterized in population PK/PD analysis model with sparse data from 15 seriously ill pediatric patients. Argatroban clearance in these seriously ill pediatric patients (0.16 L/hr/kg) was 50% lower compared to argatroban clearance in healthy adults (0.31 L/hr/kg). Four pediatric patients with elevated bilirubin (secondary to cardiac complications or hepatic impairment) had, on average, 80% lower clearance (0.03 L/hr/kg) when compared to pediatric patients with normal bilirubin levels. These PK/PD analysis models based on a goal of aPTT prolongation of 1.5 to 3 times the baseline value and avoidance of an aPTT > 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 health 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 of argatroban is not established in pediatric patients. In addition, the described dosage did not take into account multiple factors that could affect the dosage such as current aPTT, target aPTT, and the clinical status of the patient.

8.5 Geriatric Use Of the total number of subjects (1340) in clinical studies of argatroban, 35% were 65 and over. In the clinical studies of adult patients with HIT (with or without thrombosis), the effectiveness of argatroban was not affected by age. No trends were observed across age groups for both aPTT and the ACT. The safety analysis did suggest that older patients tended to have an increased incidence of adverse reactions compared to younger patients; however, older patients had increased underlying conditions, which may predispose them to adverse reactions. The studies were not sized appropriately to detect differences in safety between age groups.

8.6 Hepatic Impairment Dose reduction and careful titration are required when administering argatroban to patients with hepatic impairment. Reversal of anticoagulation effect may be prolonged in this population [see Dosage and Administration (2.4) , Warnings and Precautions (5.2) , Clinical Pharmacology (12.3) ] .

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 (K i ) 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.