Argatroban Drug Information

Heparin-Induced Thrombocytopenia Argatroban Injection is indicated for prophylaxis or treatment of thrombosis

in adult patients with heparin-induced thrombocytopenia (HIT).

Percutaneous Coronary Intervention Argatroban Injection is indicated as an anticoagulant in adult

patients with or at risk for HIT undergoing percutaneous coronary intervention (PCI).

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 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* Major Hemorrhagic Reactions a Argatroban-treated Patients (Study 1 and Study 2) (n = 568) % Historical Control c (n = 193) % Overall bleeding 5.3

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

Minor Hemorrhagic Reactions a Argatroban-treated Patients (Study 1 and Study 2) (n

= 568) % Historical Control c (n = 193) % Gastrointestinal 14.4

Genitourinary and hematuria 11.6 0.8 Decrease in hemoglobin and hematocrit 10.4 0

Groin 5.4

Hemoptysis 2.9 0.8 Brachial 2.4 0.8 * 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 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 a With HIT b Argatroban-treated Patients (Study 1 and Study 2) (n = 568) % Historical Control c (n = 193) % Dyspnea 8.1

Hypotension 7.2 2.6 Fever 6.9 2.1 Diarrhea 6.2 1.6 Sepsis 6.0 12.4

Cardiac arrest 5.8

Nausea 4.8 0.5 Ventricular tachycardia 4.8 3.1 Pain 4.6 3.1 Urinary tract

infection 4.6

Coughing 2.8 1.6 Abnormal renal function 2.8 4.7 Abdominal pain 2.6 1.6

Cerebrovascular disorder 2.3 4.1 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. Adverse 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 a Argatroban-treated Patients (n = 112) b % Retroperitoneal

Gastrointestinal 0.9 Intracranial 0 Minor Hemorrhagic Reactions a Argatroban-treated Patients (n =

112) b % Groin (bleeding or hematoma)

Gastrointestinal (includes hematemesis) 2.6 Genitourinary (includes hematuria) 1.8 Decrease in hemoglobin and/or

hematocrit

CABG (coronary arteries) 1.8 Access site 0.9 Hemoptysis 0.9 Other 0.9 a)

Patients may have experienced more than 1 adverse reaction. b) 91 patients who underwent 112 interventions. CABG = coronary artery bypass graft. Table 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 a in Patients With HIT Undergoing PCI Argatroban Procedures a (n = 112) b % Chest pain

Abdominal pain 3.6 Fever 3.6 Myocardial infarction 3.6 a) Patients may have

experienced more than 1 adverse reaction. b) 91 patients who underwent 112 interventions. 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. Table 8 Serious Adverse Reactions in Patients With HIT Undergoing PCI a Coded Term 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 1 (0.9%) Vascular disorder 1 (0.9%) a) Individual reactions may also have been reported elsewhere (see Table 6 and 7). b) 91 patients underwent 112 procedures. Some patients may have experienced more than 1 reaction.

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.

Postmarketing 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

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.

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).

Aspirin/Acetaminophen No drug-drug interactions have been demonstrated between argatroban and concomitantly administered

aspirin or acetaminophen.

Thrombolytic Agents

The safety and effectiveness of argatroban with thrombolytic agents have not been established .

Glycoprotein IIb/IIIa Antagonists

The safety and effectiveness of argatroban with glycoprotein IIb/IIIa antagonists have not been established.

Pregnancy 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 (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%-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 . L abor 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.

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. Dosing was 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 and following argatroban discontinuation in three other patients. Major bleeding occurred among 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 pharmacokinetic 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 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 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.

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

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. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.