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warnings and cautions
5 WARNINGS AND PRECAUTIONS • Hemorrhage can occur. Unexplained fall in hematocrit or blood pressure may indicate hemorrhage. ( 5.1 ) • 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. Unexplained fall in hematocrit or blood pressure may indicate hemorrhage. Intracranial and retroperitoneal hemorrhage [see Adverse Reactions (6.1 )] 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. 5.2 Use 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 [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 (2.3) and Clinical Pharmacology (12.3) ] . 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. 5.3 Laboratory 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 [see Dosage and Administration (2.5) and Clinical Pharmacology (12.2) ] .
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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Adverse Events in Patients with HIT (with or without Thrombosis) 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. 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 events were collected retrospectively. Adverse events are separated into hemorrhagic and non-hemorrhagic events. 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 Events in Patients with HIT with or without thrombosis DIC = disseminated intravascular coagulation. BKA = below-the-knee amputation. Major Hemorrhagic Events Patients may have experienced more than 1 adverse event. 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 6.7 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 One patient experienced intracranial hemorrhage 4 days after discontinuation of argatroban and following therapy with urokinase and oral anticoagulation. 0.5 Minor Hemorrhagic Events Argatroban-Treated Patients (Study 1 and Study 2) (n = 568) % Historical Control (n = 193) % 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 events sorted by decreasing frequency of occurrence (≥ 2%) among argatroban-treated HIT/HITTS patients. Table 5: Non-hemorrhagic Adverse Events in Patients Patients may have experienced more than 1 adverse event. 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 8.8 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 Adverse Events 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 events are separated into hemorrhagic (Table 6) and non-hemorrhagic (Table 7) events. 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 Events in Patients with HIT Undergoing PCI CABG = coronary artery bypass graft. Major Hemorrhagic Events Patients may have experienced more than 1 adverse event. Argatroban-Treated Patients (n = 12) 91 patients who underwent 112 interventions. % Retroperitoneal 0.9 Gastrointestinal 0.9 Intracranial 0 Minor Hemorrhagic Events Argatroban-Treated Patients (n = 12) % 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 events (> 2%), sorted by decreasing frequency of occurrence among argatroban-treated PCI patients. Table 7: Non-hemorrhagic Adverse Events Patients may have experienced more than 1 adverse event. in Patients with HIT Undergoing PCI Argatroban Procedures (n = 112) 91 patients who underwent 112 interventions. % Chest pain 15.2 Hypotension 10.7 Back pain 8.0 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 events in 17 PCI patients (19.6% in 112 interventions). Table 8 lists the serious adverse events occurring in argatroban-treated patients with or at risk for HIT undergoing PCI. Table 8: Serious Adverse Events in Patients with HIT Undergoing PCI Individual events may also have been reported elsewhere (see Table 6 and 7). Coded Term Argatroban Procedures 91 patients underwent 112 procedures. Some patients may have experienced more than 1 event. (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 [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. 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.
adverse reactions table
<table ID="_RefID0ELEAG" width="100%"><caption>Table 4: Major and Minor Hemorrhagic Adverse Events in Patients with HIT<footnote ID="_Ref383436719">with or without thrombosis</footnote></caption><col width="46%"/><col width="29%"/><col width="25%"/><tfoot><tr><td align="left" colspan="3" valign="top">DIC = disseminated intravascular coagulation. </td></tr><tr><td align="left" colspan="3" valign="top">BKA = below-the-knee amputation. </td></tr></tfoot><tbody><tr><td align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Major Hemorrhagic Events</content><footnote ID="_Ref383436725">Patients may have experienced more than 1 adverse event.</footnote></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Argatroban-Treated</content></paragraph><paragraph><content styleCode="bold">Patients (Study 1 and Study 2)</content></paragraph><paragraph><content styleCode="bold">(n = 568)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Historical Control</content><footnote ID="_Ref383436732">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.</footnote></paragraph><paragraph><content styleCode="bold">(n = 193)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Overall bleeding </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5.3</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6.7</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Gastrointestinal </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2.3</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.6</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Genitourinary and hematuria </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.9</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.5</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Decrease in hemoglobin and hematocrit </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.7</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Multisystem hemorrhage and DIC </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.5</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Limb and BKA stump </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.5</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Intracranial hemorrhage </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0<footnote ID="_Ref383436771">One patient experienced intracranial hemorrhage 4 days after discontinuation of argatroban and following therapy with urokinase and oral anticoagulation.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.5</paragraph></td></tr><tr><td align="center" colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Minor Hemorrhagic Events</content><footnoteRef IDREF="_Ref383436725"/></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Argatroban-Treated</content></paragraph><paragraph><content styleCode="bold">Patients (Study 1 and Study 2)</content></paragraph><paragraph><content styleCode="bold">(n = 568)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Historical Control</content><footnoteRef IDREF="_Ref383436732"/></paragraph><paragraph><content styleCode="bold">(n = 193)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Gastrointestinal </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>14.4</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18.1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Genitourinary and hematuria </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11.6</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.8</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Decrease in hemoglobin and hematocrit </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>10.4</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Groin </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5.4</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3.1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Hemoptysis </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2.9</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.8</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>Brachial </paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>2.4</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>0.8</paragraph></td></tr></tbody></table>