ARGATROBAN
Generic: ARGATROBAN
Basic Information
Manufacturer
Accord Healthcare Inc.
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
INTRAVENOUS
FDA Set ID
46cdf9e6-839c-49c8-9ee1-c30cfdd9368d
Indications & Usage
1 INDICATIONS AND USAGE 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).
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).
Adverse Reactions
6 ADVERSE REACTIONS 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.
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.
6.2 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
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.
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.
6.2 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