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)
1.1Heparin-Induced Thrombocytopenia Argatroban
in sodium chloride injection is indicated for prophylaxis or treatment of thrombosis in adult patients with heparin-induced thrombocytopenia (HIT).
1.2Percutaneous 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).
Contraindications
Argatroban in sodium chloride injection is contraindicated in: Patients with major bleeding, [ see Warnings and Precautions (5.1) ] Patients with a history of hypersensitivity to argatroban products. Airway, skin, and generalized hypersensitivity reactions have been reported [ see Adverse Reactions (6.1) ] . Major bleeding (4) History of hypersensitivity to this product (4)
Warnings and precautions
Risk of hemorrhage: Hemorrhage at any site can occur (unexplained fall in hematocrit of 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 )
Hemorrhage can occur at any site in the body in patients receiving Argatroban in sodium chloride injection. An unexplained fall in hematocrit or hemoglobin or a fall in blood pressure may indicate hemorrhage. Intracranial and retroperitoneal hemorrhage [ see Adverse Reactions (6.1) ] have been reported. The risk of hemorrhage with Argatroban in sodium chloride injection 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 in sodium chloride injection with antiplatelet agents, thrombolytics, and other anticoagulants may increase the risk of bleeding.
5.2Use 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 in sodium chloride injection 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 in sodium chloride injection 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.
5.3Laboratory Tests
Anticoagulation effects associated with Argatroban in sodium chloride injection 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 in sodium chloride injection, the therapeutic ranges for these tests have not been identified for Argatroban in sodium chloride injection 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 in sodium chloride injection 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) ] .
Interactions
7.1Heparin If Argatroban
in sodium chloride injection 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 in sodium chloride injection therapy.
7.2Oral Anticoagulant Agents
Pharmacokinetic drug-drug interactions between Argatroban in sodium chloride injection and warfarin (7.5 mg single oral dose) have not been demonstrated. However, the concomitant use of Argatroban in sodium chloride injection 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) , Clinical Pharmacology (12.2) ] .
7.3Aspirin/Acetaminophen
No drug-drug interactions have been demonstrated between Argatroban in sodium chloride injection and concomitantly administered aspirin or acetaminophen [ see Clinical Pharmacology (12.3) ] .
7.4Thrombolytic Agents
The safety and effectiveness of Argatroban in sodium chloride injection with thrombolytic agents have not been established [ see Adverse Reactions (6.1) ].
7.5Glycoprotein IIb/IIIa Antagonists
The safety and effectiveness of Argatroban in sodium chloride injection with glycoprotein IIb/IIIa antagonists have not been established.
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
Limited data from published literature and postmarketing reports do not suggest an association between Argatroban in sodium chloride injection 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 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 in sodium chloride injection, 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 in sodium chloride injection 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 dose for humans, based on body surface area) have revealed no evidence of harm to the fetus.
Adverse reactions
The following serious 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 Eugia US LLC at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical 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 adverse reactions, presented separately by major and minor bleeding, sorted by decreasing occurrence among argatroban-treated patients with HIT (with or without thrombosis).
Table 4. DIC = disseminated intravascular coagulation. BKA = below-the-knee amputation. 1. with or without thrombosis 2. Patients may have experienced more than 1 adverse reaction. 3. One patient experienced intracranial hemorrhage 4 days after discontinuation of argatroban and following therapy with urokinase and oral anticoagulation. 4. 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.
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 4 (n = 193) % Overall bleeding 5.3
6.7 Gastrointestinal 2.3
1.6Genitourinary
and hematuria 0.9
0.5Decrease
in hemoglobin and hematocrit 0.7 0 Multisystem hemorrhage and DIC 0.5 1 Limb and BKA stump 0.5 0 Intracranial hemorrhage 0 3
0.5Minor Hemorrhagic Reactions 2 Argatroban-Treated Patients (Study 1 and Study 2)
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. 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 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
4.1Adverse 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 a 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%. Table 6. CABG = coronary artery bypass graft. 1. Patients may have experienced more than 1 adverse reaction. 2. 91 patients who underwent 112 interventions. Major and Minor Hemorrhagic Adverse Reactions in Patients With HIT Undergoing PCI Major Hemorrhagic Reactions 1 Argatroban-Treated Patients (n = 112) 2 % Retroperitoneal
0.9 Gastrointestinal
0.9Intracranial 0 Minor Hemorrhagic Reactions 1 Argatroban-Treated Patients
(n = 112) 2 % Groin (bleeding or hematoma)
3.6Gastrointestinal
(includes hematemesis)
2.6Genitourinary
(includes hematuria)
1.8Decrease
in hemoglobin and/or hematocrit
1.8CABG
(coronary arteries)
1.8 Access site
0.9 Hemoptysis
0.9 Other
0.9Table
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. 1. Patients may have experienced more than 1 adverse reaction. 2. 91 patients who underwent 112 interventions. Non-hemorrhagic Adverse Reactions 1 in Patients With HIT Undergoing PCI Argatroban Procedures 1 (n = 112) 2 % 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 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. 1. Individual adverse reactions may also have been reported elsewhere (see Table 6 and 7). 2. 91 patients underwent 112 procedures. Some patients may have experienced more than 1 adverse reaction. Serious Adverse Reactions in Patients With HIT Undergoing PCI 1 Coded Term Argatroban Procedures 2 (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 in sodium chloride injection 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 intracran
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Composition
Active ingredients
ARGATROBAN 50MG/50ML (1MG/ML)
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
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