ARGATROBAN (Page 2 of 6)

2.4 Dosing in Patients with Hepatic Impairment

For adult patients with HIT and moderate or severe hepatic impairment (based on Child-Pugh classification), an initial dose of 0.5 mcg/kg/min is recommended, based on the approximately 4-fold decrease in argatroban clearance relative to those with normal hepatic function. Monitor the aPTT closely, and adjust the dosage as clinically indicated.

Monitoring Therapy

Achievement of steady state aPTT levels may take longer and require more dose adjustments in patients with hepatic impairment compared to patients with normal hepatic function.

For patients with hepatic impairment undergoing PCI and who have HIT or are at risk for HIT, carefully titrate argatroban until the desired level of anticoagulation is achieved. Use of Argatroban in PCI patients with clinically significant hepatic disease or AST/ALT levels ≥3 times the upper limit of normal should be avoided [see Warnings and Precautions (5.2)] .

2.5 Conversion to Oral Anticoagulant Therapy

Initiating Oral Anticoagulant Therapy

When converting patients from Argatroban in Sodium Chloride Injection to oral anticoagulant therapy, consider the potential for combined effects on International Normalized Ratio (INR). To avoid prothrombotic effects and to ensure continuous anticoagulation when initiating warfarin, overlap Argatroban in Sodium Chloride Injection and warfarin therapy. There are insufficient data available to recommend the duration of the overlap. Initiate therapy using the expected daily dose of warfarin. A loading dose of warfarin should not be used.

The relationship between INR and bleeding risk is altered when argatroban and warfarin are co-administered. The combination of argatroban and warfarin does not cause further reduction in the vitamin-K dependent factor Xa activity than that which is seen with warfarin alone. The relationship between INR obtained on combined therapy and INR obtained on warfarin alone is dependent on both the dose of argatroban and the thromboplastin reagent used. The INR value on warfarin alone (INR _w ) can be calculated from the INR value on combination argatroban and warfarin therapy [see Drug Interactions (7.2) and Clinical Pharmacology (12.2)] .

Co-Administration of Warfarin and Argatroban in Sodium Chloride injection at Doses Up to 2 mcg/kg/min:

Measure INR daily while Argatroban in Sodium Chloride Injection and warfarin are co-administered. In general, with doses of Argatroban in Sodium Chloride Injection up to 2 mcg/kg/min, Argatroban in Sodium Chloride Injection can be discontinued when the INR is > 4 on combined therapy. After Argatroban in Sodium Chloride Injection is discontinued, repeat the INR measurement in 4 to 6 hours. If the repeat INR is below the desired therapeutic range, resume the infusion of Argatroban in Sodium Chloride Injection and repeat the procedure daily until the desired therapeutic range on warfarin alone is reached.

Co-Administration of Warfarin and Argatroban in Sodium Chloride injection at Doses Greater than 2 mcg/kg/min:

For doses greater than 2 mcg/kg/min, the relationship of INR between warfarin alone to the INR on warfarin plus argatroban is less predictable. In this case, in order to predict the INR on warfarin alone, temporarily reduce the dose of Argatroban in Sodium Chloride Injection to a dose of 2 mcg/kg/min. Repeat the INR on Argatroban in Sodium Chloride Injection and warfarin 4 to 6 hours after reduction of the Argatroban in Sodium Chloride Injection dose and follow the process outlined above for administering Argatroban in Sodium Chloride Injection at doses up to 2 mcg/kg/min.

3 DOSAGE FORMS AND STRENGTHS

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

4 CONTRAINDICATIONS

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)] .

5 WARNINGS AND PRECAUTIONS

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)] .

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Risk of Hemorrhage [see Warnings and Precautions (5.1)]

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.