ARGATROBAN (Page 2 of 6)

2.4 Dosing in Patients with Hepatic Impairment

Initial Dosage:

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 greater than or equal to 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 to oral anticoagulant therapy, consider the potential for combined effects on INR with coadministration of argatroban and warfarin. A loading dose of warfarin should not be used. Initiate therapy using the expected daily dose of warfarin. To avoid prothrombotic effects and to ensure continuous anticoagulation when initiating warfarin, it is suggested that argatroban and warfarin therapy be overlapped. There are insufficient data available to recommend the duration of the overlap.

CoAdministration of Warfarin and Argatroban Injection at Doses up to 2 mcg/kg/min:

Measure INR daily while Argatroban Injection and warfarin are coadministered. In general, with doses of Argatroban Injection up to 2 mcg/kg/min, Argatroban Injection can be discontinued when the INR is greater than 4 on combined therapy. After Argatroban 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 Injection and repeat the procedure daily until the desired therapeutic range on warfarin alone is reached.

CoAdministration of Warfarin and Argatroban Injection at Doses Greater than 2 mcg/kg/min:

For doses of argatroban 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 Injection to a dose of 2 mcg/kg/min. Repeat the INR on Argatroban Injection and warfarin 4 to 6 hours after reduction of the Argatroban Injection dose and follow the process outlined above for administering Argatroban Injection at doses up to 2 mcg/kg/min.

3 DOSAGE FORMS AND STRENGTHS

250 mg of argatroban in 2.5 mL of sterile solution for injection in a single-dose vial.

4 CONTRAINDICATIONS

Argatroban is contraindicated in

Patients with major bleeding [see Warnings and Precautions (5.1)].
Patients with 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. Unexplained fall in hematocrit or blood pressure may indicate hemorrhage. Intracranial and retroperitoneal hemorrhage [see Adverse Reactions (6.1)] has 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 greater than or equal to 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)].

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 greater than or equal to 2 g/dL, that led to a transfusion of greater than or equal to 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 thrombosisa) Patients may have experienced more than 1 adverse event.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.

Major Hemorrhagic Eventsa

Argatroban-Treated Patients (Study 1 and Study 2) (n = 568) %

Historical Controlc (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

0b

0.5

Minor Hemorrhagic Eventsa

Argatroban-Treated Patients (Study 1 and Study 2) (n = 568) %

Historical Controlc (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 (greater than or equal to 2%) among argatroban-treated HIT/HITTS patients.

Table 5: Non-hemorrhagic Adverse Events in Patientsa with HITb
Argatroban-Treated Patients (Study 1 and Study 2) (n = 568) % Historical Controlc (n = 193) %
a) Patients may have experienced more than 1 adverse event.b) with or without thrombosisc) 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.

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 greater than or equal to 5 g/dL, that led to a transfusion of greater than or equal to 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
a) Patients may have experienced more than 1 adverse event.b) 91 patients who underwent 112 interventions.CABG = coronary artery bypass graft.

Major Hemorrhagic Eventsa

Argatroban-Treated Patients (n = 12)b %

Retroperitoneal

0.9

Gastrointestinal

0.9

Intracranial

0

Minor Hemorrhagic Eventsa

Argatroban-Treated Patients (n = 12)b %

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 (greater than 2%), sorted by decreasing frequency of occurrence among argatroban-treated PCI patients.

Table 7: Non-hemorrhagic Adverse Eventsa in Patients with HIT Undergoing PCI
Argatroban Proceduresa (n = 112)b %
a) Patients may have experienced more than 1 adverse event.b) 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 PCIa
Coded Term Argatroban Proceduresb (n = 112)
a) Individual events 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 event.

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.

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