Argatroban

FULL PRESCRIBING INFORMATION

Indications and Usage for Argatroban

Heparin-Induced Thrombocytopenia

Argatroban Injection is indicated for prophylaxis or treatment of thrombosis in adult patients with heparin-induced thrombocytopenia (HIT).

Percutaneous Coronary Intervention

Argatroban Injection is indicated as an anticoagulant in adult patients with or at risk for HIT undergoing percutaneous coronary intervention (PCI).

Argatroban Dosage and Administration

Each 125 mL glass vial contains 125 mg of Argatroban (1mg/mL); and, as supplied, is ready for intravenous infusion. Dilution is not required.

Argatroban Injection is a clear, colorless to pale yellow solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Do not use if the solution is cloudy, contains precipitates, or if the flip-off seal is not intact.

Dosing in Patients With Heparin-Induced Thrombocytopenia

Initial Dosage:

Before administering Argatroban, discontinue heparin therapy and obtain a baseline aPTT. The recommended initial dose of Argatroban for adult patients without hepatic impairment is 2 mcg/kg/min, administered as a continuous infusion (see Table 1).

Table 1. Recommended Doses and Infusion Rates for 2 mcg/kg/min Dose of Argatroban for Patients With HIT* and Without Hepatic Impairment (1 mg/mL Concentration)
Body Weight (kg)	Dose (mcg/min)	Infusion Rate (mL/hr)
50	100	6
60	120	7
70	140	8
80	160	10
90	180	11
100	200	12
110	220	13
120	240	14
130	260	16
140	280	17

* with or without thrombosis

Monitoring Therapy:

For use in HIT, therapy with Argatroban Injection is monitored using the aPTT with a target range of 1.5 to 3 times the initial baseline value (not to exceed 100 seconds). Tests of anticoagulant effects (including the aPTT) typically attain steady-state levels within 1 to 3 hours following initiation of Argatroban Injection. Check the aPTT 2 hours after initiation of therapy and after any dose change to confirm that the patient has attained the desired therapeutic range.

Dosage Adjustment:

After the initiation of Argatroban Injection, adjust the dose (not to exceed 10 mcg/kg/min) as necessary to obtain a steady-state aPTT in the target range [see Clinical Studies (14.1)].

Dosing in Patients Undergoing Percutaneous Coronary Interventions

Initial Dosage:

Initiate an infusion of Argatroban Injection at 25 mcg/kg/min and administer a bolus of 350 mcg/kg via a large bore intravenous line over 3 to 5 minutes (see Table 2). Check an activated clotting time (ACT) 5 to 10 minutes after the bolus dose is completed. The PCI procedure may proceed if the ACT is greater than 300 seconds.

Dosage Adjustment:

If the ACT is less than 300 seconds, an additional intravenous bolus dose of 150 mcg/kg should be administered, the infusion dose increased to 30 mcg/kg/min, and the ACT checked 5 to 10 minutes later (see Table 2).

If the ACT is greater than 450 seconds, decrease the infusion rate to 15 mcg/kg/min, and check the ACT 5 to 10 minutes later (Table 3).

Continue titrating the dose until a therapeutic ACT (between 300 and 450 seconds) has been achieved; continue the same infusion rate for the duration of the PCI procedure.

In case of dissection, impending abrupt closure, thrombus formation during the procedure, or inability to achieve or maintain an ACT over 300 seconds, additional bolus doses of 150 mcg/kg may be administered and the infusion dose increased to 40 mcg/kg/min. Check the ACT after each additional bolus or change in the rate of infusion.

Table 2. Recommended Starting and Maintenance Doses (Within the Target ACT Range) of Argatroban Injection in Patients Undergoing PCI Without Hepatic Impairment (1 mg/mL Concentration)
Body Weight (kg)	Starting Bolus Dose (350 mcg/kg)		Starting and Maintenance Continuous Infusion Dosing For ACT 300-450 seconds 25 mcg/kg/min
	Bolus Dose (mcg)	Bolus Volume (mL)	Continuous Infusion Dose (mg/min)	Continuous Infusion Rate (mL/hr)
50	17500	18	1250	75
60	21000	21	1500	90
70	24500	25	1750	105
80	28000	28	2000	120
90	31500	32	2250	135
100	35000	35	2500	150
110	38500	39	2750	165
120	42000	42	3000	180
130	45500	46	3250	195
140	49000	49	3500	210

NOTE: 1 mg = 1000 mcg; 1 kg = 2.2 lbs

Table 3. Recommended Dose Adjustments of Argatroban Injection for Patients Outside of ACT Target Range Undergoing PCI Without Hepatic Impairment (1 mg/mL Concentration)
Body Weight (kg)	If ACT Less than 300 seconds Dosage Adjustment† 30 mcg/kg/min				If ACT Greater than 450 seconds Dosage Adjustment* 15 mcg/kg/min
	Additional Bolus Dose (mcg)	Bolus Volume (mL)	Continuous Infusion Dose (mcg/min)	Continuous Infusion Rate (mL/hr)	Continuous Infusion Dose (mcg/min)	Continuous Infusion Rate (mL/hr)
50	7500	8	1500	90	750	45
60	9000	9	1800	108	900	54
70	10500	11	2100	126	1050	63
80	12000	12	2400	144	1200	72
90	13500	14	2700	162	1350	81
100	15000	15	3000	180	1500	90
110	16500	17	3300	198	1650	99
120	18000	18	3600	216	1800	108
130	19500	20	3900	234	1950	117
140	21000	21	4200	252	2100	126

NOTE: 1 mg = 1000 mcg; 1 kg = 2.2 lbs

† Additional intravenous bolus dose of 150 mcg/kg should be administered if ACT less than 300 seconds.

* No bolus dose is given if ACT greater than 450 seconds

Monitoring Therapy:

For use in PCI, therapy with Argatroban Injection is monitored using ACT. Obtain ACTs before dosing, 5 to 10 minutes after bolus dosing, following adjustments in the infusion rate, and at the end of the PCI procedure. Obtain additional ACTs every 20 to 30 minutes during a prolonged procedure.

Continued Anticoagulation after PCI:

If a patient requires anticoagulation after the procedure, Argatroban Injection may be continued, but at a rate of 2 mcg/kg/min and adjusted as needed to maintain the aPTT in the desired range. [see Dosage and Administration (2.1)].

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)].

Dosing in Pediatric Patients With Heparin-Induced Thrombocytopenia/ Heparin-Induced Thrombocytopenia and Thrombosis Syndrome

Initial Dosage:

Initial Argatroban infusion doses are lower for seriously ill pediatric patients compared to adults with normal hepatic function [see Use in Specific Populations (8.4)].

Monitoring Therapy:

In general, therapy with Argatroban is monitored using the aPTT. Tests of anticoagulant effects (including the aPTT) typically attain steady-state levels within one to three hours following initiation of Argatroban in patients without hepatic impairment [see Warnings and Precautions (5.2)]. Dose adjustment may be required to attain the target aPTT. Check the aPTT two hours after initiation of therapy and after any dose change to confirm that the patient has attained the desired therapeutic range.

Dosage Adjustment: [see Use in Specific Populations (8.4)]

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 International Normalized Ratio (INR). To avoid prothrombotic effects and to ensure continuous anticoagulation when initiating warfarin, overlap Argatroban 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 (INRW) 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 Injection at Doses Up to 2 mcg/kg/min:

Measure INR daily while Argatroban Injection and warfarin are co-administered. In general, with doses of Argatroban Injection up to 2 mcg/kg/min, Argatroban Injection can be discontinued when the INR is >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.

Co-Administration of Warfarin and Argatroban 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 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.

Dosage Forms and Strengths

Argatroban Injection is supplied in a single use vial containing 125 mg Argatroban in 125 mL aqueous sodium chloride solution (1 mg/mL). The solution is ready for intravenous infusion.

Contraindications

Argatroban is contraindicated in:

• Patients with major bleeding,


• Patients with a history of hypersensitivity to Argatroban. Airway, skin, and generalized hypersensitivity reactions have been reported [see Adverse Reactions (6.4)].

Warnings and Precautions

Risk of Hemorrhage

Hemorrhage can occur at any site in the body in patients receiving Argatroban. An unexplained fall in hematocrit or hemoglobin or a fall in blood pressure should lead to consideration of a hemorrhagic event. Argatroban 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.

Use in Hepatic Impairment

Use caution when administering Argatroban to patients with hepatic impairment by starting with a lower dose and carefully titrating until the desired level of anticoagulation is achieved. 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)]. 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.

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)].

Adverse Reactions

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 Events 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 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*
Major Hemorrhagic Events*
	Argatroban- Treated Patients (Study 1 and Study 2) (n = 568) %	Historical Control† (n = 193) %
* with or without thrombosis
* Patients may have experienced more than 1 adverse event. † 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. ‡ One patient experienced intracranial hemorrhage 4 days after discontinuation of Argatroban and following therapy with urokinase and oral anticoagulation.
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‡	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

DIC = disseminated intravascular coagulation.

BKA = below-the-knee amputation.

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* With HIT†
	Argatroban- Treated Patients (Study 1 and Study 2) (n = 568) %	Historical Control‡ (n = 193) %
* Patients may have experienced more than 1 adverse event. † with or without thrombosis ‡ 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 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 events are separated into hemorrhagic (Table 6) and non-hemorrhagic (Table7) 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
Major Hemorrhagic Events*
	Argatroban-Treated Patients (n = 112)† %
* Patients may have experienced more than 1 adverse event. † 91 patients who underwent 112 interventions.
Retroperitoneal	0.9
Gastrointestinal	0.9
Intracranial	0
Minor Hemorrhagic Events*
	Argatroban-Treated Patients (n = 112)† %
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

CABG = coronary artery bypass graft.

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* in Patients With HIT Undergoing PCI
	Argatroban Procedures* (n = 112)† %
* Patients may have experienced more than 1 adverse event. † 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*
Coded Term	Argatroban Procedures† (n = 112)
* Individual events may also have been reported elsewhere (see Table 6 and 7). † 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 (