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Argatroban Injection, USP Dosage and Administration

2 DOSAGE AND ADMINISTRATION

Argatroban Injection must be diluted 100-fold prior to infusion. Argatroban Injection should not be mixed with other drugs prior to dilution.

2.1 Preparation for Intravenous Administration

Argatroban Injection should be diluted in 0.9% Sodium Chloride Injection, 5% Dextrose Injection, or Lactated Ringer's Injection to a final concentration of 1 mg/mL. The contents of each 2.5-mL vial should be diluted 100-fold by mixing with 250 mL of diluent. Use 250 mg (2.5 mL) per 250 mL of diluent or 500 mg (5 mL) per 500 mL of diluent.

The constituted solution must be mixed by repeated inversion of the diluent bag for 1 minute. Upon preparation, the solution may show slight but brief haziness due to the formation of microprecipitates that rapidly dissolve upon mixing. Use of diluent at room temperature is recommended. Colder temperatures can slow down the rate of dissolution of precipitates. The final solution must be clear before use. The pH of the intravenous solution prepared as recommended is 3.2 to 7.5. Solutions prepared as recommended are stable at controlled room temperature, 20°C to 25°C (68°F to 77°F) (see USP) in ambient indoor light for 24 hours; therefore, light-resistant measures such as foil protection for intravenous lines are unnecessary. Solutions are physically and chemically stable for up to 96 hours when protected from light and stored at controlled room temperature, 20°C to 25°C (68°F to 77°F) (see USP), or at refrigerated conditions, 5°C± 3°C (41°F± 5°F). Prepared solutions should not be exposed to direct sunlight. No significant potency losses have been noted following simulated delivery of the solution through intravenous tubing.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

2.2 Dosing in Patients with Heparin-Induced Thrombocytopenia

Initial Dosage

Before administering argatroban, discontinue heparin therapy and obtain a baseline activated partial thromboplastin time (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 Final Concentration)
*
with or without thrombosis

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

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)].

2.3 Dosing in Patients Undergoing Percutaneous Coronary Intervention

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 3).

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 Final Concentration)
NOTE: 1 mg = 1000 mcg; 1 kg = 2.2 lbs

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
(mcg/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

Table 3 Recommended Dose Adjustments of Argatroban Injection for Patients Outside of ACT Target Range Undergoing PCI Without Hepatic Impairment (1 mg/mL Final Concentration)
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

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

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)].

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 ≥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 co-administration 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.

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 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.

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