Argatroban

ARGATROBAN- argatroban injection
Par Pharmaceutical, Inc.

1 INDICATIONS AND USAGE

1.1 Heparin-Induced Thrombocytopenia

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

1.2 Percutaneous Coronary Intervention

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

2 DOSAGE AND ADMINISTRATION

2.1 Preparation for Intravenous Administration

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

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)
Body Weight (kg) Dose (mcg/min) Infusion Rate (mL/hr)
*
with or without thrombosis

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

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)
*
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

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

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