Eagle Pharmaceuticals, Inc.

Eagle Pharmaceuticals, Inc. Drugs

• Diclofenac Sodium And M...
  

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  Diclofenac Sodium And Misoprostol Delayed-release

  

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  Carefully consider the potential benefits and risks of diclofenac sodium and misoprostol delayed-release tablets and other treatment options before deciding to use diclofenac sodium and misoprostol delayed-release tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

  After observing the response to initial therapy with diclofenac sodium and misoprostol delayed-release tablets, the dose and frequency should be adjusted to suit an individual patient's needs.

  For the relief of rheumatoid arthritis and osteoarthritis the recommended dose is given below.

  Diclofenac sodium and misoprostol delayed-release tablets are administered as diclofenac sodium and misoprostol delayed-release tablets 50/0.2 mg (50 mg diclofenac sodium/200 mcg misoprostol) or as diclofenac sodium and misoprostol delayed-release tablets 75/0.2 mg (75 mg diclofenac sodium/200 mcg misoprostol).

  Note: See SPECIAL DOSING CONSIDERATIONS section, below.

  Osteoarthritis: The recommended dosage for maximal GI mucosal protection is diclofenac sodium and misoprostol delayed-release tablets 50/0.2 mg tid. For patients who experience intolerance, diclofenac sodium and misoprostol delayed-release tablets 75/0.2 mg bid or diclofenac sodium and misoprostol delayed-release tablets 50/0.2 mg bid can be used, but are less effective in preventing ulcers. This fixed combination product, diclofenac sodium and misoprostol delayed-release tablets, is not recommended for patients who would not receive the appropriate dose of both ingredients. Doses of the components delivered with these regimens are as follows:

  OA regimen Diclofenac sodium (mg/day) Misoprostol(mcg/day) Diclofenac sodium and misoprostol delayed-release tablets 50/0.2 mg tid 150 600 bid 100 400 Diclofenac sodium and misoprostol delayed-release tablets 75/0.2 mg bid 150 400

  Rheumatoid Arthritis: The recommended dosage is diclofenac sodium and misoprostol delayed-release tablets 50/0.2 mg tid or qid. For patients who experience intolerance, diclofenac sodium and misoprostol delayed-release tablets 75/0.2 mg bid or diclofenac sodium and misoprostol delayed-release tablets 50/0.2 mg bid can be used, but are less effective in preventing ulcers. This fixed combination product, diclofenac sodium and misoprostol delayed-release tablets, is not recommended for patients who would not receive the appropriate dose of both ingredients. Doses of the components delivered with these regimens are as follows:

  RA regimen Diclofenac sodium (mg/day) Misoprostol(mcg/day) Diclofenac sodium and misoprostol delayed-release tablets 50/0.2 mg qid 200 800 tid 150 600 bid 100 400 Diclofenac sodium and misoprostol delayed-release tablets 75/0.2 mg bid 150 400

  SPECIAL DOSING CONSIDERATIONS: Diclofenac sodium and misoprostol delayed-release tablets contain misoprostol, which provides protection against gastric and duodenal ulcers (see CLINICAL STUDIES). For gastric ulcer prevention, the 200 mcg qid and tid regimens are therapeutically equivalent, but more protective than the bid regimen. For duodenal ulcer prevention, the qid regimen is more protective than the tid or bid regimens. However, the qid regimen is less well tolerated than the tid regimen because of usually self-limited diarrhea related to the misoprostol dose (see ADVERSE REACTIONS— Gastrointestinal), and the bid regimen may be better tolerated than tid in some patients.

  Dosages may be individualized using the separate products (misoprostol and diclofenac), after which the patient may be changed to the appropriate dose of diclofenac sodium and misoprostol delayed-release tablets. If clinically indicated, misoprostol co-therapy with diclofenac sodium and misoprostol delayed-release tablets, or use of the individual components to optimize the misoprostol dose and/or frequency of administration, may be appropriate. The total dose of misoprostol should not exceed 800 mcg/day, and no more than 200 mcg of misoprostol should be administered at any one time. Doses of diclofenac higher than 150 mg/day in osteoarthritis or higher than 225 mg/day in rheumatoid arthritis are not recommended.

  For additional information, it may be helpful to refer to the package inserts for misoprostol immediate release tablets and diclofenac sodium delayed release tablets.

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• Ryanodex Dantrolene Sod...
  

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  Ryanodex Dantrolene Sodium

  

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  2.1 Dosage for Treatment of Malignant Hyperthermia

  In addition to RYANODEX treatment, institute the following supportive measures:

  Discontinue use of malignant hyperthermia (MH)-triggering anesthetic agents (i.e., volatile anesthetic gases and succinylcholine). Manage the metabolic acidosis Institute cooling when necessary Administer diuretics to prevent late kidney injury due to myoglobinuria (the amount of mannitol in RYANODEX is insufficient to maintain diuresis) [see Description (11)]

  Administer RYANODEX by intravenous push at a minimum dose of 1 mg/kg. If the physiologic and metabolic abnormalities of MH continue, administer additional intravenous boluses up to the maximum cumulative dosage of 10 mg/kg.

  If the physiologic and metabolic abnormalities reappear, repeat RYANODEX dosing by intravenous push starting with 1 mg/kg.

  2.2 Dosage for Prevention of Malignant Hyperthermia

  The recommended prophylactic dose of RYANODEX is 2.5 mg/kg administered intravenously over a period of at least 1 minute, starting approximately 75 minutes prior to surgery. Avoid agents that trigger MH.

  If surgery is prolonged, administer additional individualized RYANODEX doses during anesthesia and surgery [see Clinical Pharmacology (12.3)].

  2.3 Dosage for Pediatric Patients

  The recommended weight-based dose of RYANODEX for pediatric patients in the treatment and prevention of MH is the same as for adults for these indications [see Dosage and Administration (2.1, 2.2)].

  2.4 Reconstitution and Administration Instructions

  The supplied lyophilized powder must be reconstituted prior to administration:

  Reconstitute each vial of RYANODEX lyophilized powder by adding 5 mL of sterile water for injection (without a bacteriostatic agent). Do not reconstitute with any other solution (e.g., 5% dextrose injection, 0.9% sodium chloride injection). Shake the vial to ensure an orange-colored uniform suspension. Visually inspect the vial for particulate matter and discoloration prior to administration. Must use the contents of the vial within 6 hours after reconstitution. Store reconstituted suspensions at controlled room temperature (68°F to 77°F or 20°C to 25°C).

  Do not dilute or transfer the reconstituted RYANODEX suspension to another container to infuse the product.

  Administer the reconstituted RYANODEX suspension either:

  Into the intravenous catheter while an intravenous infusion of 0.9% sodium chloride injection, or 5% dextrose injection is freely running; or Into the indwelling catheter - after assuring its patency - without a freely running infusion. Flush the line to assure that there is no residual RYANODEX remaining in the catheter [see Warnings and Precautions (5.3)].

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• Argatroban
  

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  Argatroban

  

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  Each 50 mL glass vial contains 50 mg argatroban (1 mg/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 solution is cloudy, contains precipitates, or if the white flip top cap is not intact.

  Vial may be inverted for use with a medical infusion set.

  2.1 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)

  *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)].

  2.2 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 2).

  If the ACT is greater than 450 seconds, the infusion rate should be decreased to 15 mcg/kg/min, and the ACT checked 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)

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

  Body Weight (kg) Starting Bolus Dose (350 mcg/kg) Starting 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 Table 3. Recommended Dose Adjustments of Argatroban Injection for Patients Outside of ACT Target Range Undergoing PCI Without Hepatic Impairment (1 mg/mL 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)].

  2.3 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 who have HIT or are at risk for HIT, carefully titrate argatroban until the desired level of anticoagulation is achieved. Use of Argatroban in PC 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)].

  2.4 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)]

  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 the 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 coadministered. 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 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.

  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.

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• Argatroban
  

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  Argatroban

  

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  Each 50 mL glass vial contains 50 mg argatroban (1 mg/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 solution is cloudy, contains precipitates, or if the white flip top cap is not intact.

  Vial may be inverted for use with a medical infusion set.

  2.1 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)

  *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)].

  2.2 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 2).

  If the ACT is greater than 450 seconds, the infusion rate should be decreased to 15 mcg/kg/min, and the ACT checked 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)

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

  Body Weight (kg) Starting Bolus Dose (350 mcg/kg) Starting 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 Table 3. Recommended Dose Adjustments of Argatroban Injection for Patients Outside of ACT Target Range Undergoing PCI Without Hepatic Impairment (1 mg/mL 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)].

  2.3 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 who have HIT or are at risk for HIT, carefully titrate argatroban until the desired level of anticoagulation is achieved. Use of Argatroban in PC 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)].

  2.4 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)]

  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 the 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 coadministered. 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 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.

  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.

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