Argatroban

Argatroban

Usual Diluents

Standard Dilutions   [Amount of drug] [Infusion volume] [Infusion rate]

Stability / Miscellaneous

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. 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, 20º to 25ºC (68º to 77ºF) (see USP) in ambient indoor light for 24 hours; therefore, light-resistant measure 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, 20º to 25ºC (68º to 77ºF) (see USP) or at refrigerated conditions, 5º±3ºC (41º±5ºF). 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.
------
Important:   Also available as a pre-diluted product:  Argatroban Injection is supplied in a single use vial, containing 50mg Argatroban in 50 mL aqueous solution (1 mg/mL)
Storage:   Store the vials in original cartons at 20° - 25° C (68° - 77° F) (see USP Controlled Room Temperature). Do not refrigerate or freeze. Retain in the original carton to protect from light.

Argatroban Injection Single Use Vial
50 mg per 50 mL (1 mg per mL)
Do not dilute prior to administration
For Intravenous Infusion Only
------

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 .

Actions: Argatroban is a direct thrombin inhibitor that reversibly binds to the thrombin active site. It is capable of inhibiting the action of both free and clot-associated thrombin. No dosage adjustment is necessary in patients with renal dysfunction.

Indications: as an anticoagulant for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia. Argatroban is indicated as an anticoagulant in patients with or at risk for heparin-induced thrombocytopenia undergoing percutaneous coronary intervention (PCI). Excessive anticoagulation, with or without bleeding, may be controlled by discontinuing Argatroban or by decreasing the infusion dosage. In clinical studies at therapeutic levels, anticoagulation parameters generally return to baseline within 2 to 4 hours after discontinuation of the drug. Reversal of anticoagulant effect may take longer in patients with hepatic impairment.

Monitoring therapy: Tests of anticoagulant effects (including the aPTT) typically attain steady-state levels within 1-3 hours following initiation of Argatroban. Dose adjustment may be required to attain the target aPTT. Check the aPTT 2 hours after initiation of therapy to confirm that the patient has attained the desired therapeutic range.

Dosage adjustment: After the initial dose of Argatroban, the dose can be adjusted as clinically indicated (not to exceed 10 mcg/kg/min), until the steady-state aPTT is 1.5 to 3 times the initial baseline value (not to exceed 100 seconds). For patients with moderate hepatic impairment, an initial dose of 0.5 mcg/kg/min is recommended, based on the approximate 4-fold decrease in Argatroban clearance relative to those with normal hepatic function. The aPTT should be monitored closely and the dosage should be adjusted as clinically indicated

CLINICAL PHARMACOLOGY

Mechanism of Action
Argatroban is a direct thrombin inhibitor that reversibly binds to the thrombin active site. Argatroban does not require the co-factor antithrombin III for antithrombotic activity. Argatroban exerts its anticoagulant effects by inhibiting thrombin-catalyzed or -induced reactions, including fibrin formation; activation of coagulation factors V, VIII, and XIII; activation of protein C; and platelet aggregation.

Argatroban is highly selective for thrombin with an inhibitory constant (Ki) of 0.04 µM. At therapeutic concentrations, Argatroban has little or no effect on related serine proteases (trypsin, factor Xa, plasmin, and kallikrein).

Argatroban is capable of inhibiting the action of both free and clot-associated thrombin.

Argatroban does not interact with heparin-induced antibodies. Evaluation of sera in 12 healthy subjects and 8 patients who received multiple doses of Argatroban did not reveal antibody formation to Argatroban (see CLINICAL STUDIES).

Pharmacokinetics
Distribution: Argatroban distributes mainly in the extracellular fluid as evidenced by an apparent steady-state volume of distribution of 174 mL/kg (12.18 L in a 70-kg adult). Argatroban is 54% bound to human serum proteins, with binding to albumin and a1-acid glycoprotein being 20% and 34%, respectively.

Metabolism: The main route of Argatroban metabolism is hydroxylation and aromatization of the 3-methyltetrahydroquinoline ring in the liver. The formation of each of the 4 known metabolites is catalyzed in vitro by the human liver microsomal cytochrome P450 enzymes CYP3A4/5. The primary metabolite (M1) exerts 3- to 5-fold weaker anticoagulant effects than Argatroban. Unchanged Argatroban is the major component in plasma. The plasma concentrations of M1 range between 0% and 20% of that of the parent drug. The other metabolites (M2 to M4) are found only in very low quantities in the urine and have not been detected in plasma or feces. These data, together with the lack of effect of erythromycin (a potent CYP3A4/5 inhibitor) on Argatroban pharmacokinetics, suggest that CYP3A4/5-mediated metabolism is not an important elimination pathway in vivo.

Total body clearance is approximately 5.1 mL/kg/min (0.31 L/kg/hr) for infusion doses up to 40 mcg/kg/min. The terminal elimination half-life of Argatroban ranges between 39 and 51 minutes.

There is no interconversion of the 21-(R):21-(S) diastereoisomers. The plasma ratio of these diastereoisomers is unchanged by metabolism or hepatic impairment, remaining constant at 65:35 (± 2%).

Excretion: Argatroban is excreted primarily in the feces, presumably through biliary secretion. In a study in which 14C-Argatroban (5 mcg/kg/min) was infused for 4 hours into healthy subjects, approximately 65% of the radioactivity was recovered in the feces within 6 days of the start of infusion with little or no radioactivity subsequently detected. Approximately 22% of the radioactivity appeared in the urine within 12 hours of the start of infusion. Little or no additional urinary radioactivity was subsequently detected. Average percent recovery of unchanged drug, relative to total dose, was 16% in urine and at least 14% in feces

INDICATIONS AND USAGE
Argatroban is indicated as an anticoagulant for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia.

Argatroban is indicated as an anticoagulant in patients with or at risk for heparin-induced thrombocytopenia undergoing percutaneous coronary intervention (PCI).

CONTRAINDICATIONS
Argatroban is contraindicated in patients with overt major bleeding, or in patients hypersensitive to this product or any of its components (see WARNINGS).

WARNINGS
Argatroban is intended for intravenous administration. All parenteral anticoagulants should be discontinued before administration of Argatroban.

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

PRECAUTIONS

Hepatic Impairment
Caution should be exercised 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. 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 PRECAUTIONS, Pediatric Use). 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). Use of high doses of Argatroban in PCI patients with clinically significant hepatic disease or AST/ALT levels ≥3 times the upper limit of normal should be avoided. Such patients were not studied in PCI trials.

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. Plasma Argatroban concentrations also correlate well with anticoagulant effects (see CLINICAL PHARMACOLOGY).

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. Alternative approaches for monitoring concurrent Argatroban and warfarin therapy are described in a subsequent section (see DOSAGE AND ADMINISTRATION).

Drug Interactions
Heparin: Since heparin is contraindicated in patients with heparin-induced thrombocytopenia, the co-administration of Argatroban and heparin is unlikely for this indication. However, if Argatroban is to be initiated after cessation of heparin therapy, allow sufficient time for heparin’s effect on the aPTT to decrease prior to initiation of Argatroban therapy.

Aspirin/Acetaminophen: Pharmacokinetic or pharmacodynamic drug-drug interactions have not been demonstrated between Argatroban and concomitantly administered aspirin (162.5 mg orally given 26 and 2 hours prior to initiation of Argatroban 1 mcg/kg/min over 4 hours) or acetaminophen (1,000 mg orally given 12, 6, and 0 hours prior to, and 6 and 12 hours subsequent to, initiation of Argatroban 1.5 mcg/kg/min over 18 hours).

Oral Anticoagulant Agents: Pharmacokinetic drug-drug interactions between Argatroban and warfarin (7.5 mg single oral dose) have not been demonstrated. However, the concomitant use of Argatroban and warfarin (5 to 7.5 mg initial oral dose, followed by 2.5 to 6 mg/day orally for 6 to 10 days) results in prolongation of the prothrombin time (PT) and International Normalized Ratio (INR) (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Thrombolytic Agents: The safety and effectiveness of Argatroban with thrombolytic agents have not been established (see ADVERSE REACTIONS, Intracranial Bleeding).

Glycoprotein IIb/IIIa Antagonists: The safety and effectiveness of Argatroban with glycoprotein IIb/IIIa antagonists have not been established.

Co-Administration: Concomitant use of Argatroban with antiplatelet agents, thrombolytics, and other anticoagulants may increase the risk of bleeding (see WARNINGS). Drug-drug interactions have not been observed between Argatroban and digoxin or erythromycin (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions).

Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term studies in animals have been performed to evaluate the carcinogenic potential of Argatroban.

Argatroban was not genotoxic in the Ames test, the Chinese hamster ovary cell (CHO/HGPRT) forward mutation test, the Chinese hamster lung fibroblast chromosome aberration test, the rat hepatocyte, and WI-38 human fetal lung cell unscheduled DNA synthesis (UDS) tests, or the mouse micronucleus test.

Argatroban at intravenous doses up to 27 mg/kg/day (0.3 times the recommended maximum human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.

Pregnancy
Teratogenic Effects: Pregnancy Category B. Teratology studies have been performed in rats with intravenous doses up to 27 mg/kg/day (0.3 times the recommended maximum human dose based on body surface area) and rabbits at intravenous doses up to 10.8 mg/kg/day (0.2 times the recommended maximum human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to Argatroban. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers
Experiments in rats show that Argatroban is detected in milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Argatroban, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Geriatric Use
In the clinical studies of adult patients with HIT or HITTS, the effectiveness of Argatroban was not affected by age.

Pediatric Use
The safety and effectiveness of Argatroban, including the appropriate anticoagulation goals and duration of therapy, have not been established among pediatric patients.

Argatroban was studied among 18 seriously ill pediatric patients who required an alternative to heparin anticoagulation. Most patients were diagnosed with HIT or suspected HIT. Age ranges of patients were <6 months, n = 8; six months to <8 years, n = 6; 8 to 16 years, n = 4. All patients had serious underlying conditions and were receiving multiple concomitant medications. Thirteen patients received Argatroban solely as a continuous infusion (no bolus dose). Dosing was initiated in the majority of these 13 patients at 1 mcg/kg/min. Dosing was titrated as needed to achieve and maintain an aPTT of 1.5 to 3 times the baseline value. Most patients required multiple dose adjustments to maintain anticoagulation parameters within the desired range. During the 30-day study period, thrombotic events occurred during Argatroban administration to two patients and following Argatroban discontinuation in three other patients. Major bleeding occurred among two patients; one patient experienced an intracranial hemorrhage after 4 days of Argatroban therapy in the setting of sepsis and thrombocytopenia. Another patient completed 14 days of Argatroban treatment in the study, but experienced an intracranial hemorrhage while receiving Argatroban following completion of the study treatment period.

When Argatroban is used among seriously ill pediatric patients with HIT/HITTS who require an alternative to heparin and who have normal hepatic function, initiate a continuous infusion of Argatroban at a dose of 0.75 mcg/kg/min. Initiate the infusion at a dose of 0.2 mcg/kg/min among seriously ill pediatric patients with impaired hepatic function (see CLINICAL PHARMACOLOGY, Pharmacokinetics). Check the aPTT two hours after the initiation of the Argatroban infusion and adjust the dose to achieve the target aPTT. These dose recommendations are based upon a goal of aPTT prolongation of 1.5 to 3 times the baseline value and avoidance of an aPTT >100 seconds. Increments of 0.1 to 0.25 mcg/kg/min for pediatric patients with normal hepatic function and increments of 0.05 mcg/kg/min or lower for pediatric patients with impaired hepatic function may be considered but dose selection must take into account multiple factors including the current Argatroban dose, the current aPTT, target aPTT, and the clinical status of the patient. These dose recommendations are based upon a goal of aPTT prolongation of 1.5 to 3 times the baseline value and avoidance of an aPTT >100 seconds

DOSAGE AND ADMINISTRATION
Each 2.5-mL vial contains 250 mg of Argatroban; and, as supplied, is a concentrated drug (100 mg/mL), which must be diluted 100-fold prior to infusion. Argatroban should not be mixed with other drugs prior to dilution in a suitable intravenous fluid.

Preparation for Intravenous Administration
Argatroban 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. The pH of the intravenous solution prepared as recommended is 3.2 to 7.5.

Heparin-Induced Thrombocytopenia (HIT/HITTS)
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 8).

Table 8. Recommended Doses and Infusion Rates for 2 mcg/kg/min Dose of Argatroban for Patients With HIT/HITTS (Without Hepatic Impairment) (1 mg/mL Final Concentration)

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. Dose adjustment may be required to attain the target aPTT. Check the aPTT two hours after initiation of therapy and any dose change to confirm that the patient has attained the desired therapeutic range.

Dosage Adjustment: After the initial dose of Argatroban, the dose can be adjusted as clinically indicated (not to exceed 10 mcg/kg/min), until the steady-state aPTT is 1.5 to 3 times the initial baseline value (not to exceed 100 seconds) (see CLINICAL STUDIES for mean values of aPTT obtained after initial doses of Argatroban).

Percutaneous Coronary Interventions (PCI) in HIT/HITTS Patients
Initial Dosage: An infusion of Argatroban should be started at 25 mcg/kg/min and a bolus of 350 mcg/kg administered via a large bore intravenous (IV) line over 3 to 5 minutes (see Table 9). Activated clotting time (ACT) should be checked 5 to 10 minutes after the bolus dose is completed. The procedure may proceed if the ACT is greater than 300 seconds.

Dosage Adjustment: If the ACT is less than 300 seconds, an additional IV 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 9). 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 (see Table 9). Once a therapeutic ACT (between 300 and 450 seconds) has been achieved, this infusion dose should be continued for the duration of the procedure.

Table 9. Recommended Doses and Infusion Rates of Argatroban for Patients Undergoing PCI (Without Hepatic Impairment) (1 mg/mL Final Concentration)

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

* Initial IV bolus dose of 350 mcg/kg should be administered.

† Additional IV bolus dose of 150 mcg/kg should be administered if ACT <300 seconds.

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. The ACT should be checked after each additional bolus or change in the rate of infusion.

Monitoring therapy: Therapy with Argatroban is monitored using ACT. ACTs should be obtained before dosing, 5 to 10 minutes after bolus dosing and after change in the infusion rate, and at the end of the PCI procedure. Additional ACTs should be drawn about every 20 to 30 minutes during a prolonged procedure.

Continued Anticoagulation after PCI: If a patient requires anticoagulation after the procedure, Argatroban may be continued, but at a lower infusion dose [see DOSAGE AND ADMINISTRATION, Heparin-Induced Thrombocytopenia (HIT/HITTS)].

Dosing in Special Populations
Hepatic Impairment: For adult patients with heparin-induced thrombocytopenia with hepatic impairment, the initial dose of Argatroban should be reduced. For adult patients with moderate hepatic impairment, an initial dose of 0.5 mcg/kg/min is recommended, based on the approximate 4-fold decrease in Argatroban clearance relative to those with normal hepatic function. The aPTT should be monitored closely, and the dosage should be adjusted as clinically indicated (see PRECAUTIONS).

Hepatic Impairment in HIT/HITTS Patients Undergoing PCI: Carefully titrate Argatroban until the desired level of anticoagulation is achieved (see PRECAUTIONS, Hepatic Impairment).

Renal Impairment: No dosage adjustment is necessary in patients with renal impairment (see SPECIAL POPULATIONS, Renal Impairment).

Pediatric HIT/HITTS Patients: Initial Argatroban infusion doses are lower for seriously ill pediatric patients compared to adults with normal hepatic function (see PRECAUTIONS, Pediatric Use).

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 PRECAUTIONS, Hepatic Impairment). 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 PRECAUTIONS, Pediatric Use.

CONVERSION TO ORAL ANTICOAGULANT THERAPY

Initiating Oral Anticoagulant Therapy
Once the decision is made to initiate oral anticoagulant therapy, recognize 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 at Doses Up to 2 mcg/kg/min
Use of Argatroban with warfarin results in prolongation of INR beyond that produced by warfarin alone. To avoid prothrombotic effects and to ensure continuous anticoagulation when initiating warfarin, it is suggested that warfarin be co-administered before discontinuing Argatroban. There are insufficient data available to recommend the duration of the co-administration. The previously established relationship between INR and bleeding risk is altered. 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 CLINICAL PHARMACOLOGY, Figure 2 explanation and PRECAUTIONS, Drug Interactions).

INR should be measured daily while Argatroban and warfarin are co-administered. In general, with doses of Argatroban up to 2 mcg/kg/min, Argatroban can be discontinued when the INR is >4 on combined therapy. After Argatroban 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 and repeat the procedure daily until the desired therapeutic range on warfarin alone is reached.

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

STABILITY/COMPATIBILITY
Argatroban is a clear, colorless to pale yellow, slightly viscous solution. If the solution is cloudy, or if an insoluble precipitate is noted, the vial should be discarded.

Solutions prepared as recommended are stable at 25°C (77°F), with excursions permitted to 15° to 30°C (59° to 86°F) 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° to 25°C (68° to 77°F) (see USP), or at refrigerated conditions, 5° ± 3°C (41°± 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.

HOW SUPPLIED
Argatroban Injection is supplied in 2.5-mL solution in single-use vials at the concentration of 100 mg/mL. Each vial contains 250 mg of Argatroban.

NDC 0007-4407-01 (Package of 1)

Storage
Store the vials in original cartons at room temperature [25°C (77°F), with excursions permitted to 15° to 30°C (59° to 86°F)]. Do not freeze. Retain in the original carton to protect from light.

Manufactured, Distributed, and Marketed by GlaxoSmithKline

Research Triangle Park, NC 27709

©2009, GlaxoSmithKline. All rights reserved.

March 2009 ARG:11PI