Argatroban
Argatroban Prescribing Information
Dosing and Administration, Dosing in Pediatric Patients with Heparin Induced Thrombocytopenia-Heparin Induced Thrombocytopenia and Thrombosis Syndrome (
Anticoagulant Therapy
When converting patients from argatroban injection 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.
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.
For doses of argatroban injection greater than 2 mcg/kg/min, the relationship of INR between warfarin alone to the INR on warfarin plus argatroban injection 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.
Argatroban injection must be diluted 100-fold by mixing with 0.9% Sodium Chloride Injection, 5% Dextrose Injection or Lactated Ringer’s Injection to a final concentration of 1 mg/mL. (
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.
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.
The dose for heparin-induced thrombocytopenia without hepatic impairment is 2 mcg/kg/min administered as a continuous infusion. (
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.
Dosing in Patients with Heparin-Induced Thrombocytopenia
Before administering argatroban injection, discontinue heparin therapy and obtain a baseline activated partial thromboplastin time (aPTT). The recommended initial dose of argatroban injection for adult patients without hepatic impairment is 2 mcg/kg/min, administered as a continuous infusion (see Table 1).
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 | ||
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.
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
The dose for patients with or at risk for heparin-induced thrombocytopenia undergoing percutaneous coronary intervention is started at 25 mcg/kg/min and a bolus of 350 mcg/kg administered via a large bore intravenous line over 3 to 5 minutes. (
Dosing in Patients with Heparin-Induced Thrombocytopenia
Before administering argatroban injection, discontinue heparin therapy and obtain a baseline activated partial thromboplastin time (aPTT). The recommended initial dose of argatroban injection for adult patients without hepatic impairment is 2 mcg/kg/min, administered as a continuous infusion (see Table 1).
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 | ||
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.
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
250 mg of argatroban in 2.5 mL of sterile solution for injection in a single-dose vial.
- Lactation: Discontinue nursing or drug, taking into account the importance of the drug to the mother. ()
8.2 LactationRisk SummaryThere are no data on the presence of argatroban in human milk, or its effects on milk production. Argatroban is present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for argatroban and any potential adverse effects on the breastfed infant from argatroban or from the underlying maternal condition.
- Pediatric Use: Safety and effectiveness have not been established.
Argatroban is contraindicated in
- Patients with major bleeding [see].
5.1
Risk of HemorrhageHemorrhage can occur at any site in the body in patients receiving argatroban. Unexplained fall in hematocrit or blood pressure may indicate hemorrhage. Intracranial and retroperitoneal hemorrhage
[see Adverse Reactions (6.1)]has been reported. The risk of hemorrhage with argatroban may be increased in 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.
- Patients with history of hypersensitivity to argatroban. Airway, skin, and generalized hypersensitivity reactions have been reported [see].
6.1 Clinical Trials ExperienceAdverse Events in Patients with HIT (With or Without Thrombosis)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.
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 4Major and Minor Hemorrhagic Adverse Events in Patients With HIT*Major Hemorrhagic EventsaArgatroban-Treated Patients(Study 1 and Study 2)(n = 568)%Historical Controlc(n = 193)%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
0b
0.5
Minor Hemorrhagic EventsaArgatroban-Treated Patients(Study 1 and Study 2)(n = 568)%Historical Controlc(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
*with or without thrombosis
a) Patients may have experienced more than 1 adverse event.
b) One patient experienced intracranial hemorrhage 4 days after discontinuation of argatroban and following therapy with urokinase and oral anticoagulation.
c) 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.
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 5Non-hemorrhagic Adverse Events in PatientsaWith HITbArgatroban-Treated Patients(Study 1 and Study 2)(n = 568)%Historical Controlc(n = 193)%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
a) Patients may have experienced more than 1 adverse event.
b) with or without thrombosis
c) 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.
Adverse Events in Patients with or at Risk for HIT Undergoing PCIThe 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 (Table 7) 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 6Major and Minor Hemorrhagic Adverse Events in Patients With HIT Undergoing PCIMajor Hemorrhagic EventsaArgatroban-Treated Patients(n = 12)b%Retroperitoneal
0.9
Gastrointestinal
0.9
Intracranial
0
Minor Hemorrhagic EventsaArgatroban-Treated Patients(n = 12)b%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
a) Patients may have experienced more than 1 adverse event.
b) 91 patients who underwent 112 interventions.
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 7Non-hemorrhagic Adverse Eventsain Patients With HIT Undergoing PCIArgatroban Proceduresa(n = 112)b%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
a) Patients may have experienced more than 1 adverse event.
b) 91 patients who underwent 112 interventions.
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 8Serious Adverse Events in Patients With HIT Undergoing PCIaCoded TermArgatroban Proceduresb(n = 112)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 (0.9%)
Gastrointestinal disorder (GERD)
1 (0.9%)
Cerebrovascular disorder
1 (0.9%)
Lung edema
1 (0.9%)
Vascular disorder
1 (0.9%)
a) Individual events may also have been reported elsewhere (see Table 6 and 7).
b) 91 patients underwent 112 procedures. Some patients may have experienced more than 1 event.
Intracranial Bleeding in Other PopulationsIncreased risks for intracranial bleeding have been observed in investigational studies of argatroban for other uses. In a study of patients with acute myocardial infarction receiving both argatroban and thrombolytic therapy (streptokinase or tissue plasminogen activator), the overall frequency of intracranial bleeding was 1% (8 out of 810 patients). Intracranial bleeding was not observed in 317 subjects or patients who did not receive concomitant thrombolysis
[see Drug Interactions (7.4)].The safety and effectiveness of argatroban for cardiac indications other than PCI in patients with HIT have not been established. Intracranial bleeding was also observed in a prospective, placebo-controlled study of argatroban in patients who had onset of acute stroke within 12 hours of study entry. Symptomatic intracranial hemorrhage was reported in 5 of 117 patients (4.3%) who received argatroban at 1 to 3 mcg/kg/min and in none of the 54 patients who received placebo. Asymptomatic intracranial hemorrhage occurred in 5 (4.3%) and 2 (3.7%) of the patients, respectively.
Allergic ReactionsOne hundred fifty-six allergic reactions or suspected allergic reactions were observed in 1,127 individuals who were treated with argatroban in clinical pharmacology studies or for various clinical indications. About 95% (148/156) of these reactions occurred in patients who concomitantly received thrombolytic therapy (e.g., streptokinase) or contrast media.
Allergic reactions or suspected allergic reactions in populations other than patients with HIT (with or without thrombosis) include (in descending order of frequency):
- Airway reactions (coughing, dyspnea): 10% or more
- Skin reactions (rash, bullous eruption): 1 to <10%
- General reactions (vasodilation): 1 to 10%
Limited data are available on the potential formation of drug-related antibodies. Plasma from 12 healthy volunteers treated with argatroban over 6 days showed no evidence of neutralizing antibodies. No loss of anticoagulant activity was noted with repeated administration of argatroban to more than 40 patients.
- Hemorrhage can occur. Unexplained fall in hematocrit or blood pressure may indicate hemorrhage. ()
5.1
Risk of HemorrhageHemorrhage can occur at any site in the body in patients receiving argatroban. Unexplained fall in hematocrit or blood pressure may indicate hemorrhage. Intracranial and retroperitoneal hemorrhage
[see Adverse Reactions (6.1)]has been reported. The risk of hemorrhage with argatroban may be increased in 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.
- Hepatic impairment: Adjust starting dose and titrate carefully in patients with HIT who have moderate or severe hepatic impairment. Avoid use in PCI in patients with clinically significant hepatic impairment. ()
5.2
Use in Hepatic ImpairmentWhen administering argatroban to patients with hepatic impairment, start with a lower dose and carefully titrate 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 Use in Specific Populations (8.6)].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 (2.3)andClinical Pharmacology (12.3)]. Avoid the use of high doses of argatroban in patients undergoing PCI who have clinically significant hepatic disease or AST/ALT levels ≥3 times the upper limit of normal.