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DRUGS & SUPPLEMENTS
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Argatroban in Sodium Chloride Injection is a direct thrombin inhibitor indicated:
Argatroban in Sodium Chloride Injection is indicated for prophylaxis or treatment of thrombosis in adult patients with heparin-induced thrombocytopenia (HIT).
Argatroban in Sodium Chloride Injection is indicated as an anticoagulant in adult patients with or at risk for HIT undergoing percutaneous coronary intervention (PCI).
Each 250 mL polyolefin bag contains 250 mg of Argatroban in Sodium Chloride ; and, as supplied, is ready for intravenous infusion. Dilution is not required.
Argatroban in Sodium Chloride 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 the solution is cloudy, contains precipitates, or if the flip-off seal is not intact.
Heparin-Induced Thrombocytopenia (2.1)
The dose for heparin-induced thrombocytopenia without hepatic impairment is 2 mcg/kg/min administered as a continuous infusion (2.1)
Percutaneous Coronary Intervention (2.2)
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 (2.2)
Initial Dosage
Before administering Argatroban in Sodium Chloride Injection, discontinue heparin therapy and obtain a baseline aPTT. The recommended initial dose of Argatroban in Sodium Chloride 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 |
a with or without thrombosis
Monitoring Therapy
For use in HIT, therapy with Argatroban in Sodium Chloride 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 in Sodium Chloride 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 in Sodium Chloride 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)].
Initial Dosage
Initiate an infusion of Argatroban in Sodium Chloride 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. 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, 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.
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 to 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 |
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 |
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Monitoring Therapy
For use in PCI, therapy with Argatroban in Sodium Chloride 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 in Sodium Chloride 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)].
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 in Sodium Chloride 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 in Sodium Chloride Injection until the desired level of anticoagulation is achieved. Use of Argatroban in Sodium Chloride Injection in PCI patients with clinically significant hepatic disease or AST/ALT levels greater than or equal to 3 times the upper limit of normal should be avoided [see Warnings and Precautions (5.2)].
Initial Dosage
Initial Argatroban in Sodium Chloride infusion doses are lower for seriously ill pediatric patients compared to adults with normal hepatic function [see Use in Specific Populations ].
Monitoring Therapy
In general, therapy with Argatroban in Sodium Chloride 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 Sodium Chloride 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:
Initiating Oral Anticoagulant Therapy
When converting patients from Argatroban in Sodium Chloride to oral anticoagulant therapy, consider the potential for combined effects on International Normalized Ratio (INR). To avoid prothrombotic effects and to ensure continuous anticoagulation when initiating warfarin, overlap Argatroban in Sodium Chloride 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 in Sodium Chloride and warfarin are coadministered. The combination of Argatroban in Sodium Chloride 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 in Sodium Chloride and the thromboplastin reagent used. The INR value on warfarin alone (INRW) can be calculated from the INR value on combination Argatroban in Sodium Chloride and warfarin therapy [see Drug Interactions (7.2) and Clinical Pharmacology (12.2)].
Coadministration of Warfarin and Argatroban in Sodium Chloride Injection at Doses Up to 2 mcg/kg/min
Measure INR daily while Argatroban in Sodium Chloride Injection and warfarin are coadministered. In general, with doses of Argatroban in Sodium Chloride Injection up to 2 mcg/kg/min, Argatroban in Sodium Chloride Injection can be discontinued when the INR is greater than 4 on combined therapy. After Argatroban in Sodium Chloride 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 in Sodium Chloride Injection and repeat the procedure daily until the desired therapeutic range on warfarin alone is reached.
Coadministration of Warfarin and Argatroban in Sodium Chloride 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 in Sodium Chloride is less predictable. In this case, in order to predict the INR on warfarin alone, temporarily reduce the dose of Argatroban in Sodium Chloride Injection to a dose of 2 mcg/kg/min. Repeat the INR on Argatroban in Sodium Chloride Injection and warfarin 4 to 6 hours after reduction of the Argatroban in Sodium Chloride Injection dose and follow the process outlined above for administering Argatroban in Sodium Chloride Injection at doses up to 2 mcg/kg/min.
Argatroban in Sodium Chloride Injection is supplied in a single use polyolefin bag containing 250 mg Argatroban in Sodium Chloride in 250 mL aqueous sodium chloride solution (1 mg/mL). The solution is ready for intravenous infusion.
Argatroban in Sodium Chloride Injection is supplied as a single use polyolefin bag containing 250 mg Argatroban in Sodium Chloride in 250 mL aqueous sodium chloride solution (1 mg/mL) (3)
Argatroban in Sodium Chloride is contraindicated in:
Hemorrhage can occur at any site in the body in patients receiving Argatroban in Sodium Chloride. An unexplained fall in hematocrit or hemoglobin or a fall in blood pressure should lead to consideration of a hemorrhagic event. Argatroban in Sodium Chloride Injection 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.
Concomitant use of Argatroban in Sodium Chloride with antiplatelet agents, thrombolytics, and other anticoagulants may increase the risk of bleeding.
Use caution when administering Argatroban in Sodium Chloride to patients with hepatic impairment by starting with a lower dose and carefully titrating until the desired level of anticoagulation is achieved. Upon cessation of Argatroban in Sodium Chloride 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 in Sodium Chloride . Use of Argatroban in Sodium Chloride in PCI patients with clinically significant hepatic disease or AST/ALT levels ≥ 3 times the upper limit of normal should be avoided.
Anticoagulation effects associated with Argatroban in Sodium Chloride 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 in Sodium Chloride, the therapeutic ranges for these tests have not been identified for Argatroban in Sodium Chloride therapy. In clinical trials in PCI, the activated clotting time (ACT) was used for monitoring Argatroban in Sodium Chloride anticoagulant activity during the procedure. The concomitant use of Argatroban in Sodium Chloride and warfarin results in prolongation of the PT and INR beyond that produced by warfarin alone .
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.
To report SUSPECTED ADVERSE REACTIONS, contact TEVA USA, PHARMACOVIGILANCE at 1-866-832-8537 or drug.safetyArgatroban in Sodium Chloridetevapharm.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
The following safety information is based on all 568 patients treated with Argatroban in Sodium Chloride 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).
*with or without thrombosis | ||
DIC = disseminated intravascular coagulation. | ||
BKA = below-the-knee amputation. | ||
Major Hemorrhagic Events | ||
Argatroban-Treated Patients (Study 1 and Study 2) (n = 568) % | Historical Control (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 | 0 | 0.5 |
Minor Hemorrhagic Events | ||
Argatroban-Treated Patients (Study 1 and Study 2) (n = 568) % | Historical Control (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 |
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.
Argatroban-Treated Patients (Study 1 and Study 2) (n = 568) % | Historical Control (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 |
The following safety information is based on 91 patients initially treated with Argatroban in Sodium Chloride and 21 patients subsequently re-exposed to Argatroban in Sodium Chloride for a total of 112 PCIs with Argatroban in Sodium Chloride anticoagulation. Adverse events are separated into hemorrhagic 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 Sodium Chloride in the PCI trials was 1.8%.
CABG = coronary artery bypass graft. | |
Major Hemorrhagic Events | |
Argatroban-Treated Patients (n = 112) % | |
Retroperitoneal | 0.9 |
Gastrointestinal | 0.9 |
Intracranial | 0 |
Minor Hemorrhagic Events | |
Argatroban-Treated Patients (n = 112) % | |
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 |
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.
Argatroban in Sodium Chloride Procedures (n = 112) % | |
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 |
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.
Coded Term | Argatroban in Sodium Chloride Procedures (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%) |
Increased risks for intracranial bleeding have been observed in investigational studies of Argatroban in Sodium Chloride for other uses. In a study of patients with acute myocardial infarction receiving both Argatroban in Sodium Chloride 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 .
The safety and effectiveness of Argatroban in Sodium Chloride 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 Sodium Chloride 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 in Sodium Chloride 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.
One hundred fifty-six allergic reactions or suspected allergic reactions were observed in 1,127 individuals who were treated with Argatroban in Sodium Chloride 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):
Limited data are available on the potential formation of drug-related antibodies. Plasma from 12 healthy volunteers treated with Argatroban in Sodium Chloride over 6 days showed no evidence of neutralizing antibodies. No loss of anticoagulant activity was noted with repeated administration of Argatroban in Sodium Chloride to more than 40 patients.
If Argatroban in Sodium Chloride 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 in Sodium Chloride therapy.
Pharmacokinetic drug-drug interactions between Argatroban in Sodium Chloride and warfarin have not been demonstrated. However, the concomitant use of Argatroban in Sodium Chloride 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 Dosage and Administration (2.5) and Clinical Pharmacology (12.2)].
No drug-drug interactions have been demonstrated between Argatroban in Sodium Chloride and concomitantly administered aspirin or acetaminophen [see Clinical Pharmacology (12.3)].
The safety and effectiveness of Argatroban in Sodium Chloride with thrombolytic agents have not been established .
The safety and effectiveness of Argatroban in Sodium Chloride with glycoprotein IIb/IIIa antagonists have not been established.
Pregnancy Category B
There are no adequate and well-controlled studies of Argatroban in Sodium Chloride use in pregnant women. Developmental studies performed in rats with Argatroban in Sodium Chloride at intravenous doses up to 27 mg/kg/day (0.3 times the maximum recommended human dose, based on body surface area) and in rabbits at intravenous doses up to 10.8 mg/kg/day (0.2 times the maximum recommended human dose, based on body surface area) have revealed no evidence of impaired fertility or harm to the fetus. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
It is not known whether Argatroban in Sodium Chloride is excreted in human milk. Argatroban in Sodium Chloride is detected in rat milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Argatroban in Sodium Chloride, 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.
The safety and effectiveness of Argatroban in Sodium Chloride, including the appropriate anticoagulation goals and duration of therapy, have not been established among pediatric patients. Argatroban in Sodium Chloride 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 in Sodium Chloride solely as a continuous infusion. 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 in Sodium Chloride administration to two patients and following Argatroban in Sodium Chloride discontinuation in three other patients. Major bleeding occurred among two patients; one patient experienced an intracranial hemorrhage after 4 days of Argatroban in Sodium Chloride therapy in the setting of sepsis and thrombocytopenia. Another patient completed 14 days of Argatroban in Sodium Chloride treatment in the study, but experienced an intracranial hemorrhage while receiving Argatroban in Sodium Chloride following completion of the study treatment period.
When Argatroban in Sodium Chloride 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 in Sodium Chloride 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 . Check the aPTT two hours after the initiation of the Argatroban in Sodium Chloride 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 in Sodium Chloride 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.
Of the total number of subjects (1340) in clinical studies of Argatroban in Sodium Chloride, 35% were 65 and over. In the clinical studies of adult patients with HIT (with or without thrombosis), the effectiveness of Argatroban in Sodium Chloride was not affected by age. No trends were observed across age groups for both aPTT and the ACT. The safety analysis did suggest that older patients tended to have an increased incidence of events compared to younger patients; however, older patients had increased underlying conditions, which may predispose them to events. The studies were not sized appropriately to detect differences in safety between age groups.
Dose reduction and careful titration are required when administering Argatroban in Sodium Chloride to patients with hepatic impairment. Reversal of anticoagulation effect may be prolonged in this population .
Excessive anticoagulation, with or without bleeding, may be controlled by discontinuing Argatroban in Sodium Chloride or by decreasing the Argatroban in Sodium Chloride dose. In clinical studies, anticoagulation parameters generally returned from therapeutic levels to baseline within 2 to 4 hours after discontinuation of the drug. Reversal of anticoagulant effect may take longer in patients with hepatic impairment.
No specific antidote to Argatroban in Sodium Chloride is available; if life-threatening bleeding occurs and excessive plasma levels of Argatroban in Sodium Chloride are suspected, discontinue Argatroban in Sodium Chloride immediately and measure aPTT and other coagulation parameters. When Argatroban in Sodium Chloride was administered as a continuous infusion (2 mcg/kg/min) prior to and during a 4-hour hemodialysis session, approximately 20% of Argatroban in Sodium Chloride was cleared through dialysis.
Single intravenous doses of Argatroban in Sodium Chloride at 200, 124, 150, and 200 mg/kg were lethal to mice, rats, rabbits, and dogs, respectively. The symptoms of acute toxicity were loss of righting reflex, tremors, clonic convulsions, paralysis of hind limbs, and coma.
Argatroban in Sodium Chloride is a synthetic direct thrombin inhibitor and the chemical name is 1-[5-[amino]1-oxo-2-[[(1,2,3,4-tetrahydro-3-methyl-8-quinolinyl)sulfonyl]amino]pentyl]-4-methyl-2-piperidinecarboxylic acid, monohydrate. Argatroban in Sodium Chloride has 4 asymmetric carbons. One of the asymmetric carbons has an R configuration (stereoisomer Type I) and an S configuration (stereoisomer Type II). Argatroban in Sodium Chloride consists of a mixture of R and S stereoisomers at a ratio of approximately 65:35.
The molecular formula of Argatroban in Sodium Chloride is C23H36N6O5S∙H2O. Its molecular weight is 526.66 g/mol. The structural formula is:
Figure 4. Time to First Event for the Composite Efficacy Endpoint: HITTS Patients STUDY 1
In Study 2, a total of 264 patients were enrolled as follows: HIT (n = 125) or HITTS (n = 139). There was a significant improvement in the composite efficacy outcome for argatroban-treated patients, versus the same historical control group from Study 1, among patients having HIT (25.6% vs. 38.8%), patients having HITTS (41.0% vs. 56.5%), and patients having either HIT or HITTS (33.7% vs. 43.0%). Time-to-event analyses showed significant improvements in the time-to-first event in patients with HIT or HITTS treated with Argatroban in Sodium Chloride versus those in the historical control group. The between-group differences in the proportion of patients who remained free of death, amputation, or new thrombosis were statistically significant in favor of Argatroban in Sodium Chloride.
Anticoagulant Effect
In Study 1, the mean (± SE) dose of Argatroban in Sodium Chloride administered was 2.0 ± 0.1 mcg/kg/min in the HIT arm and 1.9 ± 0.1 mcg/kg/min in the HITTS arm. Seventy-six percent of patients with HIT and 81% of patients with HITTS achieved a target aPTT at least 1.5-fold greater than the baseline aPTT at the first assessment occurring on average at 4.6 hours (HIT) and 3.9 hours (HITTS) following initiation of Argatroban in Sodium Chloride therapy. No enhancement of aPTT response was observed in subjects receiving repeated administration of Argatroban in Sodium Chloride.
Platelet Count Recovery
In Study 1, 53% of patients with HIT and 58% of patients with HITTS, had a recovery of platelet count by Day 3. Platelet Count Recovery was defined as an increase in platelet count to > 100,000/µL or to at least 1.5-fold greater than the baseline count (platelet count at study initiation) by Day 3 of the study.
Figure 3. Figure 4.
In 3 similarly designed trials, Argatroban in Sodium Chloride was administered to 91 patients with current or previous clinical diagnosis of HIT or heparin-dependent antibodies, who underwent a total of 112 percutaneous coronary interventions (PCIs) including percutaneous transluminal coronary angioplasty (PTCA), coronary stent placement, or atherectomy. Among the 91 patients undergoing their first PCI with Argatroban in Sodium Chloride, notable ongoing or recent medical history included myocardial infarction (n = 35), unstable angina (n = 23), and chronic angina (n = 34). There were 33 females and 58 males. The average age was 67.6 years (median 70.7, range 44 to 86), and the average weight was 82.5 kg (median 81.0 kg, range 49 to 141).
Twenty-one of the 91 patients had a repeat PCI using Argatroban in Sodium Chloride an average of 150 days after their initial PCI. Seven of 91 patients received glycoprotein IIb/IIIa inhibitors. Safety and efficacy were assessed against historical control populations who had been anticoagulated with heparin.
All patients received oral aspirin (325 mg) 2 to 24 hours prior to the interventional procedure. After venous or arterial sheaths were in place, anticoagulation was initiated with a bolus of Argatroban in Sodium Chloride of 350 mcg/kg via a large-bore intravenous line or through the venous sheath over 3 to 5 minutes. Simultaneously, a maintenance infusion of 25 mcg/kg/min was initiated to achieve a therapeutic activated clotting time (ACT) of 300 to 450 seconds. If necessary to achieve this therapeutic range, the maintenance infusion dose was titrated (15 to 40 mcg/kg/min) and/or an additional bolus dose of 150 mcg/kg could be given. Each patient’s ACT was checked 5 to 10 minutes following the bolus dose. The ACT was checked as clinically indicated. Arterial and venous sheaths were removed no sooner than 2 hours after discontinuation of Argatroban in Sodium Chloride and when the ACT was less than 160 seconds.
If a patient required anticoagulation after the procedure, Argatroban in Sodium Chloride could be continued, but at a lower infusion dose between 2.5 and 5 mcg/kg/min. An aPTT was drawn 2 hours after this dose reduction and the dose of Argatroban in Sodium Chloride then was adjusted as clinically indicated (not to exceed 10 mcg/kg/min), to reach an aPTT between 1.5 and 3 times baseline value (not to exceed 100 seconds).
In 92 of the 112 interventions (82%), the patient received the initial bolus of 350 mcg/kg and an initial infusion dose of 25 mcg/kg/min. The majority of patients did not require additional bolus dosing during the PCI procedure. The mean value for the initial ACT measurement after the start of dosing for all interventions was 379 sec (median 338 sec; 5th percentile-95th percentile 238 to 675 sec). The mean ACT value per intervention over all measurements taken during the procedure was 416 sec (median 390 sec; 5th percentile-95th percentile 261 to 698 sec). About 65% of patients had ACTs within the recommended range of 300 to 450 seconds throughout the procedure. The investigators did not achieve anticoagulation within the recommended range in about 23% of patients. However, in this small sample, patients with ACTs below 300 seconds did not have more coronary thrombotic events, and patients with ACTs over 450 seconds did not have higher bleeding rates.
Acute procedural success was defined as lack of death, emergent coronary artery bypass graft (CABG), or Q-wave myocardial infarction. Acute procedural success was reported in 98.2% of patients who underwent PCIs with Argatroban in Sodium Chloride anticoagulation compared with 94.3% of historical control patients anticoagulated with heparin (p = NS). Among the 112 interventions, 2 patients had emergency CABGs, 3 had repeat PTCAs, 4 had non-Q-wave myocardial infarctions, 3 had myocardial ischemia, 1 had an abrupt closure, and 1 had an impending closure (some patients may have experienced more than 1 event). No patients died.
Argatroban in Sodium Chloride Injection is supplied as a single use polyolefin bag containing 250 mg Argatroban in Sodium Chloride in 250 mL of aqueous sodium chloride solution (1 mg/mL). The polyolefin bag has a single port which is sealed with a rubber stopper and flip-off seal, and is stored in an aluminum foil overpouch with clear window.
NDC 0703-0020-32 one carton containing 5 polyolefin bags of Argatroban in Sodium Chloride Injection (each bag contains 250 mg of Argatroban in Sodium Chloride).
Storage
Store the bag in its original carton at 20º to 25º C (68º to 77°F). Do not freeze. Retain in the original carton to protect from light.
Inform patients of the risks associated with Argatroban in Sodium Chloride Injection as well as the plan for regular monitoring during administration of the drug. Specifically, inform patients to report:
Manufactured In Hungary By:
Teva Pharmaceutical Works Ltd. Hungary
H-2100 Gödöllö
Táncsics M. út 82 Hungary
Manufactured For:
TEVA PHARMACEUTICALS USA, INC.
North Wales, PA 19454
Rev. B 5/2016
Argatroban in Sodium Chloride
Injection in 0.9%
Sodium Chloride
250 mg/250 mL
(1 mg/mL)
Each milliliter contains:
For Intravenous Infusion Only
Do not dilute.
Single Use Bags. Discard Unused Portion
Sterile
Contains 5 Single Use Bags
TEVA
Depending on the reaction of the Argatroban in Sodium Chloride after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Argatroban in Sodium Chloride not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.
Is Argatroban in Sodium Chloride addictive or habit forming?Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
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The information was verified by Dr. Rachana Salvi, MD Pharmacology