Intracranial bleeding was not observed in subjects or patients who did not receive concomitant thrombolysis [see Drug Interactions 7. 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 patients 4. Asymptomatic intracranial hemorrhage occurred in 5 4. Allergic Reactions One hundred fifty-six allergic reactions or suspected allergic reactions were observed in 1, individuals who were treated with argatroban in clinical pharmacology studies or for various clinical indications.
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Intracranial bleeding was not observed in subjects or patients who did not receive concomitant thrombolysis [ see Drug Interactions 7. 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 patients 4. Asymptomatic intracranial hemorrhage occurred in 5 4. Allergic Reactions One hundred fifty-six allergic reactions or suspected allergic reactions were observed in 1, individuals who were treated with Argatroban in clinical pharmacology studies or for various clinical indications.
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. There are risks to the mother associated with untreated thrombosis in pregnancy and a risk of hemorrhage in the mother and fetus associated with use of anticoagulants see Clinical Considerations.
In animal reproduction studies, there was no evidence of adverse developmental outcomes with intravenous administration of Argatroban during organogenesis in rats and rabbits at doses up to 0. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
In the U. Published data describe that women with a previous history of venous thrombosis are at high risk for recurrence during pregnancy. Monitor neonates for bleeding [see Warnings and Precautions 5. Labor or Delivery All patients receiving anticoagulants, including pregnant women, are at risk for bleeding.
Lactation Risk Summary There are no data on the presence of Argatroban in human milk, or its effects on milk production. Argatroban is present in rat milk. Data Argatroban is detected in rat milk. Pediatric Use Safety and effectiveness have not been established in pediatric patients. Argatroban was studied among 18 seriously ill pediatric patients who required an alternative to heparin anticoagulation. All patients had serious underlying conditions and were receiving multiple concomitant medications.
Thirteen patients received Argatroban solely as a continuous infusion no bolus dose. Most patients required multiple dose adjustments to maintain anticoagulation parameters within the desired range. During the 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 and another patient experienced an intracranial hemorrhage after receiving Argatroban for greater than 14 days. Argatroban clearance in these seriously ill pediatric patients 0. Additionally, based on an evaluation of aPTT every two hours, increasing the dosage by 0. For patients with hepatic impairment a starting infusion rate of 0.
In addition, the described dosage did not take into account multiple factors that could affect the dosage such as current aPTT, target aPTT, and the clinical status of the patient. In the clinical studies of adult patients with HIT with or without thrombosis , the effectiveness of Argatroban was not affected by age. The safety analysis did suggest that older patients tended to have an increased incidence of adverse reactions compared to younger patients; however, older patients had increased underlying conditions, which may predispose them to adverse reactions.
The studies were not sized appropriately to detect differences in safety between age groups. Reversal of anticoagulation effect may be prolonged in this population [ see Dosage and Administration 2. 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.
The symptoms of acute toxicity were loss of righting reflex, tremors, clonic convulsions, paralysis of hind limbs, and coma.
The chemical name for Argatroban monohydrate is 1-[5-[ aminoiminomethyl amino]oxo[[ 1,2,3,4-tetrahydromethylquinolinyl sulfonyl]amino]pentyl]methylpiperidinecarboxylic acid, monohydrate.
Argatroban has 4 asymmetric carbons. Argatroban consists of a mixture of R and S stereoisomers at a ratio of approximately Its molecular weight is It is supplied in a clear glass single-dose vial containing 50 mg of Argatroban in 50 mL sodium chloride solution. The pH of the solution is between 4.
Argatroban - Clinical Pharmacology Mechanism of Action Argatroban in sodium chloride injection 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 inhibits thrombin with an inhibition constant Ki of 0. 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. Pharmacodynamics When Argatroban is administered by continuous infusion, anticoagulant effects and plasma concentrations of Argatroban follow similar, predictable temporal response profiles, with low intersubject variability.
Immediately upon initiation of Argatroban infusion, anticoagulant effects are produced as plasma Argatroban concentrations begin to rise. Steady-state levels of both drug and anticoagulant effect are typically attained within 1 to 3 hours and are maintained until the infusion is discontinued or the dosage adjusted.
However, concurrent therapy, compared to warfarin monotherapy, exerts no additional effect on vitamin K—dependent factor Xa activity.
The relationship between INR on co-therapy and warfarin alone is dependent on both the dose of Argatroban and the thromboplastin reagent used. Data for 2 commonly utilized thromboplastins with ISI values of 0.
These data are based on results obtained in normal individuals [ see Dosage and Administration 2. Metabolism: The main route of Argatroban metabolism is hydroxylation and aromatization of the 3-methyltetrahydroquinoline ring in the liver. The primary metabolite M1 exerts 3- to 5-fold weaker anticoagulant effects than Argatroban. Unchanged Argatroban is the major component in plasma. 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.
Total body clearance is approximately 5. The terminal elimination half-life of Argatroban ranges between 39 and 51 minutes. There is no interconversion of the 21— R — S diastereoisomers.
Excretion: Argatroban is excreted primarily in the feces, presumably through biliary secretion. Little or no additional urinary radioactivity was subsequently detected.
Patients with hepatic impairment were not studied in percutaneous coronary intervention PCI trials. At a dose of 2. Renal Impairment: No dosage adjustment is necessary in patients with renal dysfunction.
Some patients may have experienced more than 1 event. Intracranial bleeding was not observed in subjects or patients who did not receive concomitant thrombolysis [see Drug Interactions 7. 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.
HIGHLIGHTS OF PRESCRIBING INFORMATION
It is used to thin the blood so that clots will not form. It is used to treat blood clots. If you have an allergy to argatroban or any other part of argatroban. If you are allergic to argatroban; any part of argatroban; or any other drugs, foods, or substances.