Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Mitsubishi Tanabe Pharma Europe Ltd, Dashwood House, 69 Old Broad Street, London EC2M 1QS, United Kingdom
Pharmacotherapeutic group: Antithrombotic agents, direct thrombin inhibitors
ATC code: B01AE03
Argatroban, a synthetic L-arginine derivative, is a direct thrombin inhibitor (molecular weight 526.65) that binds reversibly to thrombin. Argatroban exerts its anticoagulant effect independently of antithrombin III and inhibits fibrin formation; activation of coagulation factors V, VIII and XIII; activation of protein C; and platelet aggregation.
Argatroban is highly selective for thrombin; inhibitory constant (Ki) values in studies in vitro with synthetic tripeptides ranged from 5 to 39 nM.
Argatroban is capable of inhibiting the action of both free and clot-associated thrombin. It does not interact with heparin-induced antibodies. There was no evidence of formation of antibodies against argatroban in patients who received multiple doses of argatroban.
Evidence of the efficacy of Exembol in HIT type II derives from data from two studies where a total of 568 adult patients were treated with Exembol. The average treatment duration employed in these clinical studies was 6 days with a maximum of 14 days. In the first prospective trial, an improvement in the composite outcome at 37 days (death, amputation, new thrombosis) was observed in the Exembol group versus the historical controls (n=46) The reduction of the incidence of the primary endpoint was consistent in the subgroups of patients having HIT type II without thromboembolic complications (25.6% vs 38.8%), p=0.014 by categorical analysis; p=0.007 by time-to-event analysis) and HIT type II with thromboembolic complications (43.8% vs 56.5%, p=0.131 by categorical analysis; p=0.018 by time-to event analysis).
The studies were not statistically powered for individual endpoints. However, in the first prospective study, the reduction of the incidence of individual endpoints for patients having HIT type II without and with thromboembolic complications respectively was as follows: mortality (16.9 vs 21.8%, n.s) and (18.1 vs 28.3%, n.s), amputation (1.9 vs 2.0%, n.s) and (11.1 vs 8.7%, n.s), new thromboses (6.9 vs 15%, p=0.027) and (14.6 vs 19.6%, n.s).
In the second follow-on study, similar outcomes were observed.
The efficacy and safety of the use of Exembol in patients under 18 years of age has not been established. However, limited results from a prospective clinical study conducted in the USA in 18 seriously ill paediatric patients with (suspected) HIT Type II requiring an alternative to heparin anticoagulation are available.
The age range of the patients participating in this study were less than six months (8 patients), six months to less than 8 years (6 patients) and 8 to 16 years (4 patients). All patients had serious underlying conditions and were receiving multiple concomitant medications.
Thirteen patients received Exembol solely as a continuous infusion (no bolus dose). In the majority of these 13 patients dosing was initiated at 1 microgram/kg/min to achieve an aPTT of 1.5 to 3 times the baseline value (not exceeding 100 seconds). Most patients required multiple dose adjustments to maintain anticoagulation parameters within the desired range.
During the 30-day study period thrombotic events occurred during Exembol administration in two patients and following Exembol discontinuation in three other patients. Major bleeding occurred among two patients; one patient experienced an intracranial haemorrhage after 4 days of Exembol therapy in the setting of sepsis and thromobocytopenia. Another patient completed 14 days of treatment but experienced an intracranial haemorrhage while receiving Exembol following completion of the study treatment period.
As only limited data are available, an initial continuous infusion rate of 0.75 microgram/kg/min has been suggested in seriously ill paediatric patients with normal hepatic function. A reduced starting dose of 0.2 microgram/kg/min would be suggested in seriously ill paediatric patients with impaired hepatic function (see Section 5.2). The dose should be adjusted to achieve target aPTT 1.5-3 times the baseline value, not exceeding 100 seconds.
Steady-state levels of both argatroban and anticoagulant effect are typically attained within 1-3 hours and are maintained until the infusion is discontinued or the dosage adjusted. Steady-state plasma argatroban concentrations increase proportionally with dose (for infusion doses up to 40 microgram/kg/min in healthy subjects) and are well correlated with steady-state anticoagulant effects. For infusion doses up to 40 microgram/kg/min, argatroban increases, in a dose-dependent fashion, the activated partial thromboplastin time (aPTT), the activated clotting time (ACT), the International Normalized Ratio (INR) and the thrombin time (TT) in healthy volunteers and cardiac patients.
Argatroban distributes mainly in the extra-cellular fluid. The volume of distribution (Vdβ) was 391 ± 155 ml/kg (mean ± SD). Argatroban is 54% bound in human serum proteins, with binding to albumin and α1-acid glycoprotein being 20% and 34% respectively.
The metabolism of argatroban has not yet been fully characterized. The metabolites identified (M-1, M-2, and M-3) are formed by hydroxylation and aromatization of the 3-methyltetrahydroquinoline ring in the liver. The formation of the metabolites is catalysed in vitro by cytochrome P450 enzymes CYP3A4/5, but this is not a major path of elimination in vivo. The primary metabolite (M1) exerts 40-fold weaker antithrombin effect than argatroban. Metabolites M-1, M-2 and M-3 were detected in the urine, and M-1 was detected in plasma and faeces.
There is no interconversion of the 21-(R) and 21-(S) diastereoisomers. The ratio of diastereoisomers is unchanged by metabolism or hepatic impairment, remaining constant at 65:35 (±2%).
On termination of the infusion, the concentration of argatroban decreased rapidly. The apparent terminal elimination half life (mean ± SD) is 52 ± 16 min. Clearance (mean ± SD) was 5.2 ± 1.3 ml/kg/min.
Argatroban is excreted mainly in the faeces, presumably through biliary secretion. Following intravenous infusion of 14C-radiolabelled argatroban 21.8 ± 5.8% of the dose was excreted in urine and 65.4 ± 7.1% in the faeces.
Clearance is approximately 15% lower then in younger persons. No age related dose adjustment is necessary.
Compared with patients with normal renal function (creatinine clearance ≥80ml/min) who had a terminal half-life of 47±22 min, patients with severely impaired renal function (creatinine clearance ≤29ml/min) had only slight prolongation of this value (65±35 min). No initial dose regimen adjustment with respect to renal function is necessary.
In patients with hepatic impairment (Child Pugh score 7 to 11) clearance was 26% of that of healthy volunteers. Initial dose reduction is required in patients with moderate hepatic impairment. Exembol is contraindicated in patients with severe hepatic impairment.
Argatroban clearance is decreased in seriously ill paediatric patients. Based on population pharmacokinetic modelling, clearance in paediatric patients (0.17 L/hr/kg) was 50% lower compared to healthy adults (0.31 L/hr/kg). Population pharmacokinetic data also indicate that the infusion rate should be adjusted according to body weight.
Based on population pharmacokinetic modelling, patients with elevated bilirubin (secondary to cardiac complications or hepatic impairment) had, on average, 80% lower clearance (0.03 L/hr/kg) when compared to paediatric patients with normal bilirubin levels.
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and genotoxicity. Toxicity studies with continuous intravenous infusions and reproduction toxicity studies using daily intravenous bolus injections achieved only limited systemic exposure to argatroban (2 times the exposure seen in humans). Although these studies do not suggest any particular risk to humans, their value is limited by the low systemic exposure realised.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
