Argatroban

PRIOR VERIFY CARRY-FORWARD: the previous draft of this file was HELD for (a) an interactions entry ('inhibitors of the bile salt export pump') that does not exist anywhere in this bundle - it was cross-contamination from the bosentan source - and (b) a MISSING hepaticAdjustment field, which on a hepatically-cleared drug let the renderer show a renal row with a blank hepatic slot and risked a 4x overdose in Child-Pugh B. Both are fixed here: this draft carries no interactions key at all (the UK SPC 4.5 text is truncated at the source-fetch limit, so no interaction is asserted from the UK source; the US section 7 items are summarised at the end of these notes), and hepaticAdjustment is populated. || WHY maxDose IS BLANK: the only ceiling the sources state is a WEIGHT-BASED INFUSION RATE, not an absolute dose, so it cannot go in the maxDose field. Verbatim, SPC 4.2: 'The maximum recommended dose is 10 microgram/kg/min.' US 2.2: 'adjust the dose (not to exceed 10 mcg/kg/min) as necessary to obtain a steady-state aPTT in the target range.' Treat 10 microgram/kg/min as the rate ceiling for HIT. || INITIATION, verbatim (SPC 4.2): 'Treatment with Exembol should be initiated under the guidance of a physician with experience in coagulation disorders. The initial dosage in adult patients without hepatic impairment in HIT type II is 2 microgram/kg/min, administered as a continuous infusion... Before Exembol is administered, heparin therapy should be discontinued and a baseline aPTT value obtained.' 4.4 adds: 'All parenteral anticoagulants should be discontinued before administration of Exembol. When Exembol is to be started after cessation of heparin therapy, sufficient time should be allowed for the effect of heparin on the aPTT to decrease prior to start of Exembol therapy (about 1-2 hours).' || TITRATION TABLE (SPC 4.2), standard start 2 mcg/kg/min - aPTT < 1.5 x baseline: increase by 0.5 mcg/kg/min, next aPTT 2 hours; aPTT 1.5-3.0 x baseline (not exceeding 100 s): no change, check at 2 hours and, after 2 consecutive aPTTs in range, at least once per day; aPTT > 3.0 x baseline or > 100 s: 'Stop infusion until the aPTT is 1.5-3.0 times baseline. Resume at half of the previous infusion rate', next aPTT 2 hours. For the 0.5 mcg/kg/min start (critically ill / hepatically impaired) the same table applies but increments are 0.1 mcg/kg/min and the next aPTT is at 4 hours. || CRITICALLY ILL / POST-CARDIAC-SURGERY HIT type II, verbatim: 'therapy could be initiated with a starting infusion rate of 0.5 microgram/kg/min (maximum 10 microgram/kg/min) and adjusted to the target aPTT range of 1.5-3.0 times baseline value (not exceeding 100 seconds). In critically ill/ICU patients with severe (multiple) organ failure (as assessed by SOFA-II APACHE-II or comparable scores) a reduced maintenance dose is recommended.' Standard infusion rates at 0.5 microgram/kg/min (1 mg/ml): 50 kg = 1.5 ml/hr, 60 kg = 1.8, 70 kg = 2.1, 80 kg = 2.4, 90 kg = 2.7, 100 kg = 3.0, 110 kg = 3.3, 120 kg = 3.6, 130 kg = 3.9, 140 kg = 4.2 ml/hr. || HIT type II UNDERGOING PCI (a DIFFERENT regimen - do not confuse with the HIT infusion above), verbatim: 'when there is no alternative, therapy could be initiated with a bolus dose of 350 microgram/kg over 3 to 5 minutes followed by an infusion dose of 25 microgram/kg/min. 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 sec. If the ACT is below 300 sec, an additional bolus dose of 150 microgram/kg should be administered, the infusion rate be increased to 30 microgram/kg/min... If the ACT is higher than 450 sec, the infusion rate should be decreased to 15 microgram/kg/min... Once a therapeutic ACT between 300 to 450 sec has been achieved, the infusion dose should be continued for the duration of the procedure.' The US label adds that in dissection, impending abrupt closure, thrombus formation, or inability to hold ACT over 300 seconds, 'additional bolus doses of 150 mcg/kg may be administered and the infusion dose increased to 40 mcg/kg/min.' SPC: 'Specific dosing information on patients with hepatic impairment undergoing PCI is not available. Therefore, the use of Exembol for treatment of patients with hepatic impairment requiring PCI is not recommended.' || HAEMODIALYSIS, verbatim: 'Based on the data, therapy could be initiated with an initial bolus (250 microgram/kg) followed by continuous infusion of 2 microgram/kg/min. The infusion is stopped 1 hour before the end of the procedure. The target ACT range is 170-230 seconds (measured using the Haemotec device). In patients that are already being treated with Exembol no bolus dose is required.' || CONVERSION TO ORAL ANTICOAGULATION, verbatim: 'Use of oral anticoagulants (of the coumarin type) should be delayed until substantial resolution of thrombocytopaenia (e.g. platelets >100 x 10 9 /l)... The intended maintenance dose should be started with no loading dose.' Quick-type PT assay: 'with doses of Exembol up to 2 microgram/kg/min, Exembol can be discontinued when the INR reaches a minimum of 4 on combined therapy.' Owren-type PT assay: 'The target value for INR on co-therapy should be as recommended for the oral anticoagulant alone i.e. 2-3.' For both assays: 'Co-therapy of Exembol and oral anticoagulants (of the coumarin type) is recommended for a minimum of 5 days. INR should be measured daily... The INR measurement should be repeated 4-6 hours after discontinuation of Exembol.' For doses above 2 microgram/kg/min, 'the dose of Exembol should be temporarily reduced to 2 microgram/kg/min in order to improve the prediction of INR on oral anticoagulants alone.' || ELDERLY: 'The standard initial dosage recommendations for use in adults are applicable to elderly patients.' || EXCIPIENT CAUTIONS (4.4): contains ethanol - at the maximum 10 microgram/kg/min in a 70 kg adult this gives 57.6 mg/kg of ethanol, a blood alcohol rise of about 9.6 mg/100 ml; contains sorbitol (avoid in hereditary fructose intolerance); '177 mg sodium per vial (50 ml), equivalent to 9% of the WHO recommended maximum daily intake of 2 g sodium for an adult.' 'There is no specific antidote to Exembol.' || PAEDIATRIC (why paedDose is null), SPC 4.2 verbatim: 'Limited data from a prospective clinical study in 18 children (neonates to 16 years old) and published data is available. The safe and effective dose or the effective target range for aPTT or activated clotting time (ACT) of Exembol has not been clearly established in this patient population. Currently available data are described in Section 5.1 and 5.2 but no recommendation on a posology can be made.' The US 8.4 offers exploratory figures only ('For patients with normal hepatic function, a starting infusion rate of 0.75 mcg/kg/min may have comparable aPTT responses as a starting dose of 2 mcg/kg/min in healthy adults'; 'For patients with hepatic impairment a starting infusion rate of 0.2 mcg/kg/min with increasing dosing by increments of 0.05 mcg/kg/min'), immediately followed by 'the safety and effectiveness of argatroban is not established in pediatric patients.' These are continuous infusion RATES, not per-dose figures, and are explicitly unvalidated, so no paediatric dose is published here; verify any under-18 use against a children's formulary and specialist haematology advice. || INTERACTIONS - the UK SPC 4.5 text was NOT retrieved (the fetch ends at '4.5 Interaction with other medicinal [...TRUNCATED]'), so nothing is asserted from the UK source. From the US section 7: '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'; with warfarin, 'the concomitant use of argatroban and warfarin... results in prolongation of the prothrombin time (PT) and International Normalized Ratio (INR)'; 'No drug-drug interactions have been demonstrated between argatroban and concomitantly administered aspirin or acetaminophen'; and for thrombolytics and glycoprotein IIb/IIIa antagonists, 'Safety and effectiveness of concomitant use with argatroban have not been established' (the SPC agrees: 'The efficacy and safety of Exembol use in combination with GPIIb/IIIa inhibitors has not been established').