EXEMBOL Solution for infusion Ref.[6214] Active ingredients: Argatroban

Paediatric population

Currently available data are described in section 5.1 and 5.2 but no recommendation on a posology can be made.

Initial Dosage

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 (see Method of Administration). Before Exembol is administered, heparin therapy should be discontinued and a baseline aPTT value obtained.

Standard recommendations

Monitoring

In general, therapy with Exembol is monitored using the activated partial thromboplastin time (aPTT).

Tests of anticoagulant effects (including the aPTT) attain steady-state levels typically within 1-3 hours following initiation of Exembol.

The target range for steady-state aPTT is 1.5-3.0 times the initial baseline value, but not exceeding 100 seconds.

Dose adjustment may be required to attain the target aPTT (see Dose Modifications).

aPTT should be checked two hours after the start of the infusion to confirm that the aPTT is within the desired therapeutic range. Thereafter, the aPTT should be monitored at least once per day.

Dose modifications

After the initial dose of Exembol, the dose can be adjusted based on the clinical course until the steady-state aPTT is within the desired therapeutic range (1.5 to 3.0 times the initial baseline value but not exceeding 100 seconds). In case of an elevated aPTT (greater than 3 times baseline or 100 seconds), the infusion should be discontinued until the aPTT is within the desired range of 1.5 to 3 times baseline (typically within 2 hours of discontinuation of infusion), and the infusion restarted at one half of the previous infusion rate. The aPTT should be checked again after 2 hours.

The maximum recommended dose is 10 microgram/kg/min. The maximum recommended duration of treatment is 14 days, although there is limited clinical experience of administration for longer periods (see section 5.1).

Method of administration

Exembol is supplied as a 1 mg/ml ready to use solution for intravenous infusion (50 mg/50 ml (see section 6.6). It is recommended for use with a syringe driver to control the rate of administration.

Standard infusion rates for the 2 microgram/kg/min recommended initial dosage (1 mg/ml concentration) are detailed in the table below. The standard infusion rates for patients with moderate hepatic impairment (Child-Pugh Class B), after cardiac surgery and critically ill patients with a starting infusion rate of 0.5 microgram/kg/min are also detailed in the table below:

Additional Information on Special Populations

Older people

The standard initial dosage recommendations for use in adults are applicable to elderly patients.

Paediatric population

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.

Renal impairment

The standard initial dosage recommendations for use in adults are applicable to patients with renal impairment (see section 5.2).

Limited data is available from the use of Exembol in haemodialysis. 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. Exembol clearance by high flux membranes used during haemodialysis and continuous venovenous haemofiltration was clinically insignificant.

Hepatic impairment

For patients with moderate hepatic impairment (Child-Pugh Class B), an initial dose of 0.5 microgram/kg/min is recommended (see section 4.4 and section 5.2). The aPTT should be monitored closely and the dosage should be adjusted as indicated clinically. Exembol is contra-indicated in patients with severely impaired liver function.

Patients with HIT Type II after cardiac surgery and critically ill patients

Limited data is available from the use of Exembol in patients with HIT Type II after cardiac surgery and critically ill patients/intensive care unit (ICU) patients with (multiple) organ system failure. Based on the data 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.

The clinical status of the patient, especially acute changes in hepatic function, should be taken into account and the infusion rate should be carefully adjusted to maintain the aPTT in the desired range.

An increase in the frequency of monitoring is recommended to ensure the target aPTT values are achieved and maintained.

Patients with HIT Type II undergoing percutaneous coronary intervention (PCI)

Limited data is available from the use of Exembol in patients with HIT Type II undergoing percutaneous coronary intervention. Based on the data, 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, and the ACT should be checked 5 to 10 minutes later. If the ACT is higher than 450 sec, the infusion rate should be decreased to 15 microgram/kg/min and ACT values be checked 5 to 10 minutes later. Once a therapeutic ACT between 300 to 450 sec has been achieved, the infusion dose should be continued for the duration of the procedure. ACT measurements were recorded using both Haemotec and Haemochrom devices.

The efficacy and safety of Exembol use in combination with GPIIb/IIIa inhibitors has not been established.

NOTE: 1 mg/ml = 1000 microgram (mcg)/ml
^† Additional IV bolus dose of 150 mcg/kg should be administered if ACT <300 seconds.

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.

Recommendations for use in patients scheduled for a conversion to oral anticoagulation

Use of oral anticoagulants (of the coumarin type) should be delayed until substantial resolution of thrombocytopaenia (e.g. platelets >100 × 109/l) to avoid coumarin associated microvascular thrombosis and venous limb gangrene. The intended maintenance dose should be started with no loading dose.

For both the Quick and Owren type PT 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 while Exembol and oral anticoagulants are co-administered. On co-therapy the target value for INR should be within the therapeutic range according to the type of assay used (see above) for at least 2 days before Exembol is discontinued.

The INR measurement should be repeated 4-6 hours after discontinuation of Exembol. If the repeat INR is below the desired therapeutic range, the infusion of Exembol should be resumed and the procedure repeated daily until the desired therapeutic range on oral anticoagulants alone is reached.

For doses greater than 2 microgram/kg/min, the relationship between INR on oral anticoagulants alone or INR on oral anticoagulants plus Exembol is less predictable. With such higher doses, 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 (see above). The INR on Exembol and oral anticoagulants should be measured 4 to 6 hours after reduction of the Exembol dose.

Excessive anticoagulation, with or without bleeding, may be controlled by discontinuing Exembol or by decreasing the infusion rate. In clinical studies, anticoagulation parameters return to baseline generally within 2 to 4 hours after discontinuation of Exembol. Reversal of anticoagulant effect may take longer in patients with hepatic impairment.

No specific antidote to Exembol is available. If life-threatening bleeding occurs and excessive plasma levels of argatroban are suspected, Exembol should be discontinued immediately and aPTT and other coagulation tests should be performed. Symptomatic and supportive therapy should be provided to the patient.

Lethal single intravenous doses of argatroban for mice, rats, rabbits, and dogs were 200, 124, 150, and 200 mg/kg respectively. The symptoms of acute toxicity were loss of righting reflex, tremors, clonic convulsions, paralysis of hind limbs, and coma.

Each vial contains 200 mg ethanol.

Shelf life as packaged for sale: 36 months.

Shelf life after first opening: The product should be used immediately.

Keep vial in the outer carton in order to protect from light.

In use, the solution should not be exposed to direct sunlight.

Do not refrigerate or freeze.

Clear 50 ml glass vial sealed with an ethylene tetrafluorethylene (ETFE)-coated chlorobutyl rubber stopper and aluminium crimp-seal with a polypropylene flip-off cap. Each vial contains 50 ml of solution for infusion.

Vials are supplied in cardboard cartons of 4 or 12 vials. Not all pack-sizes may be marketed.

Exembol 1 mg/ml Solution for Infusion is ready to use and requires no dilution before administration.

The drug product is unpreserved and intended for single use only. The solution should be used immediately after opening. Any unused solution should be discarded.

The solution should be inspected visually prior to use. Only clear solutions without visible particles should be used.

Light resisting measures such as foil protection for intravenous lines are not necessary. No significant potency losses have been noted following simulated delivery of the solution through intravenous tubing.

Any unused product or waste material should be disposed of in accordance with local requirements.