Who can administer
May be administered by registered competent doctor or nurse/midwife
Important information
- Ordered on advice of consultant haematologist only
- Unlicensed preparation in Ireland
- IMPORTANT: The ACT is NOT the same as the aPTT. Results are not interchangeable.
- See under Dose for adjustments required in renal or hepatic impairment
Available preparations
Exembol 250mg per 2.5ml vial (contains ethanol 1g / 2.5ml vial)
Reconstitution
- Already in solution
- Dilute further prior to administration
Infusion fluids
- Sodium chloride 0.9% or Glucose 5%
- Mix by repeated inversion of the infusion bag for 1 minute
Methods of intravenous administration
Continuous intravenous infusion (administer using an electronically controlled infusion device)
- Add 250mg (2.5ml) vial to 250ml infusion fluid (no need to remove 2.5ml from bag)
- Using a 1mg per ml solution (250mg in 250ml) - set up the continuous infusion
- Adjust dose as per 'Dose'
Slow intravenous injection (Percutaneous intervention only, see dose under Further Information)
- Given over 3 to 5 minutes
Dose in adults
Heparin induced thrombocytopenia (HIT)
- All patients with HIT must be managed in conjunction with haematology
- If baseline aPTT elevated- discuss target aPTT with Haematology
- APTTr; the patient's activated partial thromboplastin time divided by either the laboratory's normal value or the patient's own baseline value
- Prior to commencement stop heparin and take baseline aPTT, PT and fibrinogen (CLAUSS) (ref 1)
- Argatroban is a direct thrombin inhibitor. Its anticoagulant effect is measured by the APTTr and INR, which increase in a dose dependent manner. Dose adjustments are based on the APTTr as shown in the table below.
- Daily monitoring is sufficient after 2 consecutive aPTT within target range if no dose adjustments were made (ref 1)
- Argatroban interferes with the Clauss Fibrinogen assay resulting in falsely low results. The derived fibrinogen assay may be more reliable but both will be abnormal at higher argatroban concentrations(ref 1)
- The lab MUST be informed that patient is receiving argatroban(ref 1)
| Table 1: Recommended starting doses and monitoring intervals (see table 3 below for flow rates) |
|
Argatroban dose (mcg/kg/minute) |
Interval to check aPTT after initial dose and each dose change thereafter |
|
Standard dose
|
2 |
2 hours |
| Critically ill patients* |
0.5 |
4 hours |
| Moderate hepatic impairment** |
0.5 |
4 hours |
| * Multi-system organ failure, ICU patients, heart failure, post cardiac surgery, anasarca |
| ** Moderate hepatic impairment (Child Pugh B) |
| Table 2: Dose modifications and monitoring intervals (see Table 3 below for flow rates) |
|
Standard dosing schedule
|
Critically ill/Hepatically impaired patients
|
| Initial infusion rate 2mcg/kg/minute |
Initial infusion rate 0.5mcg/kg/min |
| aPTT |
Infusion rate change |
Next aPTT |
Infusion rate change |
Next aPTT |
| <1.5 patient's baseline |
Increase by 0.5mcg/kg/min |
2 hours |
Increase by 0.1mcg/kg/min |
4 hours |
|
1.5 to 3 times patient's baseline
(and less than 100 seconds)
|
No change
Ideal range: 1.5 to 2.5 patient's baseline aPTT as per Dr Gilmore
|
2 hours
After 2 consecutive aPTT within target range, check at least 24 hours
|
No change |
4 hours
After 2 consecutive aPTT within target range, check at least every 24 hours
|
| > 3 times patient's baseline or if over 100 seconds |
Discontinue infusion until APTT is within desired range (typically within 2 hours of discontinuation) - restart at 50% of the previous rate
|
2 hours |
Discontinue infusion until APTT is within desired range (typically within 2 hours of discontinuation) - restart at 50% of the previous rate
|
4 hours |
- The maximum recommended dose is 10 microgram/kg/minute
- The maximum recommended duration of treatment is 14 days, although there is limited experience with administration for longer periods
| Table 3: Infusion rate in ml/HOUR of a 1mg/1ml infusion |
| Dose/Weight (kg) |
0.1micrograms/kg/min |
0.5micrograms/kg/min |
1micrograms/kg/min |
2micrograms/kg/min |
| 50 |
0.3 |
1.5 |
3 |
6 |
| 60 |
0.36 |
1.8 |
3.6 |
7.2 |
| 70 |
0.42 |
2.1 |
4.2 |
8.4 |
| 80 |
0.48 |
2.4 |
4.8 |
9.6 |
| 90 |
0.54 |
2.7 |
5.4 |
10.8 |
| 100 |
0.6 |
3 |
6 |
12 |
| 110 |
0.66 |
3.3 |
6.6 |
13.2 |
| 120 |
0.72 |
3.6 |
7.2 |
14.4 |
| 130 |
0.78 |
3.9 |
7.8 |
15.6 |
| 140 |
0.84 |
4.2 |
8.4 |
16.8 |
| 150 |
0.9 |
4.5 |
9 |
18 |
Patients with HIT Type II undergoing percutaneous coronary intervention (PCI)
- Limited data is available from the use of argatroban 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
- This is 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 seconds
- If the ACT is below 300 seconds, 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 seconds 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 seconds 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 argatroban use in combination with GPIIb/IIIa inhibitors has not been established.
Renal impairment
- No initial dosage adjustment necessary in mild to severe renal impairment. Monitor aPTT closely.
- Haemodialysis: limited data. Consult haematologist and see specialist texts
Liver impairment
- Use with extreme caution in hepatic impairment
- See Tables 1 and 2 above for doses
- Reversal of the anticoagulant effects of argatroban may take longer in this setting (more than four hours)
- Argatroban is contraindicated in patients with severe hepatic impairment
Changing to oral anticoagulation (ref 1)
- A Haematology Consultant (ideally with Special Interest in Coagulation) will decide on the timing, duration and choice of oral anticoagulant
- Patients with HIT require a minimum of three months of oral anticoagulation
- If starting DOAC
- stop argatroban and start DOAC
- Rivaroxaban, apixaban and dabigatran have all been used in this situation
- If starting warfarin therapy for patient on argatroban
- Warfarin should only be commenced when there is resolution of thrombocytopenia (to avoid coumarin-associated microvascular thrombosis and venous limb gangrene)
- To avoid prothrombotic effects and to ensure continuous anticoagulation, argatroban must be continued during the initiation of warfarin therapy
- A minimum overlap of argatroban and warfarin of at least 5 days is advised
- Argatroban has a significant effect on the INR
- NO loading doses of warfarin to be given
- Start with the intended maintenance dose of warfarin (no greater than 5mg daily)
- Discontinue argatroban when INR reaches up to 4 for at least two days, on COMBINED therapy (INR should be 2 greater than desired target range- eg in patients with target INR of 2 to 3, INR on combined argatroban and warfarin should be 4 to 5) (ref 3)
- Repeat INR 4 to 6 hours after stopping argatroban, to ensure INR is therapeutic prior to permanent discontinuation of argatroban(ref 3)
- If INR is below the desired therapeutic range recommence argatroban and repeat the procedure above (steps 2 to 6)
- Take INR at least daily
Monitoring
Storage
- Store below 250C
- Do not refrigerate or freeze
- The diluted solution is stable for 24 hours if kept at 250C or less (do not expose the diluted solution to direct sunlight)
References
UK SPC (Exembol) 31/10/2024
1. Dr Ruth Gilmore, Consultant Haematologist, 26/03/2025
2. Heparin induced thrombocytopenia - a comprehensive clinical review, Salter et al. JACC Vol 67, No 21, 2016
Therapeutic classification
Parenteral anticoagulants
