The diagnosis should be confirmed by the HIPAA (heparin-induced platelet activation assay) or equivalent test. It typically presents 5–10 days after the start of heparin treatment and involves the development of antibodies, which bind to heparin platelet factor 4 (PF4) complexes.This can contribute to the development of new thrombi. HIT is associated with an increased thromboembolic risk. Suitable anticoagulants include lepirudin,warfarin, epoprostenol, argatroban and danaparoid.
Lepirudin is a direct irreversible thrombin inhibitor with an elimination half-life of 60–90 min in normal renal function. Lepirudin is almost mexclusively excreted and metabolised renally, and therefore in renal impairment it accumulates.Dose reduction must be made in renal impairment. The elimination half-life of lepirudin is prolonged in severe renal impairment to as much as 2 days.The effect of lepirudin can be monitored using APTT or Ecarin clotting time (ECT). ECT is not widely available.
Uses
HIT (type II)
Contraindications
Known hypersensitivity to lepirudin, hirudins or any of the excipients
Pregnancy and lactation
Administration
Lepirudin comes in a vial containing 50 mg dry powder
Dosage in normal renal function
Lepirudin is administered as an initial loading dose followed by a continuous infusion.
• Loading dosage: 0.4 mg/kg (see table overleaf) as IV bolus over 5 min
Solution for loading dose:
For the IV loading dosage injection a concentration of 5 mg/ml must be used
Reconstitute one 50-mg vial with 1 ml sodium chloride 0.9% and shake the vial gently
Draw up the contents of one vial (50 mg) in a 10-ml syringe, and make up to 10 ml with sodium chloride 0.9% to give 5 mg/ml
Injection volume (ml) for loading dose (0.4mg/kg) in normal renal function:
Body
weight (kg)
|
Injection volume (ml) of 5 mg/ml solution
|
50
|
4.0
|
60
|
4.8
|
70
|
5.6
|
80
|
6.4
|
90
|
7.2
|
100
|
8.0
|
>110
|
8.8
|
Note: patients with a body weight of over 110 kg should receive the dosage based on a body weight of 110 kg. Do not exceed this dose.
• Continuous infusion: 0.15 mg/kg/h (see following table) as a continuous IV infusion
Solution for continuous infusion:
• For the continuous infusion a concentration of 2 mg/ml must be used.
• Reconstitute 2 x 50-mg vials, each with 1 ml sodium chloride 0.9% and shake the vial gently
• Draw up the contents of the 2 vials (100 mg) in a 50-ml syringe, and make up to 50 ml with sodium chloride 0.9% to give 2 mg/ml
• Syringes must be changed every 12 hours
Initial infusion rate (ml/h) for maintenance dose (0.15 mg/kg/h) in normal renal function:
Body
weight (kg)
|
Injection volume (ml) of 2 mg/ml solution
|
50
|
3.8
|
60
|
4.5
|
70
|
5.3
|
80
|
6.0
|
90
|
6.8
|
100
|
7.5
|
>110
|
8.3
|
Note: patients with a body weight of over 110 kg should receive the dosage based on a body weight of 110 kg. Do not exceed this dose.
Monitoring and dose modification of lepirudin:
• Target APTT should be 1.5–2.5 times average control value
• APTT should be monitored at least once daily but may need to be checked more frequently (8 hourly) in some circumstances, e.g. in patients with renal impairment or an increased risk of bleeding
• The first APTT should be checked after 4 hours of commencing treatment with lepirudin
• The infusion rate should be adjusted according to the APTT
• If the APTT is below the target range then the infusion speed should be increased by 20% and APTT rechecked 4 hours later
• If the APTT is above the target range the infusion should be stopped for 2 hours and when restarted the infusion speed reduced by 50%
and the APTT rechecked 4 hours later Dosage in renal impairment:
• Lepirudin is administered as an initial loading dose followed by a continuous infusion
• Loading dosage: 0.2 mg/kg (see below table) as IV bolus dose over 5 minutes Solution for loading dose:
• For the IV loading dosage injection a concentration of 5mg/ml must be used
• Reconstitute one 50-mg vial with 1 ml sodium chloride 0.9% and shake the vial gently
• Draw up the contents of one vial (50 mg) in a 10-ml syringe, and make up to 10 ml with sodium chloride 0.9% to give 5 mg/ml
Injection volume (ml) for loading dose (0.2 mg/kg) in renal impairment:
Body
weight (kg)
|
Injection volume (ml) of 5 mg/ml solution
|
50
|
2.0
|
60
|
2.4
|
70
|
2.8
|
80
|
3.2
|
90
|
3.6
|
100
|
4.0
|
>110
|
4.4
|
Note: patients with a body weight of over 110 kg should receive the dosage based
on a body weight of 110 kg. Do not exceed this dose.
• Continuous infusion
The initial infusion rate depends on the degree of renal impairment (see the following two tables). Adjust to APTT.
Solution for continuous infusion:
• For the continuous infusion a concentration of 2 mg/ml must be used
• Reconstitute 2 x 50-mg vials, each with 1 ml sodium chloride 0.9% and shake the vial gently
• Draw up the contents of the 2 vials (100 mg) in a 50-ml syringe, and make up to 50 ml with sodium chloride 0.9% to give 2 mg/ml
• Syringes must be changed every 12 hours
Reduction of infusion rate according to renal impairment:
Creatinine
clearance
(ml/min)
|
Creatinine
value
(mg/l [umol/l])
|
Adjusted
infusion rate
(% of original dose)
|
45–60
|
16–20 (141–177)
|
50
|
30–44
|
21–30 (178–265)
|
30
|
15–29
|
31–60 (266–530)
|
15
|
<15
|
>60 (530)
|
avoid
or STOP infusion
|
Body
weight
(kg)
|
Infusion
rate (ml/h) of 2 mg/ml solution
|
|||
Dosage
0.15
mg/
kg/h
(normal
renal
function)
|
Dosage
0.075
mg/
kg/h
(renal
impairment
CC
45–60
ml/min)
|
Dosage
0.045
mg/
kg/h
(renal
impairment
CC
30–44
ml/min)
|
Dosage
0.0225
mg/
kg/h
(renal
impairment
CC
15–29
ml/min)
|
|
50
|
3.8
|
1.9
|
1.1
|
0.6
|
60
|
4.5
|
2.3
|
1.4
|
0.7
|
70
|
5.3
|
2.6
|
1.6
|
0.8
|
80
|
6.0
|
3.0
|
1.8
|
0.9
|
90
|
6.8
|
3.4
|
2.0
|
1.0
|
100
|
7.5
|
3.8
|
2.3
|
1.1
|
>110
|
8.3
|
4.1
|
2.5
|
1.2
|
Note: patients with a body weight of over 110 kg should receive the dosage based on a body weight of 110 kg. Do not exceed this dose.
Monitoring and dose modification of lepirudin:
• Target APTT should be 1.5–2.5 times average control value
• APTT should be monitored at least once daily but may need to be checked more frequently (8 hourly) in some circumstances, e.g. in
patients with renal impairment or an increased risk of bleeding
• The first APTT should be checked after 4 hours of commencing treatment with lepirudin
• The infusion rate should be adjusted according to the APTT
• If the APTT is below the target range then the infusion speed should be increased by 20% and APTT rechecked 4 hours later
• If the APTT is above the target range the infusion should be stopped for 2 hours and when restarted the infusion speed reduced by 50%
and the APTT rechecked 4 hours later
Dosage for patients undergoing CVVH
Lepirudin is administered as an initial loading dose followed by a continuous infusion.
• Loading dosage: 0.2 mg/kg (see below table) as IV bolus over 5 min
Solution for loading dose:
For the IV loading dosage injection a concentration of 5 mg/ml must be used.
Reconstitute one 50-mg vial with 1 ml sodium chloride 0.9% and shake the vial gently.
Draw up the contents of one vial (50 mg) in a 10-ml syringe, and make up to 10 ml with sodium chloride 0.9% to give 5 mg/ml.
Injection volume (ml) for loading dose (0.2 mg/kg) in patients undergoing CVVH:
Body weight (kg)
|
Injection volume (ml) of
5 mg/ml solution
|
50
|
2.0
|
60
|
2.4
|
70
|
2.8
|
80
|
3.2
|
90
|
3.6
|
100
|
4.0
|
>110
|
4.4
|
Note: patients with a body weight of over 110 kg should receive the dosage based on a body weight of 110 kg. Do not exceed this dose.
• Continuous infusion
Start at 15 μg/kg/h (one-tenth the dose for normal renal function) adjust to APTT (see following table)
Solution for continuous infusion:
Reconstitute one 50-mg vial with 1 ml sodium chloride 0.9% and shake the vial gently
For the continuous infusion a concentration of 0.2 mg/ml (one-tenth the usual dilution) must be used
Draw up the contents of one vial (50 mg) in a 10-ml syringe, and make up to 10 ml with sodium chloride 0.9% to give 5 mg/ml
From above solution (5 mg/ml), draw 2 ml and further dilute up to 50 ml sodium chloride 0.9% to give 0.2 mg/ml solution
Start the infusion at 5 ml/h (-15 μg/kg/h)
The infusion rate should be adjusted according to the APTT
The first APTT should be checked after 4 hours of commencing treatment with lepirudin
Target APTT should be 1.5–2.5 times average control value
Syringes must be changed every 12 hours
Infusion rate change adjusted to APTT:
APTT (s)
|
Infusion rate
|
Check APPT
|
<40
|
Increase by 2 ml/h
|
in 4 h
|
41–60
|
Increase by 1 ml/h
|
in 4 h
|
61–80
|
No change
|
in 8 h
|
81–100
|
Reduce by 1 ml/h
|
in 4 h
|
101–120
|
Reduce by 2 ml/h
|
in 4
h
|
>120
|
STOP
|
Adverse effects
Bleeding
Allergic reactions
Fever
Injection site reactions including pain
Cautions
Significant hepatic impairment
Re-exposure – some patients experienced mild, possibly allergic reactions
during or after the end of a second course
Paediatrics – safety not been established
Elderly
Organ failure
Renal: reduce dose
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