Enoxaparin

ADMINISTRATION ROUTES:

SC

ALTERNATIVE NAMES:

Clexane

ICU INDICATIONS:

1. Therapeutic anticoagulation
2. Venous thromboembolism prophylaxis

PRESENTATION AND ADMINISTRATION:

SC:

Pre-filled syringes:

• Clexane: 20 mg/0.2 mL, 40 mg/0.4 mL, 60 mg/0.6 mL, 80 mg/0.8 mL, 100 mg/1 mL
• Clexane Forte: 120 mg/0.8 mL, 150 mg/1 mL

Do NOT remove air bubble from pre-mixed syringe prior to injection

Inject at 90 degrees to the skin on the lower abdomen. Alternate between the left and right anterolateral abdominal wall.

Do not rub injection site after administration as this increases risk of bruising.

DOSAGE:

SC:

Venous thromboembolism prophylaxis:

Weight	Dose if GFR ≥ 30 mL/min	Dose if GFR < 30 mL/min OR whilst on CVVHDF
< 50 kg	20 mg OD	20 mg OD
50 - 99 kg	40 mg OD	20 mg OD
100 - 149 kg	40 mg BD	40 mg OD
≥ 150 kg	60 mg BD	60 mg OD

Once-daily prophylactic enoxaparin should always be administered at night (usually at 6 pm). Most invasive procedures occur during daylight hours so administering at night reduces the risk of procedural bleeding.

The morning dose of twice-daily prophylactic enoxaparin can be withheld in anticipation of invasive procedures during the day.

See Laboratory Tests section below for advice on anti-Xa level monitoring for patients on prophylactic enoxaparin.

Therapeutic dose:

GFR (mL/min) or CRRT Mode	BMI ≤ 40	BMI > 40
> 60	1 mg/kg BD OR 1.5 mg/kg OD	0.8 mg/kg BD
30 – 60	0.8 mg/kg BD	0.8 mg/kg BD
15 - 29 or on CVVHDF	1 mg/kg OD	0.5 mg/kg BD
< 15*	1 mg/kg OD	0.5 mg/kg BD

*Caution: bleeding risk is increased when enoxaparin is used in patients with GFR < 15 due to accumulation. Consider using unfractionated heparin in this population.

Note: Doses should be based on actual body weight and rounded to the nearest 10 mg.

See Laboratory Tests section below for advice on Anti-Xa level monitoring for patients on therapeutic dose enoxaparin.

DOSAGE IN PAEDIATRICS:

SC:

Venous thromboembolism prophylaxis:

Most children do not require enoxaparin prophylaxis unless deemed high risk of venous thrombosis. For those that do, dosage differs by age.

< 1 year old:

0.75 mg/kg BD

1 - 18 years old:

0.5 mg/kg BD

Therapeutic dose:

< 1 year old:

1.5 mg/kg BD

1 - 18 years old:

1 mg/kg BD

For more detailed information on dosing, administration and monitoring of enoxaparin in children, refer to Starship Guideline for Low Molecular Weight Heparin (LMWH).

CLINICAL PHARMACOLOGY:

Low molecular weight heparin

CONTRAINDICATIONS:

1. Hypersensitivity to enoxaparin
2. Active bleeding
3. Presence of an external ventricular drain
4. Planned surgery or procedures, such as lumbar puncture, pericardiocentesis or insertion of drains
5. Uncontrolled or severe hypertension (systolic > 180 or diastolic > 110)
6. Angiodysplasia
7. Clinically significant bleeding disorder (including coagulopathy, platelet count < 50 & platelet disorders)
8. History of immune mediated heparin-induced thrombocytopenia / thrombosis (HITT) within the past 100 days or in the presence of circulating antibodies
9. Recent central nervous system or posterior eye chamber surgery

Patients with traumatic brain injury must always be discussed with the neurosurgical team before commencing any anticoagulation, including enoxaparin.

WARNINGS:

Bleeding Risk:

Every patient being considered for enoxaparin therapy should be assessed for their risk of bleeding. This assessment should be documented in the clinical notes. Risk of bleeding with enoxaparin is increased in the following groups:

• Age > 65
• BMI < 20
• Renal impairment
• Require a prolonged period of treatment
• Taking concomitant antiplatelet (e.g. aspirin, clopidogrel or ticagrelor) or NSAID
• Have had previous upper GI bleeding
• Have moderate hypertension (BP 140 - 180 systolic, 90 - 110 diastolic, even if on treatment)
• Have multiple medical co- morbidities (especially diabetes, previous CVA or heart failure)
• Have undiagnosed iron deficiency anaemia (in non-menstruating women)

PRECAUTIONS:

General:

Many ICU procedures require reversal of anticoagulation. As enoxaparin is not readily reversed, therapeutic systemic heparinisation may be a more appropriate choice for ICU patients as it has a shorter half-life and can be reversed.

Heparin-induced thrombocytopenia / thrombosis (HITT):

HITT is a rare (<1%) but serious complication of heparin therapy, typically occurring 5 – 10 days after initiation (earlier if prior heparin exposure within last 3 months). Though less common with enoxaparin (three-fold lower risk than with unfractionated heparin), monitoring is still advised. For patients on therapeutic dose enoxaparin, check platelets at baseline and monitor daily in ICU. A 30 – 50% drop from baseline may suggest HITT if no other cause is identified. Diagnosis requires a positive heparin-PF4 antibody test. If HITT is suspected, stop enoxaparin and consult haematology. If HITT is confirmed, document clearly and avoid future use of heparin or enoxaparin.

Hyperkalaemia:

Rarely causes hyperkalaemia, possibly by suppressing aldosterone. Risk is higher in patients with kidney dysfunction, potassium-sparing medications, supplements, or tissue hematomas.

Laboratory Tests:

Prothrombin Time (PT) and Activated Partial Thromboplasin Time (aPTT) are insensitive measures of enoxaparin activity so are not recommended to assess enoxaparin efficacy. Instead Anti-Xa levels are the preferred method of monitoring of enoxaparin efficacy. However, routine anti-Xa monitoring is not recommended for most patients.

If Anti-Xa levels are measured according to the recommendations below, blood samples should be sent in a sodium citrate (light blue) tube.

Anti-Xa levels should be measured only after 48 hours of uninterrupted enoxaparin dosing (i.e. after achieving steady state). Levels taken earlier than 48 hours are uninterpretable and should not be sent.

Patients on enoxaparin for less than 48 hours do not require anti-Xa monitoring.

1. Prophylactic enoxaparin

Weight-based dosing (as outlined above) generally provides appropriate prophylaxis without the need for adjustment. Current evidence does not support routine monitoring of anti-Xa levels in prophylactic dosing, as studies have shown inconsistent correlations with bleeding or VTE outcomes.

Anti-Xa monitoring may be considered in selected patients:

• Weight < 50 kg or > 150 kg
• Severe renal impairment (eGFR/CrCl <30 mL/min), including patients on renal replacement therapies
• When there are specific concerns regarding bleeding risk or drug accumulation

If monitoring is undertaken, measure peak levels:

• Take sample 4 hours post-dose
  • For once-daily dosing, obtain level after the third dose
  • For twice-daily dosing, obtain level after the fifth dose
• Target prophylactic anti-Xa level range: 0.2 – 0.6 IU/mL
• Dose adjustments should be made in consultation with a clinical pharmacist

Note: There is no routine role for anti-Xa monitoring during pregnancy if renal function is normal and standard dosing (based on pre-pregnancy weight) is used.

2. Therapeutic dose enoxaparin

For patients on therapeutic enoxaparin, take peak and/or trough levels:

Trough Levels:

• Not routinely recommended as bleeding risk does not consistently correlate with trough levels
• Exceptions where trough levels are indicated is in patients with severe renal impairment (GFR < 30 mL/min) or on renal replacement therapies
  • Ensure peak levels are also obtained in these patients (see below)
• For twice-daily dosing:
  • Take sample 12 hours post-dose, i.e. immediately before the next dose
  • Acceptable trough: ≤ 0.5 IU/mL
    • If > 0.5 IU/mL then switch to once-daily dosing
• For once-daily dosing:
  • Take sample 20 hours post-dose
  • Acceptable trough: ≤ 0.4 IU/mL
    • If level is > 0.4 IU/mL, consult with a clinical pharmacist

Peak Levels:

• Best correlate with clinical efficacy and bleeding risk and are recommended for patients on therapeutic doses of enoxaparin when one or more of the following situations apply:
  • Moderate renal impairment (GFR <60 mL/min)
  • BMI < 20 or > 40
  • Pregnancy: Routine monitoring is not typically required; however, it may be considered when precise anticoagulation control is critical (e.g. pregnant patients receiving enoxaparin for mechanical heart valves)
  • Receiving treatment dose enoxaparin for longer than 14 days
  • Patients with changing renal function or on renal replacement therapies
  • Any other factors from the 'increased bleeding risk' list above
• Samples should be taken 4 hours post-dose
• Peak level targets:
  • For twice-daily dosing: Peak level 0.5 – 1.2 IU/mL
  • For once-daily dosing: Peak level 1 – 2 IU/mL

In patients who are not bleeding and have stable renal function, the dose should be adjusted using the following nomogram:

Enoxaparin Dose Adjustment for THERAPEUTIC ONCE DAILY DOSING

Peak Anti-Xa Level (IU/mL)	Withhold Next Dose	Dose Change	Next Peak Anti-Xa Level
< 0.5	No	Increase by 50%	48 hours
0.51 - 0.99	No	Increase by 25%	48 hours
1 - 2	No	No	1 week
2.1 - 3	No	Decrease by 30%	48 hours
>3	Yes. Check every 6 hours until anti-Xa < 0.5	Decrease by 50%	48 hours after next dose. Consider change to heparin

Enoxaparin Dose Adjustment for THERAPEUTIC TWICE DAILY DOSING

Peak Anti-Xa Level (IU/mL)	Withhold Next Dose	Dose Change	Next Peak Anti-Xa Level
< 0.25	No	Increase by 50%	48 hours
0.25 - 0.49	No	Increase by 25%	48 hours
0.5 - 1.2	No	No	1 week
1.21 - 1.5	No	Decrease by 25%	48 hours
1.51 - 2	For 3 hours	Decrease by 30%	48 hours after next dose
> 2	Yes. Check every 6 hours until anti-Xa < 0.5	Decrease by 50%	48 hours after next dose. Consider change to heparin

If reversal of the anticoagulant effects of enoxaparin is required due to the need for an emergency procedure or significant bleeding occurs, partial reversal (60 - 75%) can be achieved by administering protamine. The dose required is dependent on the dose and time the enoxaparin was administered:

• If < 8 hours have passed since enoxaparin administration, give 1 mg protamine for every 1 mg of enoxaparin given
• If ≥ 8 hours have passed since enoxaparin administration, give 0.5 mg protamine for every 1 mg of enoxaparin given

See Protamine Monograph for more information

Drug/Laboratory Test Interactions:

None noted

IMPORTANT DRUG INTERACTIONS IN ICU:

Increased risk of bleeding when combined with other anti-platelet and anticoagulant agents

ADVERSE REACTIONS:

General:

Bleeding, anaphylaxis, fever

Cardiovascular System:

Peripheral oedema

Haematological System:

Anaemia, thrombocytopaenia, HITT

Dermatologic:

Ecchymoses

Gastrointestinal System:

Nausea

Hepatic:

Increase in transferase levels

Local:

Haematoma (at injection site), skin necrosis

Neurological:

Confusion