Thrombosis

Therapeutic indications

Clexane® 2000/4000IU are indicated for prophylaxis of venous thromboembolism in moderate to high risk surgery; prevention of clotting in the extracorporeal circulation during hemodialysis (generally, session lasting 4 hours or less). In addition, Clexane® 4000IU is indicated for the prophylaxis of deep vein thrombosis in patients who are bedridden due to acute medical illness, including: heart failure (NYHA class III or IV) , acute respiratory failure; or an episode of acute infection or acute rheumatic disorder associated with at least one other risk factor for venous thromboembolism. Clexane® 6000IU and 8000IU are indicated for use in the following situations: Curative treatment of non-clinically serious, established deep vein thrombosis, with or without pulmonary embolism, excluding pulmonary embolism likely to require thrombolytic therapy or surgery; Treatment of unstable angina and acute non-Q-wave myocardial infarction (MI), when administered in combination with aspirin; Treatment of acute ST-segment elevation myocardial infarction in combination with a thrombolytic agent in patients to be managed or not by subsequent Percutaneous Coronary Intervention (PCI).

POSOLOGY AND METHOD OF ADMINISTRATION

Subcutaneous route

(except for patients on hemodialysis – Clexane® 20 and 40mg while for the 60 and 80mg presentations - except for patients with acute ST-segment elevation myocardial infarction in whom an IV bolus should be administered). All presentations are for use in adults. Clexane® is not intended for intramuscular administration. Subcutaneous injection technique: 20 & 40mg pre-filled syringes are ready for immediate use. For 60 & 80mg presentations, the amount of drug to be injected should be adjusted based on the patient’s body weight. No air should be expelled before administering the injection.

Prophylaxis of venous thromboembolism in surgery

1 injection daily. In surgery involving moderate thrombogenic risk and in patients who are not at high risk for thromboembolism, effective prevention is achieved by daily injection of 2 000 IU anti-Xa (0.2 ml).

Surgery involving high thrombogenic risk

Hip and knee surgery - The dose is 4 000 IU anti-Xa (0.4 ml) injected once daily. In general surgery, the duration of LMWH treatment must be less than 10 days, unless the patient is at specific risk for venous thromboembolism. The therapeutic benefit of prophylaxis with one enoxaparin injection at a dose of 4 000 IU anti-Xa/day for 4-5 weeks after hip surgery has been established. In patients undergoing repeated hemodialysis sessions, prevention of clotting in the extra renal purification system is obtained by injecting an initial dose of 100 IU anti-Xa /kg in the arterial line of the dialysis circuit at the beginning of the session. This dose, administered as a single intravascular bolus injection, is only suitable for hemodialysis sessions of 4 hours or less.

Prophylactic treatment in the medical setting:

Dose administered

40 mg, i.e. 4 000 IU anti-Xa/0.4 ml, administered once daily by subcutaneous injection.

Duration of treatment

6 to 14 days.

Intravenous (bolus) injection technique / Use of Clexane® 30 000 IU anti-Xa/3ml in multiple-dose vials for the treatment of acute ST-segment elevation myocardial infarction: Treatment is initiated with an IV bolus injection, immediately followed by a subcutaneous injection. The multiple-dose vial should be used to withdraw the initial dose of 3 000 IU, i.e. 0.3 ml, using a graduated 1 ml syringe (insulin syringe or equivalent). The enoxaparin dose should be injected intravenously. It should not be mixed or co-administered with other medicinal products. In the hospital setting, the multiple-dose vial is then used to withdraw the following doses: the dose required for the first SC injection of 100 IU/kg, given at the same time as the IV bolus, then for the subsequent SC injections of 100 IU/kg, to be repeated every 12 hours, the 30 IU/kg dose for IV bolus injection if subsequent percutaneous coronary intervention is to be carried out.

Curative treatment of non-clinically serious deep vein thrombosis (DVT), with or without pulmonary embolism:

Twice daily injections at 12-hour intervals. The dose per injection is 100 IU anti-Xa/kg.

Curative treatment of unstable angina/non-Q-wave MI

100 IU anti-Xa /kg administered by SC injection every 2 hours, in combination with aspirin (recommended doses: 75 to 325 mg orally, following a minimum loading dose of 160 mg) for about 2 to 8 days, until clinical stabilization is achieved.

Treatment of acute ST-segment elevation MI in combination with thrombolytic therapy in patients to be managed or not by subsequent percutaneous coronary intervention

An initial IV bolus injection of 3 000 anti-Xa IU followed by an SC injection of 100 anti-Xa IU/kg within 15 minutes, then every 12 hours (i.e. a maximum of 10 000 anti-Xa IU for the 1st 2 SC doses. The 1st dose of enoxaparin should be administered between 15 minutes before and 30 minutes after the start of thrombolytic therapy (whether fibrin specific or non-fibrin specific). The recommended duration of treatment is 8 days; see full prescribing information. Patients aged 75 years and over treated for acute ST-segment elevation MI, the initial IV bolus injection should not be administered. An SC dose of 75 anti-Xa IU/kg every 12 hours should be administered (maximum of 7500 anti-Xa IU for the 1st 2 injections only).

CONTRA-INDICATIONS

Hypersensitivity to enoxaparin, heparin or its derivatives, including other LMWHs; history of serious type II heparin-induced thrombocytopenia (HIT); bleeding or tendency to bleed; organic lesion likely to bleed; clinically significant active bleeding; intracerebral haemorrhage; spinal or epidural anesthesia; severe kidney failure (creatinine clearance around 30 ml/min; intracerebral hemorrhage. Enoxaparin generally not recommended in acute, extensive ischaemic stroke, acute infectious endocarditis, mild to moderate kidney failure and in combination with the following agents: Acetylsalicylic acid at analgesic, antipyretic and anti-inflammatory doses, NSAIDs (systemic use), Dextran 40 (parenteral use).

SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE

Particular care is required not to replace one LMWH dosage regimen by another one or by that of another synthetic polysaccharide, as each regimen has been validated by specific clinical studies. The recommended therapeutic regimens must be respected, failure of which can lead to hemorrhage, particularly in at-risk patients (e.g. the elderly, patients with renal failure). If bleeding occurs, the origin of the hemorrhage must be investigated and appropriate treatment instituted. Before LMWH treatment is initiated, it is essential to evaluate kidney function, particularly in subjects aged 75 years or over.

In patients diagnosed with severe renal failure (CrCl of about 30 ml/min) the use of LMWH as curative treatment is contraindicated. In all cases, special monitoring is essential in the elderly and/or patients with renal failure, as well as in patients with treatment prolonged beyond 10 days. The use of LMWH is not recommended in children. The risk of thromboembolic events would appear to be higher in pregnant women. Platelets should be monitored in patients on LMWH at risk of heparin-induced thrombocytopenia (i.e. HIT type II). Close neurological monitoring is recommended due to the risk of spinal hematoma. Monitoring of the treatment should be intensified in the following cases: liver failure; history of gastrointestinal ulcers or any other organic lesion likely to bleed; chorioretinal vascular disease; postoperatively, following cerebral or spinal cord surgery.

INTERACTIONS

Potassium salts, potassium-sparing diuretics, angiotensin-converting-enzyme inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs, heparin (low molecular weight or unfractionated), cyclosporin, tacrolimus and trimethoprim, Dextran 40 (parenteral use), Oral anticoagulants, Platelet aggregation inhibitors (other than acetylsalicylic acid as analgesic, antipyretic and anti-inflammatory treatment): abciximab, beraprost, clopidogrel, eptifibatide, iloprost, ticlopidine, tirofiban.

FERTILITY, PREGNANCY AND LACTATION

As a precautionary measure, enoxaparin should preferably not be administered prophylactically during the 1st trimester of pregnancy. Prophylactic enoxaparin treatment during the 2nd and 3rd trimesters should only be considered if necessary. If epidural anesthesia is planned, prophylactic heparin treatment should be interrupted whenever possible at the latest within 12 hours before anesthesia. As a precautionary measure, enoxaparin should preferably not be administered at curative doses throughout pregnancy. Epidural or spinal anesthesia must never be performed in patients given curative LMWH treatment. Treatment with enoxaparin is not contraindicated in breastfeeding women.

UNDESIRABLE EFFECTS

Haemorrhage, Thrombocytosis, Thrombocytopaenia, Allergic reactions,Increase in Hepatic enzymes, Erythema, Pruritus, Urticaria, Injection site reaction, pain or erythema.

OVERDOSE

If hemorrhage occurs, certain patients can be treated with protamine sulfate, taking the following factors into account:

• Its efficacy is far lower than that reported in overdoses with unfractionated heparin;

• Due to its adverse effects (particularly anaphylactic shock), the benefit/risk ratio of protamine sulfate should be carefully weighed before prescription.

Neutralization of the anti-Xa activity is then obtained by slow IV injection of protamine (sulfate or hydrochloride).
The protamine dose required depends on:

• The heparin dose injected (the activity of 100 Anti-Xa IU of low molecular weight heparin is neutralized by 100 anti-heparin units of protamine), if enoxaparin sodium was administered within the last 8 hours,

• The time elapsed since the heparin injection.

If enoxaparin sodium was given more than 8 hours previously, or if a 2nd dose of protamine appears to be necessary, 50 anti-heparin units of protamine per 100 Anti-Xa IU enoxaparin sodium may be administered as an infusion;

If the injection of enoxaparin sodium was given more than 12 hours previously, it is not necessary to administer protamine.

These recommendations apply to patients with normal renal function receiving repeated doses. Nevertheless, the anti-Xa activity cannot be completely neutralized.

Furthermore, the neutralization may be transient due to the absorption pharmacokinetics of LMWH, which may require dividing the total calculated dose of protamine into several injections (2-4) given over 24 hours.

PHARMACODYNAMIC PROPERTIES

Pharmacotherapeutic group: Antithrombotic agent;
ATC code: B01AB05.
Subcutaneously administered enoxaparin is rapidly and almost completely absorbed (nearly 100%).
Peak plasma activity is observed between 3 and 4 hours after administration.

Date of last abbreviation of prescribing information: March 2019.
More detailed Information on request: Refer to Summary of Product Characteristics or
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