GHEMAXAN Solution for injection Ref.[49862] Active ingredients: Enoxaparin

General

Enoxaparin sodium cannot be used interchangeably (unit for unit) with other LMWHs. These medicinal products differ in their manufacturing process, molecular weights, specific anti-Xa and anti‑II activities, units, dosage and clinical efficacy and safety. This results in differences in pharmacokinetics and associated biological activities (e.g. anti-thrombin activity and platelet interactions). Special attention and compliance with the instructions for use specific to each proprietary medicinal product are therefore required.

History of HIT (>100 days)

Use of enoxaparin sodium in patients with a history of immune-mediated HIT within the past 100 days or in the presence of circulating antibodies is contraindicated (see section 4.3). Circulating antibodies may persist for several years. Enoxaparin sodium is to be used with extreme caution in patients with a history (>100 days) of heparin-induced thrombocytopenia without circulating antibodies. The decision to use enoxaparin sodium in such a case must be made only after a careful benefit‑risk assessment and after non-heparin alternative treatments are considered (e.g. danaparoid sodium or lepirudin).

Monitoring of platelet counts

The risk of antibody-mediated HIT also exists with LMWHs. Should thrombocytopenia occur, it usually appears between the 5th and 21^st day after the start of enoxaparin sodium treatment.

The risk of HIT is higher in post-operative patients and mainly after cardiac surgery and in patients with cancer. Therefore, it is recommended that platelet counts be measured before the initiation of therapy with enoxaparin sodium and then regularly thereafter during treatment.

If there are clinical symptoms suggestive of HIT (any new episode of arterial and/or venous thromboembolism, any painful skin lesion at the injection site, any allergic or anaphylactoid reactions on treatment), the platelet count should be measured. Patients must be aware that these symptoms may occur and if so, that they should inform their primary care physician. In practice, if a confirmed significant decrease in the platelet count is observed (30 to 50% of the initial value), enoxaparin sodium treatment must be immediately discontinued and the patient switched to another non-heparin anticoagulant alternative treatment.

Haemorrhage

As with other anticoagulants, bleeding may occur at any site. If bleeding occurs, the origin of the haemorrhage should be investigated and appropriate treatment instituted. Enoxaparin sodium, as with any other anticoagulant therapy, should be used with caution in conditions with increased potential for bleeding, such as:

• impaired haemostasis,
• history of peptic ulcer,
• recent ischaemic stroke,
• severe arterial hypertension,
• recent diabetic retinopathy,
• neuro- or ophthalmologic surgery,
• concomitant use of medicinal products affecting haemostasis (see section 4.5).

Laboratory tests

At doses used for prophylaxis of venous thromboembolism, enoxaparin sodium does not influence bleeding time and global blood coagulation tests significantly, nor does it affect platelet aggregation or binding of fibrinogen to platelets. At higher doses, increases in activated partial thromboplastin time (aPTT) and activated clotting time (ACT) may occur. Increases in aPTT and ACT are not linearly correlated with increasing enoxaparin sodium antithrombotic activity and are therefore unsuitable and unreliable for monitoring enoxaparin sodium activity.

Spinal/epidural anaesthesia or lumbar puncture

Spinal/epidural anaesthesia or lumbar puncture must not be performed within 24 hours of administration of enoxaparin sodium at therapeutic doses (see also section 4.3). There have been cases of neuraxial haematomas reported with the concurrent use of enoxaparin sodium and spinal/epidural anaesthesia or spinal puncture procedures, resulting in long-term or permanent paralysis. These events are rare with enoxaparin sodium dosage regimens of 4,000 IU (40 mg) once daily or lower. The risk of these events is higher with the use of post-operative indwelling epidural catheters, with the concomitant use of additional medicinal products affecting haemostasis such as non-steroidal anti-inflammatory drugs (NSAIDs), with traumatic or repeated epidural or spinal puncture or in patients with a history of spinal surgery or spinal deformity.

To reduce the potential risk of bleeding associated with the concurrent use of enoxaparin sodium and epidural or spinal anaesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of enoxaparin sodium (see section 5.2). Placement and removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of enoxaparin sodium is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. For patients with creatinine clearance of 15‑30 mL/minute, additional considerations are necessary because elimination of enoxaparin sodium is more prolonged (see section 4.2).

Should the physician decide to administer anticoagulation in the context of epidural or spinal anaesthesia/analgesia or lumbar puncture, frequent monitoring must be performed to detect any signs and symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness or weakness in lower limbs) or bowel and/or bladder dysfunction. Instruct patients to report immediately if they experience any of the above signs or symptoms. If signs or symptoms of spinal haematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression, even though such treatment may not prevent or reverse neurological sequelae.

Skin necrosis/cutaneous vasculitis

Skin necrosis and cutaneous vasculitis have been reported with LMWHs and should lead to prompt treatment discontinuation.

Percutaneous coronary revascularisation procedures

To minimise the risk of bleeding following vascular instrumentation during the treatment of unstable angina, NSTEMI and acute STEMI, adhere precisely to the intervals recommended between enoxaparin sodium injection doses. It is important to achieve homeostasis at the puncture site after PCI. If a closure device is used, the sheath can be removed immediately. If a manual compression method is used, the sheath should be removed 6 hours after the last IV/SC enoxaparin sodium injection. If treatment with enoxaparin sodium is to be continued, the next scheduled dose should be given no sooner than 6 to 8 hours after sheath removal. The site of the procedure should be observed for signs of bleeding or haematoma formation.

Acute infective endocarditis

Use of heparin is usually not recommended in patients with acute infective endocarditis due to the risk of cerebral haemorrhage. If such use is considered absolutely necessary, the decision must be made only after a careful individual benefit-risk assessment.

Mechanical prosthetic heart valves

The use of enoxaparin sodium has not been adequately studied for thromboprophylaxis in patients with mechanical prosthetic heart valves. Isolated cases of prosthetic heart valve thrombosis have been reported in patients with mechanical prosthetic heart valves who have received enoxaparin sodium for thromboprophylaxis. Confounding factors, including underlying diseases and insufficient clinical data, limit the evaluation of these cases. Some of these cases were pregnant women in whom thrombosis led to maternal and foetal death.

Pregnant women with mechanical prosthetic heart valves

The use of enoxaparin sodium for thromboprophylaxis in pregnant women with mechanical prosthetic heart valves has not been adequately studied. In a clinical study of pregnant women with mechanical prosthetic heart valves given enoxaparin sodium (100 IU/kg (1 mg/kg) twice daily) to reduce the risk of thromboembolism, 2 out of 8 women developed clots resulting in blockage of the valve and leading to maternal and foetal death. There have been isolated post-marketing reports of valve thrombosis in pregnant women with mechanical prosthetic heart valves while receiving enoxaparin sodium for thromboprophylaxis. Pregnant women with mechanical prosthetic heart valves may be at higher risk for thromboembolism.

Elderly

No increased bleeding tendency is observed in the elderly within the prophylactic dosage ranges. Elderly patients (especially patients eighty years of age and older) may be at increased risk for bleeding complications within the therapeutic dosage ranges. Careful clinical monitoring is advised and dose reduction might be considered in patients older than 75 years treated for STEMI (see sections 4.2 and 5.2).

Renal impairment

In patients with renal impairment, there is an increase in exposure to enoxaparin sodium, which increases the risk of bleeding. In these patients, careful clinical monitoring is advised and biological monitoring by anti-Xa activity measurement might be considered (see sections 4.2 and 5.2).

Enoxaparin sodium is not recommended for patients with end-stage renal disease (creatinine clearance <15 mL/min) due to lack of data in this population outside the prevention of thrombus formation in extracorporeal circulation during haemodialysis In patients with severe renal impairment (creatinine clearance 15‑30 mL/min), since exposure to enoxaparin sodium is significantly increased, a dosage adjustment is recommended for therapeutic and prophylactic dosage ranges (see section 4.2).

No dose adjustment is recommended in patients with moderate (creatinine clearance 30‑50 mL/min) and mild (creatinine clearance 50‑80 mL/min) renal impairment.

Hepatic impairment

Enoxaparin sodium should be used with caution in patients with hepatic impairment due to an increased potential for bleeding. Dose adjustment based on monitoring of anti-Xa levels is unreliable in patients with liver cirrhosis and not recommended (see section 5.2).

Low weight

An increase in exposure to enoxaparin sodium at the prophylactic dosage (non-weight adjusted) has been observed in low-weight women (<45 kg) and low-weight men (<57 kg), which may lead to a higher risk of bleeding. Therefore, careful clinical monitoring is advised in these patients (see section 5.2).

Obese patients

Obese patients are at higher risk for thromboembolism. The safety and efficacy of prophylactic doses in obese patients (BMI >30 kg/m²) have not been fully established and there is no consensus for dose adjustment. These patients should be observed carefully for signs and symptoms of thromboembolism.

Hyperkalaemia

Heparins can suppress adrenal secretion of aldosterone leading to hyperkalaemia (see section 4.8), particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis and those taking medicinal products known to increase potassium (see section 4.5). Plasma potassium should be monitored regularly, especially in patients at risk.

Traceability

LMWHs are biological medicinal products. In order to improve LMWH traceability, it is recommended that healthcare professionals record the trade name and batch number of the administered product in the patient’s file.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium-free’.

Acute generalized exanthematous pustulosis

Acute generalized exanthematous pustulosis (AGEP) has been reported with frequency not known in association with enoxaparin treatment. At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, enoxaparin should be withdrawn immediately and an alternative treatment considered (as appropriate).

Concomitant use not recommended

Medicinal products affecting haemostasis (see section 4.4).

It is recommended that some agents which affect haemostasis should be discontinued prior to enoxaparin sodium therapy unless strictly indicated. If the combination is indicated, enoxaparin sodium should be used with careful clinical and laboratory monitoring when appropriate.

These agents include medicinal products such as:

• Systemic salicylates, acetylsalicylic acid at anti-inflammatory doses, and NSAIDs including ketorolac,
• Other thrombolytics (e.g. alteplase, reteplase, streptokinase, tenecteplase, urokinase) and anticoagulants (see section 4.2).

Concomitant use with caution

The following medicinal products may be administered with caution concomitantly with enoxaparin sodium:

• Other medicinal products affecting haemostasis such as:
  • Platelet aggregation inhibitors, including acetylsalicylic acid, used at an antiaggregant dose (cardioprotection), clopidogrel, ticlopidine and glycoprotein IIb/IIIa antagonists indicated in acute coronary syndrome due to the risk of bleeding,
  • Dextran 40,
  • Systemic glucocorticoids.

Medicinal products increasing potassium levels

Medicinal products that increase serum potassium levels may be administered concurrently with enoxaparin sodium under careful clinical and laboratory monitoring (see sections 4.4 and 4.8).

Pregnancy

In humans, there is no evidence that enoxaparin crosses the placental barrier during the second and third trimester of pregnancy. There is no information available concerning the first trimester.

Animal studies have not shown any evidence of foetotoxicity or teratogenicity (see section 5.3). Animal data have shown that enoxaparin passage through the placenta is minimal.

Enoxaparin sodium should be used during pregnancy only if the physician has established a clear need.

Pregnant women receiving enoxaparin sodium should be carefully monitored for evidence of bleeding or excessive anticoagulation and should be warned of the haemorrhagic risk. Overall, the data suggest that there is no evidence for an increased risk of haemorrhage, thrombocytopenia or osteoporosis with respect to the risk observed in non-pregnant women, other than that observed in pregnant women with prosthetic heart valves (see section 4.4).

If epidural anaesthesia is planned, it is recommended that enoxaparin sodium treatment be withdrawn beforehand (see section 4.4).

Breastfeeding

It is unknown whether unchanged enoxaparin is excreted in human milk. In lactating rats, the passage of enoxaparin or its metabolites in milk is very low. The oral absorption of enoxaparin sodium is unlikely. Ghemaxan can be used during breastfeeding.

Fertility

There are no clinical data for enoxaparin sodium in fertility. Animal studies did not show any effect on fertility (see section 5.3).

Enoxaparin sodium has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

Enoxaparin sodium has been evaluated in more than 15,000 patients who received enoxaparin sodium in clinical trials, performed with a reference product. These included 1,776 for prophylaxis of deep vein thrombosis following orthopaedic or abdominal surgery in patients at risk for thromboembolic complications, 1,169 for prophylaxis of deep vein thrombosis in acutely ill medical patients with severely restricted mobility, 559 for treatment of DVT with or without PE, 1,578 for treatment of unstable angina and non-Q-wave myocardial infarction and 10,176 for treatment of acute STEMI.

The enoxaparin sodium regimen administered during these clinical trials varies depending on the indication. The enoxaparin sodium dose was 4,000 IU (40 mg) SC once daily for prophylaxis of deep vein thrombosis following surgery or in acutely ill medical patients with severely restricted mobility. In treatment of DVT with or without PE, patients receiving enoxaparin sodium were treated with either a 100 IU/kg (1 mg/kg) SC dose every 12 hours or a 150 IU/kg (1.5 mg/kg) SC dose once a day. In the clinical studies for treatment of unstable angina and non-Q-wave myocardial infarction, doses were 100 IU/kg (1 mg/kg) SC every 12 hours and, in the clinical study for treatment of acute STEMI, the enoxaparin sodium regimen was a 3,000 IU (30 mg) IV bolus followed by 100 IU/kg (1 mg/kg) SC every 12 hours.

In clinical studies, haemorrhages, thrombocytopenia and thrombocytosis were the most commonly reported reactions (see section 4.4 and ‘Description of selected adverse reactions’ below).

Acute generalized exanthematous pustulosis (AGEP) has been reported in association with enoxaparin treatment (see section 4.4).

Tabulated summary list of adverse reactions

Other adverse reactions observed in clinical studies and reported in post-marketing experience (* indicates reactions from post-marketing experience) are detailed below. Frequencies are defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) or not known (cannot be estimated from the available data). Within each system organ class, adverse reactions are presented in order of decreasing seriousness.

Blood and lymphatic system disorders

Common: haemorrhage, haemorrhagic anaemia*, thrombocytopenia, thrombocytosis

Rare: eosinophilia*

Rare: cases of immuno-allergic thrombocytopenia with thrombosis; in some of these, thrombosis was complicated by organ infarction or limb ischaemia (see section 4.4).

Immune system disorders

Common: allergic reaction

Rare: anaphylactic/anaphylactoid reactions including shock*

Nervous system disorders

Common: headache*

Vascular disorders

Rare: spinal haematoma* (or neuraxial haematoma). These reactions have resulted in varying degrees of neurologic injuries including long-term or permanent paralysis (see section 4.4).

Hepatobiliary disorders

Very common: hepatic enzymes increased (mainly transaminases > 3 times the upper limit of normal)

Uncommon: hepatocellular liver injury *

Rare: cholestatic liver injury*

Skin and subcutaneous tissue disorders

Common: urticaria, pruritus, erythema

Uncommon: bullous dermatitis

Rare: alopecia*

Rare: cutaneous vasculitis*, skin necrosis* usually occurring at the injection site (these phenomena have usually been preceded by purpura or erythematous plaques, infiltrated and painful). Injection site nodules* (inflammatory nodules, which were not cystic enclosure of enoxaparin). They resolve after a few days and should not cause treatment discontinuation.

Not known: Acute generalized exanthematous pustulosis (AGEP)

Musculoskeletal and connective tissue disorders

Rare: osteoporosis* following long-term therapy (longer than 3 months) General disorders and administration site conditions

Common: injection site haematoma, injection site pain, other injection site reaction (such as oedema, haemorrhage, hypersensitivity, inflammation, mass, pain or reaction)

Uncommon: local irritation, skin necrosis at injection site

Investigations

Rare: hyperkalaemia* (see sections 4.4 and 4.5).

Description of selected adverse reactions

Haemorrhages

These included major haemorrhages, reported at most in 4.2% of the patients (surgical patients). Some of these cases have been fatal.

In surgical patients, haemorrhage complications were considered major: (1) if the haemorrhage caused a significant clinical event, or (2) if accompanied by haemoglobin decrease ≥2 g/dL or transfusion of 2 or more units of blood products. Retroperitoneal and intracranial haemorrhages were always considered major.

As with other anticoagulants, haemorrhage may occur in the presence of associated risk factors such as: organic lesions liable to bleed, invasive procedures or the concomitant use of medicinal products affecting haemostasis (see sections 4.4 and 4.5).

^* such as haematoma, ecchymosis other than at injection site, wound haematoma, haematuria, epistaxis and gastrointestinal haemorrhage.

Thrombocytopenia and thrombocytosis

^* Platelets increased >400 G/L

Paediatric population

The safety and efficacy of enoxaparin sodium in children have not been established (see section 4.2).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

SC injection

Do not mix with other products.

IV (bolus) injection (for acute STEMI indication only)

Enoxaparin sodium may be safely administered with normal saline solution (0.9%) or 5% dextrose in water (see section 4.2).