CRUSIA Solution for injection Ref.[50445] Active ingredients: Enoxaparin

Spinal/Epidural anaesthesia

Spinal/epidural anaesthesia or lumbar puncture must not be performed within 24 hours of administration of CRUSIA at therapeutic doses (see also section 4.3).

There have been cases of intraspinal haematomas, reported with the concurrent use of CRUSIA and spinal/epidural anaesthesia resulting in long-term or permanent paralysis.

The risk is greater with higher CRUSIA dosage regimens, use of post-operative indwelling catheters or the concomitant use of additional medicines affecting haemostasis such as NSAIDs (refer to interactions with other medicines or other forms of interaction). The risk also appears to be increased by traumatic or repeated neuraxial puncture.

Placement and removal of the catheter is best performed when the anticoagulant effect of CRUSIA is low, however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. For patients with creatinine clearance [15-30 ml/minute], additional considerations are necessary because elimination of enoxaparin sodium is more prolonged (see section 4.2). Neuraxial techniques should be avoided in patients administered a dose of CRUSIA 2 hours pre-operatively (general surgery).

Placement or removal of a catheter should be delayed for 10-12 hours after administration of DVT prophylactic doses of CRUSIA, whereas patients receiving higher doses of CRUSIA (1 mg/kg twice daily or 1,5 mg/kg once daily) will require longer delays (24 hours). The subsequent CRUSIA dose should be given no sooner than 2 hours after catheter removal.

Should the medical practitioner decide to administer anticoagulation in the context of epidural/spinal anaesthesia, extreme vigilance and frequent monitoring must be exercised to detect any signs and symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or weakness in lower limbs), bowel and/or bladder dysfunction. Patients should be instructed to inform their medical practitioner immediately if they experience any of the above signs or symptoms. If signs or symptoms of spinal haematoma are suspected, urgent diagnosis and treatment including spinal cord decompression should be initiated.

General

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

History of HIT (>100 days)

Heparin-induced thrombocytopenia

Use of enoxaparin sodium as contained in CRUSIA in patients with a history of immune mediated HIT (heparininduced thrombocytopenia) within the past 100 days or in the presence of circulating antibodies is contraindicated (see section 4.3). Circulating antibodies may persist several years. CRUSIA 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 CRUSIA in such a case must be made only in consultation with an expert in the field 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 the 21st day following the beginning of CRUSIA treatment.

The risk of HIT is higher in postoperative patients and mainly after cardiac surgery and in patients with cancer. Therefore, it is recommended that the platelet counts be measured before the initiation of therapy with CRUSIA and then regularly thereafter during the 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), platelet count should be measured. Patients must be aware that these symptoms may occur and if so, that they should inform their primary care medical practitioner.

In practice, if a confirmed significant decrease of the platelet count is observed (30 to 50 % of the initial value), CRUSIA treatment must be immediately discontinued, and the patient switched to another non-heparin anticoagulant alternative treatment.

Haemorrhage

Bleeding may occur at any site because of the anticoagulant effects. If bleeding occurs, the origin of the haemorrhage should be investigated, and appropriate treatment instituted.

CRUSIA should be used with caution in conditions with increased potential for bleeding, such as:

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

Laboratory tests

At doses used for prophylaxis of venous thromboembolism, CRUSIA 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 therefore, are unsuitable and unreliable for monitoring enoxaparin sodium activity.

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 the vascular instrumentation during the treatment of unstable angina, NSTEMI and acute STEMI, adhere precisely to the intervals recommended between CRUSIA injection doses. It is important to achieve haemostasis at the puncture site after PCI. In case a closure device is used, the sheath can be removed immediately. If a manual compression method is used, sheath should be removed 6 hours after the last IV/SC CRUSIA injection. If the treatment with CRUSIA 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 hematoma 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 CRUSIA 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 CRUSIA for thromboprophylaxis. Confounding factors, including underlying disease 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 CRUSIA 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 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 with the prophylactic dosage ranges. Elderly patients (especially patients eighty years of age and older) may be at an increased risk for bleeding complications with 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 of enoxaparin sodium as contained in CRUSIA 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).

CRUSIA 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 of 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

CRUSIA 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 of enoxaparin sodium with prophylactic dosages (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) has not been fully determined 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, taking medicines known to increase potassium (see section 4.5). Plasma potassium should be monitored regularly especially in patients at risk.

Traceability

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

Concomitant use not recommended

Medicines affecting haemostasis (see section 4.4)

It is recommended that some medicines which affect haemostasis should be discontinued prior to CRUSIA therapy unless strictly indicated. If the combination is indicated, CRUSIA should be used with careful clinical and laboratory monitoring when appropriate. These medicines include medicines 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 medicines may be administered with caution concomitantly with CRUSIA:

Other medicines affecting haemostasis such as:

• Platelet aggregation inhibitors including acetylsalicylic acid used at antiaggregant dose (cardio protection), clopidogrel, ticlopidine, and glycoprotein IIb/IIIa antagonists indicated in acute coronary syndrome due to the risk of bleeding,
• Dextran 40,
• Systemic glucocorticoids.

Medicines increasing potassium levels

Medicines that increase serum potassium levels may be administered concurrently with CRUSIA 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 fetotoxicity or teratogenicity (see section 5.3). Animal data have shown that enoxaparin passage through the placenta is minimal.

CRUSIA should be used during pregnancy only if the medical practitioner has established a clear need.

Pregnant women receiving CRUSIA 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 nonpregnant women, other than that observed in pregnant women with prosthetic heart valves (see section 4.4).

If an epidural anaesthesia is planned, it is recommended to withdraw CRUSIA treatment before (see section 4.4).

Breastfeeding

It is not known whether unchanged enoxaparin is excreted in human breast milk. In lactating rats, the passage of enoxaparin or its metabolites in milk is very low. The oral absorption of CRUSIA is unlikely. CRUSIA syringes can be used during breastfeeding.

Fertility

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

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

Summary of the safety profile

It has been reported during clinical trials with enoxaparin sodium, that the enoxaparin sodium regimen administered varied depending on indications. 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. Reports have shown 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 enoxaparin sodium regimen was a 3 000 IU (30 mg) IV bolus followed by 100 IU/kg (1 mg/kg) SC every 12 hours.

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

Tabulated list of adverse reactions

Other adverse reactions observed in reported clinical studies and reported in post-marketing experience (* indicates reactions from post-marketing experience) are detailed below.

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.

Haemorrhage may occur in the presence of associated risk factors such as: organic lesions liable to bleed, invasive procedures or the concomitant use of medications affecting haemostasis (see sections 4.4 and 4.5).

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

Thrombocytopenia and thrombocytosis

^β: Platelet increased >400 G/L

Paediatric population

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8.

SC injection: Do not mix with other products.