The adverse drug reaction profiles reported in clinical studies that compared CRUSIA to the reference biologic drug were comparable. The description of adverse reactions in this section is based on clinical experience with the reference biologic drug.
Summary of the safety profile: Enoxaparin sodium has been evaluated in more than 15,000 patients who received enoxaparin sodium in clinical trials. 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.
Enoxaparin sodium regimen administered during these clinical trials varies depending on indications. The enoxaparin sodium dose was 4000 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 the treatment of DVT with or without PE, patients receiving enoxaparin sodium were treated with either 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 the 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 3000 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 Precautions and Description of selected adverse reactions as follows).
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 as follows.
Frequencies are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to <1/1,000); and very rare (< 1/10,000) or not known (cannot be estimated from available data). Within each system organ class, adverse reactions are presented in order of decreasing seriousness.
Blood and the lymphatic system disorders: Common: Haemorrhage, haemorrhagic anaemia*, thrombocytopenia, thrombocytosis.
Rare: Eosinophilia*, cases of immuno-allergic thrombocytopenia with thrombosis; in some of them thrombosis was complicated by organ infarction or limb ischaemia (see Precautions).
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 Precautions).
Hepato-biliary disorders: Very common: Hepatic enzyme increases (mainly transaminases > 3 times the upper limit of normality).
Uncommon: Hepatocellular liver injury*. Rare: Cholestatic liver injury*.
Skin and subcutaneous tissue disorders: Common: Urticaria, pruritus, erythema. Uncommon: Bullous dermatitis.
Rare: Alopecia*, cutaneous vasculitis*, skin necrosis* usually occurring at the injection site (these phenomena have been usually 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.
Musculoskeletal, connective tissue and bone disorders: Rare: Osteoporosis* following long term therapy (greater 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 the injection site.
Investigations: Rare: Hyperkalaemia* (see Precautions and Interactions).
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 medications affecting haemostasis (see Precautions and Interactions). (See Table 6.)
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Thrombocytopenia and thrombocytosis: (See Table 7.)
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Paediatric population: The safety and efficacy of enoxaparin sodium in children have not been established (see Dosage & Administration).