Adverse reactions : תופעות לוואי

4.8    Undesirable effects

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 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 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 generalised 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); 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 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).

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.
• Not known: Acute generalised exanthematous pustulosis (AGEP)

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 injection site

Investigations
• Rare: Hyperkalaemia* (see sections 4.4 and 4.5).

Description of selected adverse reactions
Haemorrages
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 sections 4.4 and 4.5).

System         Prophylaxis in        Prophylaxis in         Treatment in      Treatment in      Treatment in Organ          surgical patients     medical patients       patients with     patients with     patients with Class                                                       DVT with or       unstable angina   acute STEMI without PE        and non-Q-wave
MI
Very common:          Common:                Very common:      Common:           Common: Blood          Haemorrhage α         Haemorrhage α          Haemorrhage α     Haemorrhage α     Haemorrhage α and                                                                           Rare: lymphatic      Rare:                                        Uncommon:         Retroperitoneal   Uncommon: system         Retroperitoneal                              Intracranial      haemorrhage       Intracranial disorders      haemorrhage                                  haemorrhage,                        haemorrhage, Retroperitoneal                     Retroperitoneal haemorrhage                         haemorrhage

α
: such as haematoma, ecchymosis other than at injection site, wound haematoma, haematuria, epistaxis and gastro-intestinal haemorrhage.

Thrombocytopenia and thrombocytosis (see section 4.4 monitoring of platelet counts) 
System       Prophylaxis in         Prophylaxis in      Treatment in          Treatment in      Treatment in Organ        surgical patients      medical patients    patients with         patients with     patients with Class                                                   DVT with or           unstable angina   acute STEMI without PE            and non-Q-wave
MI
Blood        Very common:           Uncommon:           Very common:          Uncommon:         Common: and          Thrombocytosisβ        Thrombocytopen      Thrombocytosis        Thrombocytopen    Thrombocytosisβ β lympha                              ia                                        ia                Thrombocytopen tic          Common:                                                                            ia system       Thrombocytopen                             Common:                                 Very rare: disord       ia                                         Thrombocytopen                          Immuno-allergic ers                                                     ia                                      thrombocytopeni a
β
: Platelet increased >400 G/L

Pediatric 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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form at https://sideeffects.health.gov.il/.