INHIXA

Posology Prophylaxis of venous thromboembolic disease in moderate and high risk surgical patients Individual thromboembolic risk for patients can be estimated using validated risk stratification model. In patients at moderate risk of thromboembolism, the recommended dose of enoxaparin sodium is 2,000 IU (20 mg) once daily by subcutaneous injection.

Preoperative initiation (2 hours before surgery) of enoxaparin sodium 2,000 IU (20 mg) was proven effective and safe in moderate risk surgery. g. mobility). Prophylaxis should be continued until the patient no longer has significantly reduced mobility.

In patients at high risk of thromboembolism, the recommended dose of enoxaparin sodium is 4,000 IU (40 mg) once daily given by subcutaneous injection preferably started 12 hours before surgery. g. high risk patient waiting for a deferred orthopaedic surgery), the last injection should be administered no later than 12 hours prior to surgery and resumed 12 hours after surgery.

o For patients who undergo major orthopaedic surgery an extended thromboprophylaxis up to 5 weeks is recommended. o For patients with a high venous thromboembolism (VTE) risk who undergo abdominal or pelvic surgery for cancer an extended thromboprophylaxis up to 4 weeks is recommended.

Prophylaxis of venous thromboembolism in medical patients The recommended dose of enoxaparin sodium is 4,000 IU (40 mg) once daily by subcutaneous injection. g. mobility). The benefit is not established for a treatment longer than 14 days.

5 mg/kg) or as twice daily injections of 100 IU/kg (1 mg/kg). The regimen should be selected by the physician based on an individual assessment including evaluation of the thromboembolic risk and of the risk of bleeding. 5 mg/kg) administered once daily should be used in uncomplicated patients with low risk of VTE recurrence.

The dose regimen of 100 IU/kg (1 mg/kg) administered twice daily should be used in all other patients such as those with obesity, with symptomatic PE, cancer, recurrent VTE or proximal (vena iliaca) thrombosis. Enoxaparin sodium treatment is prescribed for an average period of 10 days.

2). In the extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of its recurrence in patients with active cancer, physicians should carefully assess the individual thromboembolic and bleeding risks of the patient.

5 mg/kg) once daily SC injection up to 6 months. The benefit of continuous anticoagulant therapy should be reassessed after 6 months of treatment. Prevention of thrombus formation during haemodialysis The recommended dose is 100 IU/kg (1 mg/kg) of enoxaparin sodium.

75 mg/kg) for single vascular access. During haemodialysis, enoxaparin sodium should be introduced into the arterial line of the circuit at the beginning of the dialysis session. 5 to 1 mg/kg) may be given. No data are available in patients using enoxaparin sodium for prophylaxis or treatment and during haemodialysis sessions.

Acute coronary syndrome: treatment of unstable angina and NSTEMI and treatment of acute STEMI • For treatment of unstable angina and NSTEMI, the recommended dose of enoxaparin sodium is 100 IU/kg (1 mg/kg) every 12 hours by subcutaneous injection administered in combination with antiplatelet therapy.

Treatment should be maintained for a minimum of 2 days and continued until clinical stabilization. The usual duration of treatment is 2 to 8 days. Acetylsalicylic acid is recommended for all patients without contraindications at an initial oral loading dose of 150–300 mg (in acetylsalicylic acid-naive patients) and a maintenance dose of 75-325 mg/day long-term regardless of treatment strategy.

• For treatment of acute STEMI, the recommended dose of enoxaparin sodium is a single intravenous bolus of 3,000 IU (30 mg) plus a 100 IU/kg (1 mg/kg) subcutaneous dose followed by 100 IU/kg (1 mg/kg) administered subcutaneously every 12 hours (maximum 10,000 IU (100 mg) for each of the first two subcutaneous doses).

Appropriate antiplatelet therapy such as oral acetylsalicylic acid (75 mg to 325 mg once daily) should be administered concomitantly unless contraindicated. The recommended duration of treatment is 8 days or until hospital discharge, whichever comes first.

When administered in conjunction with a thrombolytic (fibrin specific or non-fibrin specific), enoxaparin sodium should be given between 15 minutes before and 30 minutes after the start of fibrinolytic therapy. o For dose in patients ≥ 75 years of age, see paragraph “Elderly”.

o For patients managed with PCI, if the last subcutaneous dose of enoxaparin sodium was given less than 8 hours before balloon inflation, no additional dosing is needed. 3 mg/kg) enoxaparin sodium should be administered. […]

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 DVT following orthopaedic or abdominal surgery in patients at risk for thromboembolic complications, 1,169 for prophylaxis of DVT 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 DVT following surgery or in acutely ill medical patients with severely restricted mobility.

5 mg/kg) SC dose once a day. In the clinical trials 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.

4 and 'Description of selected adverse reactions' below). The safety profile of enoxaparin for extended treatment of DVT and PE in patients with active cancer is similar to its safety profile for the treatment of DVT and PE. 4). Tabulated list of adverse reactions Other adverse reactions observed in clinical trials 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. 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). 4).

Hepatobiliary 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* • Rare: 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. 5). 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. 5). System organ class Prophylaxis in surgical patients Prophylaxis in medical patients Treatment in patients with DVT with or without PE Extended treatment of DVT and PE in patients with active cancer Treatment in patients with unstable angina and non-Q-wave MI Treatment in patients with acute STEMI Blood and lymphati c system disorder s Very common: Haemorrhag e α Rare: Retroperiton eal haemorrhag e Common: Haemorrhage α Very common: Haemorrhage α Uncommon: Intracranial haemorrhage, Retroperitone al haemorrhage Common β: Haemorrhage Common: Haemorrhag e α Rare: Retroperiton eal haemorrhage Common: Haemorrha ge α Uncommon: Intracranial haemorrhag e, Retroperito neal haemorrhag e α: such as haematoma, ecchymosis other than at injection site, wound haematoma, haematuria, epistaxis and gastro-intestinal haemorrhage.

4 monitoring of […]

4. 4). 2) Severe renal impairment 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 extra corporeal circulation during haemodialysis.

Dose table for patients with severe renal impairment (creatinine clearance [15- 30] mL/min): Indication Dosing regimen Prophylaxis of venous thromboembolic disease 2,000 IU (20 mg) subcutaneously once daily Treatment of DVT and PE 100 IU/kg (1 mg/kg) body weight subcutaneously once daily Extended treatment of DVT and PE in patients with active cancer 100 IU/kg (1 mg/kg) body weight SC once daily Treatment of unstable angina and NSTEMI 100 IU/kg (1 mg/kg) body weight subcutaneously once daily Treatment of acute STEMI (patients under 75) Treatment of acute STEMI (patients over 75) 1 x 3,000 IU (30 mg) intravenous bolus plus 100 IU/kg (1 mg/kg) body weight subcutaneously and then 100 IU/kg (1 mg/kg) body weight subcutaneously every 24 hours No intravenous initial bolus, 100 IU/kg (1 mg/kg) body weight subcutaneously and then 100 IU/kg (1 mg/kg) body weight subcutaneously every 24 hours The recommended dose adjustments do not apply to the haemodialysis indication.

Moderate and mild renal impairment Although 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, careful clinical monitoring is advised.

3). Method of administration Inhixa is not indicated for intramuscular use and should not be administered by this route. For the prophylaxis of venous thromboembolic disease following surgery, treatment of DVT and PE, extended treatment of DVT and PE in patients with active cancer, treatment of unstable angina and NSTEMI, enoxaparin sodium should be administered by subcutaneous injection.

• For acute STEMI, treatment is to be initiated with a single intravenous bolus injection immediately followed by a subcutaneous injection. • For the prevention of thrombus formation in the extra corporeal circulation during haemodialysis, it is administered through the arterial line of a dialysis circuit.

The use of a tuberculin syringe or equivalent is recommended when using multidose vials to assure withdrawal of the appropriate volume of the medicinal product. SC injection technique Injection should be made preferably when the patient is lying down.

Enoxaparin sodium is administered by deep SC injection. When using pre-filled syringes, the air bubble should not be expelled from the syringe before the injection in order to avoid the loss of the medicinal product. When the quantity of the medicinal product to be injected requires to be adjusted based on the patient’s body weight, the graduated pre-filled syringes should be used to reach the required volume by discarding the excess before injection.

In some cases it is not possible to achieve an exact dose due to the graduations on the syringe, and in such case the volume shall be rounded up to the nearest graduation. The administration should be alternated between the left and right anterolateral or posterolateral abdominal wall.

The whole length of the needle should be introduced vertically into a skin fold gently held between the thumb and index finger. The skin fold should not be released until the injection is complete. The injection site should not be rubbed after administration.

IV (bolus) injection (for acute STEMI indication only) For acute STEMI, treatment is to be initiated with a single intravenous bolus injection immediately followed by a subcutaneous injection. For intravenous injection, either the multidose vial or pre-filled syringe can be used.

Enoxaparin sodium should be administered through an intravenous line. It should not be mixed or co-administered with other medicinal products. 9%) solution for infusion or 5% glucose in water for injections prior to and following the intravenous bolus administration of enoxaparin sodium to clear the port of the medicinal product.

9%) solution for infusion or 5% glucose in water for injections. Initial 3,000 IU (30 mg) bolus For the initial 3,000 IU (30 mg) bolus, using an enoxaparin sodium graduated pre- filled syringe, the excessive volume has to be expelled to retain only 3,000 IU (30 mg) in the syringe.

The 3,000 IU (30 mg) dose can then be directly injected into the intravenous line. 3 mg/kg) is to be administered if last subcutaneous administration was given more than 8 hours before balloon inflation. In order to assure the accuracy of the small volume to be injected, it is recommended to dilute the medicinal product to 300 IU/mL (3 mg/mL).

e. 9%) solution for infusion or 5% glucose in water for injections) as follows: 30 mL of the solution should be withdrawn from the infusion bag with a syringe and discarded. The complete contents of the 6,000 IU (60 mg) enoxaparin sodium pre- filled syringe should be injected into the 20 mL remaining in the […]

4).