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Inhixa 2,000 IU (20 mg) in 0.2 mL solution for injection in pre-filled syringe

Last Updated on eMC 10-Aug-2017 View changes  | Techdow Pharma Ltd Contact details

 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

Inhixa 2,000 IU (20 mg) in 0.2 mL solution for injection in pre-filled syringe

2. Qualitative and quantitative composition

Each pre-filled syringe of 0.2 mL contains 2,000 IU (20 mg) of enoxaparin sodium.

Each mL contains 100 mg enoxaparin sodium.

Produced from porcine intestinal mucosa.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Solution for injection in pre-filled syringe.

Clear, colourless to pale yellow solution.

4. Clinical particulars
4.1 Therapeutic indications

Inhixa is indicated for adults for:

- Prophylaxis of venous thromboembolism, particularly in patients undergoing orthopaedic, general or oncological surgery.

- Prophylaxis of venous thromboembolism in patients bedridden due to acute illnesses including acute heart failure, acute respiratory failure, severe infections, as well as exacerbation of rheumatic diseases causing immobilisation of the patient (applies to strengths of 40 mg/0.4 mL).

- Treatment of deep vein thrombosis (DVT), complicated or uncomplicated by pulmonary embolism.

- Treatment of unstable angina and non-Q-wave myocardial infarction, in combination with acetylsalicylic acid (ASA).

- Treatment of acute ST-segment elevation myocardial infarction (STEMI) including patients who will be treated conservatively or who will later undergo percutaneous coronary angioplasty (applies to strengths of 60 mg/0.6 mL, 80 mg/0.8 mL, and 100 mg/1 mL).

- Blood clot prevention in the extracorporeal circulation during haemodialysis.

4.2 Posology and method of administration

Posology

Adults

Prophylaxis of venous thromboembolism especially in patients undergoing orthopaedic, general or oncological surgery

In patients with moderate risk of venous thromboembolism (e.g. after abdominal surgery), the recommended dose is 20 mg of enoxaparin sodium subcutaneously once daily. Usually, treatment with enoxaparin sodium is prescribed for 7 to 10 days. In some patients, this treatment time may be prolonged. In case there is an increased risk of venous thrombosis and embolism, enoxaparin sodium should be administered until the ambulation of the patient. In patients undergoing general surgery, the initial dose should be given 2 hours pre-operatively. In patients with a higher risk of venous thromboembolism (e.g. before orthopaedic surgery), the recommended dose is 40 mg of enoxaparin sodium subcutaneously once daily, with the initial dose administered approximately 12 hours before surgery.

Prophylaxis of venous thromboembolism, especially in patients immobilised because of severe conditions, including acute heart failure, acute respiratory failure, severe infections, as well as exacerbation of rheumatic diseases causing immobilisation of the patient (applies to 40 mg/0.4 mL strength)

The recommended dose of enoxaparin sodium is 40 mg subcutaneously once daily. Treatment with enoxaparin sodium is prescribed for a minimum of 6 days and continued until the return to full ambulation, for a maximum of 14 days.

Treatment of deep vein thrombosis complicated or not complicated by pulmonary embolism

Enoxaparin sodium may be administered subcutaneously, either at a dose of 1.5 mg/kg body weight (bw) once daily, or at a dose of 1 mg/kg bw twice daily. The recommended dose in patients with thromboembolic complications is 1 mg/kg bw administered subcutaneously twice daily. Treatment is usually prescribed for 5 days. Oral anticoagulant therapy should be initiated when appropriate and treatment with enoxaparin sodium should be continued until antithrombotic efficacy has been reached.

Treatment of unstable angina and non-Q-wave myocardial infarction in combination with administration of oral ASA

The recommended dose of enoxaparin sodium is 1 mg/kg bw subcutaneously every 12 hours administered concurrently with oral ASA at a dose of 100 to 325 mg once daily.

In these patients, enoxaparin sodium should be prescribed for at least 2 days and the treatment should be continued to achieve its objective. The usual duration of treatment is 2 to 8 days.

Treatment of acute STEMI, including patients treated conservatively or subject to further percutaneous transluminal coronary angioplasty (applies to strengths of 60 mg/0.6 mL, 80 mg/0.8 mL, 100 mg/1 mL)

The recommended dose of enoxaparin sodium is a single intravenous injection of 30 mg and additionally, immediately after the intravenous injection, a 1 mg/kg subcutaneous dose, followed by 1 mg/kg administered subcutaneously every 12 hours (maximum 100 mg for each of the first two doses only, followed by 1 mg/kg bw subcutaneously). For dosage in patients ≥ 75 years of age, see section 4.2, Elderly.

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. All patients should receive ASA immediately after the diagnosis of acute STEMI as long as there will be no contraindications (the medicinal product is administered at a dose of 75 mg to 325 mg once daily).

Treatment with enoxaparin sodium may be prescribed for 8 days or carried out until hospital discharge, whichever comes first.

For patients managed with percutaneous coronary intervention (PCI): If the last enoxaparin sodium subcutaneous administration was given less than 8 hours before balloon inflation, no additional dosing is needed. If the last subcutaneous administration was given more than 8 hours before balloon inflation, an intravenous bolus of 0.3 mg/kg bw of enoxaparin sodium should be administered.

Prevention of extracorporeal thrombus formation during haemodialysis

The recommended dose of enoxaparin sodium, equivalent to 1 mg/kg bw introduced into the arterial line at the beginning of a dialysis session is usually sufficient for a 4 hour session.

If fibrin rings are found, such as after a longer than normal session, a further dose of 0.5 to 1 mg/kg bw may be given. For patients at a high risk of haemorrhage, the dose should be reduced to 0.5 mg/kg bw for double vascular access or 0.75 mg/kg for single vascular access.

Special patient groups

Elderly

For treatment of acute STEMI in elderly patients ≥75 years of age, an initial intravenous bolus must not be used.

Initiate dosing with 0.75 mg/kg bw subcutaneous every 12 hours (maximum 75 mg for the first two doses only) must be followed by 0.75 mg/kg dosing for the remaining doses.

For other indications, no dose reduction is necessary in the elderly patients, except for patients with renal impairment (see also section 4.2, Renal impairment; section 4.4, Haemorrhage in the elderly; Renal impairment, and section 5.2).

Paediatric population

The safety and efficacy of enoxaparin sodium in children below the age of 12 years has not been established. No data are available.

Renal impairment

Severe renal impairment

A dose adjustment is required for patients with severe renal impairment (creatinine clearance < 30 mL/min), according to the following tables, since enoxaparin sodium exposure is significantly increased in this patient population:

Recommended dose adjustments for therapeutic dose ranges of enoxaparin sodium

Standard dosing

Dosing in severe renal impairment

1 mg/kg bw subcutaneously twice daily

1 mg/kg bw subcutaneously once daily

1.5 mg/kg bw subcutaneously once daily

1 mg/kg bw subcutaneously once daily

For treatment of acute ST-segment elevation myocardial infarction (STEMI) in patients <75 years of age

30 mg single intravenous bolus plus a 1 mg/kg subcutaneous dose followed by 1 mg/kg twice daily.

(Maximum 100 mg for each of the first two subcutaneous doses)

30 mg single intravenous bolus plus a 1 mg/kg subcutaneous dose followed by 1 mg/kg once daily.

(Maximum 100 mg for first subcutaneous dose only)

For treatment of acute STEMI in elderly patients ≥ 75 years of age

0.75 mg/kg subcutaneously twice daily without initial bolus.

(Maximum 75 mg for each of the first two subcutaneous doses)

1 mg/kg subcutaneously once daily without initial bolus.

(Maximum 100 mg for first subcutaneous dose only)

Dose adjustments for prophylactic dose ranges of enoxaparin sodium

Standard dosing

Dosing in severe renal impairment

40 mg subcutaneously once daily

20 mg subcutaneously once daily

20 mg subcutaneously once daily

20 mg subcutaneously once daily

The recommended dose adjustments do not apply to the haemodialysis indication.

Moderate and mild renal impairment

Although no dose adjustments are recommended in patients with moderate renal impairment (creatinine clearance 30-50 mL/min) or mild renal impairment (creatinine clearance 50-80 mL/min), careful clinical monitoring is advised during the treatment with enoxaparin sodium.

See also section 4.4, Renal impairment, and section 5.2.

Hepatic impairment

In the absence of clinical studies, caution should be exercised in patients with hepatic impairment.

Body weight

No dose adjustments are recommended in obese or low body weight patients (see sections 4.4 and 5.2).

Spinal and/or epidural anaesthesia

Caution should be exercised in patients receiving spinal and (or) epidural anaesthesia. Dose adjustment may be necessary (see section 4.4).

Method of administration

Subcutaneous injection

Enoxaparin sodium is administered by subcutaneous injection for the prevention of venous thromboembolism, for the treatment of DVT, for the treatment of unstable angina and non-Q-wave myocardial infarction and for the treatment of acute STEMI.

Intravenous injection

In the treatment of acute STEMI, treatment should begin with a single rapid intravenous injection, immediately followed by a subcutaneous injection.

Injection through the arterial line of the extracorporeal circuit

In order to prevent extracorporeal clot formation during haemodialysis, enoxaparin sodium is given by injection into the arterial line of the extracorporeal circulation.

Inhixa must not be administered by the intramuscular route.

Subcutaneous injection technique

Injection is best done when the patient is in the supine position by deep subcutaneous injection. 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 held between the thumb and index finger. The skin fold should not be released until the injection is complete.

After administration of enoxaparin sodium, the injection site should not be rubbed.

If a pre-filled 20 mg and 40 mg syringe is used, the air bubble from the syringe prior to injection must not be removed, as this may result in a reduction of the dose.

4.3 Contraindications

- Hypersensitivity to the active substance, heparin or its derivatives, including low molecular weight heparin.

- Acute bacterial endocarditis,

- Severe blood coagulation disorders,

- Major bleeding,

- Thrombocytopenia in patients with a positive in-vitro aggregation test in the presence of enoxaparin,

- Active gastric and/or duodenal ulceration,

- Stroke (excluding apoplexy after the blockage of the arteries),

- Increased risk of bleeding.

4.4 Special warnings and precautions for use

Increased risk of haemorrhage

Bleeding may occur anywhere (see section 4.8). If bleeding occurs, its location should be specified and appropriate therapy should be introduced. Enoxaparin sodium should be used with caution in situations of increased risk of bleeding, such as:

- disorders of haemostasis (clotting disorders or abnormal clot dissolving)

- gastric and/or duodenal ulcer in history,

- recent ischemic stroke,

- decompensated severe hypertension,

- diabetic retinopathy,

- recent completed neurosurgical or ophthalmological procedures,

- concomitant use of medicinal products affecting haemostasis.

Heparin-induced thrombocytopenia

In patients with thrombocytopenia caused by the use of heparin, with or without thrombosis, enoxaparin sodium should be used with extreme caution.

The risk of thrombocytopenia due to the use of heparin may persist for several years. Where thrombocytopenia caused by heparin use is suspected, platelet aggregation tests carried out in vitro have limited diagnostic value. Any decision on the use of the enoxaparin sodium in these cases must be made only after consultation with an expert in this field.

Platelet count monitoring

When using low molecular weight heparins, there is a risk of heparin-induced thrombocytopenia with the formation of antibodies. Thrombocytopenia typically occurs between the 5th and the 21st day following the beginning of treatment with enoxaparin sodium. Therefore, it is recommended that the platelet counts be measured before the initiation of therapy with enoxaparin sodium and then regularly thereafter during the treatment. Upon observation of a significant decrease of the platelet count (30 to 50 % of the initial value), enoxaparin sodium treatment must be immediately discontinued and the patient switched to another therapy.

Hyperkalaemia

Heparin can suppress adrenal secretion of aldosterone leading to hyperkalaemia, particularly in patients with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, a raised plasma potassium or taking potassium-sparing diuretics. The risk of hyperkalaemia appears to be greater during longer treatment, but hyperkalaemia is usually reversible. Plasma potassium should be measured in patients at risk before starting heparin therapy and monitored regularly thereafter particularly if treatment is prolonged beyond about 7 days.

Spinal and/or epidural anaesthesia

Simultaneous administration of enoxaparin sodium and performance of spinal/epidural anaesthesia can result in intramedullary haematoma. This can lead to long-term or permanent paralysis. Such complications rarely occur with the use of enoxaparin sodium in doses of 40 mg per day or less. The risk of intramedullary haematoma is increased when higher doses of enoxaparin sodium are administered, permanent epidural catheters used after surgery or when other medicinal products affecting haemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), are concomitantly used (see section 4.5). The risk of intramedullary haematoma also appears to be greater in the case of post-traumatic lesions and multiple punctures of the cerebrospinal axis, or in patients after surgery or with spinal deformities in history.

In order to reduce the potential risk of bleeding into the spinal canal associated with the concurrent use of enoxaparin sodium and anaesthesia or analgesia using the subarachnoid or epidural routes of administration, the pharmacokinetic profile of the medicinal product should be considered (see section 5.2). It is recommended to introduce or remove a catheter at a time when the antithrombotic effect of enoxaparin is low. However, the exact time needed to reach a sufficiently low anticoagulant effect in each patient is not known.

Placement or removal of a catheter should be performed at least 12 hours after the administration of low doses of enoxaparin sodium (20 mg once daily, 30 mg once or twice daily or 40 mg once daily) and at least 24 hours after administration of high doses of enoxaparin sodium (0.75 mg/kg bw twice daily, 1 mg/kg bw twice daily or 1.5 mg/kg bw once daily). Anti-Xa levels are still detectable at these time points. The delay in the introduction or removal of a catheter does not ensure that the intramedullary haematoma does not occur. Patients receiving the 0.75 mg/kg bw twice-daily dose or the 1 mg/kg bw twice-daily dose should not receive the second enoxaparin dose in the twice-daily regimen to allow a longer delay before catheter placement or removal. Likewise, although a specific recommendation for timing of a subsequent enoxaparin dose after catheter removal cannot be made, consider delaying this next dose for at least 4 hours, based on a benefit-risk assessment considering both the risk for thrombosis and the risk for bleeding in the context of the procedure and patient risk factors. For patients with creatinine clearance <30 mL/minute, additional considerations are necessary because elimination of enoxaparin is more prolonged. In these patients one should consider doubling the timing of removal of a catheter, at least 24 hours for the lower prescribed dose of enoxaparin (30 mg once daily) and at least 48 hours for the higher dose (1 mg/kg bw/day).

Should the physician decide to administer anticoagulation in the context of epidural/spinal anaesthesia or lumbar puncture, it is necessary to exercise caution and regular monitoring of the patient to detect possible signs and symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or weakness in the lower limbs), bowel and/or urinary bladder dysfunction. Patients should be instructed to inform their nurse or physician 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.

Percutaneous coronary intervention (PCI)

To minimise the risk of bleeding following vascular instrumentation during the treatment of unstable angina, non-Q-wave myocardial infarction and acute ST-elevation myocardial infarction, adhere precisely to the intervals recommended between enoxaparin sodium 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, sheath should be removed 6 hours after the last intravenous/subcutaneous 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.

Prosthetic heart valves

There are no adequate studies assessing anticoagulant properties of enoxaparin sodium in patients with prosthetic heart valves and thus, the use of enoxaparin is not recommended. Limited data and confounding factors from patients with prosthetic heart valves treated with enoxaparin (including pregnant women and fetus which may be at increased risk of thromboembolic events -see section 4.6) contradicts enoxaparin use in prosthetic heart valve patients.

Haemorrhage in the elderly

No increased bleeding tendency is observed in the elderly within the prophylactic dose ranges. Elderly patients (especially patients aged eighty years and above) may be at an increased risk for bleeding complications within the therapeutic dose ranges. Careful clinical monitoring is advised in this group of patients (see sections 4.2 and 5.2).

Renal impairment

In patients with renal impairment, increased exposure to enoxaparin sodium is associated with an increased risk of bleeding. Due to the much higher concentration of enoxaparin sodium in blood serum in patients with severe renal impairment (creatinine clearance < 30 mL/min) dose adjustments are recommended in therapeutic and prophylactic dose ranges. Although no dose adjustments is necessary in patients with moderate (creatinine clearance 30 to 50 mL/min) and mild (creatinine clearance 50 to 80 mL/min) renal impairment, careful clinical monitoring of these patients should be carried out during treatment with enoxaparin sodium (see also sections 4.2 and 5.2).

Low body weight patients

An increase in the concentration of enoxaparin sodium after using prophylactic doses (non-weight adjusted) has been observed in low-weight female patients (<45 kg) and low-weight male patients (<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 (with 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.

Laboratory tests

At doses used for prophylaxis of venous thromboembolism, enoxaparin sodium does not influence bleeding time and general blood clotting parameters, nor does it affect platelet aggregation or binding of fibrinogen to platelets. While taking enoxaparin sodium at higher doses, prolongation of the activated partial thromboplastin time (APTT) and activated clotting time (ACT) may occur. The prolonged APTT and ACT are not linearly correlated with increasing antithrombotic activity of enoxaparin sodium. Therefore, measurements of APTT and ACT are unsuitable and unreliable for monitoring enoxaparin sodium activity. Risk assessment and clinical monitoring are the best indicators of the potential risk of bleeding.

Generally, it is not necessary to routinely monitor anti-Xa activity.

However, monitoring of anti-Xa activity should be considered in patients treated with low molecular weight heparin with increased risk of bleeding (e.g., patients with renal impairment, elderly or with extreme body weight) or active bleeding.

Sodium content

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

4.5 Interaction with other medicinal products and other forms of interaction

It is recommended that agents which affect haemostasis should be discontinued prior to enoxaparin therapy unless their use is essential, such as: systemic salicylates, ASA, NSAIDs including ketorolac, dextran, and clopidogrel, systemic glucocorticoids, thrombolytics and anticoagulants, and other antiplatelet agents, including glycoprotein IIb/IIIa antagonists. If the combination cannot be avoided, enoxaparin should be used with careful clinical and laboratory monitoring for blood clotting.

4.6 Fertility, pregnancy and lactation

Pregnancy

Animal studies have not shown any evidence of foetotoxicity or teratogenicity. In the pregnant rat, the transfer of 35S-enoxaparin across the maternal placenta to the foetus is minimal.

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

As there are no adequately powered and well-controlled studies in pregnant women and because animal studies are not always predictive of human response, this medicinal product should be used during pregnancy only if the physician has established a clear need.

The use of enoxaparin for thromboprophylaxis in pregnant women with mechanical prosthetic heart valves has not been adequately studied. In a clinical study (carried out in Africa) of pregnant women with mechanical prosthetic heart valves who were given enoxaparin 1 mg/kg bw 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 for thromboprophylaxis. Pregnant women with mechanical prosthetic heart valves may be at higher risk for thromboembolism. Enoxaparin sodium is not recommended for use in pregnant women with prosthetic heart valves (see section 4.4).

Breast-feeding

In lactating rats, the concentration of 35S-enoxaparin or its labelled metabolites in milk is very low.

It is not known whether unchanged enoxaparin is excreted in human breast milk. The oral absorption of enoxaparin is unlikely. However, as a precaution, lactating mothers receiving enoxaparin should be advised to avoid breast-feeding.

4.7 Effects on ability to drive and use machines

Enoxaparin has no effect on the ability to drive and operate machines.

4.8 Undesirable effects

Summary of the safety profile

Haemorrhages

In clinical studies, haemorrhages were the most commonly reported reaction. These included major haemorrhages, reported at most in 4.2 % of the patients (surgical patients1). Some of these cases have been fatal. As with other anticoagulants, haemorrhage may occur during enoxaparin therapy 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).

Tabulated list of adverse reactions

Enoxaparin was evaluated at 15,000 patients receiving enoxaparin in clinical trials. The tests included 1,776 patients at risk of thromboembolism taking enoxaparin in preventing venous thromboembolism after orthopaedic or abdominal surgery, 1,169 patients bedridden due to acute medical illness, given enoxaparin in preventing venous thromboembolism, 559 patients administered enoxaparin in the treatment of DVT, complicated or uncomplicated by pulmonary embolism, 1,578 patients receiving enoxaparin in the treatment of unstable angina and non-Q-wave myocardial infarction and 10,176 patients receiving enoxaparin in the treatment of acute ST segment elevation myocardial infarction.

The adverse reactions observed in clinical studies and reported in 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 available data).

The post-marketing adverse reactions are derived from spontaneous reports and therefore, their frequency is “not known” (cannot be estimated from the available data).

MedDRA system organ class

All indications

Prophylaxis in surgical patients

Prophylaxis in medical patients

Treatment in patients with DVT with or without PE

Treatment in patients with unstable angina and non-Q-wave MI

Treatment in patients with acute STEMI

Vascular disorders

Not known:

Cases of spinal haematoma (or neuraxial haematoma) have been reported with the concurrent use of enoxaparin sodium as well as spinal/epidural anaesthesia or spinal puncture and post operative indwelling catheters. These reactions have resulted in varying degrees of neurologic injuries including long term or permanent paralysis (see section 4.4)

Very common:

Haemorrhage *

Rare:

Retroperitoneal haemorrhage

Common:

Haemorrhage *

Very common:

Haemorrhage *

Uncommon:

Intracranial haemorrhage, Retroperitoneal haemorrhage

Common:

Haemorrhage *

Rare:

Retroperitoneal haemorrhage

Common:

Haemorrhage *

Uncommon:

Intracranial haemorrhage, Retroperitoneal haemorrhage

Blood and lymphatic system disorders

Not known:

Haemorrhagic anaemia; cases of immune-allergic thrombocytopenia with thrombosis; in some of them thrombosis was complicated by organ infarction or limb ischaemia (see section 4.4); eosinophilia

Very common:

Thrombocytosis**

Common:

Thrombocytopenia

Uncommon:

Thrombocytopenia

Very common:

Thrombocytosis **

Common:

Thrombocytopenia

Uncommon:

Thrombocytopenia

Common:

Thrombocytosis**

Thrombocytopenia

Very rare:

Immuno-allergic thrombocytopenia

Immune system disorders

Common:

Allergic reaction

Rare: Anaphylactic / anaphylactoid reaction

Not known:

Anaphylactic / anaphylactoid reaction including shock

Nervous system disorders

Not known:

Headache

Hepatobiliary disorders

Very common:

Hepatic enzymes increase (mainly transaminases ***)

Not known:

Hepatocellular liver injury; cholestatic liver injury

Skin and subcutaneous tissue disorders

Common:

Urticaria, pruritus, erythema

Uncommon:

Bullous dermatitis

Not known:

- Cutaneous vasculitis, skin necrosis usually occurring at the injection site (these phenomena have been usually preceded by purpura or erythematous plaques, infiltrated and painful). Treatment with enoxaparin sodium must be discontinued.

- Injection site nodules (inflammatory nodules, which were not cystic enclosure of enoxaparin). They resolve after a few days and should not cause treatment discontinuation.

- Alopecia

Musculoskeletal and connective tissue disorders

Not known:

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†

Uncommon:

Local irritation; skin necrosis at injection site

Investigations

Rare:

Hyperkaliemia

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

**: Platelet increased > 400 x 109/L

***: transaminases levels > 3 times the upper limit of normality

†: such as injection site oedema, haemorrhage, hypersensitivity, inflammation, mass, pain, or reaction (NOS) at the site of injection.

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

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 the Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Signs and symptoms

Accidental overdose of enoxararin sodium after intravenous, extracorporeal or subcutaneous administration may lead to haemorrhagic complications. Orally administered enoxaparin is poorly absorbed and even large doses should not lead to any serious consequences. This may be checked by plasma assays of anti-Xa and anti-IIa activities.

Treatment

The anticoagulant effects can be largely neutralised by the slow intravenous injection of protamine sulphate or protamine hydrochloride.

The dose of Protamine depends on the dose of enoxaparin given; 1 mg of protamine sulphate neutralises the anticoagulant activity of 1 mg of enoxaparin sodium if enoxaparin sodium was administered during the last 8 hours. If enoxaparin sodium was administered more than 8 hours prior to administration of protamine or, if it is determined that it is necessary to give a second dose of protamine, protamine can be infused at a dose of 0.5 mg per 1 mg of enoxaparin sodium.

12 hours after the injection of enoxaparin sodium administration of protamine may not be necessary. However, even high doses of protamine do not fully neutralise the anti-Xa activity of enoxaparin sodium (maximum 60%).

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antithrombotic agents, heparin group. ATC code: B01A B05

Mechanism of action

Enoxaparin is a low molecular weight heparin with a mean molecular weight of approximately 4,500 daltons.

In vitro purified enoxaparin has a high anti factor Xa blood clotting (anti-Xa) (approximately 100 IU/mg) and a low anti factor IIa (anti-IIa) or antithrombin (approximately 28 IU / mg). The antithrombotic activity is mediated by antithrombin III (ATIII), resulting in human antithrombotic effect.

In addition to the anti-Xa and anti-IIa, further anticoagulant and anti-inflammatory properties have been identified in studies in healthy volunteers and patients, as well as in preclinical models. These include ATIII-dependent inhibition of other coagulation factors like factor VIIa, induction of endogenous tissue factor pathway inhibitor (TFPI) release as well as a reduced release of von Willebrand factor (vWF) from the vascular endothelium into the blood circulation. These factors are known to contribute to the overall anti-thrombotic effect of enoxaparin.

Clinical efficacy

Treatment of unstable angina and non-Q-wave myocardial infarction

In a large multicentre, double-blind study, they examined 3,171 patients admitted in the acute phase of unstable angina or non-Q-wave myocardial infarction. Randomly selected patients received oral ASA at a dose of 100 to 325 mg once daily in combination with intravenous infusion of unfractionated heparin at a dose adjusted individually to APTT or in combination with enoxaparin, administered subcutaneously at a dose of 1 mg/kg bw every 12 hours.

Patients were treated in hospital until clinical stabilisation, revascularisation or discharge. Hospitalisation time ranged from 2 to 8 days. Clinical data were collected for 30 days of treatment.

Enoxaparin compared with unfractionated heparin significantly reduces the recurrence rate of coronary heart disease, heart attacks and death. Reduction of the risk of the aforementioned complications by 16.2% on the 14th day of treatment was held up to 30th day of the treatment. In addition, in fewer patients of the group treated with enoxaparin it was necessary to carry out revascularisation by using the method of percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass graft (CABG) (reduction of the risk of recurrent coronary heart disease, myocardial infarction or death by 15.8% on day 30 of treatment).

Treatment of ST segment elevation acute myocardial infarction

In a large multicentre clinical trial, 20479 patients with acute STEMI who could be treated with fibrinolytic therapy were randomised to a group receiving 30 mg enoxaparin in a single intravenous bolus injection and, in addition, immediately after intravenous injection, subcutaneously 1 mg/kg bw, followed by 1 mg/kg bw subcutaneously every 12 hours; or to a group receiving intravenous heparin at a dose adjusted to the individual APTT for 48 hours.

All patients were also treated with ASA for at least 30 days. Enoxaparin dosing regimen was adjusted in patients with severe renal impairment and in elderly patients (≥ 75 years). Injectable enoxaparin was administered until hospital discharge or for a maximum of 8 days (the incident which occurred earlier). 4716 patients were treated with percutaneous coronary angioplasty with administration of anticoagulant following the rules for masking investigational medicinal product.

In the case of a group of patients treated with enoxaparin, percutaneous coronary intervention was performed without discontinuation of enoxaparin (without changing the product) administered according to the scheme established in previous studies, i.e.:

- No additional dose if the last dose was administered subcutaneously before the end of 8 hours prior to filling the balloon,

- Intravenously 0.3 mg/kg bw of enoxaparin if the last dose was administered subcutaneously over 8 hours before filling the balloon.

When the efficacy of enoxaparin and unfractionated heparin were compared, the rate of the primary efficacy endpoint, including death or myocardial re-infarction in the first 30 days after randomisation, was 9.9% in the enoxaparin group, as compared to 12.0% in the unfractionated heparin group, that is a 17% reduction in the relative risk (p < 0.001).

The therapeutic benefits of enoxaparin, seen as a better performance efficacy, appeared after 48 hours. There was the reduction of relative risk of recurrent myocardial infarction by 35% compared to treatment with unfractionated heparin (p <0.001).

The beneficial effect of enoxaparin on the primary efficacy endpoint was a constant in all key subgroups distinguished on the basis of age, sex, location of myocardial infarction, diabetes, a history of prior myocardial infarction, the type of fibrinolytic and time to initiation of treatment with the IMP.

The treatment benefits of enoxaparin, evident for a number of efficacy outcomes, emerged at 48 hours, at which time there was a 35% reduction in the relative risk of myocardial re-infarction, as compared with unfractionated heparin (p < 0.0001).

The beneficial effect of enoxaparin on the primary endpoint was consistent across key subgroups including age, gender, infarct location, history of diabetes, history of prior myocardial infarction, fibrinolytic administered and time to treatment with study medicinal product.

There was a significant therapeutic benefit from the use of enoxaparin in comparison to UFH in patients undergoing percutaneous coronary angioplasty within 30 days after the random sampling (relative risk reduction of 23%) or conservative treatment (reduction of relative risk of 15%, p = 0.27 for interaction).

The rate of the 30-day composite endpoint of death, myocardial re-infarction or intracranial haemorrhage (a measure of net clinical benefit) was significantly lower (p < 0.0001) in the enoxaparin group (10.1%) as compared to the heparin group (12.2%), representing a 17% relative risk reduction in favour of treatment with enoxaparin sodium.

The beneficial effect of enoxaparin on the primary endpoint observed during the first 30 days was held over a 12-month observation period.

5.2 Pharmacokinetic properties

General characteristics

The pharmacokinetics of enoxaparin have been studied on the basis of plasma levels of anti-Xa activity and activity of anti-IIb at the recommended doses following single and repeated subcutaneous administration, and following single intravenous injection.

Quantitation of pharmacokinetic activity of anti-Xa and anti-IIa was validated by using the amidolytic method with specific substrates and enoxaparin standard calibrated against the international standard (NIBSC) for low molecular weight heparins (LMWHs).

Bioavailability and absorption

The absolute bioavailability of enoxaparin after subcutaneous injection, based on anti-Xa activity, is approximately 100%. The volume of injected medicinal product and concentration dose range from 100 to 200 mg/mL did not affect the pharmacokinetics of a medicinal administration to healthy volunteers.

The mean peak plasma anti-Xa activity is observed 3 to 5 hours after subcutaneous injection. Levels of approximately 0.2, 0.4, 1.0 and 1.3 IU/mL of anti-Xa were seen in healthy volunteers, following a single subcutaneous administration of 20 mg, 40 mg, 1 mg/kg and 1.5 mg/kg, respectively.

A 30 mg intravenous bolus immediately followed by a 1 mg/kg subcutaneous every 12 hours provided initial peak anti-Factor Xa levels of 1.16 IU/mL (n=16) and average exposure corresponding to 88% of steady state levels. Steady state is achieved on the second day of treatment.

Enoxaparin pharmacokinetics appears to be linear over the recommended dose ranges. Intra-patient and inter-patient variability is low. After repeated subcutaneous administration of 40 mg once daily and 1.5 mg/kg once daily regimens in healthy volunteers, the steady-state is reached on day 2 with an average exposure ratio about 15% higher than after a single dose.

Steady-state enoxaparin activity levels are well predicted by single dose pharmacokinetics.

After repeated subcutaneous administration of the 1 mg/kg twice daily regimen, the steady-state is reached from day 3 to 4 with mean exposure about 65% higher than after a single dose and mean peak and trough levels of about 1.2 and 0.52 IU/mL, respectively. Based on enoxaparin sodium pharmacokinetics, this difference in steady state is expected and within the therapeutic range.

Plasma anti-IIa activity after subcutaneous administration is approximately ten-fold lower than anti-Xa activity. The mean maximum plasma anti-IIa activity is observed approximately 3 to 4 hours following subcutaneous injection and reaches 0.13 IU/mL and 0.19 IU/mL following repeated administration of 1 mg/kg twice daily and 1.5 mg/kg once daily, respectively.

Distribution

The volume of distribution of enoxaparin anti-Xa activity is about 5 litres and is close to the blood volume.

Biotransformation

Enoxaparin is metabolised mainly in the liver where it breaks down to molecules of lower molecular weight and significantly reduced biological activity as a result of disulphide bond cleavage (desulphation and depolymerisation).

Elimination

Enoxaparin sodium is a low clearance active substance with a mean anti-Xa plasma clearance of 0.74 L/h after a 1.5 mg/kg bw 6-hour intravenous infusion. Elimination appears monophasic with a half-life of about 4 hours after a single-subcutaneous dose to about 7 hours after repeated dosing. Renal clearance of active fragments represents about 10% of the administered dose and total renal excretion of active and non-active fragments 40% of the dose.

Characteristics of different patient groups

Elderly

Based on the results of a population pharmacokinetic analysis, the enoxaparin sodium kinetic profile is not different in elderly subjects compared to younger subjects when renal function is normal. However, since renal function is known to decline with age, elderly patients may show reduced elimination of enoxaparin sodium (see sections 4.2, 4.4 and 5.2).

Renal Impairment

A linear relationship between anti-Xa plasma clearance and creatinine clearance at steady-state has been observed, which indicates decreased clearance of enoxaparin sodium in patients with reduced renal function.

Anti-Xa exposure represented by AUC, at steady-state, is marginally increased in mild (creatinine clearance 50-80 mL/min) and moderate (creatinine clearance 30-50 mL/min) renal impairment after repeated subcutaneous 40 mg once daily doses. In patients with severe renal impairment (creatinine clearance < 30 mL/min), the AUC at steady state is significantly increased by an average of 65% after repeated, once daily subcutaneous doses of 40 mg (see sections 4.4 and 4.2).

Weight

After repeated, once daily subcutaneous doses of 1.5 mg/kg, mean AUC of anti-Xa activity is marginally higher at steady state in obese healthy volunteers (BMI 30-48 kg/m2) compared to non-obese control subjects, while Amax is not increased. There is a lower weight-adjusted clearance in obese subjects with subcutaneous dosing.

When non-weight adjusted dosing was administered, it was found after a single-subcutaneous 40 mg dose, that anti-Xa exposure is 50% higher in low-weight women (<45 kg) and 27% higher in low-weight men (<57 kg) when compared to normal weight control subjects (see section 4.4).

Haemodialysis

A study in this group of patients showed that the enoxaparin elimination rate is similar to the corresponding values in the control group, but the area under the curve (AUC) was two-fold higher after a single 0.25 or 0.50 mg/kg bw intravenous dose.

5.3 Preclinical safety data

No long-term studies in animals have been performed to evaluate the carcinogenic potential of enoxaparin.

Enoxaparin was not mutagenic in in vitro tests, including the Ames test, mouse lymphoma cell forward mutation test, and human lymphocyte chromosomal aberration test, and the in vivo rat bone marrow chromosomal aberration test.

Enoxaparin was found to have no effect on fertility or reproductive performance of male and female rats at subcutaneous doses up to 20 mg/kg/day. Teratology studies have been conducted in pregnant rats and rabbits at subcutaneous doses of enoxaparin up to 30 mg/kg/day. There was no evidence of teratogenic effects or foetotoxicity due to enoxaparin.

Besides the anticoagulant effects of enoxaparin, there was no evidence of adverse effects at 15 mg/kg/day in the 13-week subcutaneous toxicity studies both in rats and dogs and at 10 mg/kg/day in the 26-week subcutaneous and intravenous toxicity studies both in rats and monkeys.

6. Pharmaceutical particulars
6.1 List of excipients

Water for injections

6.2 Incompatibilities

Subcutaneous Injection

Inhixa should not be mixed with any other injections or infusions.

Intravenous (bolus) injection for acute STEMI indication only

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

Pre-filled syringe

3 years

Diluted medicinal product with sodium chloride 9 mg/ml (0.9%) solution for injection or 5% glucose

8 hours

6.4 Special precautions for storage

Store below 25 °C. Do not freeze.

6.5 Nature and contents of container

0.2 mL of solution in a clear, colourless type I neutral glass syringe barrel with fixed needle and needle shield closed by chlorobutyl rubber stopper and a blue polypropylene plunger rod. The syringe can be additionally equipped with needle guard.

Packs of 2 and 10 pre-filled syringes with or without needle guard.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

The pre-filled syringe is ready for immediate use (see section 4.2).

Intravenous (bolus) injection for acute STEMI indication only: Inhixa may be safely administered with sodium chloride 9 mg/ml (0.9%) solution for injection or 5% glucose in water.

The solution should be inspected visually prior to use. It must not be used if there is any change in the appearance of the solution.

The Inhixa pre-filled syringes are for single dose use only; discard any unused medicinal product. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Each used syringe should be disposed of in special containers at pharmacies or hospitals - not together with household garbage.

7. Marketing authorisation holder

Techdow Europe AB

Banérgatan 36

75237 Uppsala

Sweden

8. Marketing authorisation number(s)

EU/1/16/1132/001

EU/1/16/1132/002

EU/1/16/1132/011

EU/1/16/1132/012

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 15/09/2016

10. Date of revision of the text

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

Company contact details

Techdow Pharma Ltd

Company image
Address

30 Crown Place, London, EC2A 4ES

Medical Information e-mail
Stock Availability

August 2017

Medical Information Direct Line

01271 334 609

Customer Care direct line

01271 334 609

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Active ingredients

enoxaparin sodium

Legal categories

POM - Prescription Only Medicine

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