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Enoxapo
Sponsor
ARTGs
Device/Product name
Enoxapo
Active Ingredient
Enoxaparin sodium
Date of decision
Published
Submission type
New biosimilar medicine
ATC codes
B01AB05
Decision
Approved
What was the decision based on
The decision was based on quality (chemistry and manufacturing), nonclinical (pharmacology and toxicology), clinical (pharmacology, safety and efficacy) and risk management plan information submitted by the sponsor. The benefit-risk profile of Enoxapo was considered favourable for the therapeutic use approved.
What steps were involved in the decision process
Registration timeline
The following table summarises the key steps and dates for this application.
| Description | Date |
|---|---|
| Submission dossier accepted and first round evaluation commenced | 22 July 2013 |
| First round evaluation completed | 19 March 2014 |
| Sponsor provides responses on questions raised in first round evaluation | 30 May 2014 |
| Second round evaluation completed | 23 July 2014 |
| Delegate's overall benefit-risk assessment and request for Advisory Committee advice | 4 November 2014 |
| Sponsor's pre-Advisory Committee response | 18 November 2014 |
| Advisory Committee meeting | 1 December 2014 |
| Registration decision (Initial rejection) | 13 February 2015 |
| Number of working days from submission dossier acceptance to initial registration decision* | 253 |
| Registration decision (Confirmation of initial decision) | 9 July 2015 |
| Administrative Appeals Tribunal (AAT) decision | 25 February 2019 |
| Registration decision (Outcome: approval) | 4 February 2020 |
| Completion of administrative activities and registration on ARTG | 10 February 2020 |
*Statutory timeframe for standard applications is 255 working days
Date of entry onto ARTG
Original publication date
Black triangle scheme
No
Dose forms
Solution for injection
Strength
20 mg/0.2 mL, 40 mg/0.4 mL, 60 mg/0.6 mL, 80 mg/0.8 mL, 100 mg/1.0 mL, 120 mg/0.8 mL, 150 mg/1.0 mL
Other ingredients
Water for injections
Containers
Prefilled syringe
Pack sizes
10
Routes of administration
Subcutaneous injection, intravenous injection
Dosage
Prophylaxis of venous thrombosis
Prophylaxis against thromboembolism should be tailored according to the patient's risk. Risk factors include age over 40 years, history of deep vein thrombosis or pulmonary embolism, surgery and other trauma, prolonged immobilisation, cardiac disease, obesity, malignancy, varicose veins, hypercoagulable states, pregnancy and the puerperium, oral contraceptives, severe infection, inflammatory bowel disease.
- High Risk Patients
In patients with high risk of thromboembolism, an Enoxaparin dosage of 40 mg (0.4 mL; anti-Xa: 4,000 IU) should be administered subcutaneously once daily. In high risk patients undergoing surgery, the initial dose should be given approximately 12 hours preoperatively. The timing of the first dose may need to be modified if spinal/epidural anaesthesia is to be performed (see Section 4.4 - Special Warnings and Precautions for Use: Spinal/Epidural Anaesthesia).
- Moderate Risk Patients
In patients with a moderate risk of thromboembolism, the recommended Enoxaparin dosage is 20 mg (0.2 mL; anti-Xa: 2,000 IU) subcutaneously once daily. In moderate risk patients undergoing surgery, the initial dose should be given approximately 2 hours preoperatively. The timing of the first dose may need to be modified if spinal/epidural anaesthesia is to be performed (see Section 4.4 - Special Warnings and Precautions for Use: Spinal/Epidural Anaesthesia).
Duration of therapy
High to Moderate Risk: Prophylaxis should be continued for 7 to 10 days or until the risk of thromboembolism has diminished.
Prolonged thromboprophylaxis
Therapy with 40 mg once daily for 30 post-operative days has been proven to be beneficial in total hip replacement surgery.
Under normal conditions of use, Enoxaparin does not modify global clotting tests and therefore there is no need to perform these tests in order to monitor therapy.
Prophylaxis of venous thromboembolism in medical patients
The recommended dose should be 40 mg once daily by subcutaneous injection for a minimum of 6 days, continuing for a maximum of 14 days or less if the patient returns to full ambulation earlier than 14 days.
Treatment of deep venous thrombosis
The initial clinical trials which established the efficacy of Enoxaparin in the treatment of deep venous thrombosis were conducted on patients who were initially treated with heparin and then changed to Enoxaparin when a definitive diagnosis was established. However, the use of heparin prior to Enoxaparin is not currently recommended. The average duration of therapy in the clinical trials was 10 days. No data are available on the safety of long term treatment. Data on use in patients over 65 years of age in these trials were limited.
The recommended dosage for treatment of established deep vein thrombosis with Enoxaparin is 1.5 mg/kg body weight once daily (150 IU anti-Xa activity/kg bodyweight) or 1 mg/kg body weight (100 IU anti-Xa activity/kg bodyweight) twice daily subcutaneously. In high risk patients, e.g. the obese or patients with baseline iliac vein thrombosis or cancer, a dose of 1 mg/kg body weight administered twice daily may be more beneficial.
Warfarin sodium therapy should be initiated when appropriate (usually within 72 hours of commencing Enoxaparin initiation). Enoxaparin should be continued for a minimum of 5 days and until a therapeutic oral anticoagulant effect has been achieved (International Normalization Ratio 2.0 to 3.0).
Treatment of unstable angina and non-Q-wave-myocardial infarction
The recommended dose of Enoxaparin is 1 mg/kg (100 IU anti-Xa activity/kg) every 12 hours by subcutaneous injection, administered concurrently with oral aspirin.
Treatment with Enoxaparin in these patients should be prescribed for a minimum of 2 days and a maximum of 8 days.
Treatment of acute ST-segment elevation myocardial infarction
In patients with acute ST-segment elevation myocardial infarction, administered in conjunction with a fibrinolytic (fibrin-specific or non-fibrin specific), the recommended dose of Enoxaparin is a single IV bolus of 30 mg plus a 1 mg/kg SC dose, followed by 1 mg/kg administered SC every 12 hours (maximum 100 mg for each of the first two SC doses only, followed by 1 mg/kg dosing for the remaining doses). For dosage in patients ≥ 75 years of age, see Section 4.2 - Dose and Method of Administration: Use in Renal Impairment and Use in the Elderly.
When administered in conjunction with thrombolytic (fibrin-specific or non-fibrin specific), Enoxaparin should be given between 15 minutes before and 30 minutes after the start of fibrinolytic therapy. All patients should receive aspirin as soon as they are identified as having STEMI (unless contraindicated). The recommended duration of Enoxaparin treatment is 8 days or until hospital discharge, whichever comes first.
For patients further managed with Percutaneous Coronary Intervention (PCI): If the last Enoxaparin SC administration was given less than 8 hours before balloon inflation, no additional dosing is needed. If the last Enoxaparin SC administration was given more than 8 hours before balloon inflation, an IV bolus of 0.3 mg/kg of Enoxaparin should be administered (see Section 4.4 - Special Warnings and Precautions for Use: Percutaneous Coronary Revascularisation Procedures).
Haemodialysis
In patients undergoing repeated sessions of haemodialysis, the prevention of thrombosis in the extracorporeal blood circuit is obtained by injection of a dose of 1 mg/kg (100 IU anti-Xa activity/kg) into the arterial line of the dialysis circuit at the start of the session. This dose is usually sufficient for a 4-hour haemodialysis session. If fibrin rings are formed, a fresh injection of 0.5 to 1 mg/kg (50 to 100 IU anti-Xa activity/kg) should be made depending on the time before the end of the dialysis.
In haemodialysed patients with a high risk of haemorrhage, (in particular, in pre or postoperative dialysed patients) or with a progressive haemorrhagic disorder, the dialysis sessions may be carried out by using a dose of 0.5 mg/kg (50 IU anti-Xa activity/kg) (double vascular access) or 0.75 mg/kg (75 IU anti-Xa activity/kg) (single vascular access).
For further information refer to the Product Information.
Pregnancy category
CDrugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.The use of any medicine during pregnancy requires careful consideration of both risks and benefits by the treating health professional. This must not be used as the sole basis of decision making in the use of medicines during pregnancy. The TGA does not provide advice on the use of medicines in pregnancy for specific cases. More information is available from obstetric drug information services in your State or Territory.
What was approved
Enoxapo (enoxaparin sodium) was approved for the following therapeutic use:
- Prevention of thromboembolic disorders of venous origin in patients undergoing orthopaedic and general surgery.
- Prophylaxis of venous thromboembolism in medical patients bedridden due to acute illness.
- Prevention of thrombosis in extra-corporeal circulation during haemodialysis.
- Treatment of established deep vein thrombosis.
- Treatment of unstable angina and non-Q-wave myocardial infarction, administered concurrently with aspirin.
- Treatment of acute ST-segment Elevation Myocardial Infarction (STEMI) as an adjunctive to thrombolytic treatment, including patients to be managed medically or with subsequent Percutaneous Coronary Intervention (PCI).
What is this medicine and how does it work
Enoxapo is a biosimilar medicine to Clexane.Enoxaparin sodium is a low molecular weight heparin (molecular weight approx. 4,500 Da, ranging between 4,100 Da to 4,600 Da). The drug substance is the sodium salt.In comparison with natural heparin, enoxaparin is characterised by a clear increase in the ratio between anti-Xa and anti-Ila activities which is always greater than 4. It has several actions on the coagulation pathway through binding to anti-thrombin III. The antithrombotic activity is related to inhibition of thrombin generation and inhibition of two main coagulation factors: Factor Xa and Thrombin. Enoxaparin also induces a sustained release of the Tissue Factor Pathway Inhibitor in vivo.In the experimental animal, enoxaparin was found to have potent anti-thrombotic properties with a minimum effect on bleeding.
What post-market commitments will the sponsor undertake
- Implement the Enoxapo Australian Risk Management Plan (AUS-RMP) version 2.0, dated 22 May 2014, included with submission PM-2012-03777-1-3, and any future updates as agreed with the TGA as a condition of registration.
- Batch release testing and compliance with Certified Product Details (CPD)
- Batch release testing
- It is a condition of registration that all batches of Enoxapo imported into/manufactured in Australia must comply with the product details and specifications approved during evaluation and detailed in the Certified Product Details (CPD).
- It is a condition of registration that up to five (5) initial batches of Enoxapo imported into/manufactured in Australia is not released for sale until samples and/or the manufacturer's release data have been assessed and endorsed for release by the TGA Laboratories Branch. Outcomes of laboratory testing are published biannually in the TGA Database of Laboratory Testing Results.
- The sponsor should be prepared to provide product samples, reference materials and documentary evidence as defined by the TGA Laboratories branch. The Sponsor must contact Biochemistry.Testing@health.gov.au for specific material requirements related to the batch release testing/assessment of the product. More information is available at Testing of biological medicines.
This batch release condition will be reviewed and may be modified on the basis of actual batch quality and consistency. This condition remains in place until the sponsor is notified in writing of any variation.
- Certified Product Details
- The Certified Product Details (CPD), as described in Guidance 7: Certified Product Details of the Australian Regulatory Guidelines for Prescription Medicines (ARGPM), in PDF format, for the above products should be provided upon registration of these therapeutic goods. In addition, an updated CPD should be provided when changes to finished product specifications and test methods are approved in a Category 3 application or notified through a self-assessable change.
- Batch release testing
- For all injectable products the Product Information must be included with the product as a package insert.