IN USE PRODUCT SAFETY ASSESSMENT REPORT FORINHIXA (ENOXAPARIN BIOSIMILAR)

SUMMARY OF ASSESSMENT AND ITS FINDINGS

BACKGROUND

Until recently, Clexane was the only enoxaparin product on the market. Inhixa®▼, an enoxaparin biosimilar1, was launched in the UK in September 2017.2. As there are now two enoxaparin products available, this review discusses practical safety considerations associated with the introduction of this biosimilar product, including the need to ensure prescribing of product by brand name.

DETAILS OF PRODUCT (S) ASSESSED

Inhixa pre-filled syringes (Techdow Pharma Ltd):3

2,000 IU (20 mg) in 0.2 mL4,000 IU (40 mg) in 0.4 mL6,000 IU (60 mg) in 0.6 mL8,000 IU (80 mg) in 0.8 mL10,000 IU (100 mg) in 1 mL

The products were compared with the originator enoxaparin product, Clexane4 (20, 40, 60, and 100mg strengths) using the validated UKMi product assessment tool.

Assessments were carried out with reference to: high resolution images supplied by the manufacturers; summaries of product characteristics (SmPCs) and package inserts; and the European Medicines Agency Public Assessment Reports (EPAR) for Inhixa. The photographic images are reproduced at the end of the report along with a summary of the assessment process.

ASSESSMENT

Similarities

Identical licensed indications Virtually identical SPCs Both fitted with plastic cylinder needle guards Higher strength syringes (60mg upwards) are calibrated for both products

allowing administration of graduated doses

Differences

Inhixa®▼ has black triangle status so it is subject to additional monitoring

Inhixa pre-filled syringes are fitted with an “active” locking system which requires the plunger to remain pressed down after drug administration and pressed down further after removal of the needle from the site of administration to release the guard over the needle. Clexane pre-filled syringes are fitted with an automatic safety system so once the plunger is fully pressed down the safety device is activated automatically and when the needle is removed from the site of administration, a protective sleeve will automatically cover the needle.

Section 6.6 of the Inhixa SPC includes instructions for use of syringe without

needle guard (available outside UK) first followed by instructions for use of syringe with needle guard (available in UK) but the text does not highlight very clearly that these instructions refer to two different syringe types, so a user unfamiliar with use may not read beyond first set of instructions and assume they apply to the UK product. However, the Patient Information Leaflet (PIL) does contain instructions for only the UK device and it is presumed that users will refer to that resource for instructions on administration (feedback has been provided to the manufacturer).

Some users may find the needle sheath on Inhixa difficult to remove.

The PIL provides instructions on use though on first attempt, it may not be so clear how needle guard is released. Also some users may initially find it difficult to activate the needle guard by maintaining pressure on the plunger when withdrawing the needle and pushing on it further as advised in the instructions. If that is the case then some may find that releasing the pressure and then pressing down on plunger again more easily releases the needle guard, though this is not mentioned in the PIL. However, there may be some patients with insufficient strength in the hands to carry out this process and they may be more suited to Clexane for self-administration as the needle guard comes down automatically after withdrawal of the needle from the injection site (feedback has been provided to the manufacturer).

The syringe plungers for Inhixa are colour coded to help differentiate the various strengths. The plungers for Clexane are bigger and are all white; different strengths are reflected in coloured stickers at base of syringe.

The critical information on the Inhixa syringe labels is difficult to read due to the label design. Syringe labels are transparent and this is more problematic for some strengths than others, particularly the 10,000 unit strength (see attached images). This may increase the risk of selection error and may lead to an over reliance on colour for identification (feedback has been provided to the manufacturer). Extra vigilance is recommended when using these products after they have been removed from the outer box.

When giving part doses from a syringe, the calibrations on the Inhixa syringes are more obscured by the label and it may be visually harder to see them. The syringe barrel of Clexane is easier to visualise as there is less label over that section but the calibrations themselves are also not so easy to visualise.

On the boxes of Inhixa the strengths are better differentiated by colour than the boxes of Clexane.

Following a Europe-wide review to harmonise the product information for enoxaparin in EU countries, strength has to be expressed both in international units (IU) of anti-Xa activity and in mg (previously only expressed in mg). 5 This is reflected in the Inhixa packaging and the new livery for Clexane though old packaging is still in circulation and will only have strength expressed in mg.

Inhixa forte syringes (12,000 IU [120 mg] and 15,000 IU [150 mg] are not yet available so for these higher doses, more than one syringe will be required or Clexane is used.

CONCLUSION FOLLOWING APPLICATION OF VALIDATED ASSESSMENT TOOL

On the boxes of Inhixa the strengths are better differentiated by colour. Both Clexane and Inhixa have clear colour coding on the syringes. However there are differences in presentation of the Inhixa syringes. Compared to Clexane, the needle guard on Inhixa is more difficult to activate, and the critical information on its syringe labels is difficult to read due to the label design. In addition, when giving part doses from a syringe, the calibrations on Inhixa syringes are more obscured by the label. Less of the labelling covers the Clexane syringe barrel but the calibrations themselves are still not so easy to visualise. In addition, the SPC for Inhixa contains instructions for use of syringe without needle guard (not available in UK) and this may cause confusion, though the PIL contains only instructions for use of syringe with needle guard. Training is essential to allow users to become familiar with the different syringe mechanism and make them aware of the difficulty in reading the labels on some of the Inhixa syringes.

There will be some (largely inherent) risks associated with the introduction of biosimilar enoxaparin. These risks should be broadly manageable, but safe introduction will require specific implementation work. Potential risks are identified below; mitigating and other necessary actions are considered in the next section.

POTENTIAL NEXT STEPS AND MITIGATION ACTIONSSafe introduction of enoxaparin biosimilars to the NHS will need to consider a number of actions:

Brand name prescribingThe MHRA recommends that when prescribing biological products, it is good practice to use the brand name to ensure that automatic substitution of a biosimilar product does not occur when the medicine is dispensed6 or administered. Local education and training for prescribers, pharmacy staff, nurses, and others may be necessary to ensure prescribing, dispensing and administration of all enoxaparin products by brand name.

Training of staff and patientsAny plans to switch patients should take into consideration the differences in the mechanism for operating the needle guard of the two products. Healthcare professionals and patients accustomed to administering Clexane need to be trained how to release the needle guard with Inhixa (an automatic process with Clexane).

As there may be difficulty in reading the labels on some of the Inhixa syringes, staff should familiarise themselves with the product and colour coded strengths to avoid potential selection error.

Patients who are self-administering should be assessed to ensure they can operate the syringe safely and can read the calibrations if administering a part dose from a syringe. If using higher than 100mg doses of enoxaparin, those administering Inhixa at present will need to remember to use more than one syringe to administer the total dose.

Safe use of both available products across care settingsPrescribing systems, formularies, and protocols/guidelines will need to be updated to reflect availability of both products and flags incorporated to ensure that these products are prescribed by brand name. Staff will need to ensure that the correct product is selected for prescribing, dispensing and administration. GPs need to be aware that discharge letters for patients on enoxaparin may be for the biosimilar version so they must ensure they select the correct product on their prescribing systems.

In community pharmacy, the majority of enoxaparin dispensed is written by international nonproprietary names.7 Work is underway across Scotland to transition across to branded prescribing, and in the interim, Community Pharmacy Scotland has issued guidance advising that if a generic prescription for enoxaparin is received, pharmacists should confirm which brand the patient has been receiving, dispense this brand and endorse the prescription accordingly to ensure correct payment.8 No such guidance is currently available for England/Wales/Northern Ireland so community pharmacists are advised to follow the good practice recommended in Scotland.

PROCESS STATEMENTThis report was produced in September 2017 using photographic images obtained from pharmaceutical companies, and images taken of actual physical product. Samples of both products were also physically assessed to compare needle guard action. The product assessment was undertaken by: London and South East Regional Medicines Information; contact: yuet.wan@gstt.nhs.uk

The UKMI product safety assessment group would appreciate your views on the usefulness of this report. We have devised a short survey which we would appreciate you completing, it should take approximately 10 minutes to complete. Click the following link to complete the survey: https://www.surveymonkey.com/r/UKMiProductSafetyAssessments.

REFERENCES

1. European Medicines Agency. Inhixa. Product Assessment Report (21 July 2016): http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004264/WC500215211.pdf

2. Techdow Pharma Ltd. Inhixa (Enoxaparin sodium):Launch in UK: http://www.techdow-pharma.co.uk/news/pressemeldungen/61.html

3. Techdow Pharma Ltd. Inhixa solution for injection in pre-filled syringe. SPCs, date of revision of text. 24th August 2017: https://www.medicines.org.uk/emc/search/?q=inhixa&dt=1

4. Sanofi. Clexane pre-filled syringes. SPC; date of revision of text, 28/04/2017: https://www.medicines.org.uk/emc/medicine/24345

5. Sanofi. Direct Healthcare Professional Communication. Clexane (enoxaparin sodium): Updates to strength expression, dose regimens in DVT/PE, use in patients with severe renal impairment:https://assets.publishing.service.gov.uk/media/596f669a40f0b60a400001ba/Clexane_DHPC_300617.pdf

6. MHRA. Biosimilar products. Drug Safety Update, February 2008: https://www.gov.uk/drug-safety-update/biosimilar-products

7. Personal communication, Sanofi, 24 Oct 20178. Community Pharmacy Scotland. Clexane® (Enoxaparin) Biosimilars: practice

guidance on ensuring brand consistency, 08 Sept, 2017: http://www.communitypharmacyscotland.org.uk/news-articles/clexane-enoxaparin-biosimilars-practice-guidance-on-ensuring-brand-consistency

PRODUCT PHOTOS

Inhixa

Labelling on Inhixa syringes

Syringe calibration on Inhixa syringes

Inhixa syringe before and after activation of needle guard

CLEXANECurrent packaging

Clexane syringes

Labelling on Clexane syringe Needle guard activated

Syringe calibration on Clexane syringe

New Clexane packaging(not yet launched)

Caution with similar colouration of Inhixa 20mg and Clexane 150mg syringes

Both low strength Inhixa (20mg) and high strength Clexane (150mg) syringes have similar blue labelling so is caution required in selection of correct product for dispensing and administration.