IN USE PRODUCT SAFETY ASSESSMENT REPORT FOR FIASP® ALONGSIDE NOVORAPID® AND NOVOMIX® INSULINS

(INSULIN ASPARTS)

SUMMARY OF ASSESSMENT AND ITS FINDINGS

BACKGROUND

Fiasp®

(insulin aspart 100 units/mL) solution for injection received European approval in January 2017. It became available in the UK not long after. Fiasp

® is a new formulation of

insulin aspart (that incorporates nicotinamide and L-arginine hydrochloride). It has been

Two other insulin aspart products have been available in the UK for many years: NovoRapid

® (insulin aspart 100 units/mL) solution for injection and NovoMix

® 30 (insulin

aspart 30 units/mL plus insulin aspart [as insulin aspart protamine] 70 units/mL) suspension for injection. NovoRapid

® is a rapid-acting analogue insulin; NovoMix

® 30 is a mixture of rapid-acting

analogue insulin alone plus aspart insulin bound to protamine giving it a longer activity, hence NovoMix

® 30 has biphasic action. Historically NovoRapid

® and NovoMix

® 30 insulins have

been confused due to their similar sounding names. There are reports of prescribing / dispensing errors between the two

2. The National Patient Safety Agency (NPSA) stated that

-alike and sound-alike insulin 1.

The addition of another insulin aspart product to the two already available has the potential to create further confusion. This review aims to summarise safety concerns that should be considered.

DETAILS OF PRODUCT(S) ASSESSED

The product assessed using the validated UKMi product assessment tool3 is

Fiasp®

(insulin aspart 100 units/mL) solution for injection in a 10mL vial, 3mL Penfill cartridge, 3mL FlexTouch Pen pre-filled pen. This product is compared to the two original insulin aspart products: i. NovoRapid

® (insulin aspart 100 units/mL) solution for injection in a 10mL vial, 3mL Penfill

cartridge, 3mL FlexPen pre-filled pen, 3mL FlexTouch pre-filled pen and 1.6mL PumpCart cartridge. ii. NovoMix

® 30 (insulin aspart 30 units/mL plus insulin aspart [as insulin aspart protamine] 70

units/mL) suspension for injection in a 3mL Penfill cartridge and 3mL FlexPen pre-filled pen. A formal assessment of NovoRapid

® and NovoMix

® 30 were not undertaken.

All three products are manufactured and supplied by Novo Nordisk Limited. Assessments were carried out with reference to images of the products; European Medicines Agency assessment report Fiasp (Nov 2016)

4; and summaries of product characteristics

5-7

(SmPC) and packaging inserts8-10

. The images of Fiasp®

100 units/mL penfill cartridge, Fiasp

® 100 units/mL Flextouch pen and Fiasp

® 100 units/mL 10ml vial were obtained from

Novo Nordisk. (These images are used with the permission of Novo Nordisk, but Novo Nordisk has had no influence over, or involvement with, the writing or production of this article.)

CONCLUSION FOLLOWING APPLICATION OF VALIDATED ASSESSMENT TOOL

Overall the physical characteristics and accompanying information are considered appropriate. However with the introduction of a third insulin aspart product to the two already available (that are already known to cause confusion) there will be additional risk associated with this introduction. These risks ought to be manageable, but like most risks associated with insulin use, may be minimised with better understanding by health care professions of insulin products in general. This in itself is a challenge. The potential risks are identified below.

Interchangeability, substitution, and switching between products NovoRapid

® and Fiasp

® insulins are both insulin aspart 100 units per ml products, however

their pharmacokinetic profiles are different. Fiasp®

insulin has been modified by the addition of nicotinamide (also known as niacinamide or vitamin B3) which gives it a faster absorption and onset of action, compared to NovoRapid

®. L-arginine hydrochloride has also been added

to support the stabilisation of the product4.

Fiasp

® is reported to appear in the blood stream twice as fast as NovoRapid

® (about 5

minutes earlier). It provides four times as much available insulin during the first 15 minutes and twice as much available insulin within the first 30 minutes compared to NovoRapid

® 5.

The duration of action for Fiasp

® is reported to be shorter than for NovoRapid

5 although the

duration of action for both remains within the range of 3-5 hours5, 6

. Hypoglycaemia with Fiasp

® may also occur earlier when compared to other mealtime insulins due to the earlier

onset of action5.

These two insulin aspart 100 units per ml products (NovoRapid

® and Fiasp

®) are most likely

to be used subcutaneously at mealtimes to control post-prandial hyperglycaemia as part of a basal bolus regimen, given alongside a longer-acting insulin overnight. NovoRapid

® and

Fiasp®

may both also be used in a continuous insulin infusion (insulin pump) or administered intravenously by health care professionals

5, 6.

The insulin aspart molecule in Fiasp

® and NovoRapid

® is identical and therefore, once

systemically absorbed, Fiasp®

has the same biological action at the insulin receptor as NovoRapid

®4. However due to their different activity profiles they should not be considered

directly inter-changeable. If converting from another mealtime insulin to Fiasp it is advised to do this on a unit-to-unit basis, under medical supervision, with close glucose monitoring and may require a change in dose

5. Novo Nordisk have been unable to provide further practical advice of switching

patients from another insulin to Fiasp . NovoMix

® 30 insulin has a biphasic release therefore is most likely to be used in a

subcutaneous twice daily insulin regimen. It has a very different activity profile from NovoRapid

® or Fiasp

® hence is not bioequivalent or interchangeable with NovoRapid

® or

Fiasp®

. NovoMix 30® may not be used in a continuous insulin infusion pump nor

administered intravenously7.

So in summary none of these insulin aspart products are directly interchangeable. If Fiasp

®

and NovoRapid® are switched, even though the manufacturer recommends a unit-per-unit

conversion, caution should be exercised and the patient should be closely monitored in case dose alteration is required. Potential for confusion between products The packaging for the three different insulin aspart products (Fiasp

®, NovoRapid

®, NovoMix

30®) are distinct and therefore it is easy to distinguish between these products.

Fiasp®

packaging was changed approximately one year after its launch to help to visually distinguish it from other insulin products. Fiasp

® packaging is now white and yellow with a

bold red accent colour. This has made it more distinct from Novo Nordisk id (100 units / ml human soluble insulin) packaged in plain white and yellow; and Tresiba (100 units / ml insulin degludec) packaged in white and lime green. Images are included at the end of this document. There is a well-documented risk of confusion between the insulin aspart products NovoRapid

®

and NovoMix® at the prescribing and dispensing due to similarities in the name leading to

patient harm. The NPSA reported this risk and introduced the insulin passport initiative2

however confusion still exists and errors still happen. Insulin products should always be prescribed by brand name. As long as this recommendation is adhered to, the potential for confusion between NovoRapid

® and Fiasp

®

insulins is low at the prescribing, dispensing and administration stages. Nevertheless despite recommendations on brand name prescribing, pockets of poor prescribing may still exist in which insulin aspart is prescribed by generic name. This creates significant potential for confusion between insulin aspart products. Furthermore there is no way to differentiate generically between Fiasp

® and Novorapid

® insulin aspart

Insulin aspart products are used across a range of care settings and there are particular risks associated with this; for example, correct product selection at the transition between primary and secondary care. However, providing recommendations for brand name prescribing for all insulin products are adhered to, the risk of confusion can be reduced. Insulin requires refrigerated storage. This may restrict opportunities for physical separation of similarly named insulin. Device issues The package insert (patient information leaflet PIL) for NovoRapid

®, NovoMix

® 30 and

Fiasp®

Penfill cartridges 8-10

do not state which pens the cartridges are compatible with. This

pen is given with the insulin because these cartridges will not fit into pens that have not been manufactured by Novo Nordisk. Pharmacovigilance: known risks and on-going monitoring The current known risks with NovoRapid

® and NovoMix

® 30 will remain. Those risks

associated with NovoRapid®, will apply equally to Fiasp

®. Fiasp

® is subject to additional

monitoring as indicated by the black triangle symbol for new medicines since it is new to

market. In March 2011 the National Patient Safety Agency (NPSA) produced a Patient Safety Alert

1. The alert highlights the need for

adult patients to be issued with an insulin passport to empower them to take a more active role in avoiding insulin errors. This initiative is on-going. Novo Nordisk have produced Fiasp

®

plastic cards to be handed to patients to carry in their insulin passports (alongside the plastic cards for other insulins they may also be using with Fiasp

®). These cards are usually

available from the manufacturers.

POTENTIAL NEXT STEPS AND MITIGATION ACTIONS

Potential next steps and mitigation actions can be considered in two respects: those of particular relevance to the NHS and those of particular relevance to manufacturers.

The safe introduction of another insulin aspart product to the NHS will require a number of points to be considered: 1. Brand name prescribing Insulin products should be prescribed by the brand name, concentration and device (i.e. cartridge or disposable pen); these actions are vital to identify products appropriately at the points of dispensing and/or administration. This is particularly important with the introduction of Fiasp

® brand name prescribing is essential to support correct product selection.

Particular care will be necessary at transition of care to ensure the correct product is selected. These safety checks can be further supported by the use of the NPSA or a locally approved insulin passport. As with all insulins, the label must always be checked before each injection to avoid wrong product medication errors. Electronic prescribing systems should be reviewed to minimise the risk of prescribing the wrong product, this may include removal of the option of generic insulin aspart. Education and training for prescribers, pharmacists, pharmacy staff, nurses, and others will also be necessary to inform healthcare professionals on the availability of the new insulin aspart products, and to ensure brand name prescribing and identification occurs. Patient education to increase awareness of the product brand they are receiving will also be useful to reduce the potential for error. 2. Converting between Fiasp

®

The manufacturer states that 1 unit of Fiasp corresponds to 1 international unit of human insulin or 1 unit other fast-acting insulin analogue

5. Vigilant monitoring will highlight the need

for dose adjustment should this be necessary. 3. Storage Strategies to mitigate the risk of picking errors between the aspart products (Fiasp

®,

NovoRapid® and NovoMix

® 30) should be considered.

4. Device For patients prescribed Fiasp

® but subsequently unable to self-administer (e.g. during times

of illness and/or hospital admission) use of retractable pen needles, may be required to reduce the risk of needle stick injury to healthcare staff

11. Other potential error mitigation

actions will include ensuring the correct pen device is available and is used for the Fiasp®

insulin cartridge. Some establishments may prefer to use the Fiasp

® 10ml vial with insulin

syringes. 5. Pharmacovigilance Compliance with post-marketing surveillance systems is essential for safe introduction and on-going use. Currently Fiasp

® is subject to additional monitoring.

Insulin passports should also be completed and/or Fiasp®

cards given to patients for those newly started on Fiasp

®.

In addition to actions for the NHS, this review also highlights one issue for Novo Nordisk, the manufacturer. Clarity on cartridge compatibility with pen devices Information on the compatibility of insulin cartridges with pen devices could be improved as this information is not available in the Patient Information Leaflet provided with any of the insulin aspart cartridges (although the outer packaging for the penfill cartridges does say

References 1 National Patient Safety Agency: Patient Safety Alert: NPSA/2011/PSA003

30 March 2011, The https://webarchive.nationalarchives.gov.uk/20171030124650/http://www.nrls.npsa.nhs.uk/EasySiteWeb/getresource.axd?AssetID=130398&type=full&servicetype=Attachment [accessed 28/1/20] 2 National Patient Safety Agency: Patient Safety Alert:

use of insulin. NPSA/2011/PSA003. March 2011, Supporting Information https://webarchive.nationalarchives.gov.uk/20171030124650/http://www.nrls.npsa.nhs.uk/EasySiteWeb/getresource.axd?AssetID=130399&type=full&servicetype=Attachment [accessed 28/1/20] 3 UKMi Product Safety Assessment tool. Available at:

https://www.sps.nhs.uk/wp-content/uploads/2016/03/UKMi-product-assessment-tool-full-version.xlsx [accessed 28/1/20] 4 European Medicines Agency assessment report Fiasp (Nov 2016). Available at:

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004046/WC500220940.pdf [accessed 28/1/20] 5 Novo Nordisk. Summary of Product Characteristics for Fiasp 100 units/ml solution for

injection. Revision of text 01/2017. Available at: https://www.medicines.org.uk/emc/product/8109/smpc [accessed 28/1/20] 6 Novo Nordisk. Summary of Product Characteristics for NovoRapid 100 units/ml solution for

injection. Revision of text 06/2017. Available at: https://www.medicines.org.uk/emc/product/7919/smpc [accessed 28/1/20] 7 Novo Nordisk. Summary of Product Characteristics for NovoMix 30 100 units/ml suspension

for injection. Revision of text 12/2016. Available at: https://www.medicines.org.uk/emc/product/7915/smpc [accessed 28/1/20] 8 Novo Nordisk. Patient Information Leaflet for Fiasp 100 units/ml solution for injection in vial.

Revision of text 01/2017. Available at: https://www.medicines.org.uk/emc/product/8109/pil [accessed 28/1/20] 9 Novo Nordisk. Patient Information Leaflet for NovoRapid 100 units/ml solution for injection in

a vial. Revision of text 10/2016. Available at: https://www.medicines.org.uk/emc/product/7919/pil [accessed 28/1/20] 10

Novo Nordisk. Patient Information Leaflet for NovoMix 30 Penfil 100 units/ml suspension for injection. Revision of text 07/2014. Available at: https://www.medicines.org.uk/emc/product/7915/pil [accessed 28/1/20] 11

NHS Employers - Health, Safety and Wellbeing Partnership Group, December 2015, Managing the risks of sharps injuries. Available at: http://www.nhsemployers.org/-/media/Employers/Documents/Retain-and-improve/Health-and-wellbeing/Managing-the-risks-of-sharps-injuries-v7.pdf?dl=1 [accessed 28/1/20]

https://webarchive.nationalarchives.gov.uk/20171030124650/http:/www.nrls.npsa.nhs.uk/EasySiteWeb/getresource.axd?AssetID=130398&type=full&servicetype=Attachmenthttps://webarchive.nationalarchives.gov.uk/20171030124650/http:/www.nrls.npsa.nhs.uk/EasySiteWeb/getresource.axd?AssetID=130398&type=full&servicetype=Attachmenthttps://webarchive.nationalarchives.gov.uk/20171030124650/http:/www.nrls.npsa.nhs.uk/EasySiteWeb/getresource.axd?AssetID=130399&type=full&servicetype=Attachmenthttps://webarchive.nationalarchives.gov.uk/20171030124650/http:/www.nrls.npsa.nhs.uk/EasySiteWeb/getresource.axd?AssetID=130399&type=full&servicetype=Attachmenthttps://www.sps.nhs.uk/wp-content/uploads/2016/03/UKMi-product-assessment-tool-full-version.xlsxhttps://www.sps.nhs.uk/wp-content/uploads/2016/03/UKMi-product-assessment-tool-full-version.xlsxhttp://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004046/WC500220940.pdfhttp://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004046/WC500220940.pdfhttps://www.medicines.org.uk/emc/product/8109/smpchttps://www.medicines.org.uk/emc/product/7919/smpchttps://www.medicines.org.uk/emc/product/7915/smpchttps://www.medicines.org.uk/emc/product/8109/pilhttps://www.medicines.org.uk/emc/product/7919/pilhttps://www.medicines.org.uk/emc/product/7915/pilhttp://www.nhsemployers.org/-/media/Employers/Documents/Retain-and-improve/Health-and-wellbeing/Managing-the-risks-of-sharps-injuries-v7.pdf?dl=1http://www.nhsemployers.org/-/media/Employers/Documents/Retain-and-improve/Health-and-wellbeing/Managing-the-risks-of-sharps-injuries-v7.pdf?dl=1

Fiasp

® (insulin aspart 100 units/mL) solution for injection in a 10mL vial label

Fiasp

® (insulin aspart 100 units/mL) solution for injection in a 10mL vial outer packaging

Fiasp®

(insulin aspart 100 units/mL) solution for injection in a 3mL Penfill cartridge label

Fiasp

® (insulin aspart 100 units/mL) solution for injection in a 3mL Penfill cartridge outer

packaging

Fiasp®

(insulin aspart 100 units/mL) solution for injection in a 3mL FlexTouch Pen pre-filled pen label

Fiasp

® (insulin aspart 100 units/mL) solution for injection in a 3mL FlexTouch Pen pre-filled

pen label

NovoRapid®

(insulin aspart 100 units/mL) solution for injection in a 10mL vial, 3mL Penfill cartridge, and 3mL FlexPen pre-filled pen

NovoMix® 30 (insulin aspart 30 units/mL plus insulin aspart [as insulin aspart protamine] 70

units/mL) suspension for injection in a 3mL Penfill cartridge and 3mL FlexPen pre-filled pen