BEDFORDSHIRE AND LUTON JOINT PRESCRIBING COMMITTEE (JPC)

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1 BEDFORDSHIRE AND LUTON JOINT PRESCRIBING COMMITTEE (JPC) June 2017 Review: June 2020 (earlier if required see recommendations) Bulletin 255: Insulin aspart New Formulation - Fiasp JPC Recommendations: Support the use of Fiasp for the treatment of the following patient groups:- o T1 on CSII pump o T1 on basal bolus needing tight control or has rapid post-meal BG rise (especially dawn phenomenon) o Pregnant DM (T1 and also T2 or GDM) on insulin as in this group typically they have very rapid post-meal BG rise especially after breakfast with high peaks 1hr post-meal BG, not well captured even by Novorapid taken 30min before meal. Recommendations to be reviewed if a biosimilar insulin aspart is manufactured and licensed and/or when more experience was gained with the product (recommended patient groups may need to be expanded). Prescribers are reminded that all insulins should be prescribed by brand name. Glossary BG Blood glucose T1 Type 1 Diabetes mellitus T2 Type 2 Diabetes mellitus DM Diabetes mellitus CSII Continuous Subcutaneous Insulin Infusion GDM Gestational Diabetes Mellitus Page 1 of 9

2 New Medicine Review Bulletin Insulin aspart New Formulation - Fiasp Medicine A new formulation of Insulin aspart (Fiasp ) Document status Final Date of last revision 07 June 2017 Proposed Sector of Primary & secondary care prescribing Introduction Summary Key points Evidence level The intervention Mechanism of action Licensed indication Formulation/Availab le Products Fiasp is a new formulation of insulin aspart with a much faster onset of action, which more closely mimics the physiological response of endogenous insulin compared with insulin aspart. It can be given 2 minutes before a meal instead of the 20 minutes required for current fast acting insulins (insulin aspart Novorapid, insulin glulisine, Apidra and insulin lispro, Humalog ). The clinical efficacy of Fiasp has been investigated in four phase 3 trials, involving more than 2,100 people with Type 1 Diabetes mellitus (T1DM) or Type 2 Diabetes Mellitus (T2DM) and compared to Novorapid only (same manufacturer). Fiasp was non-inferior to NovoRapid with regard to HbA1c change from baseline in people with T1DM and T2DM as part of a basal-bolus regimen. In T1DM, the reduction in HbA1c was non-inferior and statistically significantly greater with mealtime Fiasp than with mealtime NovoRapid. Mealtime Fiasp provided superior postprandial glucose (PPG) control compared with NovoRapid based on 2-hour PPG increments during a meal test. NICE recommend rapid-acting insulin analogues for T1DM and DM in pregnancy when insulin is required. Fiasp is expected to be particularly useful for patients who have a very rapid post-prandial rise in BG: T1 on CSII pump T1 on basal bolus needing tight control or has rapid post-meal BG rise (especially dawn phenomenon) Pregnant DM (T1 and also T2 or GDM) on insulin as in this group typically they have very rapid post-meal BG rise especially after breakfast with high peaks 1hr post-meal BG, not well captured even by Novorapid taken 30min before meal. Fiasp is a new formulation of insulin aspart, a rapid-acting insulin analogue, for the treatment of patients with diabetes requiring mealtime (bolus) insulin (1-4). Fiasp is an alternative to Novorapid insulin. Fiasp has a faster onset of action, which more closely mimics the physiological response of endogenous insulin compared with insulin aspart (5) It is not proposed to replace Novorapid on formulary but to be an additional option for certain patient groups. Treatment of diabetes mellitus in adults. 100Units/mL cartridge (for penfill), pre-filled pen (Flextouch pen), 10mL vial Page 2 of 9

3 Usual dosage Treatment alternatives/ place in therapy Future alternatives National guidance The individual total daily insulin requirement in adults may vary and is usually between 0.5 and 1.0 unit/kg/day. Dosing should be individualised. Fiasp is mealtime insulin for subcutaneous administration up to 2 minutes before the start of the meal, with the option to administer up to 20 minutes after starting the meal. Insulin aspart 100 Units/mL NovoRapid (10mL vial, 3mL cartridge) NovoRapid FlexPen prefilled disposable injection device. Insulin glulisine 100 Units/mL Apidra (10mL vial, 3mL cartridge) Apidra Solostar (3mL prefilled disposable injection device) Insulin lispro 100 Units/mL Humalog (10mL vial, 3mL cartridge) Humalog KwikPen (3mL prefilled disposable injection device) Biosimilars will become available in the future. NICE guideline NG17: Type 1 diabetes in adults diagnosis and management (1) 1.Offer rapid-acting insulin analogues injected before meals, rather than rapid-acting soluble human or animal insulins, for mealtime insulin replacement for adults with T1DM 2. Do not advise routine use of rapid-acting insulin analogues after meals for adults with T1DM 3. If an adult with T1DM has a strong preference for an alternative mealtime insulin, respect their wishes and offer the preferred insulin NICE guideline NG28: Type 2 diabetes in adults management (2) 1. Start insulin therapy for adults with T2DM from a choice of insulin types and regimens: Offer NPH insulin injected once or twice daily according to need. 2. Consider starting both NPH and short-acting insulin (particularly if the person's HbA1c is 75 mmol/mol [9.0%] or higher), administered either: separately or as a pre-mixed (biphasic) human insulin preparation a. Monitor adults with T2DM who are on a basal insulin regimen (NPH insulin, insulin detemir or insulin glargine) for the need for short-acting insulin before meals (or a pre-mixed [biphasic] insulin preparation) b. Monitor adults with T2DM who are on pre-mixed (biphasic) insulin for the need for a further injection of short-acting insulin before meals or for a change to a basal bolus regimen with NPH insulin or insulin detemir or insulin glargine, if blood glucose control remains inadequate. NICE guideline NG3: Diabetes in pregnancy (3) The NICE diabetes in pregnancy guidelines recommend that metformin is offered to all women with gestational diabetes if blood glucose targets are not met using changes in diet and exercise within 1-2 weeks.(3) Offer insulin instead of metformin to women with gestational diabetes if metformin is contraindicated or unacceptable to the woman Offer addition of insulin to the treatments of changes in diet, exercise and metformin for women with gestational diabetes if blood glucose targets are not met Page 3 of 9

4 Offer immediate treatment with insulin, with or without metformin, as well as changes in diet and exercise, to women with gestational diabetes who have an FPG glucose level of 7.0 mmol/l or above at diagnosis Consider immediate treatment with insulin, with or without metformin, as well as changes in diet and exercise, for women with gestational diabetes who have an FPG level of between 6.0 and 6.9 mmol/l if there are complications such as macrosomia or hydramnios NG3 goes on to state(3) Be aware that the rapid-acting insulin analogues (aspart and lispro) have advantages over soluble insulin during pregnancy and consider their use Be aware that data from clinical trials and other sources do not suggest that the rapid-acting insulin analogues (aspart and lispro) adversely affect the pregnancy or the health of the foetus or newborn baby NICE TA151: Continuous subcutaneous insulin infusion for the treatment of diabetes mellitus (4) 1.Continuous subcutaneous insulin infusion or insulin pump therapy is recommended as a possible treatment for adults and children 12 years and over with T1DM if: a. attempts to reach target haemoglobin A1c (HbA1c) levels with multiple daily injections result in the person having disabling hypoglycaemia', or b.hba1c levels have remained high (8.5% or above) with multiple daily injections (including using long-acting insulin analogues if appropriate) despite the person and/or their carer carefully trying to manage their diabetes 2. CSII therapy is not recommended for the treatment of people with T2DM. Local Guidance Evidence for use As per NICE Guidance outlined above. The clinical efficacy of Fiasp has been investigated in four phase 3 trials, involving more than 2,100 people with T1DM or T2DM 1. Fiasp was non-inferior to NovoRapid with regard to HbA1c change from baseline in people with T1DM and T2DM as part of a basal-bolus regimen (6,7) 2. In T1DM, the reduction in HbA1c was non-inferior and statistically significantly greater with mealtime Fiasp than with mealtime NovoRapid (estimated treatment difference -0.15%, 95%CI: to -0.07, p<0.0001). Mealtime Fiasp provided superior postprandial glucose (PPG) control compared with NovoRapid based on 2-hour PPG increments during a meal test (estimated treatment difference mmol/l, 95% CI: to -0.04, p=0.0187). 1-hour PPG increment was also reduced (estimated treatment difference mmol/l, 95% CI to -0.71) (6) 3. In T2DM, Fiasp was non-inferior at reducing HbA1c compared with NovoRapid (estimated treatment difference -0.02%, 95% CI: to 0.10). 1-hour PPG increment favoured Fiasp compared with NovoRapid (estimated treatment difference: mmol/l, 95% CI: to -0.09). 2-hour PPG increments associated with Fiasp were non-inferior compared to NovoRapid (estimated treatment difference mmol/l, 95% CI to 0.08, p-value not significant) (7) Page 4 of 9

5 Safety * The safety of Fiasp has been investigated as part of the onset programme, involving more than 2,100 people with T1DM or T2DM. The safety profile of Fiasp is similar to that of NovoRapid. The NovoRapid molecule has a well-known tolerability profile based on more than 17 years of clinical experience. (6. 7, 8) Costs Tariff status Activity costs Drug & Dosage Cost per 3mL pen Annual Cost per patient Insulin aspart Units/mL Fiasp Insulin aspart Units/mL Novorapid Insulin glulisine Units/mL Apidra Insulin lispro 100 Units/mL Humalog 5.89 N.B. Doses are for general comparison and do not imply therapeutic equivalence Cost effectiveness (if available) Potential number of patients in Bedfordshire and Luton Impact per 100,000 population No cost-effectiveness studies have been identified. There is limited cost impact of this intervention since the price is the same as Novorapid and only slightly more than Apidra and Humalog. If Fiasp is used instead of Novorapid the cost pressure is zero. This will need to be revisited if a biosimilar insulin aspart is manufactured and licensed. The Specialist teams have not confirmed likely patient numbers. At the current time, the plan would be to use in new patients and in existing patients where there is a clinical need. The patient group treated was likely to increase as more experience was gained with the product. Affordability considerations Decisions from other bodies Comments sought from Bedfordshire and Luton Specialist Diabetology Teams. PAC New Drug Template Adapted from East Anglia Medicines Information, NHS Suffolk, NHS Cambridgeshire and NHS Derby templates *Consult Summary of Prescribing Characteristics for full prescribing detail. This guidance is based upon the published information available in English at the time the drug was considered. It remains open to review in the event of significant new evidence emerging. Page 5 of 9

6 List of references 1. NICE Guidance NG17. Type 1 diabetes in adults: diagnosis and management Available at Access date: January NICE guidelines NG28. Type 2 diabetes in adults: management Available at Access date: January NICE Guideline NG3 Diabetes in pregnancy: management from preconception to the postnatal period Available at Access date: January NICE TA151. Continuous subcutaneous insulin infusion for the treatment of diabetes mellitus Available at: 5. Heise T. et al. Faster-acting insulin aspart: earlier onset of appearance and greater early pharmacokinetic and pharmacodynamic effects than insulin aspart. Diabetes, Obesity and Metabolism. 2015; 17(7): Russell-Jones D, Bode B, de Block C, Franek E, Heller S, Mathieu C, et al. Double-blind mealtime faster-acting insulin aspart vs insulin aspart in basal bolus improves glycemic control in T1D: the onset 1 trial. Presented at the American Diabetes Association 76th Scientific Sessions, June 10-14, 2016, New Orleans, Louisiana Bowering K. et al. 240-OR Faster-acting insulin aspart versus insulin aspart as part of basal bolus therapy improves postprandial glycemic control in uncontrolled T2D in the double-blinded Onset 2 trial. 76th annual Scientific Sessions of the American Diabetes Association (ADA); New Orleans, US10-14 June Hermansen K, Bohl M, Schioldan AG. Insulin Aspart in the Management of Diabetes Mellitus: 15 Years of Clinical Experience. Drugs 2016; 76(1): EMA Fiasp EPAR, November _Public_assessment_report/human/004046/WC pdf 10. Morello C. et al. International Journal of General Medicine 2011: Pharmacokinetics and pharmacodynamics of short acting insulin analogues in special populations with type 2 diabetes mellitus Page 6 of 9

7 Bedfordshire and Luton Joint Prescribing Committee (JPC) Assessment against Ethical and Commissioning Principles Treatment assessed (June 2017) : A new formulation of Insulin aspart (Fiasp ) JPC Recommendations Support the use of Fiasp for the treatment of the following patient groups:- o T1 on CSII pump o T1 on basal bolus needing tight control or has rapid post-meal BG rise (especially dawn phenomenon) o Pregnant DM (T1 and also T2 or GDM) on insulin as in this group typically they have very rapid post-meal BG rise especially after breakfast with high peaks 1hr post-meal BG, not well captured even by Novorapid taken 30min before meal. Recommendations to be reviewed if a biosimilar insulin aspart is manufactured and licensed and/or when more experience was gained with the product (recommended patient groups may need to be expanded). Prescribers are reminded that all insulins should be prescribed by brand name. Glossary BG Blood glucose T1 Type 1 Diabetes mellitus T2 Type 2 Diabetes mellitus DM Diabetes mellitus CSII Continuous Subcutaneous Insulin Infusion GDM Gestational Diabetes Mellitus 1) Clinical Effectiveness The clinical efficacy of Fiasp has been investigated in four phase 3 trials, involving more than 2,100 people with T1DM or T2DM and compared to Novorapid only (same manufacturer). Fiasp was non-inferior to NovoRapid with regard to HbA1c change from baseline in people with T1DM and T2DM as part of a basal-bolus regimen. In T1DM, the reduction in HbA1c was non-inferior and statistically significantly greater with mealtime Fiasp than with mealtime NovoRapid. Mealtime Fiasp provided superior postprandial glucose (PPG) control compared with NovoRapid based on 2- hour PPG increments during a meal test. 2) Cost Effectiveness There is limited cost impact of this intervention since the price is the same as Novorapid and only slightly more than Apidra and Humalog. If Fiasp is used instead of Novorapid the cost pressure is zero. This will need to be revisited if a biosimilar insulin aspart is manufactured and licensed. 3) Equity No impact envisaged. 4) Needs of the community Page 7 of 9

8 Some groups of patients with a very rapid post-prandial rise in BG are not well controlled with current treatment options and could benefit from a more rapid acting insulin. 5) Need for healthcare (incorporates patient choice and exceptional need) NICE recommends rapid-acting insulin analogues for patients with T1DM and diabetes in pregnancy where insulin is required. A subgroup of these patients may be better controlled with the Fiasp formulation. 6) Policy drivers NICE guidance. 7) Disinvestment No overall disinvestment anticipated as the product will be used instead of currently available products. The JPC agreed the following sections within the PCT Ethical and Commissioning Framework were not relevant to JPC discussions: Health Outcomes, Access, and Affordability. Page 8 of 9

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