FIASP 100U / ml injection solution into the bottle medication leaflet

Fiasp 100 units/mL FlexTouch solution for injection in pre-filled pen

Fiasp 100 units/mL Penfill solution for injection in cartridge

Fiasp 100 units/mL solution for injection in vial

Fiasp 100 units/mL PumpCart solution for injection in cartridge

1 mL of the solution contains 100 units of insulin aspart* (equivalent to 3.5 mg).

Fiasp 100 units/mL FlexTouch solution for injection in pre-filled pen

Each pre-filled pen contains 300 units of insulin aspart in 3 mL solution.

Fiasp 100 units/mL Penfill solution for injection in cartridge

Each cartridge contains 300 units of insulin aspart in 3 mL solution.

Fiasp 100 units/mL solution for injection in vial

Each vial contains 1,000 units of insulin aspart in 10 mL solution.

Fiasp 100 units/mL PumpCart solution for injection in cartridge

Each cartridge contains 160 units of insulin aspart in 1.6 mL solution.

*Insulin aspart is produced in Saccharomyces cerevisiae by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Fiasp 100 units/mL FlexTouch solution for injection in pre-filled pen

Solution for injection (FlexTouch).

Fiasp 100 units/mL Penfill solution for injection in cartridge

Solution for injection (Penfill).

Fiasp 100 units/mL solution for injection in vial

Solution for injection.

Fiasp 100 units/mL PumpCart solution for injection in cartridge

Solution for injection (PumpCart).

Clear, colourless, aqueous solution.

Treatment of diabetes mellitus in adults, adolescents and children aged 1 year and above.

Fiasp is a mealtime insulin for subcutaneous administration up to 2 minutes before the start of themeal, with the option to administer up to 20 minutes after starting the meal (see section 5.1).

Dosing with Fiasp is individual and determined in accordance with the needs of the patient. Fiaspgiven by subcutaneous injection should be used in combination with intermediate-acting or long-acting insulin given at least once a day. In a basal-bolus treatment regimen approximately 50% of thisrequirement may be provided by Fiasp and the remaining by intermediate-acting or long-actinginsulin.

The individual total daily insulin requirement in adults, adolescents and children may vary and isusually between 0.5 and 1 unit/kg/day.

Blood glucose monitoring and insulin dose adjustment are recommended to achieve optimal glycaemiccontrol.

Adjustment of dose may be necessary if patients undertake increased physical activity, change theirusual diet or during concomitant illness. Blood glucose levels should be monitored adequately underthese conditions.

The duration of action will vary according to the dose, injection site, blood flow, temperature and levelof physical activity.

Patients on basal-bolus treatment who forget a mealtime dose are advised to monitor their bloodglucose level to decide if an insulin dose is needed. Patients should resume their usual dosing scheduleat the next meal.

The potency of insulin analogues, including Fiasp, is expressed in units. One (1) unit of Fiaspcorresponds to 1 international unit of human insulin or 1 unit of other fast-acting insulin analogues.

The early onset of action must be considered when prescribing Fiasp (see section 5.1).

Patients with type 1 diabetes mellitus

The recommended starting dose in insulin naïve patients with type 1 diabetes is approximately 50% ofthe total daily insulin dose and should be divided between the meals based on the size and compositionof the meals. The remainder of the total daily insulin dose should be administered as intermediate-acting or long-acting insulin. As a general rule, 0.2 to 0.4 units of insulin per kilogram of body weightcan be used to calculate the initial total daily insulin dose in insulin naïve patients with type 1 diabetes.

Suggested initial dose is 4 units at one or more meals. Number of injections and subsequent titrationwill depend on the individual glycaemic target and the size and composition of the meals.

Dose adjustment may be considered daily based on self-measured plasma glucose (SMPG) on theprevious day(s) according to Table 1.

* Pre-breakfast dose should be adjusted according to the pre-lunch SMPG the previous day

* Pre-lunch dose should be adjusted according to the pre-dinner SMPG the previous day

* Pre-dinner dose should be adjusted according to the bedtime SMPG the previous day

Table 1 Dose adjustment

SMPG (see above) Dose adjustmentmmol/L mg/dL Unit<4 <71 -14-6 71-108 No adjustment>6 >108 +1

Elderly patients (≥ 65 years old)

The safety and efficacy of Fiasp have been established in elderly patients aged 65 to 75 years. Closeglucose monitoring is recommended and the insulin dose should be adjusted on an individual basis(see section 5.1 and 5.2). The therapeutic experience in patients ≥ 75 years of age is limited.

Renal impairment may reduce the patient’s insulin requirements. In patients with renal impairment,glucose monitoring should be intensified and the dose adjusted on an individual basis (see section 5.2).

Hepatic impairment may reduce the patient’s insulin requirements. In patients with hepaticimpairment, glucose monitoring should be intensified and the dose adjusted on an individual basis (seesection 5.2).

Fiasp can be used in adolescents and children from the age of 1 year (see section 5.1). There is noclinical experience with the use of Fiasp in children below the age of 2 years.

Fiasp is recommended to be administered prior to the meal (0-2 minutes), with the flexibility toadminister up to 20 minutes after starting the meal in situations, when there is uncertainty about themeal intake.

Transfer from other insulin medicinal products

Close glucose monitoring is recommended during the transfer from other mealtime insulins and in theinitial weeks thereafter. Converting from another mealtime insulin can be done on a unit-to-unit basis.

Transferring a patient from another type, brand or manufacturer of insulin to Fiasp must be done understrict medical supervision and may result in the need for a change in dose.

Doses and timing of concurrent intermediate-acting or long-acting insulin medicinal products or otherconcomitant antidiabetic treatment may need to be adjusted.

Fiasp is recommended to be administered subcutaneously by injection in the abdominal wall or theupper arm (see section 5.2). Injection sites should always be rotated within the same region in order toreduce the risk of lipodystrophy and cutaneous amyloidosis (see sections 4.4 and 4.8).

Fiasp 100 units/mL FlexTouch solution for injection in pre-filled pen

The pre-filled pen (FlexTouch) delivers 1-80 units in steps of 1 unit.

FlexTouch is accompanied by a package leaflet with detailed instructions for use to be followed. Forinstructions on administration, see “Instructions for Use” at the end of the package leaflet.

The pre-filled pen is only suitable for subcutaneous injections. If administration by syringe orintravenous injection is necessary, a vial should be used. If administration by infusion pump isnecessary, a vial or a PumpCart cartridge should be used.

Fiasp 100 units/mL Penfill solution for injection in cartridge

Administration with a reusable insulin pen

If administration by syringe or intravenous injection is necessary, a vial should be used. Ifadministration by infusion pump is necessary, a vial or a PumpCart cartridge should be used (seesection 6.6).

Fiasp 100 units/mL solution for injection in vial

Administration with a syringe

The vial is to be used with insulin syringes with the corresponding unit scale (units-100 or100 units/mL).

Continuous subcutaneous insulin infusion (CSII)

Fiasp solution for injection in vial can be used for CSII in pumps suitable for insulin infusion and willcover both the bolus insulin requirement (approximately 50%) and basal insulin. It can beadministered in accordance with the instructions provided by the pump manufacturer, preferably in theabdomen. When used with an insulin infusion pump, it should not be diluted or mixed with any otherinsulin medicinal products.

Patients using CSII should be instructed in the use of the pump and use the correct reservoir andtubing for pump (see section 6.6). The infusion set (tubing and cannula) should be changed inaccordance with the instructions in the product information supplied with the infusion set.

Patients administering Fiasp by CSII must be trained to administer insulin by injection and havealternate insulin therapy available in case of pump failure.

Fiasp 100 units/mL PumpCart solution for injection in cartridge

Administration via CSII

The cartridge (PumpCart) is only for use with an insulin infusion pump system designed to be usedwith this cartridge (see section 6.6).

Fiasp will cover both the bolus insulin requirement (approximately 50%) and basal insulin. It can beadministered in accordance with the instructions provided by the pump manufacturer, preferably in theabdomen. Infusion site should be rotated within the same region to reduce the risk of lipodystrophy.

Patients using CSII should be instructed in the use of the pump and use the correct tubing for pump(see section 6.6). The infusion set (tubing and cannula) should be changed in accordance with theinstructions in the product information supplied with the infusion set.

Patients administering Fiasp by CSII must be trained to administer insulin by injection and havealternate insulin therapy available in case of pump failure.

The cartridge (PumpCart) is only suitable for CSII in pump systems suitable for insulin infusion. Ifadministration by syringe or intravenous injection is necessary, a vial should be used.

Fiasp 100 units/mL solution for injection in vial

If necessary, Fiasp can be administered intravenously by health care professionals.

For intravenous use, it should be used at concentrations from 0.5 unit/mL to 1 unit/mL insulin aspartin infusion systems - using polypropylene infusion bags.

Fiasp must not be mixed with any other insulin or any other medicinal product except those mentionedin section 6.6. For instructions on dilution of the medicinal product before administration, see section6.6

Monitoring of blood glucose is necessary during insulin infusion. Care should be taken to ensure thatthe insulin is injected into the infusion bag and not simply the entry port.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Omission of a meal or unplanned, strenuous physical exercise may lead to hypoglycaemia.

Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement (seesections 4.8 and 4.9).

Patients, whose blood glucose control is greatly improved, e.g. by intensified insulin therapy, mayexperience a change in their usual warning symptoms of hypoglycaemia and should be advisedaccordingly. Usual warning symptoms may disappear in patients with long-standing diabetes.

The timing of hypoglycaemia usually reflects the time-action profile of the administered insulinformulation. Hypoglycaemia may occur earlier after an injection/infusion when compared to othermealtime insulins due to the earlier onset of action of Fiasp (see section 5.1).

Since Fiasp should be administered up to 2 minutes before the start of the meal with the option toadminister up to 20 minutes after starting the meal, the time to onset of action must be taken intoaccount when prescribing to patients with concomitant diseases or treatment where a delayedabsorption of food might be expected.

Close monitoring of blood glucose levels is recommended if administering this medicinal product afterthe start of the last meal of the day, in order to avoid nocturnal hypoglycaemia.

Hyperglycaemia and diabetic ketoacidosis

The use of inadequate doses or discontinuation of treatment, especially in patients requiring insulin,may lead to hyperglycaemia and diabetic ketoacidosis; conditions which are potentially lethal.

Continuous subcutaneous insulin infusion (CSII)

Pump or infusion set malfunctions can lead to a fast onset of hyperglycaemia and ketosis. Promptidentification and correction of the cause of hyperglycaemia or ketosis is necessary. Interim therapywith subcutaneous injection may be required.

Misuse of PumpCart

The cartridge (PumpCart) is only for use with an insulin infusion pump system designed to be usedwith this cartridge. It must not be used with other devices not designed for the cartridge, as this mayresult in incorrect insulin dosing and subsequent hyper- or hypoglycaemia (see section 6.6).

Patients must be instructed to perform continuous rotation of the injection site to reduce the risk ofdeveloping lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulinabsorption and worsened glycaemic control following insulin injections at sites with these reactions. Asudden change in the injection site to an unaffected area has been reported to result in hypoglycaemia.

Blood glucose monitoring is recommended after the change in the injection site from an affected to anunaffected area, and dose adjustment of antidiabetic medicinal products may be considered.

Transfer from other insulin medicinal products

Transferring a patient to another type or brand of insulin should be done under strict medicalsupervision. Changes in strength, brand (manufacturer), type, origin (animal, human insulin or humaninsulin analogue) and/or method of manufacture (recombinant DNA versus animal source insulin) mayresult in the need for a change in dose. Patients transferred to Fiasp from another type of insulin mayrequire a change in dose from that used with their usual insulin medicinal products.

Concomitant illness

Concomitant illness, especially infections and feverish conditions, usually increases the patient’sinsulin requirements. Concomitant diseases in the kidney, liver or affecting the adrenal, pituitary orthyroid gland may require changes in the insulin dose.

Combination of pioglitazone and insulin medicinal products

Cases of congestive heart failure have been reported when pioglitazone were used in combination withinsulin, especially in patients with risk factors for development of congestive heart failure. This shouldbe kept in mind if treatment with the combination of Pioglitazone and insulin medicinal products isconsidered. If the combination is used, patients should be observed for signs and symptoms ofcongestive heart failure, weight gain and oedema. Pioglitazone should be discontinued if anydeterioration in cardiac symptoms occurs.

Insulin initiation and glucose control intensification

Intensification or rapid improvement in glucose control has been associated with a transitory,reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, acute painfulperipheral neuropathy and peripheral oedema. However, long-term glycaemic control decreases therisk of diabetic retinopathy and neuropathy.

Insulin administration may cause insulin antibodies to form. In rare cases, the presence of such insulinantibodies may necessitate adjustment of the insulin dose in order to correct a tendency to hyper- orhypoglycaemia.

Avoidance of accidental mix-ups/medication errors

Patients must be instructed to always check the insulin label before each injection to avoid accidentalmix-ups between this medicinal product and other insulin medicinal products.

Patients must visually verify the units of the dose prior to administering. Therefore, the requirementfor patients to self-administer is that they can read the dose scale. Patients, who are blind or have poorvision, must be instructed to always get assistance from another person who has good vision and istrained in administration of insulins.

Travelling between time zones

Before travelling between different time zones, the patient should seek the doctor’s advice.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially‘sodium-free’.

A number of medicinal products are known to interact with the glucose metabolism.

The following substances may reduce insulin requirement:

Oral antidiabetics, monoamine oxidase inhibitors (MAOIs), beta-blockers, angiotensin convertingenzyme (ACE) inhibitors, salicylates, anabolic steroids, sulphonamides and GLP-1 receptor agonist.

The following substances may increase insulin requirement:

Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growthhormone and danazol.

Beta-blocking agents may mask the symptoms of hypoglycaemia.

Octreotide/lanreotide may either increase or decrease the insulin requirement.

Alcohol may intensify or reduce the hypoglycaemic effect of insulin.

Fiasp can be used in pregnancy.

Data from two randomised controlled clinical trials conducted with insulin aspart (322 + 27 exposedpregnancies) do not indicate any adverse effect of insulin aspart on pregnancy or on the health of thefoetus/new born when compared to soluble human insulin.

Intensified blood glucose control and monitoring of pregnant women with diabetes (type 1 diabetes,type 2 diabetes or gestational diabetes) are recommended throughout pregnancy and whencontemplating pregnancy. Insulin requirements usually fall in the first trimester and increasesubsequently during the second and third trimesters. After delivery, insulin requirements normallyreturn rapidly to pre-pregnancy values.

There are no restrictions on treatment with Fiasp during breast-feeding. Insulin treatment of thebreast-feeding mother presents no risk to the baby. However, the dose may need to be adjusted.

Animal reproduction studies have not revealed any differences between insulin aspart and humaninsulin regarding fertility.

The patient’s ability to concentrate and react may be impaired as a result of hypoglycaemia. This mayconstitute a risk in situations where these abilities are of special importance (e.g., driving a car orusing machines).

Patients should be advised to take precautions to avoid hypoglycaemia while driving. This isparticularly important in those who have reduced or absent awareness of the warning signs ofhypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should beconsidered in these circumstances.

The most frequently reported adverse reaction during treatment is hypoglycaemia (see section‘Description of selected adverse reactions’ below).

Adverse reactions listed below (Table 2) are based on data from 6 completed therapeutic confirmatorytrials in adults. Frequency categories are defined according to the following convention: Very common(≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to< 1/1,000); very rare (< 1/10,000) and not known (cannot be estimated from the available data).

Table 2 Adverse reactions from clinical trials

MedDRA system organ Very common Common Uncommon Not knownclass

Immune system Hypersensitivity Anaphylacticdisorders reactions

Metabolism and Hypoglycaemianutrition disorders

Skin and subcutaneous Allergic skin Lipodystrophy Cutaneoustissue disorders manifestations amyloidosis†

General disorders and Injection/infusadministration site ion siteconditions reactions† ADR from postmarketing sources.

Allergic skin manifestations reported with Fiasp (1.8% vs. 1.5% for comparator) include eczema, rash,rash pruritic, urticaria and dermatitis.

With Fiasp generalised hypersensitivity reactions (manifested by generalised skin rash and facialoedema) was reported uncommonly (0.2% vs. 0.3% for comparator).

Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement. Severehypoglycaemia may lead to unconsciousness and/or convulsions and may result in temporary orpermanent impairment of brain function or even death. The symptoms of hypoglycaemia usually occursuddenly. They may include cold sweats, cool pale skin, fatigue, nervousness or tremor, anxiousness,unusual tiredness or weakness, confusion, difficulty in concentration, drowsiness, excessive hunger,vision changes, headache, nausea and palpitation (see sections 4.4 and 5.1). Hypoglycaemia may occurearlier after an injection/infusion of Fiasp compared to other mealtime insulins due to the earlier onsetof action.

Lipodystrophy (including lipohypertrophy, lipoatrophy) and cutaneous amyloidosis may occur at theinjection site and delay local insulin absorption. Lipodystrophy was reported at the injection/infusionsite in patients treated with Fiasp (0.5% vs. 0.2% in comparator). Continuous rotation of the injectionsite within the given injection area may help to reduce or prevent these reactions (see section 4.4).

Injection/infusion site reactions

Injection site reactions (including rash, redness, inflammation, pain and bruising) were reported inpatients treated with Fiasp (1.3% vs. 1.0% in comparator). In patients using CSII (N=261): Infusionsite reactions (including redness, inflammation, irritation, pain, bruising and itching) were reported inpatients treated with Fiasp (10.0% vs. 8.3% in comparator). These reactions are usually mild andtransitory and they normally disappear during continued treatment.

Safety and efficacy have been investigated in a therapeutic confirmatory trial in children with type 1diabetes aged 2 to less than 18 years. In the trial, 519 patients were treated with Fiasp. Overall thefrequency, type and severity of adverse reactions in the paediatric population do not indicatedifferences to the experience in the adult population. Lipodystrophy (including lipohypertrophy,lipoatrophy) at the injection site was reported more often in this trial with paediatric patients comparedto trials in adults (see above). In the paediatric population lipodystrophy was reported with a frequencyof 2.1% for Fiasp vs. 1.6% for NovoRapid.

Based on results from clinical trials with insulin aspart in general, the frequency, type and severity ofadverse reactions observed in elderly patients and in patients with renal or hepatic impairment do notindicate any differences to the broader experience in the general population. The safety profile in veryelderly patients (≥ 75 years) or patients with moderate to severe renal impairment or hepaticimpairment is limited. Fiasp has been administered to elderly patients for the investigation ofpharmacokinetic properties (see section 5.2).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

A specific overdose for insulin cannot be defined, however, hypoglycaemia may develop oversequential stages if a patient is dosed with more insulin than required:

* Mild hypoglycaemic episodes can be treated by oral administration of glucose or other productscontaining sugar. It is therefore recommended that the diabetic patient always carries glucose-containing products.

* Severe hypoglycaemic episodes, where the patient is not able to treat him/herself, can be treatedwith glucagon (0.5 to 1 mg) given intramuscularly or subcutaneously by a trained person, orwith glucose given intravenously by a healthcare professional. Glucose must be givenintravenously if the patient does not respond to glucagon within 10 to 15 minutes. Uponregaining consciousness, administration of oral carbohydrate is recommended for the patient inorder to prevent a relapse.

Pharmacotherapeutic group: Drugs used in diabetes, insulins and analogues for injection, fast-acting

ATC code: A10AB05.

Fiasp is a fast-acting insulin aspart formulation.

The primary activity of Fiasp is the regulation of glucose metabolism. Insulins, including insulinaspart, the active substance in Fiasp, exert their specific action through binding to insulin receptors.

Receptor-bound insulin lowers blood glucose by facilitating cellular uptake of glucose into skeletalmuscle and adipose tissue and by inhibiting the output of glucose from the liver. Insulin inhibitslipolysis in the adipocyte, inhibits proteolysis and enhances protein synthesis.

Fiasp is a mealtime insulin aspart formulation in which the addition of nicotinamide (vitamin B3)results in a faster initial absorption of insulin compared to NovoRapid.

The onset of action was 5 minutes earlier and time to maximum glucose infusion rate was 11 minutesearlier with Fiasp than with NovoRapid. The maximum glucose-lowering effect of Fiasp occurredbetween 1 and 3 hours after injection. The glucose-lowering effect during the first 30 minutes(AUCGIR, 0-30 min ) was 51 mg/kg with Fiasp and 29 mg/kg with NovoRapid (Fiasp/NovoRapid ratio:1.74 [1.47;2.10]95% CI). The total glucose-lowering effect and maximum (GIRmax) glucose-loweringeffect were comparable between Fiasp and NovoRapid. Total and maximum glucose-lowering effectof Fiasp increase linearly with increasing dose within the therapeutic dose range.

Fiasp has an earlier onset of action compared to NovoRapid (see section 5.2), leading to a subsequentincreased early glucose-lowering effect. This must be considered when prescribing Fiasp.

The duration of action was shorter for Fiasp compared to that of NovoRapid and lasted for 3-5 hours.

The day-to-day variability within-patients in glucose-lowering effect was low for Fiasp both for early(AUCGIR, 0-1h, CV~26%), total (AUCGIR, 0-12h, CV~18%) and maximum glucose-lowering effect(GIRmax, CV~19%).

Fiasp has been studied in 2 068 adult patients with type 1 diabetes (1 143 patients) and type 2 diabetes(925 patients) in 3 randomised efficacy and safety trials (18-26 weeks of treatment). Furthermore,

Fiasp has been studied in 777 paediatric subjects with type 1 diabetes in a randomised efficacy andsafety trial (26 weeks of treatment). No children below the age of 2 years were randomised in the trial.

Patients with type 1 diabetes mellitus

The treatment effect of Fiasp in achieving glycaemic control was assessed when administered atmealtime or postmeal. Fiasp administered at mealtime was non-inferior to NovoRapid in reducing

HbA1c, and the improvement in HbA1c was statistically significant in favour of Fiasp. Fiaspadministered postmeal achieved similar HbA1c reduction as NovoRapid dosed at mealtime (Table 3).

Table 3 Results from 26 week basal-bolus clinical trial in patients with type 1 diabetes

Fiasp mealtime Fiasp postmeal NovoRapid+ insulin detemir + insulin detemir mealtime+ insulin detemir

N 381 382 380

HbA1c (%)

Baseline  End of trial 7.6  7.3 7.6  7.5 7.6  7.4

Adjusted change from baseline -0.32 -0.13 -0.17

Estimated treatment difference -0.15 [-0.23;-0.07]CE 0.04 [-0.04;0.12]D

HbA1c (mmol/mol)

Baseline  End of trial 59.7  56.4 59.9  58.6 59.3  57.6

Adjusted change from baseline -3.46 -1.37 -1.84

Estimated treatment difference -1.62 [-2.50;-0.73]CE 0.47[-0.41;1.36]D2-hour postmeal glucoseincrement (mmol/L)A

Baseline  End of trial 6.1  5.9 6.1  6.7 6.2  6.6

Adjusted change from baseline -0.29 0.67 0.38

Estimated treatment difference -0.67 [-1.29;-0.04]CE 0.30 [-0.34;0.93]D1-hour postmeal glucoseincrement (mmol/L)A

Baseline  End of trial 5.4  4.7 5.4  6.6 5.7  5.9

Adjusted change from baseline -0.84 1.27 0.34

Estimated treatment difference -1.18[-1.65;-0.71]CE 0.93[0.46;1.40]D

Bodyweight (kg)

Baseline  End of trial 78.6  79.2 80.5  81.2 80.2  80.7

Adjusted change from baseline 0.67 0.70 0.55

Estimated treatment difference 0.12 [-0.30;0.55]C 0.16 [-0.27;0.58]D

Observed rate of severe or BGconfirmed hypoglycaemiaB perpatient year of exposure(percentage of patients)59.0 (92.7) 54.4 (95.0) 58.7 (97.4)

Estimated rate ratio 1.01 [0.88;1.15]C 0.92 [0.81;1.06]D

Baseline, end of trial values are based on the mean of the observed last available values. The 95%confidence interval is stated in ‘[]’

A Meal test

B Severe hypoglycaemia (episode requiring assistance of another person) or blood glucose (BG)confirmed hypoglycaemia defined as episodes confirmed by plasma glucose < 3.1 mmol/Lirrespective of symptoms

C The difference is for Fiasp mealtime - NovoRapid mealtime

D The difference is for Fiasp postmeal - NovoRapid mealtime

E Statistically significant in favour of Fiasp mealtime33.3% of patients treated with mealtime Fiasp reached a target HbA1c of < 7% compared to 23.3% ofpatients treated with postmeal Fiasp and 28.2% of patients treated with mealtime NovoRapid. Theestimated odds of achieving HbA1c < 7% were statistically significantly greater with mealtime Fiaspthan with mealtime NovoRapid (odds ratio: 1.47 [1.02; 2.13]95% CI). No statistical significant differencewas shown between postmeal Fiasp and mealtime NovoRapid.

Fiasp administered at mealtime provided significantly lower 1-hour and 2-hour postmeal glucoseincrement compared to NovoRapid administrated at mealtime. Fiasp administered postmeal resulted inhigher 1-hour postmeal glucose increment and comparable 2-hour postmeal glucose increment to

NovoRapid dosed at mealtime (Table 3).

Median total bolus insulin dose at trial end was similar for mealtime Fiasp, postmeal Fiasp andmealtime NovoRapid (change from baseline to end of trial: mealtime Fiasp: 0.33→0.39 units/kg/day;postmeal Fiasp: 0.35→0.39 units/kg/day; and mealtime NovoRapid: 0.36→0.38 units/kg/day).

Changes in median total basal insulin dose from baseline to end of trial were comparable for mealtime

Fiasp (0.41→0.39 units/kg/day), postmeal Fiasp (0.43→0.42 units/kg/day) and mealtime NovoRapid(0.43→0.43 units/kg/day).

The reduction in HbA1c from baseline to end of trial was confirmed to be non-inferior to that obtainedwith NovoRapid (Table 4).

Table 4 Results from 26 week basal-bolus clinical trial in patients with type 2 diabetes

Fiasp NovoRapid+ insulin glargine + insulin glargine

N 345 344

HbA1c (%)

Baseline  End of trial 8.0  6.6 7.9  6.6

Adjusted change from baseline -1.38 -1.36

Estimated treatment difference -0.02[-0.15;0.10]

HbA1c (mmol/mol)

Baseline  End of trial 63.5  49.0 62.7 48.6

Adjusted change from baseline -15.10 -14.86

Estimated treatment difference -0.24 [-1.60;1.11]2-hour postmeal glucose increment(mmol/L)A

Baseline  End of trial 7.6  4.6 7.3  4.9

Adjusted change from baseline -3.24 -2.87

Estimated treatment difference -0.36 [-0.81;0.08]1-hour postmeal glucose increment(mmol/L)A

Baseline  End of trial 6.0  4.1 5.9  4.6

Adjusted change from baseline -2.14 -1.55

Estimated treatment difference -0.59 [-1.09;-0.09]C

Bodyweight (kg)

Baseline  End of trial 89.0  91.6 88.3  90.8

Adjusted change from baseline 2.68 2.67

Estimated treatment difference 0.00 [-0.60;0.61]

Observed rate of severe or BGconfirmed hypoglycaemiaB perpatient year of exposure(percentage of patients)17.9 (76.8) 16.6 (73.3)

Estimated rate ratio 1.09 [0.88;1.36]

Baseline, end of trial values are based on the mean of the observed last available values. The 95%confidence interval is stated in ‘[]’

A Meal test

B Severe hypoglycaemia (episode requiring assistance of another person) or blood glucose (BG)confirmed hypoglycaemia defined as episodes confirmed by plasma glucose < 3.1 mmol/Lirrespective of symptoms

C Statistically significant in favour of Fiasp

Postmeal dosing has not been investigated in patients with type 2 diabetes.

74.8% of patients treated with Fiasp reached a target HbA1c of < 7% compared to 75.9% of patientstreated with NovoRapid. There was no statistical significant difference between Fiasp and NovoRapidin the estimated odds of achieving HbA1c < 7%.

Median total bolus insulin dose at trial end was similar for Fiasp and NovoRapid (change frombaseline to end of trial: Fiasp: 0.21→0.49 units/kg/day and NovoRapid: 0.21→0.51 units/kg/day).

Changes in median total basal insulin dose from baseline to end of trial were comparable for Fiasp(0.56→0.53 units/kg/day) and NovoRapid (0.52→0.48 units/kg/day).

In the three controlled clinical trials, 192 of 1,219 (16%) Fiasp treated patients with type 1 diabetes ortype 2 diabetes were ≥ 65 years of age and 24 of 1,219 (2%) were ≥ 75 years of age. No overalldifferences in safety or effectiveness were observed between elderly patients and younger patients.

Continuous subcutaneous insulin infusion (CSII)

A 6-week, randomised (2:1), double-blind, parallel-group, active controlled trial evaluatedcompatibility of Fiasp and NovoRapid administered via CSII system in adult patients with type 1diabetes. There were no microscopically confirmed episodes of infusion set occlusions in either the

Fiasp (N=25) or NovoRapid (N=12) groups. There were two patients from the Fiasp group who eachreported two treatment-emergent infusion site reactions.

In a 2-week cross-over trial, Fiasp showed a greater postmeal glucose-lowering effect after astandardised meal test with regard to 1-hour and 2-hour postmeal glucose response (treatmentdifference: -0.50 mmol/L [-1.07; 0.07]95% CI and -0.99 mmol/L [-1.95; -0.03]95% CI), respectivelycompared to NovoRapid in a CSII setting.

The efficacy and safety of Fiasp have been studied in a 1:1:1 randomised active controlled clinical trialin children and adolescents with type 1 diabetes, aged 1 to 18 years, for a period of 26 weeks (N=777).

In this trial the efficacy and safety of Fiasp administered at mealtime (0-2 minutes before meal) orpostmeal (20 minutes after meal start) and NovoRapid administered at mealtime, both used incombination with insulin degludec, were compared.

Patients in the Fiasp mealtime arm included 16 children aged 2-5 years, 100 children aged 6-11 yearsand 144 adolescents aged 12-17 years. Patients in the Fiasp postmeal arm included 16 children aged2-5 years, 100 children aged 6-11 years and 143 adolescents aged 12-17 years.

Fiasp administered at mealtime showed superior glycaemic control compared to NovoRapid mealtimewith regards to change in HbA1c (ETD: -0.17% [-0.30; -0.03]95% CI). Fiasp administered postmealshowed non-inferior glycaemic control compared to NovoRapid mealtime (ETD: 0.13% [-0.01;0.26]95% CI).

Fiasp mealtime showed a statistically significant improvement in 1- hour postmeal glucose incrementmean over all three main meals compared to NovoRapid (measured by SMPG). For Fiasp postmealthis comparison favoured NovoRapid mealtime.

No overall increased risk of severe or blood glucose confirmed hypoglycaemia was observedcompared to NovoRapid.

The observed effects and the safety profiles were comparable between all age groups.

Fiasp is a mealtime insulin aspart formulation in which the addition of nicotinamide (vitamin B3)results in a faster initial absorption of insulin. Insulin appeared in the circulation approximately4 minutes after administration (Figure 1). The onset of appearance was twice as fast (corresponding to5 minutes earlier), time to 50% maximum concentration was 9 minutes shorter with Fiasp compared to

NovoRapid with four times as much insulin available during first 15 minutes and with twice as muchinsulin available during the first 30 minutes.

Fiasp

NovoRapid

Time (min)

Insulin aspart concentration (pmol/L)

Figure 1 Mean insulin profile in patients with type 1 diabetes after subcutaneous injection.

The total insulin exposure was comparable between Fiasp and NovoRapid. The mean Cmax for a doseof 0.2 units/kg body weight is 298 pmol/L and comparable to NovoRapid.

Total exposure and maximum insulin concentration increases proportionally with increasingsubcutaneous dose of Fiasp within the therapeutic dose range.

The absolute bioavailability of insulin aspart after subcutaneous administration of Fiasp in theabdomen, deltoid and thigh was approximately 80%.

After administration of Fiasp, the fast onset of appearance is maintained regardless of injection site.

Time to maximum concentration and total insulin aspart exposure were all comparable between theabdomen, upper arm and the thigh. Early insulin exposure and maximum concentration werecomparable for the abdomen and upper arm regions, but lower for the thigh.

Continuous subcutaneous insulin infusion (CSII)

The onset of exposure in a CSII setting (time to reach maximum concentration) was 26 minutesshorter with Fiasp compared to NovoRapid resulting in approximately three times as much insulinavailable during the first 30 minutes (Figure 2).

Fiasp

NovoRapid

Time since bolus injection (min)

Figure 2 Mean insulin profiles in patients with type 1 diabetes in a CSII setting (0-5 hours)corrected for basal insulin infusion

Insulin aspart has a low binding affinity to plasma proteins (< 10%), similar to that seen with regularhuman insulin.

Volume of distribution (Vd) after intravenous administration was 0.22 L/kg (e.g., 15.4 L for a 70 kgsubject) corresponding to the extracellular fluid volume in the body.

Degradation of insulin aspart is similar to that of human insulin; all metabolites formed are inactive.

Insulin aspart concentrationbaseline-adjusted (pmol/L)

Half-life after subcutaneous administration of Fiasp is 57 minutes and comparable to NovoRapid.

Following intravenous administration of Fiasp, clearance was rapid (1 L/h/kg) and the eliminationhalf-life was 10 minutes.

In elderly patients with type 1 diabetes Fiasp showed, an earlier onset of exposure and a higher earlyinsulin exposure whilst maintaining a similar total exposure and maximum concentration compared to

NovoRapid.

Total insulin aspart exposure and maximum concentration following administration of Fiasp was 30%higher in elderly subjects compared to younger adult subjects.

The effect of gender on the pharmacokinetics of Fiasp was examined in an across-trial analysis of thepharmacokinetic trials. Fiasp showed a comparable earlier onset of exposure and a higher early insulinexposure whilst maintaining a similar total exposure and maximum concentration compared to

NovoRapid for both females and male patients with type 1 diabetes.

The early and maximum insulin exposure of Fiasp was comparable for female and male patients withtype 1 diabetes. However, total insulin exposure was larger in female compared to male patients withtype 1 diabetes.

Obesity

The initial absorption rate was slower with increasing BMI while the total exposure was similar acrossdifferent BMI levels. Compared to NovoRapid, the influence of BMI on the absorption was lesspronounced for Fiasp leading to relatively higher initial exposure.

The effect of race and ethnicity (Blacks vs. Whites and Hispanics vs. non-Hispanics) on the totalinsulin exposure of Fiasp was based on results from a population pharmacokinetic analysis in patientswith type 1 diabetes. For Fiasp no difference in exposure was found between the racial and ethnicgroups investigated.

A single dose pharmacokinetic study of insulin aspart was performed with NovoRapid in 24 subjectswith hepatic function ranging from normal to severely impaired. In subjects with hepatic impairment,absorption rate was decreased and more variable.

A single dose pharmacokinetic study of insulin aspart was performed with NovoRapid in 18 subjectswith renal function ranging from normal to severely impaired. No apparent effect of creatinineclearance values on AUC, Cmax, CL/F and Tmax of insulin aspart was found. Data were limited inpatients with moderate and severe renal impairment. Patients with renal failure necessitating dialysistreatment were not investigated.

In children (6-11 years) and adolescents (12-18 years) Fiasp showed, an earlier onset of exposure anda higher early insulin exposure whilst maintaining a similar total exposure and maximumconcentration compared to NovoRapid.

Onset and early insulin exposure of Fiasp was similar in children and adolescents to that in adults.

Total exposure of Fiasp was lower in children and adolescents compared to adults when dosed with0.2 units/kg body weight, while the maximum serum insulin aspart concentration was similar betweenage groups.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction after exposure toinsulin aspart. In in vitro tests, including binding to insulin and IGF-1 receptor sites and effects on cellgrowth, insulin aspart behaved in a manner that closely resembled human insulin. Studies alsodemonstrate that the dissociation of binding to the insulin receptor of insulin aspart is equivalent tohuman insulin.

Phenol

Metacresol

Glycerol

Zinc acetate

Disodium phosphate dihydrate

Arginine hydrochloride

Nicotinamide (vitamin B3)

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for injections

The medicinal product must not be diluted or mixed with any other medicinal products except infusionfluids as described in section 6.6.

30 months.

Fiasp 100 units/mL FlexTouch solution for injection in pre-filled pen

After first opening or carried as a spare, the medicinal product may be stored for a maximum of4 weeks. Do not store above 30°C. Can be stored in the refrigerator (2°C-8°C). Do not freeze. Keepthe cap on the pen in order to protect from light.

Fiasp 100 units/mL Penfill solution for injection in cartridge

After first opening or carried as a spare, the medicinal product may be stored for a maximum of4 weeks. Do not store above 30°C. Do not refrigerate. Do not freeze. If cartridge is carried as a spareand unused, the cartridge should be kept in the outer carton in order to protect from light.

Fiasp 100 units/mL solution for injection in vial

After first opening, the medicinal product may be stored for a maximum of 4 weeks (including time ina pump reservoir, see section 6.6). Do not store above 30°C. Can be stored in the refrigerator(2°C-8°C). Do not freeze. Keep the vial in outer carton in order to protect from light.

Fiasp 100 units/mL PumpCart solution for injection in cartridge

After first opening or carried as a spare, the medicinal product may be stored for a maximum of2 weeks below 30°C. Thereafter it can be used for up to 7 days below 37°C in an insulin infusionpump system designed to be used with this cartridge (see section 6.6). Do not refrigerate. Do notfreeze. If cartridge is carried as a spare and unused, the cartridge should be kept in the outer carton inorder to protect from light.

Fiasp 100 units/mL FlexTouch solution for injection in pre-filled pen

Store in a refrigerator (2°C-8°C). Do not freeze. Keep away from the freezing element. Keep the capon the pen in order to protect from light.

Fiasp 100 units/mL Penfill solution for injection in cartridge

Store in a refrigerator (2°C-8°C). Do not freeze. Keep away from the freezing element. Keep thecartridge in the outer carton in order to protect from light.

Fiasp 100 units/mL solution for injection in vial

Store in a refrigerator (2°C-8°C). Do not freeze. Keep away from the freezing element. Keep the vialin the outer carton in order to protect from light.

Fiasp 100 units/mL PumpCart solution for injection in cartridge

Store in a refrigerator (2°C-8°C). Do not freeze. Keep away from the freezing element. Keep thecartridge in the outer carton in order to protect from light.

For storage conditions after first opening of the medicinal product or carried as a spare, see section6.3.

Fiasp 100 units/mL FlexTouch solution for injection in pre-filled pen

Cartridge (type 1 glass) with a plunger (halobutyl) and a stopper (halobutyl/polyisoprene) contained ina multidose disposable pre-filled pen made of polypropylene, polyoxymethylene, polycarbonate andacrylonitrile butadiene styrene.

Each pre-filled pen contains 3 mL of solution.

Pack sizes of 1 (with and without needles) pre-filled pen, 5 (without needles) pre-filled pens andmultipack containing 10 (2 packs of 5) (without needles) pre-filled pens.

Fiasp 100 units/mL Penfill solution for injection in cartridge

Cartridge (type 1 glass), with a plunger (halobutyl) and a stopper (halobutyl/polyisoprene) in a carton.

Each cartridge contains 3 mL of solution.

Pack sizes of 5 and 10 cartridges.

Fiasp 100 units/mL solution for injection in vial

Vial (type 1 glass) closed with a halobutyl/polyisoprene rubber disc and a protective plastic cap inorder to obtain a tamper-proof container in a carton.

Each vial contains 10 mL of solution.

Pack sizes of 1 vial, 5 vials and a multipack containing 5 (5 packs of 1) vials.

Fiasp 100 units/mL PumpCart solution for injection in cartridge

Cartridge (type 1 glass), with a plunger (halobutyl) and a rubber closure (halobutyl/polyisoprene) in acarton.

Each cartridge contains 1.6 mL of solution.

Pack sizes of 5 cartridges and a multipack containing 25 (5 packs of 5) cartridges.

Fiasp must not be used if the solution does not appear clear and colourless.

Fiasp which has been frozen must not be used.

Fiasp 100 units/mL FlexTouch solution for injection in pre-filled pen

The pre-filled pen (FlexTouch) is designed to be used with injection needles developed according tothe pen needle ISO standard of a length between 4 mm to 8 mm and a gauge between 30G and 32G forsubcutaneous injection only.

Needles and pre-filled pens must not be shared. The cartridge must not be refilled.

The patient should discard the needle after each injection.

Fiasp 100 units/mL Penfill solution for injection in cartridge

The cartridge (Penfill) is designed to be used with Novo Nordisk reusable insulin pens and injectionneedles developed according to the pen needle ISO standard of a length between 4 mm to 8 mm and agauge between 30G and 32G for subcutaneous injection only.

Needles and cartridges must not be shared. The cartridge must not be refilled.

The patient should discard the needle after each injection.

Fiasp 100 units/mL solution for injection in vial

Needles and syringes must not be shared.

The patient should discard the needle after each injection.

Administration via CSII

When Fiasp is drawn from a vial, it can be used in an infusion pump (CSII) for a maximum of 6 days,as described in section 4.2 and in the package leaflet. Tubings in which the inner surface materials aremade of polyethylene or polyolefin have been evaluated and found compatible with pump use.

Fiasp has been shown to be stable at room temperature for 24 hours in the infusion fluids such assodium chloride 9 mg/mL (0.9%) solution for injection or 5% glucose solution for injection.

For intravenous use, it should be used at concentrations from 0.5 unit/mL to 1 unit/mL insulin aspartin infusion systems - using polypropylene infusion bags.

Fiasp 100 units/mL PumpCart solution for injection in cartridge

The cartridge must not be shared or refilled.

The cartridge (PumpCart) is only for use with the following insulin infusion pump systems: the

Accu-Chek Insight and YpsoPump insulin pumps. Tubings in which the inner surface materials aremade of polyethylene or polyolefin have been evaluated and found compatible with pump use.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsværd

Denmark

EU/1/16/1160/001

EU/1/16/1160/002

EU/1/16/1160/003

EU/1/16/1160/004

EU/1/16/1160/005

EU/1/16/1160/006

EU/1/16/1160/007

EU/1/16/1160/008

EU/1/16/1160/009

EU/1/16/1160/010

EU/1/16/1160/011

EU/1/16/1160/012

EU/1/16/1160/013

Date of first authorisation: 09 January 2017

Date of latest renewal:

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu