LYUMJEV 100U / ml JUNIOR KWIKPEN injection for pre-filled pen medication leaflet

Lyumjev 100 units/mL solution for injection in vial

Lyumjev 100 units/mL solution for injection in cartridge

Lyumjev 100 units/mL KwikPen solution for injection in pre-filled pen

Lyumjev 100 units/mL Junior KwikPen solution for injection in pre-filled pen

Lyumjev 100 units/mL Tempo Pen solution for injection in pre-filled pen

Each mL contains 100 units of insulin lispro* (equivalent to 3.5 mg).

Lyumjev 100 units/mL solution for injection in vial

Each vial contains 1000 units insulin lispro in 10 mL solution.

Lyumjev 100 units/mL solution for injection in cartridge

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

Lyumjev 100 units/mL KwikPen solution for injection in pre-filled pen

Lyumjev 100 units/mL Tempo Pen solution for injection in pre-filled pen

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

Each pre-filled pen delivers 1 - 60 units in steps of 1 unit in a single injection.

Lyumjev 100 units/mL Junior KwikPen solution for injection in pre-filled pen

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

Each Junior KwikPen delivers 0.5 - 30 units in steps of 0.5 units in a single injection.

*produced in E.coli by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Solution for injection.

Clear, colourless, aqueous solution.

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

Lyumjev is a mealtime insulin for subcutaneous injection and should be administered zero to twominutes before the start of the meal, with the option to administer up to 20 minutes after starting themeal (see section 5.1).

Lyumjev 100 units/mL is suitable for continuous subcutaneous insulin infusion (CSII) and is used forboth the bolus and basal insulin requirement.

The initial dose should take into account the type of diabetes, weight of the patient and their bloodglucose levels.

The early onset of action must be considered when prescribing Lyumjev (see section 5.1). Continuedadjustment of the dose of Lyumjev should be based on the patient’s metabolic needs, blood glucosemonitoring results, and glycaemic control goal. Dose adjustments may be needed, when switchingfrom another insulin, with changes in physical activity, changes in concomitant medicinal products,changes in meal patterns (i.e., amount and type of food, timing of food intake), changes in renal orhepatic function or during acute illness to minimize the risk of hypoglycaemia or hyperglycaemia (seesections 4.4 and 4.5).

Switching from another mealtime insulin medicinal product

If converting from another mealtime insulin to Lyumjev, the change can be done on a unit-to-unitbasis. The potency of insulin analogues, including Lyumjev, is expressed in units. One (1) unit of

Lyumjev corresponds to 1 international unit (IU) of human insulin or 1 unit of other fast-acting insulinanalogues.

Patients who forget a mealtime dose should monitor their blood glucose level to decide if an insulindose is needed, and to resume their usual dosing schedule at the next meal.

The safety and efficacy of Lyumjev has 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 sections 4.8, 5.1 and 5.2). The therapeutic experience in patients ≥ 75 years of age is limited.

Insulin requirements may be reduced in the presence of renal impairment. In patients with renalimpairment, glucose monitoring should be intensified and the dose adjusted on an individual basis.

Insulin requirements may be reduced in patients with hepatic impairment due to reduced capacity forgluconeogenesis and reduced insulin breakdown. In patients with hepatic impairment, glucosemonitoring should be intensified and the dose adjusted on an individual basis.

Lyumjev 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 Lyumjev in children below the age of 3 years. Similar to adults,dosage should be adjusted individually. Lyumjev is recommended to be administered zero to twominutes before the start of the meal, with the option to administer up to 20 minutes after starting themeal when needed.

Patients should be trained on proper use and injection technique before initiating Lyumjev. Patientsshould be told to:

* Always check insulin labels before administration.

* Inspect Lyumjev visually before use and discard for particulate matter or discolouration.

* Injection or infusion sites should always be rotated within the same region in order to reduce therisk of lipodystrophy and cutaneous amyloidosis (see section 4.4 and 4.8).

* Carry a spare or alternative administration method in case their delivery system breaks.

Lyumjev should be injected subcutaneously into the abdomen, upper arm, thigh or buttocks (seesection 5.2).

Lyumjev should generally be used in combination with an intermediate or long-acting insulin. Adifferent injection site should be used if injecting at the same time as another insulin.

When injecting a blood vessel should not be entered.

Devices should be discarded if any part looks broken or damaged.

The needle should be discarded after each injection.

Lyumjev vials

If subcutaneous administration by syringe is necessary, a vial should be used.

The syringe must have 100 units/mL markings.

Patients using vials must never share needles or syringes.

Lyumjev cartridges

Lyumjev in cartridges is only suitable for subcutaneous injections from a Lilly reusable pen.

Lyumjev cartridges should not be used with any other reusable pen as the dosing accuracy has notbeen established with other pens.

The instructions with each individual pen must be followed for loading the cartridge, attaching theneedle and administering the insulin injection.

To prevent the possible transmission of disease, each cartridge must be used by one patient only, evenif the needle on the delivery device is changed.

Lyumjev KwikPens and Lyumjev Tempo Pen

The KwikPen, Junior KwikPen and Tempo Pen are only suitable for subcutaneous injections.

Lyumjev KwikPens are available in two concentrations: Lyumjev 100 units/mL KwikPen and

Lyumjev 200 units/mL KwikPen. See the separate SmPC for Lyumjev 200 units/mL KwikPen.

The KwikPen delivers 1 - 60 units in steps of 1 unit in a single injection.

The Lyumjev 100 units/mL Junior KwikPen delivers 0.5 - 30 units in steps of 0.5 units in a singleinjection.

The Lyumjev 100 units/ml Tempo Pen delivers 1 - 60 units in steps of 1 unit in a single injection.

The number of insulin units is shown in the dose window of the pen regardless of concentration and nodose conversion should be done when transferring a patient to a new concentration or to a pen with adifferent dose step.

Lyumjev 100 units/mL Junior KwikPen is suitable for patients who may benefit from finer insulindose adjustments.

The Tempo Pen can be used with the optional transfer module Tempo Smart Button (see section 6.6).

As with any insulin injection, when using the Tempo Pen, Tempo Smart Button and the mobileapplication, the patient should be instructed to check their blood sugar levels when considering ormaking decisions about another injection if they are unsure how much they have injected.

For detailed user instructions, please refer to the instructions for use provided with the package leaflet.

To prevent the possible transmission of disease, each pen must be used by one patient only, even if theneedle is changed.

CSII (insulin pump)

Use a pump suitable for insulin infusion. Fill the pump reservoir from a Lyumjev 100 units/mL vial.

Patients using a pump should follow the instructions provided with the pump and infusion set.

Use the correct reservoir and catheter for the pump.

When filling the pump reservoir avoid damaging it by using the correct needle length on the fillingsystem. The infusion set (tubing and cannula) should be changed in accordance with the instructions inthe product information supplied with the infusion set.

A pump malfunction or obstruction of the infusion set can result in a rapid rise in glucose levels (seesection 4.4).

Lyumjev 100 units/mL is available in vials if administration of intravenous injection is necessary. Thismedicinal product must not be mixed with any other insulin or any other medicinal product exceptthose mentioned in section 6.6.

For instructions on dilution of the medicinal product before administration, see section 6.6.

Intravenous administration of Lyumjev 100 units/mL must be performed under medical supervision.

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 medicinal product should be clearly recorded.

Hypoglycaemia is the most common adverse reaction of insulin therapy (see section 4.8). The timingof hypoglycaemia usually reflects the time-action profile of the administered insulin formulations.

Hypoglycaemia may occur earlier after an injection/infusion when compared to other mealtimeinsulins due to the earlier onset of action of Lyumjev (see section 5.1).

Hypoglycaemia can happen suddenly and symptoms may differ in each individual and change overtime in the same individual. Severe hypoglycaemia can cause seizures, may lead to unconsciousness,may be life-threatening, or cause death. Symptomatic awareness of hypoglycaemia may be lesspronounced in patients with longstanding diabetes.

The use of inadequate doses or discontinuation of treatment, may lead to hyperglycaemia and diabeticketoacidosis; conditions which are potentially lethal.

Patients should be educated to recognize the signs and symptoms of ketoacidosis and to get immediatehelp when ketoacidosis is suspected.

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, and dose adjustmentof antidiabetic medications may be considered.

Changes in insulin, insulin concentration, manufacturer, type, or method of administration may affectglycaemic control and predispose to hypoglycaemia or hyperglycaemia. These changes should bemade cautiously under close medical supervision and the frequency of glucose monitoring should beincreased. For patients with type 2 diabetes, dose adjustments in concomitant anti-diabetic treatmentmay be needed (see sections 4.2 and 4.5).

In patients with renal or hepatic impairment, glucose monitoring should be intensified and doseadjusted on an individual basis (see section 4.2).

Insulin requirements may be increased during illness or emotional disturbances.

Adjustment of dose may also be necessary if patients undertake increased physical activity or changetheir usual diet. Exercise taken immediately after a meal may increase the risk of hypoglycaemia.

Hyperglycaemia and ketoacidosis due to insulin pump device malfunction

Malfunction of the insulin pump or insulin infusion set can rapidly lead to hyperglycaemia andketoacidosis. Prompt identification and correction of the cause of hyperglycaemia or ketosis isnecessary. Interim subcutaneous injections with Lyumjev may be required.

Thiazolidinediones (TZDs) used in combination with insulin

TZDs can cause dose-related fluid retention, particularly when used in combination with insulin. Fluidretention may lead to or exacerbate heart failure. Patients treated with insulin and a TZD should beobserved for signs and symptoms of heart failure. If heart failure develops, consider discontinuation ofthe TZD.

Hypersensitivity and allergic reactions

Severe, life-threatening, generalised allergy, including anaphylaxis, can occur with insulin medicinalproducts, including Lyumjev (see section 4.8). If hypersensitivity reactions occur, discontinue

Lyumjev.

Lyumjev should not be used by patients with visual impairment without help of a trained person.

To avoid medication errors between Lyumjev and other insulins, patients need to always check theinsulin label before each injection.

Patients should always use a new needle for each injection to prevent infections and a blocked needle.

In the event of a blocked needle it should be replaced with a new needle.

Tempo Pen

The Tempo Pen contains a magnet (see section 6.5) that may interfere with the functions of animplantable electronic medical device, such as a pacemaker. The magnetic field extends toapproximately 1.5 cm.

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

The following substances may reduce insulin requirement: Antidiabetic medicinal products (oral orinjectable), salicylates, sulphonamides, certain antidepressants (monoamine oxidase inhibitors(MAOIs), selective serotonin reuptake inhibitors), angiotensin converting enzyme (ACE) inhibitors,angiotensin II receptor blocking agents, or somatostatin analogues.

The following substances may increase insulin requirement: oral contraceptives, corticosteroids,thyroid hormones, danazol, sympathomimetic agents, diuretics, or growth hormone.

Alcohol may increase or decrease the blood glucose lowering effect of Lyumjev. Consumption oflarge amounts of ethanol concomitantly with insulin use may lead to severe hypoglycaemia.

Beta-blockers may blunt the signs and symptoms of hypoglycaemia.

TZDs can cause dose-related fluid retention, particularly when used in combination with insulin, andexacerbate heart failure (see section 4.4).

A large amount of data on pregnant women (more than 1 000 pregnancy outcomes) indicate nomalformative nor feto/neonatal toxicity of insulin lispro. Lyumjev can be used during pregnancyif clinically needed.

It is essential to maintain good control of an insulin-treated (insulin-dependent or gestational) diabetespatient throughout pregnancy. Insulin requirements usually fall during the first trimester and increaseduring the second and third trimesters. After delivery, insulin requirements normally return rapidly topre-pregnancy values. Patients with diabetes should be advised to inform their doctor if they arepregnant or are contemplating pregnancy. Careful monitoring of glucose control is essential inpregnant patients with diabetes.

Lyumjev can be used during breast-feeding. Patients with diabetes who are breast-feeding may requireadjustments in insulin dose, diet or both.

Insulin lispro did not induce fertility impairment in animal studies.

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 or usingmachinery).

Patients should be advised to take precautions to avoid hypoglycaemia whilst driving, this isparticularly important in those patients 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 reactions during treatment are hypoglycaemia (very common)and infusion site reactions in patients using CSII system (very common) (see sections 4.2, pct. 4.4 and4.9).

The following related adverse reactions from clinical trials are listed below as MedDRA preferredterm by system organ class and in order of decreasing incidence (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). Within each frequencygrouping, adverse reactions are presented in order of decreasing seriousness.

Table 1. Adverse reactions

MedDRA system organclass Very common Common Uncommon Not known

Metabolism and Hypoglycaemianutrition disorders

General disorders and Infusion site Allergic Oedemaaadministration site reactions reactions bconditions Injection sitereactions c

Skin and subcutaneous Lipodystrophy Cutaneoustissue disorders Rash amyloidosis

PruritusaReported in PRONTO-Pump-2bSee section 4.8 Description of selected adverse reactionscReported in PRONTO-T1D, PRONTO-T2D and PRONTO-Peds

Hypoglycaemia is the most commonly observed adverse reaction in patients using insulin. Theincidence of severe hypoglycaemia in the 26 week phase 3 adult clinical studies was 5.5% in patientswith type 1 diabetes mellitus and 0.9% in patients with type 2 diabetes (see tables 2 and 3). In study

PRONTO-Peds, severe hypoglycaemia was reported in 0.7% of paediatric patients treated with

Lyumjev.

The symptoms of hypoglycaemia usually occur suddenly. They may include listlessness, confusion,palpitations, sweating, vomiting, and headache.

There were no clinically significant differences in the frequency of hypoglycaemia with administrationof Lyumjev or the comparator (another medicinal product containing insulin lispro) across all studies.

In studies where Lyumjev and the comparator were administered at different times relative to meals,there were no clinically relevant differences in the frequency of hypoglycaemia.

Hypoglycaemia may occur earlier after an injection/infusion of Lyumjev compared to other mealtimeinsulins due to the earlier onset of action.

Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions,angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including Lyumjev.

Injection/Infusion site reactions

As with other insulin therapy, patients may experience rash, redness, inflammation, pain, bruising oritching at the site of Lyumjev injection or infusion.

In studies PRONTO-T1D and PRONTO-T2D (multiple-dose injection [MDI] administration),injection site reactions occurred in 2.7% of adult patients treated with Lyumjev. These reactions wereusually mild and normally disappeared during continued treatment. Of the 1 116 patients who received

Lyumjev, 1 discontinued treatment due to injection site reactions (< 0.1%).

In study PRONTO-Peds, injection site reactions occurred in 6.2% of paediatric patients treated with

Lyumjev. These events were mild or moderate. Of the 418 patients treated with Lyumjev,2 discontinued treatment due to injection site reactions (< 0.5%).

In study PRONTO-Pump-2, infusion site reactions were reported in 38% of patients treated with

Lyumjev. The majority of these events were mild. Of the 215 patients treated with Lyumjev,7 discontinued treatment due to infusion site reactions (3.3%).

Administration of insulin can cause formation of insulin antibodies. The presence of anti-drugantibodies did not have a clinically meaningful effect on the pharmacokinetics, efficacy, or safety of

Lyumjev.

Lipodystrophy and cutaneous amyloidosis may occur at the injection site and delay local insulinabsorption. Continuous rotation of the injection site within the given injection area may help to reduceor prevent these reactions (see section 4.4).

Oedema

Cases of oedema have been reported with insulin therapy, particularly if previous poor metaboliccontrol is improved by intensified insulin therapy.

Safety and efficacy have been investigated in a therapeutic confirmatory trial in children with type 1diabetes aged 3 to < 18 years. In the trial, 418 patients were treated with Lyumjev. The frequency, typeand severity of adverse reactions observed in the paediatric population is consistent with the safetyprofile in adult patients.

Based on results from clinical trials with insulin lispro 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 information invery elderly patients (≥ 75 years) or patients with moderate to severe renal impairment or hepaticimpairment is limited (see section 5.1).

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.

Overdose causes hypoglycaemia with accompanying symptoms that include listlessness, confusion,palpitations, sweating, vomiting, and headache.

Hypoglycaemia may occur as a result of an excess of insulin lispro relative to food intake, energyexpenditure, or both. Mild episodes of hypoglycaemia usually can be treated with oral glucose. Moresevere episodes with coma, seizure, or neurologic impairment may be treated with glucagon orconcentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessarybecause hypoglycaemia may recur after apparent clinical recovery. Adjustments in medicinal productdose, meal patterns, or exercise may be needed.

Pharmacotherapeutic group: Medicinal products used in diabetes, insulins and analogues for injection,fast-acting, ATC code: A10AB04

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

Receptor-bound insulin lowers blood glucose by stimulating peripheral glucose uptake by skeletalmuscle and fat, and by inhibiting hepatic glucose production. Insulins inhibit lipolysis and proteolysis,and enhance protein synthesis.

Lyumjev is a formulation of insulin lispro that contains citrate and treprostinil. Citrate increases localvascular permeability and treprostinil induces local vasodilation to achieve accelerated absorption ofinsulin lispro.

Early and late insulin action

A glucose clamp study was conducted in 40 type 1 diabetes patients given Lyumjev and Humalogsubcutaneously as a single 15 unit dose. Results are provided in Figure 1. Lyumjev has been shown tobe equipotent to Humalog on a unit for unit basis but its effect is more rapid with a shorter duration ofaction.

* Onset of action of Lyumjev was 20 minutes post dose, 11 minutes faster than Humalog.

* During the first 30 minutes post dose, Lyumjev had a 3-fold greater glucose lowering effectcompared to Humalog.

* Maximum glucose-lowering effect of Lyumjev occurred between 1 and 3 hours after injection.

* The late insulin action, from 4 hours until the end of the glucose clamp, was 54% lower with

Lyumjev than observed with Humalog.

* The duration of action of Lyumjev was 5 hours, 44 minutes shorter than Humalog.

* The total glucose infused during the clamp was comparable between Lyumjev and Humalog.

Figure 1. Mean glucose infusion rate (GIR) in patients with type 1 diabetes after subcutaneousinjection of Lyumjev or Humalog (15 unit dose)

Similarly, a faster early insulin action and a reduced late insulin action was observed with Lyumjev intype 2 diabetes patients.

Total and maximum glucose lowering effect of Lyumjev increased with dose within the therapeuticdose range. The early onset and total insulin action were similar when Lyumjev was administered inthe abdomen, upper arm, or thigh.

Postprandial Glucose (PPG) Lowering

Lyumjev reduced the PPG during a standardized test meal over the complete 5 hour test meal period(change from premeal area under the curve (AUC) (0 - 5 h)) compared to Humalog.

* In patients with type 1 diabetes, Lyumjev reduced the PPG during the 5 hour test meal period by32% when given at the start of the meal and 18% when given 20 minutes after the start of themeal compared to Humalog.

* In patients with type 2 diabetes, Lyumjev reduced the PPG during the 5 hour test meal period by26% when given at the start of the meal and 24% when given 20 minutes after the start of themeal compared to Humalog.

Comparison of Lyumjev 200 units/mL and Lyumjev 100 units/mL

The maximum and total glucose lowering were comparable for Lyumjev 200 units/mL or Lyumjev100 units/mL. No dose conversion is required if transferring a patient between the strengths.

The efficacy of Lyumjev was evaluated in 4 randomised, active controlled trials in adults and 1randomised, active controlled trial in paediatric patients with type 1 diabetes.

Type 1 Diabetes - Adults

PRONTO-T1D was a 26 week, treat-to-target, trial that evaluated the efficacy of Lyumjev in1 222 patients on multiple daily injection therapy. Patients were randomised to either blindedmealtime Lyumjev, blinded mealtime Humalog, or open-label postmeal Lyumjev, all in combinationwith either insulin glargine or insulin degludec. Mealtime Lyumjev or Humalog was injected 0 to2 minutes before the meal and postmeal Lyumjev was injected 20 minutes after the start of the meal.

Efficacy results are provided in Table 2 and Figure 2.

37.4% of patients treated with mealtime Lyumjev, 33.6% of patients treated with mealtime Humalogand 25.6% of patients treated with postmeal Lyumjev reached a target HbA1c of < 7%.

Basal, bolus and total insulin doses were similar among study arms at 26 weeks.

Following the 26 week period, the two blinded treatment arms continued to 52 weeks. HbA1c was notstatistically significantly different between treatments at the 52 week endpoint.

Table 2 Results from 26 week basal-bolus clinical trial in patients with type 1 diabetes

Mealtime Lyumjev Mealtime Postmeal Lyumjev+ basal insulin Humalog + + basal insulinbasal insulin

Number of randomised subjects (N) 451 442 329

HbA1c (%)

Baseline  week 26 7.34  7.21 7.337.29 7.367.42

Change from baseline -0.13 -0.05 0.08

Treatment difference -0.08 [-0.16, -0.00]C 0.13 [0.04, 0.22]D

HbA1c (mmol/mol)

Baseline  week 26 56.755.3 56.756.1 56.957.6

Change from baseline -1.4 -0.6 0.8

Treatment difference -0.8 [-1.7, 0.00]C 1.4 [0.5, 2.4]D1 hour postprandial glucose excursion (mg/dL) A

Baseline  week 26 77.3 46.4 71.5 74.3 76.387.5

Change from baseline -28.6 -0.7 12.5

Treatment difference -27.9 [-35.3, -20.6]C,E 13.2 [5.0, 21.4]D1 hour postprandial glucose excursion (mmol/L) A

Baseline  week 26 4.292.57 3.97 4.13 4.244.86

Change from baseline -1.59 -0.04 0.70

Treatment difference -1.55[-1.96, -1.14]C,E 0.73 [0.28,1.19]D2 hour postprandial glucose excursion (mg/dL) A

Baseline  week 26 112.772.7 101.6 103.9 108.0 97.2

Change from baseline -34.7 -3.5 -10.2

Treatment difference -31.2 [-41.1, -21.2]C,E -6.7 [-17.6, pct. 4.3] D.2 hour postprandial glucose excursion (mmol/L) A

Baseline  week 26 6.264.04 5.645.77 5.995.40

Change from baseline -1.93 -0.20 -0.56

Treatment difference -1.73 [-2.28, -1.18]C,E -0.37 [-0.98, -0.24]D

Body weight (Kg)

Baseline  week 26 77.377.9 77.378.2 77.678.1

Change from baseline 0.6 0.8 0.7

Treatment difference -0.2 [-0.6, 0.1]A -0.1[-0.5, 0.3]D

Severe hypoglycaemia B (% of patients) 5.5% 5.7% 4.6%

Week 26 and change from baseline values are based on the least-squares means (adjusted means).

The 95% confidence interval is stated in ‘[ ]’.

A Meal test.

B Severe hypoglycaemia is defined as episode requiring assistance of another person due to patient’sneurological impairment.

C The difference is for mealtime Lyumjev - mealtime Humalog.

D The difference is for postmeal Lyumjev - mealtime Humalog.

E Statistically significant in favour of mealtime Lyumjev.

Figure 2. Time course of blood glucose excursion during mixed-meal tolerance test at week 26 inpatients with type 1 diabetes

PPG = Postprandial glucose

Lyumjev and Humalog administered at mealtime

Lyumjev +20 = Lyumjev was injected 20 minutes after the start of the meal

*p < 0.05 for pairwise comparison on Lyumjev versus Humalog^p < 0.05 for pairwise comparison on Lyumjev +20 versus Humalog#p < 0.05 for pairwise comparison on Lyumjev +20 versus Lyumjev

Continuous glucose monitoring (CGM) in Type 1 Diabetes - Adults

A subset of patients (N = 269) participated in an evaluation of the 24 hour ambulatory glucose profilescaptured with blinded CGM. At the 26 week assessment, patients treated with mealtime Lyumjevdemonstrated statistically significant improvement in PPG control during CGM assessment of glucoseexcursions or incremental AUC 0 - 2 hours, 0 - 3 hours, and 0 - 4 hours after meals compared topatients treated with Humalog. Patients treated with mealtime Lyumjev reported statisticallysignificantly longer time in range (6 am to midnight) with 603 minutes in range, (3.9 to 10 mmol/L,71 - 180 mg/dL), and 396 minutes in range (3.9 to 7.8 mmol/L, 71 to 140 mg/dL), 44 and 41 minuteslonger than Humalog patients respectively.

Type 2 Diabetes - Adults

PRONTO-T2D was a 26 week, treat-to-target trial that evaluated the efficacy of Lyumjev in673 patients were randomised to either blinded mealtime Lyumjev or to blinded mealtime Humalog,both in combination with a basal insulin (insulin glargine or insulin degludec) in a basal-bolusregimen. Mealtime Lyumjev or mealtime Humalog was injected 0 - 2 minutes before the meal.

Efficacy results are provided in Table 3 and Figure 3.

58.2% of patients treated with mealtime Lyumjev and 52.5% of patients treated with mealtime

Humalog reached a target HbA1c of < 7%.

Basal, bolus and total insulin doses were similar among study arms at the end of the trial.

Table 3 Results from 26 week basal-bolus clinical trial in patients with type 2 diabetes

Mealtime Lyumjev Mealtime Humalog+ basal insulin + basal insulin

Number of randomised subjects (N) 336 337

HbA1c (%)

Baseline  week 26 7.286.92 7.316.86

Change from baseline -0.38 -0.43

Treatment difference 0.06 [-0.05, 0.16]

HbA1c (mmol/mol)

Baseline  week 26 56.052.1 56.451.5

Change from baseline -4.1 -4.7

Treatment difference 0.6 [-0.6, 1.8]1 hour postprandial glucose excursion (mg/dL)A

Baseline  week 26 76.663.1 77.174.9

Change from baseline -13.8 -2.0

Treatment difference -11.8 [-18.1, -5.5]C1 hour postprandial glucose excursion (mmol/L)A

Baseline  week 26 4.253.50 4.284.16

Change from baseline -0.77 -0.11

Treatment difference -0.66 [-1.01, -0.30]C2 hour postprandial glucose excursion (mg/dL)A

Baseline  week 26 99.380.4 99.697.8

Change from baseline -19.0 -1.6

Treatment difference -17.4 [-25.3, -9.5]C2 hour postprandial glucose excursion (mmol/L)A

Baseline  week 26 5.514.47 5.535.43

Change from baseline -1.06 -0.09

Treatment difference -0.96 [-1.41, -0.52]C

Body weight (Kg)

Baseline  week 26 89.891.3 90.0 91.6

Change from baseline 1.4 1.7

Treatment difference -0.2 [-0.7, 0.3]

Severe hypoglycaemia (% of patients)B 0.9% 1.8%

Week 26 and change from baseline values are based on the least-squares means (adjusted means).

The 95% confidence interval is stated in ‘[ ]’. The difference is for mealtime Lyumjev - mealtime

Humalog.

A Meal test.

B Severe hypoglycaemia is defined as episode requiring assistance of another person due to patient’sneurological impairment.

C Statistically significant in favour of mealtime Lyumjev.

Figure 3. Time course of blood glucose excursion during mixed-meal tolerance test at week 26 inpatients with type 2 diabetes

PPG = Postprandial glucose

Lyumjev and Humalog administered at mealtime

Data are LSM (SE), *p < 0.05

Type 1 Diabetes - Adults. CSII

PRONTO-Pump was a 12 week cross over design (2 periods of 6 weeks), double-blind, trial thatevaluated the compatibility and safety of Lyumjev and Humalog with an external CSII System inpatients who wore a continuous glucose monitor throughout the study. There was no statisticallysignificant treatment difference in the rate or incidence of infusion set failures (n = 49).

In period 1 of the cross over study, Lyumjev had a numerically greater reduction in mean HbA1c than

Humalog. Lyumjev reduction was -0.39% [- 4.23 mmol/mol] from a baseline of 6.97%[52.68 mmol/mol] and Humalog reduction was - 0.25% [- 2.78 mmol/mol] from a baseline of 7.17%[54.89 mmol/mol]. Lyumjev had a statistically significantly longer mean duration of time with glucosein target ranges 71 - 140 mg/dL (3.9 to 7.8 mmol/L) within 1 and 2 hours after the start of breakfastcompared to Humalog.

PRONTO-Pump-2 was a 16 week randomised (1:1), double-blind, trial that evaluated the efficacy of

Lyumjev in 432 patients with type 1 diabetes currently using continuous subcutaneous insulininfusion. Patients were randomised to either blinded Lyumjev (N = 215) or blinded Humalog(N = 217). Mealtime Lyumjev or Humalog boluses were initiated 0 to 2 minutes before the meal.

At week 16, Lyumjev was non-inferior to Humalog in reducing HbA1c. Lyumjev reductionwas -0.06% [- 0.7 mmol/mol] from a baseline of 7.56% [59.1 mmol/mol] and Humalog reductionwas -0.09% [- 1.0 mmol/mol] from a baseline of 7.54% [58.9 mmol/mol]. The treatment differencewas 0.02% [95% CI: - 0.06, 0.11] and 0.3 mmol/mol [95% CI: - 0.6, 1.2], respectively compared to

Humalog.

Following a standardized test meal, treatment with Lyumjev demonstrated statistically significantlylower 1 hour and 2 hour postprandial glucose. The treatment difference was - 1.34 mmol/L [95% CI: -2.00, - 0.68] and -1.54 mmol/L [95% CI: - 2.37, - 0.72], respectively compared to Humalog.

In the two 26 week clinical studies (PRONTO-T1D and PRONTO-T2D), 187 of 1 116 (17%)

Lyumjev treated patients with type 1 diabetes or type 2 diabetes were ≥ 65 years of age and 18 of1 116 (2%) were ≥ 75 years of age. No overall differences in safety or effectiveness were observedbetween elderly patients and younger patients.

PRONTO-Peds was a 26-week, randomised (2:2:1), treat-to-target, trial that evaluated the efficacy of

Lyumjev in 716 patients with type 1 diabetes, aged 3 to < 18 years. Patients were randomised to eitherblinded mealtime Lyumjev (N = 280), blinded mealtime Humalog (N = 298), or open-label postmeal

Lyumjev (N = 138), all in combination with basal insulin (insulin glargine, insulin degludec or insulindetemir). Mealtime Lyumjev or Humalog was injected 0 to 2 minutes before the meal and postmeal

Lyumjev was injected within 20 minutes after the start of the meal.

Insulin doses were similar in all treatment groups at baseline and at 26 weeks.

Table 4. Results from 26 week PRONTO-Peds trial in paediatric patients with type 1 diabetes

Mealtime Lyumjev Mealtime Humalog Postmeal Lyumjev+ basal insulin + basal insulin + basal insulin

Number of randomised subjects (N) 280 298 138

HbA1c (%) (mean)

Baseline  week 26 7.78  7.85 7.81  7.88 7.77  7.86

Change from baseline 0.06 0.09 0.07

Treatment difference -0.02 [-0.17, 0.13]A -0.02 [-0.20, 0.17]B

HbA1c (mmol/mol)

Baseline  week 26 61.6  62.4 61.8  62.6 61.4  62.4

Change from baseline 0.71 0.94 0.77

Treatment difference -0.23 [-1.84, 1.39]A -0.17 [-2.15, 1.81]B

Week 26 and change from baseline values are based on the least-squares means (adjusted means).

The 95% confidence interval is stated in ‘[ ]’.

AThe difference is for mealtime Lyumjev - mealtime Humalog.

B The difference is for postmeal Lyumjev - mealtime Humalog.

Absorption of insulin lispro was accelerated and the duration of exposure was shorter in healthysubjects and patients with diabetes following injection of Lyumjev compared to Humalog. In patientswith type 1 diabetes:

* Insulin lispro appeared in circulation approximately 1 minute after injection of Lyumjev, whichwas five minutes faster than Humalog.

* Time to 50% maximum concentration was 14 minutes shorter with Lyumjev compared to

Humalog.

* Following injection of Lyumjev, there was seven times more insulin lispro in circulation duringthe first 15 minutes compared to Humalog and three times more insulin lispro during the first30 minutes compared to Humalog.

* After administration of Lyumjev the time to maximum insulin lispro concentration wasachieved at 57 minutes.

* Following injection of Lyumjev there was 41% less insulin lispro in circulation after 3 hoursfollowing injection compared to Humalog.

* The duration of insulin lispro exposure for Lyumjev was 60 minutes shorter compared to

Humalog.

* The total insulin lispro exposure (ratio and 95% CI of 1.03 (0.973, 1.09)) and maximumconcentration (ratio and 95% CI of 1.06 (0.97, 1.16)) were comparable between Lyumjev and

Humalog.

In type 1 patients, the day-to-day variability (coefficient of variation [CV%]) of Lyumjev was 13% fortotal insulin lispro exposure (AUC, 0 - 10h) and 23% for maximum insulin lispro concentration(Cmax).The absolute bioavailability of insulin lispro after subcutaneous administration of Lyumjev inthe abdomen, upper arm and thigh was approximately 65%. The accelerated absorption of insulinlispro is maintained regardless of injection site (abdomen, upper arm and thigh). No exposure data areavailable following injection in the buttocks.

Maximum concentration and time to maximum concentration were comparable for the abdomen andupper arm regions; time to maximum concentration was longer and maximum concentration lower forthe thigh.

Total insulin lispro exposure and maximum insulin lispro concentration increased proportionally withincreasing subcutaneous doses of Lyumjev within the dose range from 7 units to 30 units.

CSII

The absorption of insulin lispro was accelerated when Lyumjev was administered by CSII in patientswith type 1 diabetes.

* Time to reach 50% maximum concentration was 14 minutes, 9 minutes shorter than for

Humalog.

* Following administration of Lyumjev, 1.5 times more insulin lispro was available during thefirst 30 minutes compared to Humalog.

Comparison of Lyumjev 200 units/mL and Lyumjev 100 units/mL

The results of a study in healthy subjects demonstrated that Lyumjev 200 units/mL is bioequivalent to

Lyumjev 100 units/mL following administration of a single 15 unit dose for the area under seruminsulin lispro concentration-time curve from time zero to infinity and Cmax. The accelerated insulinlispro absorption after administration of 200 units/mL was similar to that observed with Lyumjev100 units/mL. No dose conversion is required if transferring a patient between the strengths.

The geometric mean (CV%) volume of distribution of insulin lispro (Vd) was 34 L (30%) afterintravenous administration of Lyumjev as a bolus injection of a 15 unit dose in healthy subjects.

The geometric mean (CV%) clearance of insulin lispro was 32 L/hour (22%) and the median half-lifeof insulin lispro was 44 minutes after intravenous administration of Lyumjev as a bolus injection of a15 unit dose in healthy subjects.

Age, gender, and race did not affect the pharmacokinetics and pharmacodynamics of Lyumjev.

Children (8 - 11 years) and adolescents (12 - 17 years) with type 1 diabetes on multiple daily injection(MDI) and CSII therapy were studied in a cross-over design to assess the insulin lispropharmacokinetics and pharmacodynamics following a 0.2 units/kg dose of Lyumjev and Humalog.

The pharmacokinetic differences between Lyumjev and Humalog were, overall, similar in childrenand adolescents as observed in adults. Following a subcutaneous injection, Lyumjev showed anaccelerated absorption with a higher early insulin lispro exposure in children (8 - 11 years) andadolescents (12 - 17 years) whilst maintaining a similar total exposure, maximum concentration andtime to maximum concentration compared to Humalog. Following a subcutaneous bolus infusion with

CSII therapy, there was a trend towards an accelerated absorption in children and adolescents whilsttotal exposure, maximum concentration and time to maximum concentration were similar compared to

Humalog.

Renal and hepatic impairment is not known to impact the pharmacokinetics of insulin lispro.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproductionand development after exposure to insulin lispro.

Glycerol

Magnesium chloride hexahydrate

Metacresol

Sodium citrate dihydrate

Treprostinil sodium

Zinc oxide

Water for injections

Hydrochloric acid and sodium hydroxide (for pH adjustment)

This medicinal product must not be mixed with any other insulin or any other medicinal productexcept those mentioned in section 6.6.

Lyumjev 100 units/mL solution for injection in cartridge

Lyumjev 100 units/mL KwikPen solution for injection in pre-filled pen

Lyumjev 100 units/mL Junior KwikPen solution for injection in pre-filled pen

Lyumjev 100 units/mL Tempo Pen solution for injection in pre-filled pen

Before use3 years

After first use28 days

Lyumjev 100 units/mL solution for injection in vial

Before use2 years

After first use28 days

When the vial is diluted for intravenous use

Chemical, physical in-use stability has been demonstrated for 14 days at 2 - 8 °C and 20 hours at20 - 25 °C when protected from light. From a microbiological point of view, the medicinal productshould be used immediately. If not used immediately, in-use storage times and conditions prior to useare the responsibility of the user and would not normally be longer than 24 hours at 2 - 8 °C, unlessdilution has taken place in controlled and validated aseptic conditions (see section 6.6).

Store in a refrigerator (2 °C - 8 °C).

Do not freeze.

Store in the original package in order to protect from light.

After first use

Do not store above 30 °C.

Do not freeze.

Lyumjev 100 units/mL solution for injection in vial

Store in the original package in order to protect from light.

Lyumjev 100 units/mL solution for injection in cartridge

Do not refrigerate.

Keep the cap on the pen once cartridge inserted, in order to protect from light.

Lyumjev 100 units/mL KwikPen solution for injection in pre-filled pen

Lyumjev 100 units/mL Junior KwikPen solution for injection in pre-filled pen

Lyumjev 100 units/mL Tempo Pen solution for injection in pre-filled pen

Do not refrigerate.

Keep the cap on the pen in order to protect from light.

Lyumjev 100 units/mL solution for injection in vial

Type I clear glass vials, sealed with halobutyl stoppers and secured with aluminium seals.

10 mL vial: Packs of 1 or 2 vials or 5 (5 packs of 1) vials.

Lyumjev 100 units/mL solution for injection in cartridge

Type I clear glass cartridges, sealed with disc seals secured with aluminium seals and halobutylplungers.

3 mL cartridge: Packs of 2, 5 or 10 cartridges.

Lyumjev 100 units/mL KwikPen solution for injection in pre-filled pen

Type I clear glass cartridges, sealed with disc seals secured with aluminium seals and halobutylplungers.

The 3 mL cartridges are sealed in a disposable pen injector KwikPen .

The medicinal product is packed in a white carton with dark blue bands and an image of the pen. The

KwikPen is taupe, the dose knob is blue with raised ridges on side.

3 mL KwikPen: Packs of 2 pre-filled pens, 5 pre-filled pens or a multipack of 10 (2 packs of 5) pre-filled pens.

Lyumjev 100 units/mL Junior KwikPen solution for injection in pre-filled pen

Type I clear glass cartridges, sealed with disc seals secured with aluminium seals and halobutylplungers.

The 3 mL cartridges are sealed in a disposable pen injector Junior KwikPen.

The medicinal product is packed in a white carton with stripes of peach, light blue and dark blue bandsand an image of the pen. The Junior KwikPen is taupe, the dose knob is peach with raised ridges onend and side.

3 mL Junior KwikPen: Packs of 2 pre-filled pens, 5 pre-filled pens or a multipack of 10 (2 packs of 5)pre-filled pens.

Lyumjev 100 units/mL Tempo Pen solution for injection in pre-filled pen

Type I clear glass cartridges, sealed with disc seals secured with aluminium seals and halobutylplungers.

The 3 mL cartridges are sealed in a disposable pen injector Tempo Pen. The Tempo Pen contains amagnet (see section 4.4).

The medicinal product is packed in a white carton with stripes of dark blue and green bands. The

Tempo Pen is taupe, the dose knob is blue with raised ridges around the entire side.

3 mL Tempo Pen: Packs of 5 pre-filled pens or a multipack of 10 (2 packs of 5) pre-filled pens.

Not all pack sizes may be marketed.

Lyumjev must look clear and colourless. It should not be used if it is cloudy, coloured, or has particlesor clumps in it.

Lyumjev must not be used if it has been frozen.

A new needle must always be attached before each use. Needles must not be re-used. Needles are notincluded.

Lyumjev 100 units/mL solution for injection in vial

Lyumjev 100 units/mL vial can be diluted to concentrations of 0.1 to 1.0 unit/mL in 5% glucosesolution for injection or sodium chloride 9 mg/mL (0.9%) solution for injection for intravenous use.

Compatibility has been demonstrated in ethylene-propylene copolymer and polyolefin with polyvinylchloride bags.

It is recommended that the system is primed before starting the infusion to the patient.

CSII

Lyumjev 100 units/mL vial can be used to fill a continuous insulin infusion pump for a maximum of9 days. Tubings in which the inner surface materials are made of polyethylene or polyolefin have beenevaluated and found compatible with pump use.

Lyumjev 100 units/mL Tempo Pen solution for injection in pre-filled pen

The Tempo Pen is designed to work with the Tempo Smart Button. The Tempo Smart Button is anoptional product that can be attached to the Tempo Pen dose knob and aids in transmitting Lyumjevdose information from the Tempo Pen to a compatible mobile application. The Tempo Pen injectsinsulin with or without the Tempo Smart Button attached. To transmit data to the mobile application,follow the instructions provided with the Tempo Smart Button and the instructions with the mobileapplication.

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

Eli Lilly Nederland B.V.

Papendorpseweg 833528 BJ Utrecht

The Netherlands

EU/1/20/1422/001

EU/1/20/1422/002

EU/1/20/1422/003

EU/1/20/1422/004

EU/1/20/1422/005

EU/1/20/1422/006

EU/1/20/1422/007

EU/1/20/1422/008

EU/1/20/1422/009

EU/1/20/1422/010

EU/1/20/1422/011

EU/1/20/1422/012

EU/1/20/1422/016

EU/1/20/1422/017

Date of first authorisation: 24 March 2020

Date of latest renewal:

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

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