4.1. Therapeutic indications

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

4.2. Posology and method of administration

Posology

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

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

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

The early onset of action must be considered when prescribing Lyumjev (see section 5.1). Continued adjustment of the dose of Lyumjev should be based on the patient's metabolic needs, blood glucose monitoring results, and glycaemic control goal. Dose adjustments may be needed, when switching from 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 or hepatic function or during acute illness to minimize the risk of hypoglycaemia or hyperglycaemia (see sections 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-unit basis. 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 insulin analogues.

Missed doses

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

Special populations

Elderly

The safety and efficacy of Lyumjev has been established in elderly patients aged 65 to 75 years. Close glucose 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.

Renal impairment

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

Hepatic impairment

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

Paediatric population

Lyumjev can be used in adolescents and children from the age of 1 year (see section 5.1). There is no clinical 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 two minutes before the start of the meal, with the option to administer up to 20 minutes after starting the meal when needed.

Method of administration

Patients should be trained on proper use and injection technique before initiating Lyumjev. Patients should 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 the risk 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.

Subcutaneous injection

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

Lyumjev should generally be used in combination with an intermediate or long-acting insulin. A different 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 not been established with other pens.

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

To prevent the possible transmission of disease, each cartridge must be used by one patient only, even if 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 single injection.

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 no dose conversion should be done when transferring a patient to a new concentration or to a pen with a different dose step.

Lyumjev 100 units/mL Junior KwikPen is suitable for patients who may benefit from finer insulin dose 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 mobile application, the patient should be instructed to check their blood sugar levels when considering or making 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 the needle 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 filling system. The infusion set (tubing and cannula) should be changed in accordance with the instructions in the 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 (see section 4.4).

Intravenous use

Lyumjev 100 units/mL is available in vials if administration of intravenous injection is necessary. This medicinal product must not be mixed with any other insulin or any other medicinal product except those 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.

4.3. Contraindications

Hypoglycaemia.

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

4.4. Special warnings and precautions for use

Traceability

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

Hypoglycaemia

Hypoglycaemia is the most common adverse reaction of insulin therapy (see section 4.8). The timing of hypoglycaemia usually reflects the time-action profile of the administered insulin formulations. Hypoglycaemia may occur earlier after an injection/infusion when compared to other mealtime insulins 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 over time 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 less pronounced in patients with longstanding diabetes.

Hyperglycaemia

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

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

Injection technique

Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites with these reactions. A sudden 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 adjustment of antidiabetic medications may be considered.

Insulin requirements and dose adjustments

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

In patients with renal or hepatic impairment, glucose monitoring should be intensified and dose adjusted 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 change their 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 and ketoacidosis. Prompt identification and correction of the cause of hyperglycaemia or ketosis is necessary. 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. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin and a TZD should be observed for signs and symptoms of heart failure. If heart failure develops, consider discontinuation of the TZD.

Hypersensitivity and allergic reactions

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

Medication errors

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 the insulin 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 an implantable electronic medical device, such as a pacemaker. The magnetic field extends to approximately 1.5 cm.

Excipients

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

4.5. Interaction with other medicinal products and other forms of interaction

The following substances may reduce insulin requirement: Antidiabetic medicinal products (oral or injectable), 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 of large 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, and exacerbate heart failure (see section 4.4).

4.6. Fertility, pregnancy and lactation

Pregnancy

A large amount of data on pregnant women (more than 1 000 pregnancy outcomes) indicate no malformative nor feto/neonatal toxicity of insulin lispro. Lyumjev can be used during pregnancy if clinically needed.

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

Breast-feeding

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

Fertility

Insulin lispro did not induce fertility impairment in animal studies.

4.7. Effects on ability to drive and use machines

The patient's ability to concentrate and react may be impaired as a result of hypoglycaemia. This may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or using machinery).

Patients should be advised to take precautions to avoid hypoglycaemia whilst driving, this is particularly important in those patients who have reduced or absent awareness of the warning signs of hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should be considered in these circumstances.

4.8. Undesirable effects

Summary of safety profile

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, 4.4 and 4.9).

The following related adverse reactions from clinical trials are listed below as MedDRA preferred term 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 frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1. Adverse reactions

MedDRA system organ class

Very common

Common

Uncommon

Not known

Metabolism and nutrition disorders

Hypoglycaemia

General disorders and administration site conditions

Infusion site reactionsa

Allergic reactions b

Oedema

Injection site reactions c

Skin and subcutaneous tissue disorders

Lipodystrophy

Cutaneous amyloidosis

Rash

Pruritus

aReported in PRONTO-Pump-2

bSee section 4.8 Description of selected adverse reactions

cReported in PRONTO-T1D, PRONTO-T2D and PRONTO-Peds

Description of selected adverse reactions

Hypoglycaemia

Hypoglycaemia is the most commonly observed adverse reaction in patients using insulin. The incidence of severe hypoglycaemia in the 26 week phase 3 adult clinical studies was 5.5% in patients with 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 administration of 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 mealtime insulins due to the earlier onset of action.

Allergic reactions

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 or itching 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 were usually 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%).

Immunogenicity

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

Skin and subcutaneous tissue disorders

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

Oedema

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

Paediatric population

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

Other special populations

Based on results from clinical trials with insulin lispro in general, the frequency, type and severity of adverse reactions observed in elderly patients and in patients with renal or hepatic impairment do not indicate any differences to the broader experience in the general population. The safety information in very elderly patients (≥ 75 years) or patients with moderate to severe renal impairment or hepatic impairment is limited (see section 5.1).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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, energy expenditure, or both. Mild episodes of hypoglycaemia usually can be treated with oral glucose. More severe episodes with coma, seizure, or neurologic impairment may be treated with glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycaemia may recur after apparent clinical recovery. Adjustments in medicinal product dose, meal patterns, or exercise may be needed.