SEMGLEE 100U / ml solution for injection in pre-filled pen medication leaflet

Semglee 100 units/ml solution for injection in pre-filled pen

Each ml contains 100 units insulin glargine* (equivalent to 3.64 mg).

Each pen contains 3 ml of solution for injection, equivalent to 300 units.

*Insulin glargine is produced by recombinant DNA technology in Pichia pastoris.

For the full list of excipients, see section 6.1.

Solution for injection in pre-filled pen.

Clear colourless solution.

Treatment of diabetes mellitus in adults, adolescents and children aged 2 years and above.

Semglee contains insulin glargine, an insulin analogue, and has a prolonged duration of action.

It should be administered once daily at any time but at the same time each day.

The pre-filled pen delivers insulin in increments of 1 unit up to a maximum single dose of 80 units.

The dose regimen (dose and timing) should be individually adjusted. In patients with type 2 diabetesmellitus, Semglee can also be given together with orally active antidiabetic medicinal products.

The potency of this medicinal product is stated in units. These units are exclusive to Semglee and arenot the same as IU or the units used to express the potency of other insulin analogues (see section 5.1).

Special population

Elderly population (≥ 65 years old)

In the elderly, progressive deterioration of renal function may lead to a steady decrease in insulinrequirements.

In patients with renal impairment, insulin requirements may be diminished due to reduced insulinmetabolism.

In patients with hepatic impairment, insulin requirements may be diminished due to reduced capacityfor gluconeogenesis and reduced insulin metabolism.

* Adolescents and children aged 2 years and older patients

Safety and efficacy of Semglee have been established in adolescents and children aged 2 years andolder (see section 5.1). The dose regimen (dose and timing) should be individually adjusted.

* Children below 2 years of age

The safety and efficacy of Semglee have not been established. No data are available.

Switch from other insulins to Semglee

When switching from a treatment regimen with an intermediate or long-acting insulin to a regimenwith Semglee, a change of the dose of the basal insulin may be required and the concomitantantidiabetic treatment may need to be adjusted (dose and timing of additional regular insulins orfast-acting insulin analogues or the dose of oral antidiabetic medicinal products).

Switch from twice daily NPH insulin to Semglee

To reduce the risk of nocturnal and early morning hypoglycaemia, patients who are changing theirbasal insulin regimen from a twice daily NPH insulin to a once daily regimen with Semglee shouldreduce their daily dose of basal insulin by 20-30% during the first weeks of treatment.

Switch from insulin glargine 300 units/ml to Semglee

Semglee and insulin glargine 300 units/ml are not bioequivalent and are not directly interchangeable.

To reduce the risk of hypoglycemia, patients who are changing their basal insulin regimen from aninsulin regimen with once daily insulin glargine 300 units/ml to a once daily regimen with Semgleeshould reduce their dose by approximately 20%.

During the first weeks the reduction should, at least partially, be compensated by an increase inmealtime insulin, after this period the regimen should be adjusted individually.

Close metabolic monitoring is recommended during the switch and in the initial weeks thereafter.

With improved metabolic control and resulting increase in insulin sensitivity a further adjustment indose regimen may become necessary. Dose adjustment may also be required, for example, if thepatient's weight or life-style changes, change of timing of insulin dose or other circumstances arise thatincrease susceptibility to hypo- or hyperglycaemia (see section 4.4).

Patients with high insulin doses because of antibodies to human insulin may experience an improvedinsulin response with Semglee.

Semglee is administered subcutaneously.

Semglee should not be administered intravenously. The prolonged duration of action of Semglee isdependent on its injection into subcutaneous tissue. Intravenous administration of the usualsubcutaneous dose could result in severe hypoglycaemia.

There are no clinically relevant differences in serum insulin or glucose levels after abdominal, deltoidor thigh administration of Semglee. Injection sites must be rotated within a given injection area fromone injection to the next in order to reduce the risk of lipodystrophy and cutaneous amyloidosis (seesection 4.4 and 4.8).

Semglee must not be mixed with any other insulin or diluted. Mixing or diluting can change itstime/action profile and mixing can cause precipitation.

Semglee in pre-filled pen is only suitable for subcutaneous injections. If administration by syringe isnecessary, a vial should be used (see section 4.4).

Before using the pre-filled pen, the instructions for use included in the package leaflet must be readcarefully (see section 6.6).

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.

Warnings

Semglee is not the insulin of choice for the treatment of diabetic ketoacidosis. Instead, regular insulinadministered intravenously is recommended in such cases.

In case of insufficient glucose control or a tendency to hyper- or hypoglycaemic episodes, the patient'sadherence to the prescribed treatment regimen, injection sites and proper injection technique and allother relevant factors must be reviewed before dose adjustment is considered.

Transferring a patient to another type or brand of insulin should be done under strict medicalsupervision. Changes in strength, brand (manufacturer), type (regular, NPH, lente, long-acting, etc.),origin (animal, human, human insulin analogue) and/or method of manufacture may result in the needfor a change in dose.

The time of occurrence of hypoglycaemia depends on the action profile of the insulins used and may,therefore, change when the treatment regimen is changed. Due to more sustained basal insulin supplywith Semglee, less nocturnal but more early morning hypoglycaemia can be expected.

Particular caution should be exercised, and intensified blood glucose monitoring is advisable inpatients in whom hypoglycaemic episodes might be of particular clinical relevance, such as in patientswith significant stenoses of the coronary arteries or of the blood vessels supplying the brain (risk ofcardiac or cerebral complications of hypoglycaemia) as well as in patients with proliferativeretinopathy, particularly if not treated with photocoagulation (risk of transient amaurosis followinghypoglycaemia).

Patients should be aware of circumstances where warning symptoms of hypoglycaemia arediminished. The warning symptoms of hypoglycaemia may be changed, be less pronounced or beabsent in certain risk groups. These include patients:

- in whom glycaemic control is markedly improved,

- in whom hypoglycaemia develops gradually,

- who are elderly,

- after transfer from animal insulin to human insulin,

- in whom an autonomic neuropathy is present,

- with a long history of diabetes,

- suffering from a psychiatric illness,

- receiving concurrent treatment with certain other medicinal products (see section 4.5).

Such situations may result in severe hypoglycaemia (and possibly loss of consciousness) prior to thepatient's awareness of hypoglycaemia.

The prolonged effect of subcutaneous insulin glargine may delay recovery from hypoglycaemia.

If normal or decreased values for glycated haemoglobin are noted, the possibility of recurrent,unrecognised (especially nocturnal) episodes of hypoglycaemia must be considered.

Adherence of the patient to the dose and dietary regimen, correct insulin administration and awarenessof hypoglycaemia symptoms are essential to reduce the risk of hypoglycaemia. Factors increasing thesusceptibility to hypoglycaemia require particularly close monitoring and may necessitate doseadjustment. These include:

- change in the injection area. Patients must be instructed to perform continuous rotation of theinjection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. Thereis a potential risk of delayed insulin absorption and worsened glycaemic control followinginsulin injections at sites with these reactions. A sudden change in the injection site to anunaffected area has been reported to result in hypoglycaemia. Blood glucose monitoring isrecommended after the change in the injection site, and dose adjustment of antidiabeticmedications may be considered,

- improved insulin sensitivity (e.g., by removal of stress factors),

- unaccustomed, increased or prolonged physical activity,

- intercurrent illness (e.g. vomiting, diarrhoea),

- inadequate food intake,

- missed meals,

- alcohol consumption,

- certain uncompensated endocrine disorders, (e.g. in hypothyroidism and in anterior pituitary oradrenocortical insufficiency),

- concomitant treatment with certain other medicinal products (see section 4.5).

Intercurrent illness requires intensified metabolic monitoring. In many cases urine tests for ketones areindicated, and often it is necessary to adjust the insulin dose. The insulin requirement is oftenincreased. Patients with type 1 diabetes must continue to consume at least a small amount ofcarbohydrates on a regular basis, even if they are able to eat only little or no food, or are vomiting etc.and they must never omit insulin entirely.

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 (see section 5.1).

Handling of the pen

Semglee in pre-filled pen is only suitable for subcutaneous injections. If administration by syringe isnecessary, a vial should be used (see section 4.2).

Before using Semglee pen, the instructions for use included in the package leaflet must be readcarefully.

Semglee pen has to be used as recommended in these instructions for use (see section 6.6).

Medication errors have been reported in which other insulins, particularly short-acting insulins, havebeen accidentally administered instead of insulin glargine. Insulin label must always be checkedbefore each injection to avoid medication errors between insulin glargine and other insulins.

Combination of Semglee with pioglitazone

Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin,especially in patients with risk factors for development of cardiac heart failure. This should be kept inmind if treatment with the combination of pioglitazone and Semglee is considered. If the combinationis used, patients should be observed for signs and symptoms of heart failure, weight gain and oedema.

Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs.

This medicinal product contains less than 1 mmol (23 mg) sodium per dose, i.e. it is essentially‘sodium-free’.

A number of substances affect glucose metabolism and may require dose adjustment of insulinglargine.

Substances that may enhance the blood-glucose-lowering effect and increase susceptibility tohypoglycaemia include oral antidiabetic medicinal products, angiotensin converting enzyme (ACE)inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors, pentoxifylline,propoxyphene, salicylates and sulfonamide antibiotics.

Substances that may reduce the blood-glucose-lowering effect include corticosteroids, danazol,diazoxide, diuretics, glucagon, isoniazid, oestrogens and progestogens, phenothiazine derivatives,somatropin, sympathomimetic medicinal products (e.g. epinephrine [adrenaline], salbutamol,terbutaline), thyroid hormones, atypical antipsychotic medicinal products (e.g. clozapine andolanzapine) and protease inhibitors.

Beta-blockers, clonidine, lithium salts or alcohol may either potentiate or weaken theblood-glucose-lowering effect of insulin. Pentamidine may cause hypoglycaemia, which maysometimes be followed by hyperglycaemia.

In addition, under the influence of sympatholytic medicinal products such as beta-blockers, clonidine,guanethidine and reserpine, the signs of adrenergic counter-regulation may be reduced or absent.

For insulin glargine no clinical data on exposed pregnancies from controlled clinical studies areavailable. A large amount of data on pregnant women (more than 1000 pregnancy outcomes) indicateno specific adverse effects of insulin glargine on pregnancy and no specific malformative norfeto/neonatal toxicity of insulin glargine. Animal data do not indicate reproductive toxicity.

The use of Semglee may be considered during pregnancy, if clinically needed.

It is essential for patients with pre-existing or gestational diabetes to maintain good metabolic controlthroughout pregnancy to prevent adverse outcomes associated with hyperglycemia. Insulinrequirements may decrease during the first trimester and generally increase during the second andthird trimesters. Immediately after delivery, insulin requirements decline rapidly (increased risk ofhypoglycaemia). Careful monitoring of glucose control is essential.

It is unknown whether insulin glargine is excreted in human milk. No metabolic effects of ingestedinsulin glargine on the breast-fed newborn/infant are anticipated since insulin glargine as a peptide isdigested into aminoacids in the human gastrointestinal tract. Breast-feeding women may requireadjustments in insulin dose and diet.

Animal studies do not indicate direct harmful effects with respect to fertility.

The patient's ability to concentrate and react may be impaired as a result of hypoglycaemia orhyperglycaemia or, for example, as a result of visual impairment. This may constitute a risk insituations where these abilities are of special importance (e.g. driving a car or using machines).

Patients should be advised to take precautions to avoid hypoglycaemia whilst driving. This isparticularly important in those who have reduced or absent awareness of the warning symptoms ofhypoglycaemia or have frequent episodes of hypoglycaemia. It should be considered whether it isadvisable to drive or use machines in these circumstances.

Hypoglycaemia (very common), in general the most frequent adverse reaction of insulin therapy, mayoccur if the insulin dose is too high in relation to the insulin requirement (see section 4.4).

The following related adverse reactions from clinical investigations are listed below by system organclass 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; not known: cannotbe estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

MedDRA Very common Common Uncommon Rare Very rare Not knownsystem organclasses

Immune system Allergicdisorders reactions

Metabolism and Hypoglycaemianutritiondisorders

Nervous system Dysgeusiadisorders

Eyes disorders Visualimpairment

Retinopathy

Skin and Lipohypertrophy Lipoatrophy Cutaneoussubcutaneous amyloidosistissue disorders

Musculoskeletal Myalgiaand connectivetissue disorders

General Injection site Oedemadisorders and reactionsadministrationsite conditions

Severe hypoglycaemic attacks, especially if recurrent, may lead to neurological damage. Prolonged orsevere hypoglycaemic episodes may be life-threatening.

In many patients, the signs and symptoms of neuroglycopenia are preceded by signs of adrenergiccounter-regulation. Generally, the greater and more rapid the decline in blood glucose, the moremarked is the phenomenon of counter-regulation and its symptoms (see section 4.4).

Immediate-type allergic reactions to insulin are rare. Such reactions to insulin (including insulinglargine) or the excipients may, for example, be associated with generalised skin reactions,angio-oedema, bronchospasm, hypotension and shock, and may be life-threatening.

A marked change in glycaemic control may cause temporary visual impairment, due to temporaryalteration in the turgidity and refractive index of the lens.

Long-term improved glycaemic control decreases the risk of progression of diabetic retinopathy.

However, intensification of insulin therapy with abrupt improvement in glycaemic control may beassociated with temporary worsening of diabetic retinopathy. In patients with proliferative retinopathy,particularly if not treated with photocoagulation, severe hypoglycaemic episodes may result intransient amaurosis.

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).

Injection site reactions include redness, pain, itching, hives, swelling, or inflammation. Most minorreactions to insulins at the injection site usually resolve in a few days to a few weeks.

Rarely, insulin may cause sodium retention and oedema particularly if previously poor metaboliccontrol is improved by intensified insulin therapy.

In general, the safety profile for children and adolescents (≤ 18 years of age) is similar to the safetyprofile for adults.

The adverse reaction reports received from post marketing surveillance included relatively morefrequent injection site reactions (injection site pain, injection site reaction) and skin reactions (rash,urticaria) in children and adolescents (≤ 18 years of age) than in adults.

Clinical study safety data are not available for children under 2 years.

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.

Insulin overdose may lead to severe and sometimes long-term and life-threatening hypoglycaemia.

Mild episodes of hypoglycaemia can usually be treated with oral carbohydrates. Adjustments in doseof the medicinal product, meal patterns, or physical activity may be needed.

More severe episodes with coma, seizure, or neurologic impairment may be treated withintramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrateintake and observation may be necessary because hypoglycaemia may recur after apparent clinicalrecovery.

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

ATC Code: A10AE04.

Semglee is a biosimilar medicinal product. Detailed information is available on the website of the

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

Insulin glargine is a human insulin analogue designed to have a low solubility at neutral pH. It iscompletely soluble at the acidic pH of the Semglee injection solution (pH 4). After injection into thesubcutaneous tissue, the acidic solution is neutralised leading to formation of micro-precipitates fromwhich small amounts of insulin glargine are continuously released, providing a smooth, peakless,predictable concentration/time profile with a prolonged duration of action.

Insulin glargine is metabolised into 2 active metabolites M1 and M2 (see section 5.2).

Insulin receptor binding: In vitro studies indicate that the affinity of insulin glargine and itsmetabolites M1 and M2 for the human insulin receptor is similar to the one of human insulin.

IGF-1 receptor binding: The affinity of insulin glargine for the human IGF-1 receptor is approximately5 to 8-fold greater than that of human insulin (but approximately 70 to 80-fold lower than the one of

IGF-1), whereas M1 and M2 bind the IGF-1 receptor with slightly lower affinity compared to humaninsulin.

The total therapeutic insulin concentration (insulin glargine and its metabolites) found in type 1diabetic patients was markedly lower than what would be required for a halfmaximal occupation of the

IGF-1 receptor and the subsequent activation of the mitogenic-proliferative pathway initiated by the

IGF-1 receptor. Physiological concentrations of endogenous IGF-1 may activate themitogenic-proliferative pathway; however, the therapeutic concentrations found in insulin therapy,including in Semglee therapy, are considerably lower than the pharmacological concentrationsrequired to activate the IGF-1 pathway.

The primary activity of insulin, including insulin glargine, is regulation of glucose metabolism.

Insulin and its analogues lower blood glucose levels by stimulating peripheral glucose uptake,especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibitslipolysis in the adipocyte, inhibits proteolysis and enhances protein synthesis.

In clinical pharmacology studies, intravenous insulin glargine and human insulin have been shown tobe equipotent when given at the same doses. As with all insulins, the time course of action of insulinglargine may be affected by physical activity and other variables.

In euglycaemic clamp studies in healthy subjects or in patients with type 1 diabetes, the onset of actionof subcutaneous insulin glargine was slower than with human NPH insulin, its effect profile wassmooth and peakless, and the duration of its effect was prolonged.

The following graph shows the results from a study in patients:

Activity profile in patients with type 1 diabetes

*determined as amount of glucose infused to maintain constant plasma glucose levels (hourly meanvalues)

The longer duration of action of subcutaneous insulin glargine is directly related to its slower rate ofabsorption and supports once daily administration. The time course of action of insulin and insulinanalogues such as insulin glargine may vary considerably in different individuals or within the sameindividual.

In a clinical study, symptoms of hypoglycaemia or counter-regulatory hormone responses were similarafter intravenous insulin glargine and human insulin both in healthy volunteers and patients with type1 diabetes.

In clinical studies, antibodies that cross-react with human insulin and insulin glargine were observedwith the same frequency in both NPH-insulin and insulin glargine treatment groups.

Effects of insulin glargine (once daily) on diabetic retinopathy were evaluated in an open-label 5-year

NPH-controlled study (NPH given bid) in 1024 type 2 diabetic patients in which progression ofretinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale wasinvestigated by fundus photography. No significant difference was seen in the progression of diabeticretinopathy when insulin glargine was compared to NPH insulin.

The ORIGIN (Outcome Reduction with Initial Glargine INtervention) study was a multicenter,randomised, 2x2 factorial design study conducted in 12,537 participants at high cardiovascular (CV)risk with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) (12% of participants) ortype 2 diabetes mellitus treated with ≤1 antidiabetic oral agent (88% of participants). Participants wererandomised (1:1) to receive insulin glargine (n=6264), titrated to reach FPG ≤95 mg/dl (5.3 mM), orstandard care (n=6273).

The first co-primary efficacy outcome was the time to the first occurrence of CV death, nonfatalmyocardial infarction (MI), or nonfatal stroke, and the second co-primary efficacy outcome was thetime to the first occurrence of any of the first co-primary events, or revascularisation procedure(coronary, carotid, or peripheral), or hospitalisation for heart failure.

Secondary endpoints included all-cause mortality and a composite microvascular outcome.

Insulin glargine did not alter the relative risk for CV disease and CV mortality when compared tostandard of care. There were no differences between insulin glargine and standard care for the twoco-primary outcomes; for any component endpoint comprising these outcomes; for all-cause mortality;or for the composite microvascular outcome.

Mean dose of insulin glargine by study end was 0.42 U/kg. At baseline, participants had a median

HbA1c value of 6.4% and median on-treatment HbA1c values ranged from 5.9 to 6.4% in the insulinglargine group, and 6.2% to 6.6% in the standard care group throughout the duration of follow-up.

The rates of severe hypoglycaemia (affected participants per 100 participant years of exposure) were1.05 for insulin glargine and 0.30 for standard care group and the rates of confirmed non-severehypoglycaemia were 7.71 for insulin glargine and 2.44 for standard care group. Over the course of this6-year study, 42% of the insulin glargine group did not experience any hypoglycaemia.

At the last on-treatment visit, there was a mean increase in body weight from baseline of 1.4 kg in theinsulin glargine group and a mean decrease of 0.8 kg in the standard care group.

In a randomised, controlled clinical study, paediatric patients (age range 6 to 15 years) with type 1diabetes (n=349) were treated for 28 weeks with a basal-bolus insulin regimen where regular humaninsulin was used before each meal. Insulin glargine was administered once daily at bedtime and NPHhuman insulin was administered once or twice daily. Similar effects on glycohemoglobin and theincidence of symptomatic hypoglycemia were observed in both treatment groups, however fastingplasma glucose decreased more from baseline in the insulin glargine group than in the NPH group.

There was less severe hypoglycaemia in the insulin glargine group as well. One hundred forty three ofthe patients treated with insulin glargine in this study continued treatment with insulin glargine in anuncontrolled extension study with mean duration of follow-up of 2 years. No new safety signals wereseen during this extended treatment with insulin glargine.

A crossover study comparing insulin glargine plus lispro insulin to NPH plus regular human insulin(each treatment administered for 16 weeks in random order) in 26 adolescent type 1 diabetic patientsaged 12 to 18 years was also performed. As in the paediatric study described above, fasting plasmaglucose reduction from baseline was greater in the insulin glargine group than in the NPH group.

HbA1c changes from baseline were similar between treatment groups; however blood glucose valuesrecorded overnight were significantly higher in the insulin glargine/ lispro group than the NPH/regulargroup, with a mean nadir of 5.4 mM versus 4.1 mM. Correspondingly, the incidences of nocturnalhypoglycaemia were 32% in the insulin glargine/lispro group versus 52% in the NPH/regular group.

A 24-week parallel group study was conducted in 125 children with type 1 diabetes mellitus aged 2 to6 years, comparing insulin glargine given once daily in the morning to NPH insulin given once ortwice daily as basal insulin. Both groups received bolus insulin before meals.

The primary aim of demonstrating non-inferiority of insulin glargine to NPH in all hypoglycaemia wasnot met and there was a trend to an increase of hypoglycemic events with insulin glargine [insulinglargine: NPH rate ratio (95% CI) = 1.18 (0.97-1.44)].

Glycohaemoglobin and glucose variabilities were comparable in both treatment groups. No new safetysignals were observed in this study.

In healthy subjects and diabetic patients, insulin serum concentrations indicated a slower and muchmore prolonged absorption and showed a lack of a peak after subcutaneous injection of insulinglargine in comparison to human NPH insulin. Concentrations were thus consistent with the timeprofile of the pharmacodynamic activity of insulin glargine. The graph above shows the activityprofiles over time of insulin glargine and NPH insulin.

Insulin glargine injected once daily will reach steady state levels in 2-4 days after the first dose.

When given intravenously the elimination half-life of insulin glargine and human insulin werecomparable.

After subcutaneous injection of Semglee in diabetic patients, insulin glargine is rapidly metabolized atthe carboxyl terminus of the Beta chain with formation of two active metabolites M1(21A-Gly-insulin) and M2 (21A-Gly-des-30B-Thr-insulin). In plasma, the principal circulatingcompound is the metabolite M1. The exposure to M1 increases with the administered dose of

Semglee.

The pharmacokinetic and pharmacodynamic findings indicate that the effect of the subcutaneousinjection with Semglee is principally based on exposure to M1. Insulin glargine and the metabolite M2were not detectable in the vast majority of subjects and, when they were detectable their concentrationwas independent of the administered dose of Semglee.

In clinical studies, subgroup analyses based on age and gender did not indicate any difference in safetyand efficacy in insulin glargine-treated patients compared to the entire study population.

Pharmacokinetics in children aged 2 to less than 6 years with type 1 diabetes mellitus was assessed inone clinical study (see section 5.1). Plasma “trough” levels of insulin glargine and its main M1 and

M2 metabolites were measured in children treated with insulin glargine, revealing plasmaconcentration patterns similar to adults, and providing no evidence for accumulation of insulinglargine or its metabolites with chronic dosing.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

Zinc chloride

Metacresol

Glycerol

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for injections

This medicinal product must not be mixed with other medicinal products.

3 years.

Shelf-life after first use of the pen

The medicinal product may be stored for a maximum of 4 weeks not above 25°C and away from directheat or direct light. Pens in use must not be stored in the refrigerator.

The pen cap must be put back on the pen after each injection in order to protect from light.

Not in-use pens

Store in a refrigerator (2°C-8°C).

Do not freeze or place next to the freezer compartment or a freezer pack.

Keep the pre-filled pen in the outer carton in order to protect from light.

In-use pens

For storage conditions after first opening of this medicinal product, see section 6.3.

Type I colourless glass cartridge with a plunger (bromobutyl rubber), sealed using lined seals(laminate of polyisoprene and bromobutyl rubber). The cartridge is assembled in a disposable peninjector.

Each pre-filled pen contains 3 ml of solution.

Packs of 1, 3, 5, 10 and multipack containing 10 (2 packs of 5) pens.

Not all pack sizes may be marketed.

Needles are not included in the pack.

Before first use, the pen must be stored at room temperature for 1 to 2 hours.

Inspect the cartridge before use. It must only be used if the solution is clear, colourless, with no solidparticles visible, and if it is of water-like consistency. Since Semglee is a solution, it does not requireresuspension before use.

Semglee must not be mixed with any other insulin or diluted. Mixing or diluting can change itstime/action profile and mixing can cause precipitation.

Empty pens must never be reused and must be properly discarded.

To prevent the possible transmission of disease, each pen must be used by one patient only.

Insulin label must always be checked before each injection to avoid medication errors between insulinglargine and other insulins (see section 4.4).

Semglee in pre-filled pen is only suitable for subcutaneous injections. If administration by syringe isnecessary, a vial should be used (see sections 4.2 and 4.4).

Before using Semglee pre-filled pen, the instructions for use included in the package leaflet must beread carefully.

The needle sizes compatible with this pen are:

- 31G, 5 mm,

- 32G, 4-6 mm,

- 34G, 4 mm.

Viatris Limited

Damastown Industrial Park

Mulhuddart

Dublin 15

DUBLIN

Ireland

EU/1/18/1270/001

EU/1/18/1270/002

EU/1/18/1270/003

EU/1/18/1270/004

EU/1/18/1270/005

Date of first authorisation: 23 March 2018

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

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