TOUJEO 300U / ml DOUBLESTAR injection for pre-filled pen medication leaflet

Toujeo 300 units/ml SoloStar, solution for injection in a pre-filled pen

Toujeo 300 units/ml DoubleStar, solution for injection in a pre-filled pen

Each ml contains 300 units insulin glargine* (equivalent to 10.91 mg).

SoloStar pen

Each pen contains 1.5 ml of solution for injection, equivalent to 450 units.

DoubleStar pen

Each pen contains 3 ml of solution for injection, equivalent to 900 units.

* Insulin glargine is produced by recombinant DNA technology in Escherichia coli.

For the full list of excipients, see section 6.1.

Solution for injection (injection).

Clear colourless solution.

Treatment of diabetes mellitus in adults, adolescents and children from the age of 6 years.

Toujeo is a basal insulin for once-daily administration at any time of the day, preferably at the sametime every day.

The dose regimen (dose and timing) should be adjusted according to individual response.

In type 1 diabetes mellitus, Toujeo must be combined with short-/rapid-acting insulin to covermealtime insulin requirements.

In patients with type 2 diabetes mellitus, Toujeo can also be given together with otheranti-hyperglycaemic medicinal products.

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

Flexibility in dosing time

When needed, patients can administer Toujeo up to 3 hours before or after their usual time ofadministration (see section 5.1).

Patients who forget a dose, should be advised to check their blood sugar and then resume their usualonce-daily dosing schedule. Patients should be informed not to inject a double dose to make up for aforgotten dose.

Patients with type 1 diabetes mellitus

Toujeo is to be used once-daily with meal-time insulin and requires individual dose adjustments.

The recommended daily starting dose is 0.2 units/kg followed by individual dose adjustments.

Switch between insulin glargine 100 units/ml and Toujeo

Insulin glargine 100 units/ml and Toujeo are not bioequivalent and are not directly interchangeable.

- When switching from insulin glargine 100 units/ml to Toujeo, this can be done on a unit-to-unitbasis, but a higher Toujeo dose (approximately 10-18%) may be needed to achieve target rangesfor plasma glucose levels.

- When switching from Toujeo to insulin glargine 100 units/ml, the dose should be reduced(approximately by 20%) to reduce the risk of hypoglycaemia.

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

Switch from other basal insulins to Toujeo

When switching from a treatment regimen with an intermediate or long-acting insulin to a regimenwith Toujeo, a change of the dose of the basal insulin may be required and the concomitantanti-hyperglycaemic treatment may need to be adjusted (dose and timing of additional regular insulinsor fast-acting insulin analogues or the dose of non-insulin anti-hyperglycaemic medicinal products).

- Switching from once-daily basal insulins to once-daily Toujeo can be done unit-to-unit based onthe previous basal insulin dose.

- Switching from twice-daily basal insulins to once-daily Toujeo, the recommended initial Toujeodose is 80% of the total daily dose of basal insulin that is being discontinued.

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

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, if there is a change in the timing of insulin dose or if othercircumstances arise that increase susceptibility to hypo-or hyperglycaemia (see section 4.4).

Switch from Toujeo to other basal insulins

Medical supervision with close metabolic monitoring is recommended during the switch and in theinitial weeks thereafter.

Please refer to the prescribing information of the medicinal product to which the patient is switching.

Toujeo can be used in elderly people, renal and hepatic impaired patients, and children andadolescents from the age of 6 years.

In the elderly, progressive deterioration of renal function may lead to a steady decrease in insulinrequirements (see section 4.8 and 5.1).

In patients with renal impairment, insulin requirements may be diminished due to reduced insulinmetabolism (see section 4.8).

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

Toujeo can be used in adolescents and children from the age of 6 years based on the same principles asfor adult patients (see sections 5.1and 5.2). When switching basal insulin to Toujeo, dose reduction ofbasal and bolus insulin needs to be considered on an individual basis, in order to minimise the risk ofhypoglycaemia (see section 4.4).

The safety and efficacy of Toujeo in children below 6 years of age have not been established. No dataare available.

Toujeo is for subcutaneous use only.

Toujeo is administered subcutaneously by injection in the abdominal wall, the deltoid or the thigh.

Injection sites must be rotated within a given injection area from one injection to the next in order toreduce the risk of lipodystrophy and cutaneous amyloidosis (see section 4.4 and 4.8).

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

Toujeo must not be used in insulin infusion pumps.

Toujeo is available in two pre-filled pens. The dose window shows the number of units of Toujeo tobe injected. The Toujeo SoloStar and Toujeo DoubleStar pre-filled pens have been specificallydesigned for Toujeo and no dose re-calculation is required for either pen.

Before using Toujeo SoloStar pre-filled pen or Toujeo DoubleStar pre-filled pen, the instructions foruse included in the package leaflet must be read carefully (see section 6.6).

With Toujeo SoloStar pre-filled pen, a dose of 1-80 units per single injection, in steps of 1 unit, can beinjected.

With Toujeo DoubleStar pre-filled pen a dose of 2-160 units per single injection, in steps of 2 units,can be injected.

When changing from Toujeo SoloStar to Toujeo DoubleStar, if the patient’s previous dose was an oddnumber (e.g. 23 units) then the dose must be increased or decreased by 1 unit (e.g. 24 or 22 units).

Toujeo DoubleStar prefilled pen is recommended for patients requiring at least 20 units per day. (seesection 6.6).

Toujeo must not be drawn from the cartridge of the Toujeo SoloStar pre-filled pen or Toujeo

DoubleStar pre-filled pen into a syringe or severe overdose can result (see section 4.4, 4.9 and 6.6).

A new sterile needle must be attached before each injection. Re-use of needles increases the risk ofblocked needles which may cause underdosing or overdosing (see section 4.4 and 6.6).

To prevent possible transmission of disease, insulin pens should never be used for more than oneperson, even when the needle is changed (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 product should be clearly recorded.

Toujeo 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.

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.

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.

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 stenosis 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 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 factors include:

- change in the injection area,

- 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).

Switch between insulin glargine 100 units/ml and Toujeo

Since insulin glargine 100 units/ml and Toujeo are not bioequivalent and are not interchangeable,switching may result in the need for a change in dose and should only be done under strict medicalsupervision (see section 4.2).

Switch between other insulins and Toujeo

Switching a patient between another type or brand of insulin and Toujeo should be done under strictmedical supervision. Changes in strength, brand (manufacturer), type (regular, NPH, lente, long-acting, etc.), origin (animal, human, human insulin analogue) and/or method of manufacture mayresult in the need for a change in dose (see section 4.2).

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.

Combination of Toujeo 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 Toujeo is considered. If the combination isused, 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.

Medication errors prevention

Medication errors have been reported in which other insulins, particularly rapid-acting insulins, havebeen accidentally administered instead of long-acting insulins. Insulin label must always be checkedbefore each injection to avoid medication errors between Toujeo and other insulins (see section 6.6).

To avoid dosing errors and potential overdose, the patients must be instructed to never use a syringe toremove Toujeo (insulin glargine 300 units/ml) from the Toujeo SoloStar pre-filled pen or Toujeo

DoubleStar pre-filled pen (see section 4.9 and 6.6).

A new sterile needle must be attached before each injection. Patients must also be instructed to notre-use needles. Re-use of needles increases the risk of blocked needles which may cause underdosingor overdosing. In the event of blocked needle, the patients must follow the instructions described in

Step 3 of the Instructions for Use accompanying the package leaflet (see section 6.6).

Patients must visually verify the number of selected units on the dose counter of the pen. Patients whoare blind or have poor vision should be instructed to get help/assistance from another person who hasgood vision and is trained in using the insulin device.

See also section 4.2 under “Method of administration”.

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 anti-hyperglycaemic 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.

There is no clinical experience with use of Toujeo in pregnant women.

For insulin glargine no clinical data on exposed pregnancies from controlled clinical studies areavailable. A large amount of data on pregnant women (more than 1,000 pregnancy outcomes with amedicinal product containing insulin glargine 100 units/ml) indicate no specific adverse effects onpregnancy and no specific malformative nor feto/neonatal toxicity of insulin glargine.

Animal data do not indicate reproductive toxicity.

The use of Toujeo 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 hyperglycaemia. 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 require adjustments 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.

The following adverse reactions were observed during clinical studies conducted with Toujeo (seesection 5.1) and during clinical experience with insulin glargine 100 units/ml.

Hypoglycaemia, in general the most frequent adverse reaction of insulin therapy, may occur if theinsulin dose is too high in relation to the insulin requirement.

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 Not knownsystem organ rareclasses

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.

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. In Toujeo clinicalstudies in adult patients, the incidence of allergic reactions was similar in Toujeo-treated patients(5.3%) and insulin glargine 100 units/ml-treated patients (4.5%).

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. In Toujeoclinical studies in adult patients, the incidence of injection site reactions was similar in Toujeo-treatedpatients (2.5%) and insulin glargine 100 units/ml-treated patients (2.8%).

Rarely, insulin may cause oedema particularly if previously poor metabolic control is improved byintensified insulin therapy.

Safety and efficacy of Toujeo have been demonstrated in a study in children aged 6 to less than 18years. The frequency, type and severity of adverse reactions in the paediatric population do notindicate differences to the experience in the general diabetes population (see section 5.1). Clinicalstudy safety data are not available for children under 6 years.

Based on the results from clinical studies, the safety profile of Toujeo in elderly patients and inpatients with renal impairment was similar to that of the overall population (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.

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: A10A E04.

The primary activity of insulin, including insulin glargine, is regulation of glucose metabolism. Insulinand its analogues lower blood glucose levels by stimulating peripheral glucose uptake, especially byskeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis in theadipocyte, inhibits proteolysis and enhances protein synthesis.

Insulin glargine is a human insulin analogue designed to have a low solubility at neutral pH. At pH 4,insulin glargine is completely soluble. After injection into the subcutaneous tissue, the acidic solutionis neutralised leading to formation of a precipitate from which small amounts of insulin glargine arecontinuously released.

As observed in euglycaemic clamp studies in patients with type 1 diabetes, the glucose lowering effectof Toujeo was more stable and prolonged in comparison with insulin glargine 100 units/ml aftersubcutaneous injection. Figure 1 shows results from a cross-over study in 18 patients with type 1diabetes conducted for a maximum of 36 hours after injection. The effect of Toujeo was beyond 24hours (up to 36 hours) at clinically relevant doses.

The more sustained release of insulin glargine from the Toujeo precipitate compared to insulinglargine 100 units/ml is attributable to the reduction of the injection volume by two thirds that resultsin a smaller precipitate surface area.

Figure 1: Activity profile at steady state in patients with type 1 diabetes in a 36-hour euglycaemicclamp study

*GIR: Glucose infusion rate: determined as amount of glucose infused to maintain constant plasma glucose levels (hourlymean values). The end of the observation period was 36 hours.

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 half maximal occupation ofthe IGF-1 receptor and the subsequent activation of the mitogenic-proliferative pathway initiated bythe IGF-1 receptor. Physiological concentrations of endogenous IGF-1 may activate themitogenic-proliferative pathway; however, the therapeutic concentrations found in insulin therapy,including in Toujeo therapy, are considerably lower than the pharmacological concentrations requiredto activate the IGF-1 pathway.

In a clinical pharmacology study, 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 insulin glargine may be affected by physical activityand other variables.

The overall efficacy and safety of Toujeo (insulin glargine 300 units/ml) once-daily on glycaemiccontrol was compared to that of once-daily insulin glargine 100 units/ml in open-label, randomised,active-control, parallel studies of up to 26 weeks of duration, including 546 patients with type 1diabetes mellitus and 2,474 patients with type 2 diabetes mellitus (Table 1 and 2).

Results from all clinical trials with Toujeo indicated that reductions in HbA1c from baseline to end oftrial were non-inferior to insulin glargine 100 units/ml. Plasma glucose reductions at the end of thetrial with Toujeo were similar to insulin glargine 100 units/ml with a more gradual reduction duringthe titration period with Toujeo. Glycaemic control was similar when Toujeo was administered oncedaily in the morning or in the evening.

Improvement in HbA1C was not affected by, gender, ethnicity, age, diabetes duration (<10 yearsand ≥10 years), HbA1c value at baseline (<8% or ≥8%) or baseline body mass index (BMI).

At the end of these treat-to-target trials, depending on the patient population and concomitant therapy,a 10-18% higher dose was observed in the Toujeo group than in the comparator group (Table 1 and 2).

Results from clinical trials demonstrated that the incidence of confirmed hypoglycaemia (at any timeof the day and nocturnal) was lower in patients treated with Toujeo compared to insulin glargine100 units/ml-treated patients, in patients with type 2 diabetes treated in combination with eithernon-insulin anti-hyperglycaemic medicinal product or mealtime insulin.

The superiority of Toujeo over insulin glargine 100 units/ml in lowering the risk of confirmednocturnal hypoglycaemia was shown in patients with type 2 diabetes treated with basal insulin incombination with either non-insulin anti-hyperglycaemic medicinal product (18% risk reduction) ormealtime insulin (21% risk reduction) during the period from week 9 to end of study period.

Overall, these effects on hypoglycaemia risk were consistently observed whatever the age, gender,

BMI and duration of diabetes (<10 years and ≥10 years) in Toujeo-treated patients compared to insulinglargine 100 units/ml-treated patients.

In patients with type 1 diabetes, the incidence of hypoglycaemia was similar in patients treated with

Toujeo compared to insulin glargine 100 units/ml-treated patients (Table 3).

Table 1: Results from clinical trials in type 1 diabetes mellitus26 weeks of treatment

Toujeo IGlar

Treatment in combination with Meal-time insulin analogue

Number of subjects treated (mITTa) 273 273

HbA1c

Baseline mean 8.13 8.12

Adjusted Mean change from baseline -0.40 -0.44

Adjusted Mean differenceb 0.04 [-0.098 to 0.185]

Basal insulin dosec (U/kg)

Baseline mean 0.32 0.32

Mean change from baseline 0.15 0.09

Body weightd (kg)

Baseline mean 81.89 81.80

Mean change from baseline 0.46 1.02

IGlar: Insulin glargine 100 units/mla mITT: Modified intention-to-treatb Treatment difference: Toujeo- insulin glargine 100 units/ml; [95% Confidence Interval]c Change from baseline to Month 6 (observed case)d Change from baseline to Last main 6-month on-treatment value

Table 2: Results from clinical trials in type 2 diabetes mellitus26 weeks of treatment

Patients previously Patients previously Previously insulintreated with basal treated with basal naive patientsinsulin insulin

Meal-time insulin Non-insulin anti-hyperglycaemic medicinal

Treatment in combination withanalog+/-metformin products

Toujeo IGlar Toujeo IGlar Toujeo IGlar

Number of patients treateda 404 400 403 405 432 430

HbA1c

Baseline mean 8.13 8.14 8.27 8.22 8.49 8.58

Adjusted mean change from -0.90 -0.87 -0.73 -0.70 -1.42 -1.46baseline

Adjusted mean differenceb -0.03 -0.03 0.04[-0.144 to 0.083] [-0.168 to 0.099] [-0.090 to 0.174]

Basal insulin dosec (U/kg)

Baseline mean 0.67 0.67 0.64 0.66 0.19 0.19

Mean change from baseline 0.31 0.22 0.30 0.19 0.43 0.34

Body weightd (kg)

Baseline mean 106.11 106.50 98.73 98.17 95.14 95.65

Mean change from baseline 0.93 0.90 0.08 0.66 0.50 0.71

IGlar: Insulin glargine 100 units/mla mITT: Modified intention-to-treatb Treatment difference: Toujeo- insulin glargine 100 units/ml; [95% Confidence Interval]c Change from baseline to Month 6 (observed case)d Change from baseline to Last main 6-month on-treatment value

Table 3 ­ Summary of the hypoglycaemic episodes of the clinical study in patients with type 1 and type 2diabetes mellitus

Diabetic Type 1 diabetes mellitus Type 2 diabetes mellitus Type2 diabetes mellituspopulation Patients previously Patients previously Patients previouslytreated with basal treated with basal Insulin naive or oninsulin insulin basal insulin

Treatment in Non-insulin anti-

Meal-time insulincombination Meal-time insulin analog hyperglycaemicanalog+/-metforminwith medicinal products

Toujeo IGlar Toujeo IGlar Toujeo IGlar

Incidence (%) of severea hypoglycaemia (n/Total N)6.6 9.5 5.0 5.7 1.0 1.2

Entire study (18/274) (26/275) (20/404) (23/402) (8/838) (10/844)periodd

RR*: 0.69 [0.39;1.23] RR: 0.87 [0.48;1.55] RR: 0.82 [0.33;2.00]

Incidence (%) of confirmedb hypoglycaemia (n/Total N)93.1 93.5 81.9 87.8 57.6 64.5

Entire study (255/274) (257/275) (331/404) (353/402) (483/838) (544/844)period

RR: 1.00 [0.95;1.04] RR: 0.93 [0.88; 0.99] RR: 0.89 [0.83; 0.96]

Incidence (%) of confirmed nocturnalc hypoglycaemia (n/Total N)

From week 9 to 59.3 56.0 36.1 46.0 18.4 22.5end of study (162/273) (153/273) (146/404) (184/400) (154/835) (188/835)period RR: 1.06 [0.92;1.23] RR: 0.79 [0.67;0.93] RR: 0.82 [0.68;0.99]

IGlar: Insulin glargine 100 units/mla Severe hypoglycaemia: Episode requiring assistance of another person to actively administer carbohydrate,glucagon, or other resuscitative actions.b Confirmed hypoglycaemia: Any severe hypoglycaemia and/or hypoglycaemia confirmed by plasma glucosevalue ≤3.9 mmol/l.c Nocturnal hypoglycaemia: Episode that occurred between 00:00 and 05:59 hoursd 6-month treatment period

*RR: estimated risk ratio; [95% Confidence Interval]

Flexibility in dosing time

The safety and efficacy of Toujeo administered with a fixed or flexible dosing time were alsoevaluated in 2 randomized, open-label clinical studies for 3 months. Type 2 diabetic patients (n=194)received Toujeo once daily in the evening, either at the same time of the day (fixed time ofadministration) or within 3 hours before or after the usual time of administration (flexible dosingtime). Administration with a flexible dosing time had no effect on glycaemic control and the incidenceof hypoglycaemia.

Antibodies

Results from studies comparing Toujeo and insulin glargine 100 units/ml did not indicate anydifference in term of development of anti-insulin antibodies, on efficacy, safety or dose of basalinsulin between Toujeo and insulin glargine 100 units/ml.

Mean change in body weight of less than 1 kg at the end of the 6-month period was observed in

Toujeo-treated patients (see Table 1 and 2).

Results from a study on progression of diabetic retinopathy

Effects of insulin glargine 100 units/ml (once daily) on diabetic retinopathy were evaluated in anopen-label 5 year NPH-controlled study (NPH given bid) in 1024 type 2 diabetic patients in whichprogression of retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study(ETDRS) scale was investigated by fundus photography. No significant difference was seen in theprogression of diabetic retinopathy when insulin glargine100 units/ml was compared to NPH insulin.

Long term efficacy and safety outcome study

The ORIGIN (Outcome Reduction with Initial Glargine INtervention) study was a multicenter,randomized, 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). Participantswere randomized (1:1) to receive insulin glargine 100 units/ml (n=6264), titrated to reach FPG≤95 mg/dl (5.3 mM), or standard 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 100 units/ml did not alter the relative risk for CV disease and CV mortality whencompared to standard of care. There were no differences between insulin glargine and standard carefor the two co-primary outcomes; for any component endpoint comprising these outcomes; forall-cause mortality; or for the composite microvascular outcome.

Mean dose of insulin glargine 100 units/ml by study end was 0.42 U/kg. At baseline, participants had amedian HbA1c value of 6.4% and median on-treatment HbA1c values ranged from 5.9 to 6.4% in theinsulin glargine 100 units/ml group, and 6.2% to 6.6% in the standard care group throughout theduration of follow-up.

The rates of severe hypoglycaemia (affected participants per 100 participant years of exposure) were1.05 for insulin glargine 100 units/ml and 0.30 for standard care group and the rates of confirmednon-severe hypoglycaemia were 7.71 for insulin glargine 100 units/ml and 2.44 for standard caregroup. Over the course of this 6-year study, 42% of the insulin glargine 100 units/ml group did notexperience 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 100 units/ml group and a mean decrease of 0.8 kg in the standard care group.

Pediatric population

The efficacy and safety of Toujeo have been studied in a 1:1 randomized controlled open label clinicaltrial in children and adolescents with type 1 diabetes mellitus for a period of 26 weeks (n=463). Patientsin the Toujeo arm included 73 children aged <12 years and 160 children aged ≥12 years. Toujeo dosedonce daily showed similar reduction in HbA1c and FPG from baseline to week 26 compared to insulinglargine 100 units/mL.

The dose-response analysis showed that following the initial titration phase, the body weight adjusteddoses in pediatric patients are higher than in adult patients at steady state.

Overall the incidence of hypoglycaemia in patients in any category was similar in both treatment groups,with 97.9% of patients in the Toujeo group and 98.2% in the insulin glargine 100 units/mL groupreporting at least one event. Similarly, nocturnal hypoglycaemia was comparable in the Toujeo andinsulin glargine 100 units/mL treatment groups. The percentage of patients reporting severehypoglycaemia was lower in patients in the Toujeo group as compared to patients in the insulin glargine100 units/mL group, 6% and 8.8% respectively. The percentage of patients with hyperglycaemicepisodes with ketosis was lower for Toujeo versus insulin glargine 100 units/mL, 6.4% and 11.8%,respectively. No safety issues were identified with Toujeo with respect to adverse events and standardsafety parameters. Antibody development was sparse and had no clinical impact. Efficacy and safetydata for paediatric patients with type 2 diabetes mellitus have been extrapolated from data for adolescentand adult patients with type 1 diabetes mellitus and adult patients with type 2 diabetes mellitus. Resultssupport the use of Toujeo in paediatric patients with type 2 diabetes mellitus.

In healthy subjects and diabetic patients, insulin serum concentrations indicated a slower and moreprolonged absorption resulting in a flatter time-concentration profile after subcutaneous injection of

Toujeo in comparison to insulin glargine 100 units/ml.

Pharmacokinetic profiles were consistent with the pharmacodynamic activity of Toujeo.

Steady state level within the therapeutic range is reached after 3-4 days of daily Toujeo administration.

After subcutaneous injection of Toujeo, the intra-subject variability, defined as the coefficient ofvariation for the insulin exposure during 24 hours was low at steady state (17.4%).

After subcutaneous injection of insulin glargine, insulin glargine is rapidly metabolized at the carboxylterminus 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 circulating compound is the metabolite M1.

The exposure to M1 increases with the administered dose of insulin glargine. The pharmacokineticand pharmacodynamic findings indicate that the effect of the subcutaneous injection with insulinglargine is principally based on exposure to M1. Insulin glargine and the metabolite M2 were notdetectable in the vast majority of subjects and, when they were detectable their concentration wasindependent of the administered dose and formulation of insulin glargine.

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

The half-life after subcutaneous administration of Toujeo is determined by the rate of absorption fromthe subcutaneous tissue. The half-life of Toujeo after subcutaneous injection is 18-19 hoursindependent of dose.

Population pharmacokinetic analysis was conducted for Toujeo based on concentration data of itsmain metabolite M1 using data from 75 pediatric subjects (6 to <18 years of age) with type 1 diabetes.

Body weight affects the clearance of Toujeo in a nonlinear way. As a consequence, exposure (AUC) inpediatric patients is slightly lower as compared to adult patients when receiving the same body weightadjusted dose.

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.

Toujeo must not be mixed or diluted with any other insulin or other medicinal products.

Mixing or diluting Toujeo changes its time/action profile and mixing causes precipitation.

Toujeo SoloStar30 months.

Toujeo DoubleStar36 months.

Shelf life after first use of the pen

The medicinal product may be stored for a maximum of 6 weeks below 30°C and away from direct heator direct light. Pens in use must not be stored in the refrigerator. The pen cap must be put back on the penafter each injection in order to protect from light.

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.

After first use or if carried as a spare

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

SoloStar pen

Cartridge (type 1 colourless glass) with a grey plunger (bromobutyl rubber) and a flanged cap(aluminium) with a stopper (laminate of isoprene and bromobutyl rubber).The cartridge is sealed in adisposable pen injector. Each cartridge contains 1.5 ml solution.

Packs of 1, 3, 5 and 10 pens are available. Not all pack sizes may be marketed.

Needles are not included in the pack.

DoubleStar pen

Cartridge (type 1 colourless glass) with a black plunger (bromobutyl rubber) and a flanged cap(aluminium) with a stopper (laminate of isoprene and bromobutyl rubber).The cartridge is sealed in adisposable pen injector. Each cartridge contains 3 ml solution.

Packs of 1, 3, 6 (2 packs of 3), 9 (3 packs of 3) and 10 pens are available. Not all pack sizes may bemarketed.

Needles are not included in the pack.

Before first use, the pen must be stored at room temperature at least 1 hour before use.

Before using Toujeo SoloStar or Toujeo DoubleStar pre-filled pen, the Instructions for Use included inthe package leaflet must be read carefully. Toujeo pre-filled pens have to be used as recommended inthese Instructions for Use (see section 4.2). Instruct patients to perform a safety test as described in

Step 3 of the Instructions for Use. If they don’t, the full dose might not be delivered. If this occurs,patients should increase the frequency of checking their blood glucose levels and might need toadminister additional insulin.

The cartridge should be inspected before use. It must only be used if the solution is clear, colourless,with no solid particles visible, and if it is of water-like consistency. Since Toujeo is a clear solution, itdoes not require resuspension before use.

Insulin label must always be checked before each injection to avoid medication errors between Toujeoand other insulins. The strength“300” is highlighted in honey gold on the label (see section 4.4).

Patients should be informed that the dose counter of Toujeo SoloStar or Toujeo DoubleStar pre-filledpen shows the number of units of Toujeo to be injected. No dose re-calculation is required.

* The Toujeo SoloStar pen contains 450 units of Toujeo. It delivers doses of 1-80 units perinjection, in steps of 1 unit.

* The Toujeo DoubleStar pen contains 900 units of Toujeo. It delivers doses of 2-160 units perinjection, in steps of 2 units.

o To reduce potential underdose, Toujeo DoubleStar is recommended for patientsrequiring at least 20 units per day.

* If safety tests are not performed before the first use of a new pen, insulin underdose can occur.

A syringe must never be used to withdraw Toujeo from the cartridge of the pre-filled pen or severeoverdose can result (see section 4.2, pct. 4.4 and 4.9).

A new sterile needle must be attached before each injection. Needles must be discarded immediatelyafter use. Needles must not be re-used. Re-use of needles increases the risk of blocked needles whichmay cause underdosing or overdosing. Using a new sterile needle for each injection also minimizes therisk of contamination and infection. In the event of blocked needle, the patients must follow theinstructions described in Step 3 of the Instructions for Use accompanying the package leaflet (seesection 4.2 and 4.4).

Used needles should be thrown away in a puncture resistant container or disposed of in accordancewith local requirements.

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

To prevent possible transmission of disease, insulin pen should never be used by for more than oneperson, even when the needle is changed (see section 4.2).

Sanofi-Aventis Deutschland GmbH, D-65926 Frankfurt am Main, Germany

EU/1/00/133/033

EU/1/00/133/034

EU/1/00/133/035

EU/1/00/133/036

EU/1/00/133/037

EU/1/00/133/038

EU/1/00/133/039

EU/1/00/133/040

EU/1/00/133/041

Date of first authorisation: 27 June 2000

Date of latest renewal: 17 February 2015

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

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