Insulin glargine: prescribing information – dosing, contraindications, interactions, side effects

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

Posology
Lantus contains insulin glargine, an insulin analogue, and has a prolonged duration of action.
Lantus should be administered once daily at any time but at the same time each day.

The dose regimen (dose and timing) should be individually adjusted. In patients with type 2 diabetes mellitus, Lantus 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 Lantus and are not 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 insulin requirements.

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

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

Paediatric population
- Adolescents and children aged 2 years and older patients
Safety and efficacy of Lantus have been established in adolescents and children aged 2 years and older (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 Lantus have not been established. No data are available.

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

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

Switch from insulin glargine 300 units/ml to Lantus
Lantus and Toujeo (insulin glargine 300 units/ml) are not bioequivalent and are not directly interchangeable. To reduce the risk of hypoglycaemia, patients who are changing their basal insulin regimen from an insulin regimen with once daily insulin glargine 300 units/ml to a once daily regimen with Lantus should reduce their dose by approximately 20%.

During the first weeks the reduction should, at least partially, be compensated by an increase in mealtime 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 in dose regimen may become necessary. Dose adjustment may also be required, for example, if the patient's weight or life-style changes, change of timing of insulin dose or other circumstances arise that increase susceptibility to hypo- or hyperglycaemia (see section 4.4).

Patients with high insulin doses because of antibodies to human insulin may experience an improved insulin response with Lantus.

Method of administration
Lantus is administered subcutaneously.

Lantus should not be administered intravenously. The prolonged duration of action of Lantus is dependent on its injection into subcutaneous tissue. Intravenous administration of the usual subcutaneous dose could result in severe hypoglycaemia.

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

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

Lantus 100 units/ml solution for injection in a vial
For further details on handling, see section 6.6.

Lantus 100 units/ml solution for injection in a cartridge
Lantus 100 units/ml in cartridges is only suitable for subcutaneous injections from a reusable pen. If administration by syringe is necessary, a vial should be used (see section 4.4).
For further details on handling, see section 6.6.

Lantus SoloStar 100 units/ml solution for injection in a pre-filled pen
Lantus SoloStar 100 units/ml in pre-filled pen is only suitable for subcutaneous injections. If administration by syringe is necessary, a vial should be used (see section 4.4).
Before using SoloStar, the instructions for use included in the package leaflet must be read carefully (see section 6.6).

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

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

Tabulated list of adverse reactions
The following related adverse reactions from clinical investigations are listed below 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; not known: cannot be estimated from the available data).

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

MedDRA system organ classes
Very common
Common
Uncommon
Rare
Very rare
Not known
Immune system disorders

Allergic reactions

Metabolism and nutrition disorders
Hypoglycaemia

Nervous system disorders

Dysgeusia

Eyes disorders

Visual impairment

Retinopathy

Skin and subcutaneous tissue disorders

Lipohypertro- phy
Lipoatrophy

Cutaneous amyloidosis
Musculoskeletal and connective tissue disorders

Myalgia

General disorders and administration site conditions

Injection site reactions

Oedema

Description of selected adverse reactions
Metabolism and nutrition disorders
Severe hypoglycaemic attacks, especially if recurrent, may lead to neurological damage. Prolonged or severe hypoglycaemic episodes may be life-threatening.

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

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

Eyes disorders
A marked change in glycaemic control may cause temporary visual impairment, due to temporary alteration 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 be associated with temporary worsening of diabetic retinopathy. In patients with proliferative retinopathy, particularly if not treated with photocoagulation, severe hypoglycaemic episodes may result in transient amaurosis.

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).

General disorders and administration site conditions
Injection site reactions include redness, pain, itching, hives, swelling, or inflammation. Most minor reactions 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 metabolic control is improved by intensified insulin therapy.

Paediatric population
In general, the safety profile for children and adolescents (≤18 years of age) is similar to the safety profile for adults.
The adverse reaction reports received from post marketing surveillance included relatively more frequent 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 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 national reporting system listed in Appendix V.

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

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

In case of insufficient glucose control or a tendency to hyper- or hypoglycaemic episodes, the patient's adherence to the prescribed treatment regimen, injection sites and proper injection technique and all other 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 medical supervision. 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 need for a change in dose.

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.

Hypoglycaemia
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 supply with Lantus, less nocturnal but more early morning hypoglycaemia can be expected.

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

Patients should be aware of circumstances where warning symptoms of hypoglycaemia are diminished. The warning symptoms of hypoglycaemia may be changed, be less pronounced or be absent 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 the patient'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 awareness of hypoglycaemia symptoms are essential to reduce the risk of hypoglycaemia. Factors increasing the susceptibility to hypoglycaemia require particularly close monitoring and may necessitate dose adjustment. These 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 or adrenocortical insufficiency),
- concomitant treatment with certain other medicinal products (see section 4.5).

Intercurrent illness
Intercurrent illness requires intensified metabolic monitoring. In many cases urine tests for ketones are indicated, and often it is necessary to adjust the insulin dose. The insulin requirement is often increased. Patients with type 1 diabetes must continue to consume at least a small amount of carbohydrates 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 antibodies
Insulin administration may cause insulin antibodies to form. In rare cases, the presence of such insulin antibodies may necessitate adjustment of the insulin dose in order to correct a tendency to hyper- or hypoglycaemia (see section 5.1).

Pens to be used with Lantus 100 units/ml in cartridges
Lantus 100 units/ml in cartridges is only suitable for subcutaneous injections from a reusable pen. If administration by syringe is necessary, a vial should be used. The Lantus cartridges should only be used with the following pens:
- JuniorSTAR which delivers Lantus in 0.5 unit dose increments
- ClikSTAR, Tactipen, Autopen 24, AllStar and AllStar PRO which all deliver Lantus in 1 unit dose increments.
These cartridges should not be used with any other reusable pen as the dosing accuracy has only been established with the listed pens.

Not all of these pens may be marketed in your country (see section 4.2 and 6.6)

Handling of the SoloStar pre-filled pen
Lantus SoloStar 100 units/ml in pre-filled pen is only suitable for subcutaneous injections. If administration by syringe is necessary, a vial should be used (see section 4.2). Before using SoloStar, the instructions for use included in the package leaflet must be read carefully. SoloStar has to be used as recommended in these instructions for use (see section 6.6).

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

Combination of Lantus 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 in mind if treatment with the combination of pioglitazone and Lantus is considered. If the combination is 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.

Excipients
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 insulin glargine.

Substances that may enhance the blood-glucose-lowering effect and increase susceptibility to hypoglycaemia 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 and olanzapine) and protease inhibitors.

Beta-blockers, clonidine, lithium salts or alcohol may either potentiate or weaken the blood-glucose-lowering effect of insulin. Pentamidine may cause hypoglycaemia, which may sometimes 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.

Pregnancy
For insulin glargine no clinical data on exposed pregnancies from controlled clinical studies are available. A large amount of data on pregnant women (more than 1000 pregnancy outcomes) indicate no specific adverse effects of insulin glargine on pregnancy and no specific malformative nor foeto/neonatal toxicity of insulin glargine. Animal data do not indicate reproductive toxicity.
The use of Lantus may be considered during pregnancy, if clinically needed.

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

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

Fertility
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 or hyperglycaemia or, for example, as a result of visual impairment. This may constitute a risk in situations 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 is particularly important in those who have reduced or absent awareness of the warning symptoms of hypoglycaemia or have frequent episodes of hypoglycaemia. It should be considered whether it is advisable to drive or use machines in these circumstances.

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

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

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.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Drugs used in diabetes, insulins and analogues for injection, long-acting.
ATC Code: A10AE04.

Mechanism of action
Insulin glargine is a human insulin analogue designed to have a low solubility at neutral pH. It is completely soluble at the acidic pH of the Lantus injection solution (pH 4). After injection into the subcutaneous tissue, the acidic solution is neutralised leading to formation of micro-precipitates from which 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 its metabolites 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 approximately 5 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 human insulin.

The total therapeutic insulin concentration (insulin glargine and its metabolites) found in type 1 diabetic patients was markedly lower than what would be required for a half maximal 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 the mitogenic-proliferative pathway; however, the therapeutic concentrations found in insulin therapy, including in Lantus therapy, are considerably lower than the pharmacological concentrations required 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 inhibits lipolysis in the adipocyte, inhibits proteolysis and enhances protein synthesis.

In clinical pharmacology studies, intravenous insulin glargine and human insulin have been shown to be equipotent when given at the same doses. As with all insulins, the time course of action of insulin glargine 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 action of subcutaneous insulin glargine was slower than with human NPH insulin, its effect profile was smooth 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 mean values)

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

After subcutaneous injection of Lantus in diabetic patients, insulin glargine is rapidly metabolized at the 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 circulating compound is the metabolite M1. The exposure to M1 increases with the administered dose of Lantus.
The pharmacokinetic and pharmacodynamic findings indicate that the effect of the subcutaneous injection with Lantus is principally based on exposure to M1. Insulin glargine and the metabolite M2 were not detectable in the vast majority of subjects and, when they were detectable their concentration was independent of the administered dose of Lantus.

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

Paediatric population

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

Posology
Toujeo is a basal insulin for once-daily administration at any time of the day, preferably at the same time 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 cover mealtime insulin requirements.

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

The potency of this medicinal product is stated in units. These units are exclusive to Toujeo and are not 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 of administration (see section 5.1).

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

Initiation

Patients with type 1 diabetes mellitus
Toujeo is to be used once-daily with meal-time insulin and requires individual dose adjustments.

Patients with type 2 diabetes mellitus
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-unit basis, but a higher Toujeo dose (approximately 10-18%) may be needed to achieve target ranges for 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 regimen with Toujeo, a change of the dose of the basal insulin may be required and the concomitant anti-hyperglycaemic treatment may need to be adjusted (dose and timing of additional regular insulins or 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 on the previous basal insulin dose.
• Switching from twice-daily basal insulins to once-daily Toujeo, the recommended initial Toujeo dose 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 improved insulin 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 in dose regimen may become necessary. Dose adjustment may also be required, for example, if the patient's weight or life-style changes, if there is a change in the timing of insulin dose or if other circumstances 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 the initial weeks thereafter.
Please refer to the prescribing information of the medicinal product to which the patient is switching.

Special populations

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

Elderly population (≥65 years old)
In the elderly, progressive deterioration of renal function may lead to a steady decrease in insulin requirements (see section 4.8 and 5.1).

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

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

Paediatric population
Toujeo can be used in adolescents and children from the age of 6 years based on the same principles as for adult patients (see sections 5.1and 5.2). When switching basal insulin to Toujeo, dose reduction of basal and bolus insulin needs to be considered on an individual basis, in order to minimise the risk of hypoglycaemia (see section 4.4).
The safety and efficacy of Toujeo in children below 6 years of age have not been established. No data are available.

Method of administration
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 to reduce 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 is dependent on its injection into subcutaneous tissue. Intravenous administration of the usual subcutaneous 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 to be injected. The Toujeo SoloStar and Toujeo DoubleStar pre-filled pens have been specifically designed 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 for use 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 be injected.

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 odd number (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. (see section 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 of blocked 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 one person, 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.

Summary of the safety profile
The following adverse reactions were observed during clinical studies conducted with Toujeo (see section 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 the insulin dose is too high in relation to the insulin requirement.

Tabulated list of adverse reactions
The following related adverse reactions from clinical investigations are listed below 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; not known: cannot be estimated from the available data).

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

MedDRA system organ classes
Very common
Common
Uncommon Rare
Very rare
Not known
Immune system disorders

Allergic reactions

Metabolism and nutrition disorders
Hypoglycaemia

Nervous system disorders

Dysgeusia
Eyes disorders

Visual impairment

Retinopathy

Skin and subcutaneous tissue disorders

Lipohypertrophy Lipoatrophy

Cutaneous amyloidosis
Musculoskeletal and connective tissue disorders

Myalgia

General disorders and administration site conditions

Injection site reactions

Oedema

Description of selected adverse reactions
Metabolism and nutrition disorders
Severe hypoglycaemic attacks, especially if recurrent, may lead to neurological damage. Prolonged or severe hypoglycaemic episodes may be life-threatening.

In many patients, the signs and symptoms of neuroglycopenia are preceded by signs of adrenergic counter-regulation. Generally, the greater and more rapid the decline in blood glucose, the more marked is the phenomenon of counter-regulation and its symptoms.

Immune system disorders
Immediate-type allergic reactions to insulin are rare. Such reactions to insulin (including insulin glargine) 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 clinical studies 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%).

Eyes disorders
A marked change in glycaemic control may cause temporary visual impairment, due to temporary alteration 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 be associated with temporary worsening of diabetic retinopathy. In patients with proliferative retinopathy, particularly if not treated with photocoagulation, severe hypoglycaemic episodes may result in transient amaurosis.

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).

General disorders and administration site conditions
Injection site reactions include redness, pain, itching, hives, swelling, or inflammation. Most minor reactions to insulins at the injection site usually resolve in a few days to a few weeks. In Toujeo clinical studies in adult patients, the incidence of injection site reactions was similar in Toujeo-treated patients (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 by intensified insulin therapy.

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

Other special populations
Based on the results from clinical studies, the safety profile of Toujeo in elderly patients and in patients with renal impairment was similar to that of the overall population (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 national reporting system listed in Appendix V.

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

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

In case of insufficient glucose control or a tendency to hyper- or hypoglycaemic episodes, the patient's adherence to the prescribed treatment regimen, injection sites and proper injection technique and all other 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 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.

Hypoglycaemia
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 in patients in whom hypoglycaemic episodes might be of particular clinical relevance, such as in patients with significant stenosis of the coronary arteries or of the blood vessels supplying the brain (risk of cardiac or cerebral complications of hypoglycaemia) as well as in patients with proliferative retinopathy, particularly if not treated with photocoagulation (risk of transient amaurosis following hypoglycaemia).

Patients should be aware of circumstances where warning symptoms of hypoglycaemia are diminished. The warning symptoms of hypoglycaemia may be changed, be less pronounced or be absent 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 the patient'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 awareness of hypoglycaemia symptoms are essential to reduce the risk of hypoglycaemia. Factors increasing the susceptibility to hypoglycaemia require particularly close monitoring and may necessitate dose adjustment. 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 or adrenocortical 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 medical supervision (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 strict medical supervision. 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 need for a change in dose (see section 4.2).

Intercurrent illness
Intercurrent illness requires intensified metabolic monitoring. In many cases urine tests for ketones are indicated, and often it is necessary to adjust the insulin dose. The insulin requirement is often increased. Patients with type 1 diabetes must continue to consume at least a small amount of carbohydrates 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 antibodies
Insulin administration may cause insulin antibodies to form. In rare cases, the presence of such insulin antibodies may necessitate adjustment of the insulin dose in order to correct a tendency to hyper-or hypoglycaemia.

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 in mind if treatment with the combination of pioglitazone and Toujeo is considered. If the combination is 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.

Medication errors prevention
Medication errors have been reported in which other insulins, particularly rapid-acting insulins, have been accidentally administered instead of long-acting insulins. Insulin label must always be checked before 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 to remove 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 not re-use needles. Re-use of needles increases the risk of blocked needles which may cause underdosing

or 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 who are blind or have poor vision should be instructed to get help/assistance from another person who has good vision and is trained in using the insulin device.

See also section 4.2 under “Method of administration”.

Excipients
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 insulin glargine.

Substances that may enhance the blood-glucose-lowering effect and increase susceptibility to hypoglycaemia 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 and olanzapine) and protease inhibitors.

Beta-blockers, clonidine, lithium salts or alcohol may either potentiate or weaken the blood-glucose-lowering effect of insulin. Pentamidine may cause hypoglycaemia, which may sometimes 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.

Pregnancy
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 are available. A large amount of data on pregnant women (more than 1,000 pregnancy outcomes with a medicinal product containing insulin glargine 100 units/ml) indicate no specific adverse effects on pregnancy and no specific malformative nor foeto/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 control throughout pregnancy to prevent adverse outcomes associated with hyperglycaemia. Insulin requirements may decrease during the first trimester and generally increase during the second and third trimesters. Immediately after delivery, insulin requirements decline rapidly (increased risk of hypoglycaemia). Careful monitoring of glucose control is essential.

Breast-feeding
It is unknown whether insulin glargine is excreted in human milk. No metabolic effects of ingested insulin glargine on the breast-fed newborn/infant are anticipated since insulin glargine as a peptide is digested into aminoacids in the human gastrointestinal tract.

Breast-feeding women may require adjustments in insulin dose and diet.

Fertility
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 or hyperglycaemia or, for example, as a result of visual impairment. This may constitute a risk in situations 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 is particularly important in those who have reduced or absent awareness of the warning symptoms of hypoglycaemia or have frequent episodes of hypoglycaemia. It should be considered whether it is advisable to drive or use machines in these circumstances.

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

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

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.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Drugs used in diabetes, insulins and analogues for injection, long-acting.
ATC Code: A10A E04.

Mechanism of action
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 inhibits lipolysis in the adipocyte, inhibits proteolysis and enhances protein synthesis.

Pharmacodynamic effects
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 solution is neutralised leading to formation of a precipitate from which small amounts of insulin glargine are continuously released.

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

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

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

*GIR: Glucose infusion rate: determined as amount of glucose infused to maintain constant plasma glucose levels (hourly mean 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 its metabolites 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 approximately 5 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 human insulin.

Absorption and distribution
In healthy subjects and diabetic patients, insulin serum concentrations indicated a slower and more prolonged 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 of variation for the insulin exposure during 24 hours was low at steady state (17.4%).

Biotransformation
After subcutaneous injection of insulin glargine, insulin glargine is rapidly metabolized at the 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 circulating compound is the metabolite M1.
The exposure to M1 increases with the administered dose of insulin glargine. The pharmacokinetic and pharmacodynamic findings indicate that the effect of the subcutaneous injection with insulin glargine is principally based on exposure to M1. Insulin glargine and the metabolite M2 were not detectable in the vast majority of subjects and, when they were detectable their concentration was independent of the administered dose and formulation of insulin glargine.

Elimination
When given intravenously the elimination half-life of insulin glargine and human insulin were comparable.

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

Paediatric population