Toujeo

Insulin glargine.

Each mL contains 300 units insulin glargine (equivalent to 10.91 mg).
Each pen contains 1.5 mL of solution for injection, equivalent to 450 units.
(21^A-Gly-30^Ba-L-Arg-30^Bb-L-Arg-human insulin or 21^A-Gly-31^B-32^B-Di-Arg-human insulin).
Recombinant human insulin analogue.
Insulin glargine is produced by recombinant DNA technology utilising Escherichia coli (K12 strain) as the production organism.
The pH of the solution is 4.0.
Excipients/Inactive Ingredients: Zinc chloride, m-cresol, glycerol 85%; hydrochloric acid and sodium hydroxide for pH adjustment, and water for injection.

Antidiabetic agent. Long-acting insulin analogue. ATC Code: A10A E04 (insulin and analogues, long acting).
PHARMACOLOGY: PHARMACODYNAMICS: Mode 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 characteristics: Insulin glargine is a human insulin analog that has been designed to have low aqueous solubility at neutral pH. At pH 4, insulin glargine is completely soluble. After injection into the subcutaneous tissue, the acidic solution is neutralized, leading to formation of a precipitate from which small amounts of insulin glargine are continuously released.
In euglycaemic clamp studies in healthy subjects or in patients with type 1 diabetes, the onset of action of subcutaneous Lantus was slower than with NPH insulin, its effect profile was smooth and peakless, and the duration of its effect was prolonged.
As observed in euglycemic clamp studies in patients with type 1 diabetes, the glucose lowering effect of Toujeo was more constant and prolonged in comparison with Lantus after subcutaneous injection. Figure 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 prolonged glucose lowering effect of Toujeo beyond 24 hours allows adaptability in the once-daily time of administration of Toujeo (see Dosage & Administration & Clinical efficacy and safety as follows).
The difference of profile between Toujeo and Lantus is attributable to the modification of the release of insulin glargine from the precipitate.
For the same number of insulin glargine units injected, the injected volume of Toujeo is one third that of Lantus. This leads to a reduction of the precipitate surface area which provides a more sustained release of insulin glargine from the Toujeo precipitate compared to Lantus. (See figure.)

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Glucose infusion rate: determined as amount of glucose infused to maintain constant plasma glucose levels (hourly mean values). The end of the observation was 36 hours.
In clinical pharmacology study, intravenous use of insulin glargine and human insulin has been shown to be equipotent when given at the same doses.
Insulin glargine is metabolized into 2 active metabolites M1 and M2 (see Pharmacokinetics: Special Population as follows).
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 Toujeo therapy, are considerably lower than the pharmacological concentrations required to activate the IGF-1 pathway.
As with all insulins, the time course of action of insulin glargine may be affected by physical activity and other variables.
Clinical efficacy and safety: The overall efficacy and safety of Toujeo (insulin glargine 300 units/mL) once-daily on glycemic control 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 1 diabetes mellitus and 2,474 patients with type 2 diabetes mellitus (Tables 1 and 2).
Results from all clinical trials with Toujeo indicated that reductions in HbA1c from baseline to end of trial were non-inferior to insulin glargine 100 units/mL.
Plasma glucose reductions at the end of the trial with Toujeo were similar to insulin glargine 100 units/mL with a more gradual reduction during the titration period with Toujeo. Glycaemic control was similar when Toujeo was administered once daily in the morning or in the evening.
Improvement in HbA1C was not affected by gender, ethnicity, age, diabetes duration (<10 years and ≥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 (Tables 1 and 2).
Results from clinical trials demonstrated that the incidence of confirmed hypoglycaemia (at any time of the day and nocturnal) was lower in patients treated with Toujeo compared to insulin glargine 100 units/mL-treated patients, in patients with type 2 diabetes treated in combination with either non-insulin anti-hyperglycaemic medicinal product or mealtime insulin.
The superiority of Toujeo over insulin glargine 100 units/mL in lowering the risk of confirmed nocturnal hypoglycemia was shown in patients with type 2 diabetes treated with basal insulin in combination with either non-insulin anti-hyperglycaemic medicinal product (18% risk reduction) or mealtime 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 insulin glargine 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). (See Tables 1, 2 and 3.)

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Flexibility in dosing time: The safety and efficacy of Toujeo administered with a fixed or flexible dosing time were also evaluated 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 of administration) or within 3 hours before or after the usual time of administration (flexible dosing time). Administration with a flexible dosing time had no effect on glycaemic control and the incidence of hypoglycaemia.
Antibodies: Results from studies comparing Toujeo and insulin glargine 100 units/mL did not indicate any difference in term of development of anti-insulin antibodies, on efficacy, safety or dose of basal insulin between Toujeo and insulin glargine 100 units/mL.
Body weight: 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 Tables 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 an open-label 5 year NPH-controlled study (NPH given bid) in 1024 type 2 diabetic patients in which progression 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 the progression of diabetic retinopathy when insulin glargine 100 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) or type 2 diabetes mellitus (treated with ≤1 antidiabetic oral agent) (88% of participants). Participants were 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, nonfatal myocardial infarction (MI) or nonfatal stroke and the second co-primary efficacy outcome was the time 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 when compared to standard of care. There were no differences between insulin glargine and standard care for the two co-primary outcomes; for any component endpoint comprising these outcomes; for all-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 a median HbA1c value of 6.4% and median on-treatment HbA1c values ranged from 5.9 to 6.4% in the insulin glargine 100 units/mL group, and 6.2% to 6.6% in the standard care group throughout the duration of follow-up.
The rates of severe hypoglycaemia (affected participants per 100 participant years of exposure) were 1.05 for insulin glargine 100 units/mL and 0.30 for standard care group and the rates of confirmed non-severe hypoglycaemia were 7.71 for insulin glargine 100 units/mL and 2.44 for standard care group. Over the course of this 6-year study, 42% of the insulin glargine 100 units/mL group did not experience any hypoglycaemia.
At the last on-treatment visit, there was a mean increase in body weight from baseline of 1.4 kg in the insulin glargine 100 units/mL group and a mean decrease of 0.8 kg in the standard care group.
Pediatric: The efficacy and safety of Toujeo have been studied in a 1:1 randomized controlled clinical trial in children and adolescents with type 1 diabetes mellitus for a period of 26 weeks (n=463). Patients in the Toujeo arm included 73 children aged <12 years and 160 children aged ≥12 years. Toujeo dosed once daily showed similar reduction in HbA1c and FPG from baseline to week 26 compared to insulin glargine 100 units/mL. See Table 4.
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 group reporting at least one event. Similarly, nocturnal hypoglycaemia was comparable in the Toujeo and insulin glargine 100 units/mL treatment groups. The percentage of patients reporting severe hypoglycaemia was lower in patients in the Toujeo group as compared to patients in the insulin glargine 100 units/mL group, 6% and 8.8% respectively. The percentage of patients with hyperglycemic episodes 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 standard safety parameters. Antibody development was sparse and had no clinical impact. Efficacy and safety data for paediatric patients with type 2 diabetes mellitus have been extrapolated from data for adolescent and adult patients with type 1 diabetes mellitus and adult patients with type 2 diabetes mellitus. Results support the use of Toujeo in paediatric patients with type 2 diabetes mellitus. (See Table 4.)

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Patients in the pediatric study had a numerically lower incidence of severe hypoglycemia with Toujeo than LANTUS (Table 5). Clinical study safety data are not available for children under 6 years. (See Table 5.)

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PHARMACOKINETICS: Absorption, Distribution: After subcutaneous injection of Toujeo in healthy subjects and diabetic patients, the insulin serum concentrations indicated a slower and more prolonged absorption resulting in an even flatter time-concentration profile for up to 36 hours in comparison to Lantus. Concentrations were consistent with the time profile of 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%).
Metabolism: After subcutaneous injection of Toujeo in healthy subjects and diabetic patients, insulin glargine is rapidly metabolized at the carboxyl terminus of the Beta chain with formation of two active metabolites M1 (21AGly-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 Toujeo. The pharmacokinetic and pharmacodynamic findings indicate that the effect of the subcutaneous injection with Toujeo 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: The half-life of M1, the predominant metabolite of Toujeo after subcutaneous injection is 18-19 hours independent of dose.
Special Population: Gender, race: Information on the effect of gender or race on the pharmacokinetics of insulin glargine is unavailable (see Clinical efficacy and safety as previously mentioned).
Elderly patients: The effect of age on the pharmacokinetics of Toujeo has not been studied. In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemic reactions. Hypoglycemia may be difficult to recognize in the elderly. Close glucose monitoring is recommended and the insulin dose should be adjusted on an individual basis (see Special Population under Dosage & Administration, Precautions and Clinical efficacy and safety as previously mentioned).
Paediatric patients: Population pharmacokinetic analysis was conducted for Toujeo based on concentration data of its main metabolite M1 using data from 75 pediatric subjects (6 to <18 years of age) with type 1 diabetes. Body weight was a significant covariate affecting the clearance of Toujeo. After adjusting for body weight, the total exposure (AUC) to Toujeo at steady state was independent of age.
Renal impairment and Hepatic impairment: The effect of renal impairment and hepatic impairment on the pharmacokinetics of Toujeo has not been studied. However, some studies with human insulin have shown increased circulating levels of insulin in patients with renal failure and liver failure. Close glucose monitoring is recommended and the insulin dose should be adjusted on an individual basis (see Special Population under Dosage & Administration, Precautions and Clinical efficacy and safety as previously mentioned).
Toxicology: PRECLINICAL SAFETY DATA: Acute toxicity: The acute toxicity of intravenous and subcutaneous administration of insulin glargine was tested in mice and rats. The LD50 in each species was in the range of ≥1000 IU/kg.
Chronic toxicity: In repeated subcutaneous dose toxicity studies of insulin glargine in mice, rats and dogs only expected pharmacodynamic effects were observed.
Carcinogenicity: Two-year carcinogenicity studies were performed in rats and mice. The results do not indicate a risk to humans.
Genotoxicity: Insulin glargine was not mutagenic in tests for detection of gene mutations in bacteria and mammalian cells (Ames- and HGPRT-test) and in tests for detection of chromosomal aberrations (Cytogenetics in vitro in V79-cells and in vivo in Chinese hamsters).
Reproductive toxicity: Teratogenicity: In an embryotoxicity study in rats, hypoglycaemia but no maternal toxicity occurred. Insulin glargine was not embryotoxic and not teratogenic.
In an embryotoxicity study in rabbits, maternal (hypoglycaemic shock, intrauterine deaths) and embryofoetal toxicity, due to hypoglycaemia, was observed, including single anomalies in the middle- and high dose groups. Similar effects were obtained with an intermediate acting marketed insulin.
Impairment of fertility: In a combined fertility and pre- and postnatal study in rats, maternal toxicity due to dose-dependent hypoglycemia was observed. Some deaths, and consequently a reduction of the rearing rate, occurred in the high-dose group only. Similar effects were obtained with an intermediate acting marketed insulin.
Local Tolerance: Local tolerability studies with subcutaneous, intramuscular, intravenous and paravenous administration in rabbits gave no indication of risk for the use of insulin glargine in man.
Immunogenicity: Standard immunogenicity studies performed in pigs, rabbits and guinea pigs indicated a similar or lower immunogenic potential for insulin glargine than for human insulin in these species.

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

General: Insulin glargine 300 U/mL is a long-acting recombinant human insulin analogue product.
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.
Toujeo exhibits a more constant and prolonged glucose-lowering profile than Lantus.
Toujeo is given subcutaneously.
Toujeo is administered once daily, at any time during the day, preferably at the same time every day.
Toujeo allows for adaptability in the once-daily time of administration. When needed, patients can administer their injections up to 3 hours before or after their usual time of administration.
The desired blood glucose levels as well as the doses and timing of anti-hyperglycaemic medications must be determined and adjusted individually.
Dose adjustment may 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 Precautions). Any change of insulin dose should be made cautiously and only under medical supervision.
Toujeo is not the insulin of choice for the treatment of diabetic ketoacidosis. An intravenous, short-acting insulin is the preferred treatment.
Blood glucose monitoring is recommended for all patients with diabetes.
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.
Initiation of Toujeo: 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 U/kg once daily 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.
Changing 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.
Changing 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.
Change from other basal insulins to Toujeo: When changing from a treatment regimen with an intermediate-acting or another long-acting insulin product to a regimen with Toujeo, the amount and timing of short-acting insulin or fast-acting insulin analogue product or of the dose of any anti-hyperglycaemic drug may need to be adjusted.
Changing from once-daily basal insulin products to once-daily Toujeo can be done unit-to-unit based on the previous basal insulin dose.
Changing from twice-daily basal insulin products to once-daily Toujeo, the recommended initial Toujeo dose is 80% of the total daily dose of the basal insulin that is being discontinued.
A program of close metabolic monitoring under medical supervision is recommended during the change and in the initial weeks thereafter. As with all insulin analogues, this is particularly true for patients which, due to antibodies to human insulin, need high insulin doses and may experience a markedly improved insulin response with insulin glargine.
With improved metabolic control and resultant increase in insulin sensitivity (reduced insulin requirements) further adjustment of the doses of Toujeo and other insulin products or non-insulin anti-hyperglycaemic drugs in the 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.
Change from Toujeo to 100 U/mL basal insulins: Medical supervision with close metabolic monitoring is recommended during the change and in the initial weeks thereafter.
Please refer to the prescribing information of the product to which the patient is changing.
Mixing, diluting: Toujeo must not be mixed with any other insulin products. Mixing changes the time/action profile of Toujeo and causes precipitation.
Toujeo must not be diluted. Diluting changes the time/action profile of Toujeo.
Special Population: Toujeo can be used in elderly patients, renal and hepatic impaired patients. Close glucose monitoring is recommended and the insulin dose should be adjusted on an individual basis.
Elderly: In the elderly patients, progressive deterioration of renal function may lead to a steady decrease in insulin requirements (see Precautions and PHARMACOLOGY: PHARMACODYNAMICS: Clinical efficacy and safety and PHARMACOKINETICS under Actions).
Renal impairment: In patients with renal impairment, insulin requirements may be diminished due to reduced insulin metabolism (see Precautions and PHARMACOLOGY: PHARMACODYNAMICS: Clinical efficacy and safety and PHARMACOKINETICS under Actions).
Hepatic impairment: In patients with hepatic impairment, insulin requirements may be diminished due to reduced capacity for gluconeogenesis and reduced insulin metabolism (see Precautions and PHARMACOLOGY: PHARMACODYNAMICS: Clinical efficacy and safety and PHARMACOKINETICS under Actions).
Children: Toujeo can be used in pediatric patients from the age of 6 years. When switching basal insulin to Toujeo, dose reduction of basal and bolus insulin needs to be considered on an individual basis, in order to minimize the risk of hypoglycemia.
The safety and effectiveness of Toujeo have not been established in paediatric patients (under 6 years of age).
Administration: Toujeo is administered by subcutaneous tissue injection.
As with all insulins, injection sites within an injection area (abdomen, thigh or deltoid) must be rotated from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis (see Precautions and Adverse Reactions).
Toujeo is not intended for intravenous administration.
The prolonged duration of activity of insulin glargine is dependent on injection into the subcutaneous tissue. Intravenous administration of the usual subcutaneous dose could result in severe hypoglycaemia.
Toujeo is not intended to be administered via an insulin infusion pump.
Toujeo is a clear solution, not a suspension. As such it does not require resuspension before use.
With Toujeo SoloStar pre-filled pen, a dose of 1-80 units per injection, in steps of 1 unit, can be injected.
The dose counter shows the number of Toujeo units to be injected. The Toujeo SoloStar pre-filled pen has been specifically designed for Toujeo, therefore no dose re-calculation is required.
Toujeo must never be drawn from the cartridge of the pre-filled pen into a syringe or severe overdose can result (see Precautions).
Patients must also be instructed to not re-use needles.

Signs and symptoms: An excess of insulin, relative to food intake, energy expenditure or both, may lead to severe and sometimes prolonged and life-threatening hypoglycaemia.
Management: Mild episodes of hypoglycaemia can usually be treated with oral carbohydrates. Adjustments in drug dosage, meal patterns, or exercise may be needed.
More severe episodes culminating in coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycaemia may recur after apparent clinical recovery.

Toujeo must not be used in patients hypersensitive to insulin glargine or any of the excipients.

General: Insulin therapy generally requires appropriate diabetes self-management skills, including glucose monitoring, proper injection technique, and hypo- and hyperglycemia management. Patients should be instructed on such self-management procedures. Additionally, patients must be instructed in how to handle special situations such as an inadequate or skipped insulin dose, inadvertent administration of an increased insulin dose, inadequate food intake or skipped meals. The extent of patient participation in his/her diabetes management is variable and is generally determined by the physician.
Insulin treatment requires constant alertness to the possibility of hyper- and hypoglycemia. Patients and their relatives must know what steps to take if hyperglycemia or hypoglycemia occurs or is suspected and they must know when to inform a physician.
In case of insufficient glucose control or a tendency to hyper- or hypoglycemic episodes, patient's compliance with the prescribed insulin regimen, injection sites and proper injection techniques, the handling of injection devices 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 localized cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycemic 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 hypoglycemia. Blood glucose monitoring is recommended after the change in the injection site, and dose adjustment of antidiabetic medications may be considered (see Adverse Reactions).
Hypoglycemia: The time of occurrence of hypoglycemia depends on the action profiles of the insulin products used and may, therefore, change when the treatment regimen is changed.
As with all insulin products, particular caution should be exercised, and intensified blood glucose monitoring is advisable, in patients in whom sequelae of hypoglycemic episodes might be of particular clinical relevance. For example these could be patients with significant stenoses of the coronary arteries or of the blood vessels supplying the brain (risk of cardiac or cerebral complications of hypoglycemia) as well as patients with proliferative retinopathy, particularly if not treated with photocoagulation (risk of transient amaurosis following hypoglycemia).
However, under certain conditions, as with all insulin products, the warning symptoms of hypoglycemia may be changed, be less pronounced or absent, for example: If glycemic control is markedly improved; if hypoglycemia is developing gradually; in elderly patients; after transfer from animal insulin to human insulin; where an autonomic neuropathy is present; in patients with a long history of diabetes; in patients suffering from a psychiatric illness; in patients receiving concurrent treatment with certain other drugs (see Interactions).
Such situations may result in severe hypoglycemia (and possibly, loss of consciousness) prior to patient's awareness of hypoglycemia.
The prolonged effect of subcutaneous Toujeo may delay recovery from hypoglycemia.
If normal or decreased values for glycated haemoglobin are noted, the possibility of recurrent, unrecognised (especially nocturnal) episodes of hypoglycemia must be considered.
Compliance of the patient with the dosage and dietary regimen, correct insulin administration and awareness of hypoglycemia symptoms are essential to reduce the risk of hypoglycemia.
Presence of factors which increase the susceptibility to hypoglycemia requires particularly close monitoring and may necessitate dose adjustment. These factors include: change in the injection area; increase of insulin sensitivity (e.g. by removal of stress factors); unaccustomed, increased or prolonged physical exercise; intercurrent illness (e.g. vomiting, diarrhoea); inadequate food intake; alcohol consumption; certain uncompensated endocrine disorders; concomitant treatment with certain medications (see Interactions).
In patients with renal impairment, insulin requirements may be diminished due to reduced insulin metabolism (see Special Population under Dosage & Administration and PHARMACOLOGY: PHARMACODYNAMICS: Clinical efficacy and safety and PHARMACOKINETICS under Actions).
In the elderly, progressive deterioration of renal function may lead to steady decrease in insulin requirements (see Special Population under Dosage & Administration and PHARMACOLOGY: PHARMACODYNAMICS: Clinical efficacy and safety and PHARMACOKINETICS under Actions).
In patients with severe hepatic impairment, insulin requirements may be diminished due to reduced capacity for gluconeogenesis and reduced insulin metabolism (see Special Population under Dosage & Administration and PHARMACOLOGY: PHARMACOKINETICS under Actions).
Hypoglycemia can generally be corrected by immediate carbohydrate intake. So that initial corrective action can be taken immediately, patients must carry a minimum of 20 grams of carbohydrates with them at all times.
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 Dosage & Administration).
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 Dosage & Administration).
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. In patients with type 1 diabetes, carbohydrate supplies must be maintained even if patients are able to eat only little or no food, or are vomiting etc.; in patients with type 1 diabetes insulin must never be omitted 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 hypoglycemia.
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: Insulin label must always be checked before each injection to avoid medication errors between Toujeo and other insulins. Medication errors have been reported in which other insulins, particularly short-acting insulins, have been accidentally administered instead of long-acting insulins.
To avoid dosing errors and potential overdose, the patients must also be instructed to never use a syringe to remove Toujeo from the SoloStar pre-filled pen into a syringe (see Dosage & Administration and Overdosage).
Patients must also be instructed to not re-use needles. 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. In the event of blocked needles, the patients must follow the instructions described in Step 3 of the Toujeo SoloStar Instructions for Use (see Administration under Dosage & Administration).
Like for all insulin pens, patients must visually verify the number of selected units on the dose counter of the pen. Patients who are blind or have poor vision must be instructed to get help/assistance from another person who has good vision and is trained in using the insulin device.
Excipients: This medicinal product contains less than 1 mmol (23 mg) sodium per dose, i.e. it is essentially 'sodium-free'.
EFFECTS ON ABILITY TO DRIVE AND USE MACHINE: The patient's ability to concentrate and react may be impaired as a result of, for example, hypoglycemia or hyperglycemia 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 operating machinery).
Patients should be advised to take precautions to avoid hypoglycemia whilst driving. This is particularly important in those who have reduced or absent awareness of the warning symptoms of hypoglycemia or have frequent episodes of hypoglycemia. The advisability of driving should be considered in these circumstances.

Pregnancy: There are no randomized controlled clinical studies of the use of Toujeo in pregnant women. A large number (more than 1000 retrospective and prospective pregnancy outcomes with Lantus) of exposed pregnancies from Post Marketing Surveillance indicate no specific adverse effects on pregnancy or on the health of the foetus and newborn child. Furthermore a meta-analysis of eight observational clinical studies including 331 women using Lantus and 371 women using insulin NPH was performed to assess the safety of insulin glargine and insulin NPH in gestational or pregestational diabetes. No significant differences in safety-related maternal or neonatal outcomes were seen between insulin glargine and insulin NPH during pregnancy.
Animal studies, with doses of insulin glargine 100 U/mL up to 6 to 40 times the human doses, do not indicate direct harmful effects on the pregnancy.
It is essential for patients with pre-existing or gestational diabetes to maintain good metabolic control throughout pregnancy to prevent adverse outcomes associated with hyperglycemia. The use of Toujeo may be considered during pregnancy, if clinically needed.
Insulin requirements may decrease during the first trimester and generally increase during the second and third trimesters. Immediately after delivery, insulin requirements decline rapidly.
Careful monitoring of glucose control is essential in such patients.
Patients with diabetes must inform their doctor if they are pregnant or are contemplating pregnancy.
Lactation: Lactating women may require adjustments in insulin dose and diet.

The following adverse reactions were observed during clinical studies conducted with Toujeo (see PHARMACOLOGY: PHARMACODYNAMICS: Clinical efficacy and safety under Actions) and during clinical experience with insulin glargine 100 U/mL.
The following CIOMS frequency rating is used, when applicable: Very common ≥10%; Common ≥1 and <10%; Uncommon ≥0.1 and <1%; Rare ≥0.01 and <0.1%; Very rare <0.01%, Not known (cannot be estimated from available data).
Hypoglycemia: Hypoglycemia, 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.
As with all insulins, severe hypoglycemic attacks, especially if recurrent, may lead to neurological damage. Prolonged or severe hypoglycemic episodes may be life-threatening.
In many patients, the signs and symptoms of neuroglycopenia are preceded by signs of adrenergic counterregulation. Generally, the greater and more rapid the decline in blood glucose, the more marked is the phenomenon of counter-regulation and its symptoms.
For hypoglycaemia incidences from clinical trials, see table in PHARMACOLOGY: PHARMACODYNAMICS: Clinical efficacy and safety under Actions.
Eyes: A marked change in glycemic control may cause temporary visual impairment, due to temporary alteration in the turgidity and refractive index of the lens.
Long-term improved glycemic control decreases the risk of progression of diabetic retinopathy. However, as for all insulin regimens, 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 hypoglycemic episodes may result in transient amaurosis.
See PHARMACOLOGY: PHARMACODYNAMICS: Clinical efficacy and safety under Actions for additional information regarding retinopathy study results.
Skin and subcutaneous tissue disorders: Lipodystrophy, as with any insulin therapy, may occur at the injection site and delay insulin absorption. In clinical studies, in regimens, which included insulin glargine, lipohypertrophy was observed in 1 to 2% of patients, whereas lipoatrophy was uncommon.
Localized cutaneous amyloidosis at the injection site has occurred with insulins. Hyperglycemia has been reported with repeated insulin injections into areas of cutaneous amyloidosis; hypoglycemia has been reported with a sudden change to an unaffected injection site.
Continuous rotation of the injection site within a given area may help to reduce or prevent these reactions (see Precautions).
Allergic reactions: Local Allergy at the injection site: As with any insulin therapy, such reactions include redness, pain, itching, hives, swelling, or inflammation. In Toujeo clinical studies in adult patients, the incidence of overall injection site reactions was similar in Toujeo-treated patients (2.5%) and Lantus-treated patients (2.8%). Most minor reactions to insulins usually resolve in a few days to a few weeks.
Systemic Allergy: Immediate-type allergic reactions are rare. Such reactions to insulin (including insulin glargine) or the excipients may, for example, be associated with generalised skin reactions, angio-oedema, bronchospasm, and hypotension and anaphylactic 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%).
Other reactions: Insulin administration may cause anti-insulin antibodies to form. In clinical studies comparing Toujeo and Lantus, anti-insulin antibodies were observed with similar frequencies in both treatment groups. As with all insulins, in rare cases, the presence of such anti-insulin antibodies may necessitate adjustment of the insulin dose in order to correct a tendency to hyperglycemia or hypoglycemia (see PHARMACOLOGY: PHARMACODYNAMICS: Clinical efficacy and safety under Actions).
Insulin may cause, in rare cases, sodium retention and 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 trial in paediatric patients aged 6 to less than 18 years. The frequency, type and severity of adverse reactions in the paediatric population do not indicate differences from the experience in the general diabetes population.
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 PHARMACOLOGY: PHARMACODYNAMICS under Actions).

A number of substances affect glucose metabolism and may require insulin dose adjustment and particularly close monitoring.
The following are examples of substances that may increase the blood glucose lowering effect and susceptibility to hypoglycemia: Anti-hyperglycemic products, ACE inhibitors, disopyramide, fibrates, fluoxetine, MAO inhibitors, pentoxifylline, propoxyphene, salicylates, sulfonamide antibiotics.
The following are examples of substances that may reduce the blood glucose lowering effect: Corticosteroids, danazol, diazoxide, diuretics, sympathomimetic agents (such as epinephrine, salbutamol, terbutaline), glucagon, isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens and progestogens (e.g. in oral contraceptives), protease inhibitors and atypical antipsychotic medications (e.g. olanzapine and clozapine).
Beta-blockers, clonidine, lithium salts and alcohol may either potentiate or weaken the blood glucose lowering effect of insulin. Pentamidine may cause hypoglycaemia, which may sometimes be followed by hyperglycemia.
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.

INCOMPATIBILITIES: Toujeo must not be mixed with any other insulin products. Mixing changes the time/action profile of Toujeo and causes precipitation.
PREPARATION AND HANDLING: Before first use, the pen must be stored at room temperature at least 1 hour before use.
Before using Toujeo SoloStar pre-filled pen, the Instructions for Use included in the package leaflet must be read carefully. Toujeo SoloStar pre-filled pen has to be used as recommended in these Instructions for Use (see Dosage & Administration).
The cartridge should be inspected before use. It must only be used if the solution is clear, colorless, with no solid particles visible and if it is of water-like consistency. Since Toujeo is a solution, it does not require resuspension before use.
Insulin label must always be checked before each injection to avoid medication errors between Toujeo and other insulins. The strength "300" is highlighted in honey gold on the label (see Precautions).
A syringe must never be used to withdraw Toujeo from the cartridge of the SoloStar pre-filled pen or severe overdose can result (see Dosage & Administration).
Needles must be discarded immediately after use. 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. Using a new sterile needle for each injection also minimizes the risk of contamination and infection. 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 Dosage & Administration).
Used needles should be thrown away in a puncture resistant container or disposed of in accordance with 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 one person, even when the needle is changed (see Dosage & Administration).

Unopened/not in use pre-filled pen: Toujeo must be stored between +2°C (36°F) and +8°C (46°F) (in a refrigerator) and protected from light. Do not allow the insulin to freeze, discard if frozen.
Do not put Toujeo next to the freezer compartment or a freezer pack.
Keep the pre-filled pen in the outer carton in order to protect from light.
Opened/in use: Do not allow the insulin to freeze, discard if frozen.
Opened pre-filled pen must be discarded after 42 days (6 weeks) from the first use. The open pre-filled pen of Toujeo should be kept away from direct heat and light, at room temperature (below 30°C (86°F)). Do not refrigerate. The pen cap must be put back on the pen after each injection in order to protect from light.
SHELF-LIFE: 30 months.

Insulin Preparations

A10AE04 - insulin glargine ; Belongs to the class of long-acting insulins and analogues for injection. Used in the treatment of diabetes.

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