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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.)
Click on icon to see table/diagram/imageGlucose 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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Click on icon to see table/diagram/imageFlexibility 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.)
Click on icon to see table/diagram/imagePatients 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.)
Click on icon to see table/diagram/imagePHARMACOKINETICS: 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.
