Toujeo Solostar solution for injection 300 U/ml cartridge 1.5 ml mounted in a syringe pen without needle No. 3

Instructions for Toujeo Solostar solution for injection 300 U/ml cartridge 1.5 ml mounted in a syringe pen without needle No. 3

Composition

active ingredient: insulin glargine;

1 ml of solution contains 10.91 mg of insulin glargine, which is equivalent to 300 U of insulin glargine;

1 syringe pen contains 1.5 ml of solution for injection, equivalent to 450 U of insulin glargine;

Excipients: m-cresol, zinc chloride, glycerin (85%), sodium hydroxide, concentrated hydrochloric acid, water for injections.

Dosage form

Solution for injection.

Main physicochemical properties: colorless or almost colorless solution.

Pharmacotherapeutic group

Antidiabetic drugs. Long-acting insulins and analogues for injection. ATX code A10A E04.

Pharmacological properties

Pharmacodynamics.

Mechanism of action. The active ingredient of insulin glargine is a long-acting human insulin analogue produced by recombinant DNA technology using the producer microorganism Escherichia coli.

The most important action of insulin, including insulin glargine, is the regulation of glucose metabolism. Insulin and its analogues lower blood glucose levels by stimulating its uptake by peripheral tissues, particularly skeletal muscle and adipose tissue, and by inhibiting glucose production in the liver. Insulin inhibits lipolysis in adipocytes and proteolysis, while enhancing protein synthesis.

Insulin glargine is designed as a human insulin analogue with low solubility in neutral medium. Insulin glargine is completely soluble in the acidic medium (pH=4) of the drug solution. After injection into the subcutaneous tissue, the acidic solution is neutralized, resulting in the formation of a precipitate from which a small amount of insulin glargine is continuously released.

In studies using the euglycemic state fixation method in patients with type 1 diabetes mellitus, a more stable and prolonged glucose-lowering effect was observed after subcutaneous administration of Toujeo SoloStar compared with insulin glargine 100 U/ml. The results of a crossover study involving 18 patients with type 1 diabetes mellitus, obtained during a period of up to 36 hours after drug administration, are shown in Fig. 1. The effect of Toujeo SoloStar when using clinically significant doses lasted for more than 24 hours (up to 36 hours).

Treatment:

–– Tojeo SoloStar (300 Units/ml) 0.4 Units/kg

- - - Insulin glargine (100 U/ml) 0.4 U/kg

*Glucose infusion rate: defined as the amount of glucose administered to maintain a constant plasma glucose level (hourly averages). The observation period ended at 36 hours.

Fig. 1. Steady-state activity profile in patients with type 1 diabetes in a 36-hour study using the euglycemic state fixation method.

The more uniform release of insulin glargine from the Toujeo SoloStar precipitate compared to the same insulin glargine 100 U/mL formulation is due to a two-thirds reduction in injection volume, resulting in a smaller surface area of the precipitate.

Insulin glargine is metabolized to 2 active metabolites – M1 and M2 (see section “Pharmacokinetics”).

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 that of human insulin for this receptor.

Binding to the IGF-1 (insulin-like growth factor 1) receptor. The affinity of insulin glargine for the human IGF-1 receptor is approximately 5-8 times higher than that of human insulin (but approximately 70-80 times lower than that of IGF-1 for this receptor), while the metabolites M1 and M2 bind to the IGF-1 receptor with an affinity slightly lower than that of human insulin.

The total therapeutic concentration of insulin (insulin glargine and its metabolites) determined in patients with type 1 diabetes mellitus was significantly lower than that required for half-maximal binding to the IGF-1 receptor and subsequent activation of the mitogenic-proliferative pathway triggered by the IGF-1 receptor. The endogenous IGF-1 receptor at physiological concentrations can activate the mitogenic-proliferative pathway; however, the therapeutic concentrations of insulin used in insulin therapy, including Toujeo SoloStar therapy, are significantly lower than the pharmacological concentrations required to activate the IGF-1-mediated pathway.

In a clinical pharmacology study, insulin glargine and human insulin were shown to be equipotent when administered intravenously at the same doses.

As with any insulin, the action of insulin glargine may be affected by physical activity and other factors.

300 U/mL) administered once daily compared with insulin glargine 100 U/mL administered once daily in 546 patients with type 1 diabetes and 2,474 patients with type 2 diabetes (see Tables 1 and 2). Results from all clinical trials of Toujeo SoloStar showed that the reduction in HbA1c from baseline to end of the studies was at least non-inferior to the change in this parameter obtained with insulin glargine 100 U/mL. The rates of reduction in glucose concentration at the end of the trial were similar for Toujeo SoloStar and insulin glargine 100 U/mL, with a slower reduction during the dose titration period for Toujeo SoloStar.

Glycaemic control was similar between once-daily administration of Toujeo SoloStar in the morning and evening. Improvements in HbA1c were not influenced by gender, ethnicity, age, duration of diabetes (< 10 and ≥ 10 years), pre-treatment HbA1c (< 8 or ≥ 8%) or baseline body mass index (BMI).

At the end of these studies, in which drug doses were titrated to target glycemic levels, the Toujeo SoloStar group was administered doses that were 10–18% (depending on patient subgroup and concomitant therapy) higher than the doses administered in the comparator group (see Tables 1 and 2).

For patients with type 2 diabetes mellitus treated with study drugs in combination with either a non-insulin antidiabetic drug or prandial insulin, clinical trial results showed that the incidence of confirmed hypoglycemia (at any time of day and nocturnal) was lower in patients treated with Toujeo SoloStar compared with patients treated with insulin glargine 100 U/mL. The advantage of Toujeo SoloStar over insulin glargine 100 U/mL in reducing the risk of confirmed nocturnal hypoglycemia was demonstrated in patients with type 2 diabetes mellitus treated with basal insulin in combination with non-insulin antidiabetic drugs (18% risk reduction) or prandial insulin (21% risk reduction) during the treatment period from week 9 to the end of the study. Overall, these effects on reducing the risk of hypoglycemia were consistently observed regardless of age, gender, BMI, and duration of diabetes (< 10 and ≥ 10 years) in patients treated with Toujeo SoloStar compared to patients treated with insulin glargine 100 U/mL.

In patients with type 1 diabetes, the incidence of hypoglycemia was similar between Toujeo SoloStar and insulin glargine 100 U/mL (see Table 3).

Table 1

Results of clinical trials in patients with type 1 diabetes

IGlar — insulin glargine 100 units/ml.

amITT — modified population of all randomized patients (intention-to-treat).

bThe difference between treatment groups was determined by subtracting the values obtained in the Toujeo SoloStar group from the values obtained in the insulin glargine 100 units/mL group; [95% confidence interval].

cChange from baseline to Month 6 (observed case assessment).

dChange from baseline to last value obtained during the main 6-month treatment period.

Table 2

Results of clinical trials in patients with type 2 diabetes

IGlar — insulin glargine 100 units/ml.

amITT — modified population of all randomized patients (intention-to-treat).

bThe difference between treatment groups was determined by subtracting the values obtained in the Toujeo SoloStar group from the values obtained in the insulin glargine 100 units/mL group; [95% confidence interval].

cChange from baseline to month 6 (observed case assessment).

dChange from baseline to last value obtained during the main 6-month treatment period.

Table 3

Summary of the incidence of hypoglycemic episodes in a clinical trial in patients with type 1 and type 2 diabetes

IGlar — insulin glargine 100 units/ml.

aSevere hypoglycemia is an episode that requires the assistance of another person to actively administer carbohydrates, glucagon, or other resuscitative measures.

bConfirmed hypoglycemia is any episode of severe hypoglycemia and/or hypoglycemia confirmed by plasma glucose determination ≤ 3.9 mmol/L.

cNocturnal hypoglycemia is an episode that occurs between 00:00 and 05:59.

d6-month treatment period.

*HR — estimated risk ratio; [95% confidence interval].

Flexibility in the timing of drug administration. Two randomized, open-label clinical trials of 3 months duration were conducted in patients with type 2 diabetes mellitus (n=194) who received the drug once daily in the evening or at the same time during the day (fixed administration time) or within 3 hours before or after the usual time of administration (flexible administration time). The use of the drug using flexible administration time did not affect glycemic control and the incidence of hypoglycemia.

Antibodies: Results of studies comparing Toujeo SoloStar and insulin glargine 100 U/mL do not indicate any differences between these products in the incidence of insulin antibodies with respect to efficacy, safety, or basal insulin dose.

Body weight: In patients treated with Toujeo SoloStar, the mean change in body weight at the end of the 6-month treatment period was less than 1 kg.

Long-term efficacy and safety study: The ORIGIN (Outcome Reduction with Initial Glargine INtervention) study was a multicenter, randomized, 2 × 2 factorial design trial in 12,537 patients at high cardiovascular (CV) risk with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) (12% of participants) or type 2 diabetes mellitus for which they were receiving ≤ 1 oral antidiabetic drug (88% of participants). Study participants were randomized (1:1) to receive either insulin glargine 100 U/mL (n = 6264), titrated to achieve an ALP ≤ 95 mg/dL (5.3 mM), or standard therapy (n = 6273).

The first co-primary endpoint was the time to first occurrence of CV death, non-fatal myocardial infarction (MI), or non-fatal stroke, and the second co-primary endpoint was the time to first occurrence of any of these events, the first co-primary endpoint or a revascularization procedure (coronary, carotid, or peripheral), or hospitalization for heart failure. Secondary endpoints included all-cause mortality and a composite endpoint of microvascular events.

Insulin glargine 100 U/mL did not change the relative risk of CV disease or death from CV causes compared with standard therapy. There was no difference between insulin glargine and standard therapy for either of the two composite primary endpoints; for any of the composite endpoints including these adverse clinical outcomes; for all-cause mortality; or for the composite endpoint of microvascular events.

The mean dose of insulin glargine 100 U/ml at the end of the study was 0.42 U/kg. At baseline, the median HbA1c levels in participants were 6.4%, and during the study treatment, the median HbA1c levels ranged from 5.9 to 6.4% in the insulin glargine 100 U/ml group and from 6.2 to 6.6% in the standard care group throughout the follow-up period.

The rate of severe hypoglycemic episodes (expressed as the number of subjects experiencing such episodes per 100 patient-years of treatment) was 1.05 in the insulin glargine 100 U/mL group and 0.30 in the standard therapy group, and the rate of confirmed non-severe hypoglycemic episodes was 7.71 in the insulin glargine 100 U/mL group and 2.44 in the standard therapy group. During this 6-year study, 42% of subjects in the insulin glargine 100 U/mL group experienced no hypoglycemic episodes at all.

At the last visit on study treatment, there was an increase in body weight from baseline in the insulin glargine group.

100 U/ml on average by 1.4 kg and its decrease on average by 0.8 kg in the standard therapy group.

Children.

The efficacy and safety of Toujeo SoloStar were studied in an open-label, randomized (1:1), controlled clinical trial in children and adolescents with type 1 diabetes mellitus for 26 weeks (n = 463). The Toujeo SoloStar group included 73 children < 12 years of age and 160 children ≥ 12 years of age. Toujeo SoloStar, administered once daily, demonstrated similar reductions in HbA1c and FPG from baseline to week 26 compared to insulin glargine 100 U/mL.

Dose-response analysis showed that after the initial titration phase, weight-adjusted doses in children were higher than in adult patients at steady state.

Overall, the incidence of hypoglycemia in patients in any category was similar in both treatment groups: 97.9% of patients in the Toujeo SoloStar group and 98.2% of patients in the insulin glargine 100 U/mL group reported at least one episode of hypoglycemia. Similarly, nocturnal hypoglycemia was comparable between the Toujeo SoloStar and insulin glargine 100 U/mL treatment groups. The percentage of patients reporting severe hypoglycemia was lower in the Toujeo SoloStar group compared to the insulin glargine 100 U/mL group: 6% and 8.8%, respectively. The percentage of patients with episodes of hyperglycemia with ketosis was lower in the Toujeo SoloStar group compared to the insulin glargine 100 U/mL group: 6.4% and 11.8%, respectively. No safety concerns were identified with Toujeo SoloStar in terms of adverse events and standard safety parameters. Antibody formation was rare and had no clinical impact. The efficacy and safety data in children with type 2 diabetes were extrapolated from data in adolescents and adults with type 1 diabetes and adults with type 2 diabetes. The results of the study support the use of Toujeo SoloStar in children with type 2 diabetes.

Absorption and distribution: Comparison of serum insulin concentrations in healthy volunteers and diabetic patients indicated a slower and more prolonged absorption, resulting in a flatter concentration-time profile after subcutaneous injection of Toujeo SoloStar compared to insulin glargine 100 U/mL. The pharmacokinetic profiles of Toujeo SoloStar were consistent with its pharmacodynamic activity.

Steady-state concentrations within the therapeutic range are achieved after 3–4 days of daily administration of Toujeo SoloStar.

Following subcutaneous injection of Toujeo SoloStar, intra-individual variability, defined as the coefficient of variation for insulin exposure over 24 hours, was low at steady state (17.4%).

Biotransformation. After subcutaneous injection of insulin glargine in humans, it is rapidly metabolized at the carboxyl terminus of the beta chain to form two active metabolites, M1 (21A-Gly-insulin) and M2 (21A-Gly-des-30B-Tre-insulin). In plasma, metabolite M1 is the major circulating compound. Exposure to M1 increases proportionally to the administered dose of insulin glargine. Pharmacokinetic and pharmacodynamic data indicate that the effect of subcutaneous injection of insulin glargine is primarily related to exposure to M1. Insulin glargine and metabolite M2 were not detected in the vast majority of study participants, and when their content could be determined, their concentrations were independent of the administered dose and composition of the insulin glargine preparation.

Elimination: After intravenous administration of insulin glargine and human insulin, their half-lives were comparable. After subcutaneous injection of Toujeo SoloStar, the half-life is determined by the rate of absorption from the subcutaneous tissue. The half-life of Toujeo SoloStar after subcutaneous injection is 18–19 hours and is independent of dose.

Children.

A population pharmacokinetic analysis of Toujeo SoloStar was conducted based on concentrations of its major metabolite M1 using data from 75 children (aged 6 to < 18 years) with type 1 diabetes. The effect of patient weight on the clearance of Toujeo SoloStar is non-linear. As a result, the exposure (AUC – area under the drug concentration curve) in children is slightly lower compared to that in adults given the same weight-adjusted dose.

Indication

Treatment of diabetes mellitus in adults, adolescents and children aged 6 years and over.

Contraindication

Hypersensitivity to the active substance or to any excipient included in the preparation.

Interaction with other medicinal products and other types of interactions

There are a number of substances that affect glucose metabolism, and therefore their use may require adjustment of the insulin glargine dose.

Substances that may enhance the glucose-lowering effect of insulin and increase the susceptibility to hypoglycemia include antidiabetic drugs, angiotensin-converting enzyme (ACE) inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors, pentoxifylline, propoxyphene, salicylates, and sulfonamide antimicrobials.

Substances that may reduce the glucose-lowering effect of insulin include corticosteroids, danazol, diazoxide, diuretics, glucagon, isoniazid, estrogens and progestogens, phenothiazine derivatives, somatropin, sympathomimetic drugs (epinephrine (adrenaline), salbutamol, terbutaline), thyroid hormones, atypical antipsychotics (e.g. clozapine and olanzapine) and protease inhibitors.

Beta-blockers, clonidine, lithium salts or alcohol may either enhance or weaken the glucose-lowering effect of insulin. Pentamidine may cause hypoglycemia, sometimes followed by hyperglycemia.

In addition, under the influence of sympatholytic agents such as beta-blockers, clonidine, guanethidine and reserpine, signs of adrenergic counterregulation may weaken or disappear altogether.

Application features

Toujeo SoloStar is not the drug of choice for the treatment of diabetic ketoacidosis. Intravenous regular insulin is recommended instead in such cases.

If adequate glucose control is not achieved as a result of treatment or there is a tendency to episodes of hypo- or hyperglycemia, before changing the dosage of the drug, it is necessary to check whether the patient adheres to the prescribed treatment regimen, recommended drug injection sites, proper injection technique, and also assess other important factors.

Hypoglycemia. The time to onset of hypoglycemia depends on the action profile of the insulins used and may therefore vary with changes in treatment regimens. Particular caution and increased blood glucose monitoring are advisable in patients in whom hypoglycemic episodes may be particularly dangerous from a clinical point of view, such as patients with severe stenosis of the coronary arteries or blood vessels supplying the brain (risk of cardiac or cerebral complications of hypoglycemia), as well as in patients with proliferative retinopathy, especially those who have not undergone photocoagulation (risk of transient post-hypoglycemic blindness).

Patients should be aware that under certain circumstances the first symptoms of hypoglycemia may be less noticeable. Symptoms indicating the development of hypoglycemia may change, become less pronounced or be absent altogether in patients belonging to certain risk groups. These include patients:

who have significantly improved glycemic control,

in whom hypoglycemia develops gradually,

elderly,

who have switched from animal insulin to human insulin,

with autonomic neuropathy,

who have had diabetes for a long period of time,

with mental disorders,

who are simultaneously receiving therapy with certain other medicines (see section "Interaction with other medicines and other types of interactions").

In such situations, severe hypoglycemia (possibly with loss of consciousness) may occur before the patient is aware that his blood glucose level has decreased. The slow onset of action of insulin glargine when administered subcutaneously may delay the normalization of the glycemic state. If the patient has normal or reduced levels of glycosylated hemoglobin, the possibility of periodic undiagnosed (especially nocturnal) episodes of hypoglycemia should be considered.

To reduce the risk of hypoglycemia, it is very important for the patient to adhere to the dose of the drug, diet, correct insulin administration, as well as the patient's awareness of the symptoms of hypoglycemia. There are a number of factors that increase the susceptibility to hypoglycemia and require careful monitoring of the patient's condition, and sometimes dose adjustment of the drug. These include:

changing the site of insulin injection,

increased insulin sensitivity (for example, when eliminating stress factors),

unusual, excessive or prolonged physical exertion,

concomitant disease accompanied by vomiting, diarrhea,

unhealthy diet,

skipping meals,

alcohol consumption,

some endocrine system disorders (e.g. hypothyroidism, adenohypophysis or adrenal cortex insufficiency) in the decompensation stage,

simultaneous use of certain other medicines (see section "Interaction with other medicines and other types of interactions").

Switching from insulin glargine 100 U/mL to Toujeo SoloStar and vice versa. Since insulin glargine 100 U/mL and Toujeo SoloStar are not bioequivalent and are not interchangeable, switching from one product to another may require a dose adjustment and should only be done under close medical supervision (see section 4.2).

Transferring a patient from other insulins to Toujeo SoloStar and vice versa. Transferring a patient from Toujeo SoloStar to another type or brand of insulin and vice versa should be done under close medical supervision. Changes in potency, brand (manufacturer), type (regular insulin, NPH, lente, long-acting, etc.), origin (animal, human, human insulin analogue) and/or method of manufacture may require a change in insulin dose (see section “Method of administration and dosage”).

Concomitant diseases. The presence of a concomitant disease requires increased monitoring of metabolic parameters. In many cases, urine analysis for the presence of ketone bodies is indicated and insulin dose adjustment is often necessary. Insulin requirements may often increase. Patients with type 1 diabetes should continue to consume at least small amounts of carbohydrates regularly, even if they are able to eat little or no food, or if they are, for example, vomiting. They should never stop using insulin completely.

Formation of insulin antibodies. Administration of insulin preparations may induce the formation of insulin antibodies. In rare cases, the presence of insulin antibodies may necessitate dose adjustment to eliminate the tendency to hypo- or hyperglycemia.

Mistaken administration of another drug. Mistaken administration of another drug has been reported when other insulins, especially rapid-acting insulins, have been accidentally administered instead of long-acting insulins. The insulin product label should be checked before each injection to avoid the mistaken administration of other insulins instead of Toujeo SoloStar or vice versa (see section “Special precautions for use”).

To avoid dosing errors and potential overdose, patients should be instructed not to use a syringe to withdraw Toujeo SoloStar (insulin glargine 300 U/mL) from a pre-filled pen (see Overdose and Precautions below).

A new sterile needle should be attached before each injection. Patients should also be instructed not to reuse needles. Reusing a needle increases the risk of needle blockage, which may result in under- or overdosing. In the event of a blocked needle, patients should follow the instructions in step 3 of the package leaflet (see section “Special precautions for use”).

Patients should visually check the number of units selected on the dose counter of the pen. Blind patients or patients with poor vision should be instructed to have the assistance of another person with good vision trained in the use of this insulin dosing device.

See also the section “Method of administration” in the section “Method of administration and dosage”.

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

Use during pregnancy or breastfeeding

Pregnancy. There is no clinical experience with Toujeo SoloStar in pregnant women. There are no clinical data from controlled clinical trials on the use of insulin glargine during pregnancy. A large amount of data on the use of this drug in pregnant women (more than 1000 pregnancy outcomes with the use of a medicinal product containing insulin glargine 100 U/ml) indicate that insulin glargine does not cause any specific adverse effects on pregnancy and does not cause any malformations or toxicity to the fetus/newborn. Studies in laboratory animals have not shown any signs of reproductive toxicity. Toujeo SoloStar can be used during pregnancy if necessary.

To prevent the undesirable consequences associated with the development of hyperglycemia, it is very important for patients with diabetes mellitus that arose before pregnancy or with gestational diabetes to maintain adequate metabolic control throughout the entire pregnancy. Insulin requirements may decrease during the first trimester of pregnancy and, as a rule, increase during the second and third trimesters. Immediately after delivery, insulin requirements decrease sharply (the risk of hypoglycemia increases). Therefore, careful control of blood glucose levels is very important.

Breastfeeding. It is not known whether insulin glargine is excreted in human milk. No metabolic effects are expected to occur in the newborn/infant through breast milk during breastfeeding, as insulin glargine is a peptide that is broken down to amino acids in the human gastrointestinal tract. Breastfeeding women may require dose and dietary adjustments.

Fertility: Studies in laboratory animals have not shown direct harmful effects on fertility.