Toujeo solostar

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TOJEO SOLOSTAR (Toujeo® SoloStar®)

Composition:

Active substance: insulin glargine;

1 ml of solution contains 10.91 mg insulin glargine, equivalent to 300 IU insulin glargine;

1 prefilled pen contains 1.5 ml of injection solution, equivalent to 450 IU insulin glargine;

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

Pharmaceutical form. Injection solution.

Main physicochemical properties: colorless or almost colorless solution.

Pharmacotherapeutic group. Antidiabetics. Long-acting insulins and analogues for injection. ATC code A10A E04.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action. The active substance, insulin glargine, is a long-acting analog of human insulin produced by recombinant DNA technology using the producing microorganism Escherichia coli.

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

Insulin glargine is designed as an analog of human insulin with low solubility in neutral environments. Insulin glargine is fully soluble in the acidic environment (pH=4) of the formulation. After subcutaneous injection, the acidic solution is neutralized, leading to the formation of a precipitate from which small amounts of insulin glargine are continuously released.

In studies using the euglycemic clamp technique in patients with type 1 diabetes, a more stable and prolonged glucose-lowering effect was observed after subcutaneous administration of Toujeo SoloStar compared to insulin glargine 100 IU/mL. Results from a crossover study involving 18 patients with type 1 diabetes, measured over a period of up to 36 hours after administration, are shown in Figure 1. The effect of Toujeo SoloStar lasted more than 24 hours (up to 36 hours) when clinically relevant doses were administered.

Treatment:

• –– Toujeo SoloStar (300 Units/ml) 0.4 Units/kg
  • • • • Insulin glargine (100 Units/ml) 0.4 Units/kg

*GIR – glucose infusion rate: defined as the amount of glucose infused to maintain a constant plasma glucose level (hourly mean values). The observation period ended at 36 hours.

Fig. 1. Activity profile at steady state in patients with type 1 diabetes in a 36-hour euglycemic clamp study.

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

Insulin glargine is metabolized into 2 active metabolites – M1 and M2 (see section "Pharmacokinetics").

Binding to the insulin receptor. 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 affinity of human insulin for this receptor.

Binding to the IGF-1 receptor (insulin-like growth factor-1). 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 the affinity of IGF-1 for this receptor), whereas 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) observed in patients with type 1 diabetes was substantially lower than that required for half-maximal binding to the IGF-1 receptor and subsequent activation of the IGF-1 receptor-mediated mitogenic-proliferative pathway. The endogenous IGF-1 receptor may activate the mitogenic-proliferative pathway under physiological concentrations; however, therapeutic insulin concentrations used in insulin therapy, including treatment with Toujeo SoloStar, are significantly lower than the pharmacological concentrations required to activate the IGF-1 receptor-mediated pathway.

A clinical pharmacology study demonstrated that insulin glargine and human insulin are equipotent when administered intravenously at equivalent doses.

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

Clinical efficacy and safety. In open-label, randomized, active-controlled, parallel-group trials of up to 26 weeks' duration, the overall efficacy and safety of Toujeo SoloStar (insulin glargine 300 Units/ml) administered once daily for glycemic control were compared with those of insulin glargine 100 Units/ml administered once daily in 546 patients with type 1 diabetes and 2474 patients with type 2 diabetes (see Tables 1 and 2). Results from all clinical studies with Toujeo SoloStar showed that the reduction in HbA1c from baseline to end of study was at least as effective as that observed with insulin glargine 100 Units/ml. The glucose-lowering effects at the end of the treatment period with Toujeo SoloStar and insulin glargine 100 Units/ml were similar, although the reduction was slower during the dose-titration period with Toujeo SoloStar.

The glycemic control efficacy of once-daily administration of Toujeo SoloStar in the morning or evening was similar. Improvement in HbA1c levels was not influenced by patient sex, ethnicity, age, duration of diabetes (< 10 or ≥ 10 years), baseline HbA1c (< 8% or ≥ 8%), or baseline body mass index (BMI).

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

In patients with type 2 diabetes receiving the study drugs either in combination with a non-insulin antidiabetic agent or with prandial insulin, clinical trial results showed a lower frequency of confirmed hypoglycemic events (at any time of day and nocturnal) in patients treated with Toujeo SoloStar compared to those treated with insulin glargine 100 Units/ml. The advantage of Toujeo SoloStar over insulin glargine 100 Units/ml in reducing the risk of confirmed nocturnal hypoglycemia was demonstrated in patients with type 2 diabetes 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 in reducing hypoglycemia risk were consistently observed regardless of age, sex, BMI, or duration of diabetes (< 10 or ≥ 10 years) in patients treated with Toujeo SoloStar compared to those receiving insulin glargine 100 Units/ml.

In patients with type 1 diabetes, the frequency of hypoglycemia was similar with Toujeo SoloStar and insulin glargine 100 Units/ml (see Table 3).

Table 1
Results of clinical studies in patients with type 1 diabetes

Toujeo — insulin glargine 100 units/mL.

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

bTreatment group difference was calculated by subtracting values observed in the Toujeo SoloStar treatment group from those observed in the insulin glargine 100 units/mL treatment group; [95% confidence interval].

cChange from baseline to Month 6 (observed cases evaluation).

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

Table 2

Clinical study results in patients with type 2 diabetes mellitus

Lantus – insulin glargine 100 units/mL.

aITT – modified intention-to-treat population (all randomized patients).

bTreatment group difference was determined by subtracting values observed in the Toujeo SoloStar treatment group from those observed in the insulin glargine 100 units/mL group; [95% confidence interval].

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

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

Table 3

Summary of frequency of hypoglycemic episodes in the clinical trial involving patients with type 1 and type 2 diabetes mellitus

Toujeo – insulin glargine 100 units/mL.

aSevere hypoglycemia – an episode requiring assistance from another person to actively administer carbohydrates, glucagon, or other resuscitative measures.

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

cNocturnal hypoglycemia – an episode occurring between 00:00 and 05:59 hours.

d6-month treatment period.

*RR – risk ratio; [95% confidence interval].

Flexibility of administration time. Two randomized, open-label, 3-month clinical trials were conducted in patients with type 2 diabetes (n=194) who received the medication once daily in the evening either at a fixed time or within a 3-hour window before or after the usual administration time (flexible time). Using the medication with flexible administration timing did not affect glycemic control or the frequency of hypoglycemia.

Antibodies. Study results comparing Toujeo SoloStar and insulin glargine 100 units/mL did not indicate any differences between these products regarding insulin antibody formation with respect to efficacy, safety, or basal insulin dose.

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

Results of the study on the effect of treatment on progression of diabetic retinopathy. The effect of insulin glargine 100 units/mL (administered once daily) on the progression of diabetic retinopathy was evaluated in a 5-year open-label study involving 1024 patients with type 2 diabetes, in which NPH insulin (administered twice daily) was used as the comparator. Retinopathy progression was assessed by fundus photography using the ETDRS (Early Treatment Diabetic Retinopathy Study) scale, defined as progression by 3 or more steps. Comparison of insulin glargine 100 units/mL with NPH insulin showed no statistically significant differences between the two treatments regarding the effect on progression of diabetic retinopathy.

Studies on long-term efficacy and safety outcomes. The ORIGIN (Outcome Reduction with Initial Glargine INtervention) study was a multicenter, randomized, 2×2 factorial design trial involving 12,537 patients at high cardiovascular (CV) risk who had impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) (12% of participants) or type 2 diabetes treated with ≤1 oral antidiabetic agent (88% of participants). Participants were randomized (1:1) to receive either insulin glargine 100 units/mL (n=6264), with dose titrated to achieve fasting plasma glucose (FPG) ≤95 mg/dL (5.3 mmol/L), or standard therapy (n=6273).

The primary composite endpoint consisted of two components: time to first occurrence of CV death, non-fatal myocardial infarction (MI), or non-fatal stroke; and time to first occurrence of any of these events or revascularization procedures (coronary, carotid, or peripheral), or hospitalization for heart failure. Secondary endpoints included all-cause mortality and a composite microvascular events endpoint.

Insulin glargine 100 units/mL did not alter the relative risk of CV disease or CV death compared to standard therapy. No differences were observed between insulin glargine and standard therapy for either component of the primary composite endpoint, any individual component of these adverse clinical outcomes, all-cause mortality, or the composite microvascular events endpoint.

The mean dose of insulin glargine 100 units/mL at the end of the study was 0.42 units/kg. At baseline, the median HbA1c level among participants was 6.4%. During the treatment period, median HbA1c levels ranged from 5.9% to 6.4% in the insulin glargine 100 units/mL group and from 6.2% to 6.6% in the standard therapy group throughout the observation period.

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

At the final visit during ongoing treatment, body weight increased from baseline by a mean of 1.4 kg in the insulin glargine 100 units/mL group and decreased by a mean of 0.8 kg in the standard therapy group.

Pediatrics.

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

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

Overall incidence of hypoglycemia was similar between treatment groups: 97.9% of patients in the Toujeo SoloStar group and 98.2% in the insulin glargine 100 units/mL group reported at least one hypoglycemic episode. Nocturnal hypoglycemia was comparable between the Toujeo SoloStar and insulin glargine 100 units/mL treatment groups. The percentage of patients reporting severe hypoglycemia was lower in the Toujeo SoloStar group compared to the insulin glargine 100 units/mL group: 6% vs. 8.8%, respectively. The percentage of patients experiencing hyperglycemic episodes with ketosis was lower in the Toujeo SoloStar group compared to the insulin glargine 100 units/mL group: 6.4% vs. 11.8%, respectively. No safety concerns related to adverse events or standard safety parameters were identified with Toujeo SoloStar use. Antibody formation was rare and had no clinical impact. Efficacy and safety data for use in children with type 2 diabetes were extrapolated from data in adolescents and adults with type 1 diabetes and adults with type 2 diabetes. Study results support the use of Toujeo SoloStar in children with type 2 diabetes.

Pharmacokinetics.

Absorption and distribution. Comparison of insulin concentrations in serum of healthy volunteers and diabetic patients indicated slower and more prolonged absorption, resulting in a flatter "concentration-time" profile after subcutaneous injection of Toujeo SoloStar compared to insulin glargine 100 units/mL. Pharmacokinetic profiles of Toujeo SoloStar corresponded to its pharmacodynamic activity.

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

After subcutaneous injection of Toujeo SoloStar, 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, forming two active metabolites – M1 (21A-Gly-insulin) and M2 (21A-Gly-des-30B-Thr-insulin). In plasma, the predominant circulating compound is metabolite M1. M1 exposure increases proportionally with the administered dose of insulin glargine. Pharmacokinetic and pharmacodynamic data indicate that the effect of subcutaneous insulin glargine injection is primarily related to M1 exposure. Insulin glargine and metabolite M2 were not detectable in the majority of study participants; when detectable, their concentrations were independent of the administered dose and formulation of insulin glargine.

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

Pediatrics.

A population pharmacokinetic analysis of Toujeo SoloStar was performed based on concentrations of its main metabolite M1 using data from 75 children (aged 6 to <18 years) with type 1 diabetes. Patient body weight has a nonlinear effect on the clearance of Toujeo SoloStar. As a result, exposure (AUC – area under the concentration-time curve) in children is slightly lower compared to adults when receiving the same weight-adjusted dose.

Clinical characteristics.

Indications.

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

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

There are several substances that affect glucose metabolism, and therefore their use may require adjustment of glargine insulin dosage.

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

Substances that may weaken the glucose-lowering effect of insulin include corticosteroids, danazol, diazoxide, diuretics, glucagon, isoniazid, estrogens and progestogens, phenothiazine derivatives, somatropin, sympathomimetic medicinal products (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 enhance or weaken the glucose-lowering effect of insulin. Pentamidine may cause hypoglycemia, which may be followed by hyperglycemia.

In addition, under the influence of sympatholytic agents such as beta-blockers, clonidine, guanethidine, and reserpine, the signs of adrenergic counter-regulation may be reduced or even absent.

Special precautions for use.

Toujeo SoloStar is not a drug of choice for the treatment of diabetic ketoacidosis. In such cases, intravenous administration of regular insulin is recommended instead.

If adequate glucose control cannot be achieved with treatment or a tendency to episodes of hypoglycemia or hyperglycemia is observed, before changing the dosage of the drug, it is necessary to verify whether the patient adheres to the prescribed treatment regimen, recommended injection sites, proper injection technique, and to assess other important factors.

Patients should be advised to constantly rotate injection sites to reduce the risk of lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and deterioration of glycemic control following insulin injections into areas affected by these reactions. Changing the injection site to an unaffected skin area may lead to hypoglycemia. It is recommended to monitor blood glucose levels after changing the injection site and consider adjusting the dose of antidiabetic medications.

Hypoglycemia. The time to onset of hypoglycemia depends on the pharmacological profile of the insulin used and may therefore vary when changing treatment regimens. Particular caution and intensified blood glucose monitoring are recommended for patients in whom episodes of hypoglycemia may be especially dangerous from a clinical standpoint, such as patients with severe coronary or cerebral vascular stenosis (risk of cardiac or cerebral complications of hypoglycemia), as well as 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, early symptoms of hypoglycemia may be less noticeable. Symptoms indicating the development of hypoglycemia may change, become less pronounced, or even be absent in patients belonging to certain risk groups. These include patients:

• in whom significant improvement in glycemic control has occurred,
• in whom hypoglycemia develops gradually,
• elderly patients,
• who have switched from animal-sourced insulin to human insulin,
• with autonomic neuropathy,
• with long-standing diabetes mellitus,
• with psychiatric disorders,
• who are concurrently receiving therapy with certain other medicinal products (see section "Interaction with other medicinal products and other forms of interaction").

In such situations, severe hypoglycemia (possibly leading to loss of consciousness) may occur before the patient realizes that their blood glucose level has dropped. The prolonged action of insulin glargine after subcutaneous administration may delay the normalization of glycemic status. If a patient has normal or low glycated hemoglobin levels, the possibility of undiagnosed (especially nocturnal) episodes of hypoglycemia should be considered.

Adherence to the prescribed insulin dose, dietary regimen, proper insulin administration technique, and patient awareness of hypoglycemia symptoms are crucial for reducing the risk of hypoglycemia. Several factors increase the predisposition to hypoglycemia and require careful monitoring of the patient's condition, and sometimes dose adjustment. These include:

• change in insulin injection site,
• increased insulin sensitivity (e.g., after removal of stress factors),
• unusual, excessive, or prolonged physical exertion,
• concomitant illness associated with vomiting or diarrhea,
• inadequate nutrition,
• missed meals,
• alcohol consumption,
• certain endocrine disorders (e.g., hypothyroidism, hypopituitarism, or adrenal insufficiency) in the decompensated stage,
• concomitant use of certain other medicinal products (see section "Interaction with other medicinal products and other forms of interaction").

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 not interchangeable, switching from one product to the other may necessitate a dose adjustment and must be performed only under close medical supervision (see section "Dosage and administration").

Switching patients from other insulins to Toujeo SoloStar and vice versa. Switching a patient from or to another type or brand of insulin from/to Toujeo SoloStar must be carried out under close medical supervision. Changes in potency, brand (manufacturer), type (regular insulin, NPH, lente, long-acting, etc.), origin (animal, human, human insulin analog), and/or manufacturing method may lead to the need for insulin dose adjustment (see section "Dosage and administration").

Concomitant diseases. The presence of concomitant illness requires intensified monitoring of metabolic parameters. In many cases, urine testing for ketone bodies is indicated, and frequent insulin dose adjustments may be necessary. Insulin requirements often increase. Patients with type 1 diabetes must continue to consume at least a small amount of carbohydrates, even if they are only able to eat a minimal amount or cannot eat at all, or if they experience vomiting, for example. They should never completely discontinue insulin therapy.

Formation of insulin antibodies. Administration of insulin preparations may lead to the formation of insulin antibodies. In rare cases, the presence of insulin antibodies may necessitate dose adjustments to correct a tendency toward hypoglycemia or hyperglycemia.

Combination of Toujeo SoloStar with pioglitazone. Cases of heart failure have been reported when pioglitazone was used in combination with insulin, particularly in patients with risk factors for heart failure. This should be considered when evaluating the possibility of treatment with a combination of pioglitazone and Toujeo SoloStar. When using this combination, patients should be monitored for symptoms of heart failure, as well as for weight gain and edema. If cardiac symptoms worsen, pioglitazone must be discontinued.

Accidental administration of another medicinal product. Cases of accidental administration of another medicinal product have been reported, particularly when other insulins, especially rapid-acting insulins, were inadvertently administered instead of long-acting insulins. Before each injection, the insulin product label should be checked to avoid accidental administration of another insulin instead of Toujeo SoloStar or vice versa (see subsection "Special warnings regarding 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 section "Overdose" and subsection "Special warnings regarding use" below).

A new sterile needle must be attached before each injection. Patients should also be instructed not to reuse needles. Reusing needles increases the risk of needle blockage, which may result in underdosing or overdosing. In case of needle blockage, patients must follow the instructions described in step 3 of the instructions for use in the package leaflet (see subsection "Special warnings regarding use").

Patients should visually check the number of selected units on the dose counter of the pen device. Blind patients or patients with poor vision should be instructed to seek assistance from another person with good vision who has been trained to use this insulin delivery device.

See also the section "Method of administration" in the section "Dosage and administration".

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 the use of Toujeo SoloStar in pregnant women. There are no clinical data from controlled clinical trials on the use of insulin glargine during pregnancy. However, extensive data from the use of this medicinal product in pregnant women (more than 1000 pregnancy cases with a medicinal product containing insulin glargine 100 U/mL) indicate that insulin glargine does not have specific adverse effects on pregnancy course and does not cause malformations or toxic effects in the fetus/newborn. Animal studies have not shown signs of reproductive toxicity. Toujeo SoloStar may be prescribed during pregnancy if treatment is needed.

To prevent adverse outcomes associated with hyperglycemia, it is very important for patients with pre-existing diabetes or gestational diabetes to maintain adequate metabolic control throughout pregnancy. Insulin requirements may decrease during the first trimester and generally increase during the second and third trimesters. Immediately after delivery, insulin requirements drop sharply (increased risk of hypoglycemia). Therefore, careful monitoring of blood glucose levels is essential.

Breastfeeding. It is currently unknown whether insulin glargine is excreted in human milk. No metabolic effects are expected in the newborn/infant from insulin glargine passing into breast milk during breastfeeding, as insulin glargine is a peptide that is degraded into amino acids in the human gastrointestinal tract. Women who are breastfeeding may require adjustments in insulin dosage and diet.

Fertility. Animal studies have not shown any direct harmful effect on fertility.

Ability to affect reaction speed when driving or operating machinery. A patient's ability to concentrate and reaction speed may be impaired due to the occurrence of hypoglycemia or hyperglycemia, or, for example, due to visual disturbances. This may be dangerous in situations where these abilities are particularly important (e.g., when driving vehicles or operating machinery).

Patients should be advised to take necessary precautions to avoid hypoglycemia while driving. This is especially important for patients in whom early signs of hypoglycemia are weak or absent, as well as for those who frequently experience hypoglycemia. Careful consideration should be given to whether it is safe to drive or operate machinery in such conditions.

Method of Administration and Dosage.

Dosage. The Tresiba SoloStar preparation is a basal insulin preparation administered once daily at any time of day, but preferably at the same time each day.

The administration regimen (dose and timing) should be individualized based on the patient's response to treatment.

In patients with type 1 diabetes mellitus, Tresiba SoloStar should be used in combination with a short- or rapid-acting insulin to meet insulin requirements after meals.

For patients with type 2 diabetes mellitus, Tresiba SoloStar may also be used concomitantly with oral antidiabetic medicinal products.

The potency of this medicinal product is expressed in units. These units apply exclusively to Tresiba SoloStar and differ from IU or units used to express the potency of other insulin analogs (see section "Pharmacodynamics").

Flexibility of Administration Time. If necessary, patients may administer Tresiba SoloStar within a window of up to 3 hours before or after their usual administration time (see section "Pharmacodynamics"). Patients who miss a dose should be advised to monitor their blood glucose levels more frequently and then resume their usual once-daily regimen. Patients should be warned against administering a double dose to compensate for a missed dose.

Patients with type 1 diabetes mellitus. Tresiba SoloStar requires individual dose titration and should be administered once daily in combination with short-acting insulin.

Patients with type 2 diabetes mellitus. The recommended initial daily dose is 0.2 units/kg, followed by individual dose adjustments.

Switching from insulin glargine 100 units/mL to Tresiba SoloStar and vice versa. Insulin glargine 100 units/mL and Tresiba SoloStar are not bioequivalent and are not interchangeable. Switching from insulin glargine 100 units/mL to Tresiba SoloStar may be performed using the same dose in units; however, a higher dose (approximately 10–18% higher) of Tresiba SoloStar may be required to achieve target plasma glucose levels. When switching patients from Tresiba SoloStar to insulin glargine 100 units/mL, the dose should be reduced (by approximately 20%) to reduce the risk of hypoglycemia. Careful monitoring of metabolic parameters is recommended during and for the first weeks after the switch.

Switching from other basal insulins to Tresiba SoloStar. When switching from intermediate- or long-acting insulin regimens to Tresiba SoloStar, adjustments in basal insulin dose and concomitant antidiabetic therapy (doses and timing of additional regular insulin or rapid-acting insulin analogs, or doses of non-insulin antidiabetic medicinal products) may be required.

Replacement of once-daily basal insulin with Tresiba SoloStar once daily can be performed by substituting the same number of units as the previous basal insulin dose.

When replacing basal insulins administered twice daily with Tresiba SoloStar once daily, the recommended initial dose of Tresiba SoloStar is 80% of the total daily dose of the previous basal insulin preparation, which should be discontinued.

In patients receiving high insulin doses due to the presence of antibodies to human insulin, switching to Tresiba SoloStar may improve insulin response.

Careful monitoring of metabolic parameters is recommended during and for the first weeks after switching to another preparation.

Improved metabolic control and the associated increase in insulin sensitivity may require additional dose adjustments. Dose adjustments may also be necessary, for example, due to changes in the patient's body weight or lifestyle, changes in the time of day insulin is administered, or the occurrence of other factors increasing the risk of hypo- or hyperglycemia (see section "Special Warnings and Precautions for Use").

Switching from Tresiba SoloStar to other basal insulins. Medical supervision with careful monitoring of metabolic parameters is recommended during and for the first weeks after switching to another preparation. For information, refer to the prescribing information of the medicinal product to which the patient is switching.

Special Patient Populations. Tresiba SoloStar can be used in elderly patients, patients with renal or hepatic dysfunction, and in children and adolescents aged 6 years and older.

Elderly patients (aged 65 years and older). In elderly individuals, progressive decline in renal function may lead to a continuous decrease in insulin requirements (see sections "Adverse Reactions" and "Pharmacodynamics").

Renal and hepatic impairment. In patients with renal impairment, insulin requirements may be reduced due to decreased insulin metabolism (see section "Adverse Reactions"). In patients with hepatic impairment, insulin requirements may be reduced due to decreased gluconeogenic capacity and slowed insulin metabolism.

Method of Administration. Tresiba SoloStar should be administered subcutaneously only. Tresiba SoloStar is administered by subcutaneous injection into the abdominal wall, thigh, or deltoid area. Injection sites should always be rotated within the same region to reduce the risk of lipodystrophy and cutaneous amyloidosis (see sections "Special Warnings and Precautions for Use" and "Adverse Reactions").

Intravenous administration of Tresiba SoloStar is not permitted. The prolonged duration of action of the preparation depends on its subcutaneous administration. Intravenous administration of a usual subcutaneous dose may lead to severe hypoglycemia.

Tresiba SoloStar must not be used with insulin infusion pumps.

The dose window displays the number of units of Tresiba SoloStar to be administered. The prefilled pen Tresiba SoloStar is specifically designed for Tresiba SoloStar, so dose conversion for each pen is not required.

Before using the prefilled pen Tresiba SoloStar, read the instructions for use (see subsection "Special Warnings and Precautions for Use" below).

Using the prefilled pen Tresiba SoloStar, doses from 1 to 80 units can be administered in 1-unit increments per injection. The dose window displays the number of units of insulin to be administered.

The Tresiba SoloStar preparation must not be withdrawn from the cartridge of the prefilled pen into a syringe, as this may lead to severe overdose (see section "Overdose" and subsection "Special Warnings and Precautions for Use" below).

A new sterile needle must be attached before each injection. Reuse of needles increases the risk of needle blockage, which may lead to under- or overdosing (see subsection "Special Warnings and Precautions for Use").

To prevent possible transmission of infectious diseases, insulin pens must never be used by more than one person, even if the needle is changed (see subsection "Special Warnings and Precautions for Use").

Before using the prefilled pen Tresiba SoloStar, carefully read the instructions for use (see below).

Special Warnings and Precautions for Use. Before first use, the pen should be kept at room temperature for at least 1 hour.

Before using the medication, carefully read the instructions for use of the prefilled pen Tresiba SoloStar and strictly follow the recommendations provided (see below).

Before use, inspect the cartridge of the pen. It may be used only if it contains a clear, colorless solution resembling water, with no visible particles. Since Tresiba SoloStar is a solution, it does not require resuspension before use.

To avoid inadvertent administration of other insulin products, always check the label on the insulin packaging before each injection. The Tresiba SoloStar label features the strength "300" highlighted in honey-gold color.

Use of the pen. The medicinal product Tresiba SoloStar contains 300 units/mL of insulin glargine in a single-use prefilled pen with a 1.5 mL capacity.

Needles must be discarded immediately after use. A new sterile needle must be attached before each injection. Reusing needles may result in blockage, leading to underdosing or overdosing. Using a new sterile needle for each injection also minimizes the risk of contamination and infection. In case of needle blockage, patients should follow the instructions described in step 3 of the instructions for use (see below).

Do not use a standard insulin syringe to withdraw insulin from the pen. This may result in an overdose of insulin. The scale of most syringes is calibrated only for non-concentrated insulin preparations (100 units/mL).

Important Information on the Use of the Tresiba SoloStar Pen.

• The pen is intended for personal use only and must not be shared with others.
• Do not use the pen if it is damaged or if there is any doubt about its proper functioning.
• Always perform a safety test.
• Always keep a spare pen and spare needles in case the primary set is lost or damaged.

What You Need to Know for Injection.

• Before using the pen, consult your doctor or nurse on how to perform the injection.
• If you have any difficulties using the pen, for example due to vision problems, seek assistance.
• Always reread these instructions before using the pen. Failure to follow these instructions may result in administration of too high or too low a dose of insulin.

Additional Items Required for Administration of This Medicinal Product:

• a new sterile needle (see STEP 2);
• an alcohol swab;
• a puncture-resistant container for used needles and pens.

INSTRUCTIONS FOR USE OF THE TRESIBA SOLOSTAR PEN

*The plunger will not be visible until several doses have been administered.

Fig. 2. Schematic representation of the Tresiba SoloStar pen.

STEP 1. Check Your Pen.

Remove the new pen from the refrigerator at least 1 hour before injection. Injection with cold insulin solution is more painful.

A. Check the name of the medicinal product and the expiration date on the pen label.

• Ensure you have selected the correct insulin product. This is especially important if you have other pens.

• Never use the pen after its expiration date.

B. Remove the pen cap.

C. Ensure the insulin is clear.

• Do not use the pen if the insulin solution appears cloudy, discolored, or contains particles.

STEP 2. Attach a New Needle.

• Always use a new sterile needle for each injection. This helps prevent needle blockage, contamination, and infection.
• Use only needles compatible with the Tresiba SoloStar pen (e.g., needles manufactured by BD, Ypsomed, Artsana, or Owen Mumford).

A. Take a new needle and peel off the protective film.

B. Hold the needle straight and screw it onto the pen until secure. Do not overtighten the needle.

C. Remove the outer needle cap. Keep it—it will be needed later.

D. Remove the inner needle cap and discard it.

Handling Needles.

Handle needles carefully to prevent needlestick injuries and cross-contamination.

STEP 3. Perform the Safety Test.

Always perform the safety test before each injection to:

• verify that your pen and needle are working properly;
• ensure you receive the correct insulin dose.

A. Select a dose of 3 units by turning the dose selector until the dose pointer aligns with the mark between 2 and 4.

B. Press the injection button fully.

• If insulin appears at the needle tip, your pen is working correctly.

If no insulin appears:

• You may need to repeat this step up to 3 times before seeing insulin.
• If insulin still does not appear after the third attempt, the needle may be blocked. If so:
• change the needle (see STEP 6 and STEP 2);
• then repeat the safety test (STEP 3).
• If insulin still does not appear at the needle tip, do not use your pen. Use a new pen.
• Never use a syringe to withdraw insulin from your pen.

If you see air bubbles:

• You may see air bubbles in the insulin. This is normal and will not harm you.

STEP 4. Select Your Dose.

Never select a dose or press the injection button without an attached needle. This may damage your pen.

A. Ensure the needle is attached to the pen and the dose pointer indicates "0".

B. Turn the dose selector until the dose pointer aligns with your required dose.

• If you turn the selector beyond your required dose, you may turn it back in the opposite direction.
• If there are insufficient units remaining in your pen for your dose, the dose selector will stop when the remaining units in the pen are reached.
• If you cannot select the full prescribed dose, divide the dose into two injections or use a new pen.

How to Read the Dose Display Window

Even numbers are displayed at the level of the dose pointer:

Dose set at 30 units

Odd numbers are displayed as marks between even numbers:

Dose set at 29 units

Number of insulin units in your pen

• Your pen contains a total of 450 units of insulin. You can select doses from 1 to 80 units in 1-unit increments. Each pen contains more than one dose.
• You can roughly estimate the remaining insulin units in the pen by observing the plunger's position relative to the insulin scale.

STEP 5. Administer Your Required Dose.

If you find it difficult to press the injection button, do not force it, as this may damage your pen. For assistance, refer to the section below.

A. Select the injection site as shown in the figure.

Injection sites: abdominal wall, deltoid area, or thigh:

B. Insert the needle into your skin as demonstrated by your doctor or nurse.

• Do not press the injection button yet.

C. Place the thumb of your hand on the injection button. Then press it fully and hold it in this position.

• Do not press the button at an angle, as your thumb may block rotation of the dose selector.

D. Keep the injection button fully pressed. After you see "0" in the dose display window, slowly count to 5.

• This ensures administration of the full dose.

E. After holding the button and slowly counting to 5, release the injection button. Then withdraw the needle from the skin.

If you find it difficult to press the injection button:

• Change the needle (see STEP 6 and STEP 2), then repeat the safety test (see STEP 3).
• If you still find it difficult to press the button, use a new pen.
• Never use a syringe to withdraw insulin from your pen.

STEP 6. Remove the Needle.

• Handle needles carefully to prevent needlestick injuries and cross-contamination.
• Never reattach the inner needle cap.

A. Replace the outer needle cap onto the needle and unscrew the needle from the pen using the cap.

• To reduce the risk of accidental needlestick injuries, never reattach the inner needle cap.
• If another person administers the injection or if you administer it to another person, the person administering the injection must remove and dispose of the needle with special care.
• Follow recommended safety procedures for needle removal and disposal (consult your doctor or nurse) to reduce the risk of accidental needlestick injuries and transmission of infectious diseases.

B. Discard the used needle into a puncture-resistant container or according to your doctor's or local authority's recommendations.

C. Replace the pen cap back onto the pen.

• Do not return the pen to the refrigerator.

Storage Instructions.

Before first use of the pen, store in the refrigerator at 2–8 °C, protected from light. Do not freeze!

Shelf life of the pen after first use or spare pen carried with the patient: Pens should be stored for no more than 42 days at a temperature not exceeding 30 °C, protected from light.

The pen in use should not be stored in the refrigerator. After each injection, the pen cap should be replaced to protect from light.

Do not store the pen with an attached needle.

Pen Handling. Handle the pen carefully: do not drop or strike it against hard surfaces. If you suspect the pen is damaged, do not attempt to repair it; use a new one.

Protect the pen from dust and dirt: the outer surface of the pen may be cleaned by wiping with a damp cloth. Do not immerse in liquid, rinse, or lubricate the pen, as this may damage it.

Disposal of the Pen. Remove the needle before disposal. Dispose of the pen as recommended by local regulatory authorities.

Children.

Tresiba SoloStar may be used in children and adolescents aged 6 years and older on the same principles as in adult patients (see sections "Pharmacokinetics" and "Pharmacodynamics"). When switching from basal insulin to Tresiba SoloStar, reductions in basal and bolus insulin doses should be individually calculated to minimize the risk of hypoglycemia (see section "Special Warnings and Precautions for Use").

Overdose.

Symptoms. Insulin overdose may lead to severe, sometimes prolonged hypoglycemia, which may be life-threatening.

Treatment. Mild episodes of hypoglycemia can usually be corrected by oral administration of carbohydrates. Dose adjustments of the medicinal product, changes in diet, or physical activity may also be required.

More severe episodes of hypoglycemia accompanied by coma, seizures, or neurological impairment require intramuscular/subcutaneous administration of glucagon or intravenous administration of concentrated glucose solution. Since hypoglycemia may recur even after apparent clinical improvement, prolonged carbohydrate intake and patient monitoring are necessary.

Side effects

The following adverse reactions were reported during clinical trials with the use of the product Toujeo SoloStar (see section "Pharmacodynamics") and from the clinical experience with insulin glargine 100 units/mL. Hypoglycaemia is generally the most common adverse reaction observed during insulin therapy. It occurs when the insulin dose exceeds the patient's requirement.

Adverse reactions associated with the use of the product, observed during clinical trials, are listed below by "System Organ Class" in decreasing order of frequency (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); frequency not known (cannot be estimated from the available data)).

Within each category, adverse reactions are listed in order of decreasing severity.

Immune system disorders. Rare: allergic reactions.

Metabolic and nutritional disorders. Very common: hypoglycaemia.

Nervous system disorders. Very rare: dysgeusia.

Eye disorders. Rare: visual disturbances, retinopathy.

Skin and subcutaneous tissue disorders. Common: lipohypertrophy. Uncommon: lipoatrophy. Frequency not known: cutaneous amyloidosis.

Musculoskeletal and connective tissue disorders. Very rare: myalgia.

General disorders and administration site conditions. Common: injection site reactions. Rare: oedema.

Metabolic and nutritional disorders. Severe episodes of hypoglycaemia, particularly when recurrent, may lead to neurological impairment. Prolonged or severe hypoglycaemia may be life-threatening.

In many patients, symptoms of insufficient glucose supply to the brain (neuroglycopaenia) are preceded by signs of adrenergic counter-regulation. Generally, the greater and more rapid the decline in blood glucose level, the more pronounced the adrenergic counter-regulation and the more intense the associated symptoms.

Immune system disorders. Immediate-type hypersensitivity reactions to insulin are rare. Such reactions to insulin (including insulin glargine) or to excipients may include generalized skin reactions, angioedema, bronchospasm, hypotension, and shock, which may be life-threatening. In clinical trials involving adult patients, the frequency of allergic reactions was similar in patients receiving Toujeo SoloStar (5.3%) and those receiving insulin glargine 100 units/mL (4.5%).

Eye disorders. A significant change in blood glucose levels may cause a temporary disturbance in vision due to transient changes in the turgor and refractive index of the lens. The risk of progression of diabetic retinopathy is reduced with sustained normalization of blood glucose levels. However, intensification of insulin therapy with rapid improvement in glycaemic control may be accompanied by a temporary worsening of diabetic retinopathy. In patients with proliferative retinopathy, especially those who have not undergone photocoagulation, episodes of severe hypoglycaemia may lead to temporary blindness.

Skin and subcutaneous tissue disorders. Lipodystrophy and cutaneous amyloidosis may occur at the injection site, resulting in reduced insulin absorption rate at the injection site. Regular rotation of injection sites within a given injection area may reduce or prevent these phenomena (see section "Special warnings and precautions for use").

General disorders and administration site conditions. Reactions at the injection site include erythema, pain, pruritus, urticaria, swelling, or inflammation. Most minor insulin reactions at the injection site usually resolve within a period of several days to several weeks. In clinical trials of Toujeo SoloStar in adult patients, the frequency of injection site reactions was similar to that observed with insulin glargine 100 units/mL (2.5% and 2.8%, respectively).

Oedema may rarely occur with insulin therapy, particularly when improved glycaemic control is achieved in patients with previously inadequate control through intensified insulin therapy.

Children and adolescents.

The safety and efficacy of Toujeo have been demonstrated in a study involving children aged 6 to 18 years. The frequency, type, and severity of adverse reactions in children are similar to those in the general population of patients with diabetes mellitus (see section "Pharmacodynamics"). Safety data for use in children under 6 years of age are not available.

Other special populations. Based on clinical trial results, the safety profile of Toujeo SoloStar in elderly patients and in patients with renal impairment was similar to that in the general patient population (see section "Pharmacodynamics").

Reporting suspected adverse reactions. Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of this medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

Shelf life. 30 months.

Shelf life of the pen after first use or spare pen carried for use: Pens should be stored for no more than 42 days at a temperature not exceeding 30 °C, protected from light. A pen in use should not be stored in the refrigerator. After each injection, the pen cap should be replaced to protect from light.

Storage conditions.

Keep out of the reach of children.

Before first use of the pen store in a refrigerator at 2–8 °C, protected from light. Do not freeze!

Pen after first use or spare pen carried for use: see section "Shelf life".

Incompatibilities.

Toujeo SoloStar must not be mixed with any other insulin or medicinal product, or diluted with them. Mixing with other products or dilution alters its time-action profile, and mixing with other products may result in precipitation.

Packaging. No. 1, No. 3, No. 5: 1.5 mL in a cartridge contained in a disposable pen; 1, 3 or 5 pens in a cardboard box. Needles are not included in the package.

Prescription category. Prescription only.

Manufacturer. Sanofi-Aventis Deutschland GmbH, Germany.

Manufacturer's address and place of business. Bruningstrasse 50, Industriepark Höchst, 65926 Frankfurt am Main, Germany.