Tugeo SoloStar, 300 units/ml 1.5 ml cartridges in SoloStar syringe pens 5 pcs

Pharmacological action is hypoglycemic.

Pharmacodynamics

The most important action of insulin, including insulin glargine, is regulation of glucose metabolism. Insulin and its analogues decrease blood glucose concentration by stimulating glucose uptake by peripheral tissues (especially skeletal muscle and adipose tissue) and inhibiting glucose formation in the liver. Insulin suppresses lipolysis in adipocytes (fat cells) and inhibits proteolysis while increasing protein synthesis.

Pharmacodynamic characteristics

Insulin glargine is an analog of human insulin obtained by recombination of DNA of Escherichia coli bacteria (K12 strains) used as a producer strain. It has a low solubility in a neutral medium. At pH 4 (in an acidic environment), insulin glargine is completely soluble. After injection into the subcutaneous fat, the acidic reaction of the solution is neutralized, resulting in the formation of microprecipitates from which small amounts of insulin glargin are continuously released.

The onset of action of b/c injected 100 IU/ml glargin insulin was slower compared to human insulin isophan, its action curve was smooth and devoid of peaks, and its duration of action was prolonged (data from euglycemic clamp studies performed in healthy volunteers and patients with type 1 diabetes).

The hypoglycemic action of Tujeo SoloStar® after p/q administration was more constant in value and more prolonged compared to p/q administration of insulin glargine 100 units/ml (data of 36-hour cross-over euglycemic clamp study in 18 patients with type 1 diabetes). The action of Tujeo SoloStar® lasted more than 24 hours (up to 36 hours) when administered by mouth at clinically relevant doses.

The prolonged hypoglycemic action of Tujeo SoloStar® lasting more than 24 hours allows the time of administration to be changed if necessary within 3 hours before or 3 hours after the patient’s usual time of injection (see “Dosage and Administration”).

Differences in the hypoglycemic action curves of Tujeo SoloStar® and insulin glargine 100 units/ml are due to changes in the release of insulin glargine from the precipitate.

For the same number of units of glargine insulin, the administered volume of Tugeo SoloStar® is one-third that of 100 U/ml glargine insulin. This results in a smaller precipitate surface area, allowing for a more gradual release of glargine insulin from the Tugeo SoloStar® precipitate compared to the 100 U/ml glargine insulin precipitate.

In intravenous administration of equal doses of insulin glargine and human insulin, their hypoglycemic effects were similar.

Binding to insulin receptors. Insulin glargin is metabolized to two active metabolites M1 and M2 (see Pharmacokinetics). In vitro studies have shown that the affinity of insulin glargine and its metabolites M1 and M2 to human insulin receptors is similar to that of human insulin.

Binding to IGF-1 receptors. The affinity of glargine insulin for the 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), whereas compared to human insulin, glargine insulin metabolites M1 and M2 have slightly lower affinity for the IGF-1 receptor. The total therapeutic insulin concentration (the concentration of insulin glargine and its metabolites) determined in patients with type 1 diabetes was markedly lower than the concentration required for half-maximal binding to IGF-1 receptors and subsequent activation of the mitogen-proliferative pathway triggered through IGF-1 receptors. Physiological concentrations of endogenous IGF-1 can activate the mitogen-proliferative pathway, but the therapeutic insulin concentrations determined with insulin therapy, including treatment with Tujeo SoloStar®, are significantly lower than the pharmacological concentrations necessary to activate the mitogen-proliferative pathway.

The results from all clinical trials of Tugeo SoloStar® conducted with a total of 546 patients with type 1 diabetes and 2,474 patients with type 2 diabetes showed that the decrease in glycosylated hemoglobin (HbAlc) values compared to their baseline values by the end of the trials was no less than that of treatment with insulin glargine 100 units/ml.

The percentage of patients achieving the target HbA1c (below 7%) was comparable in both treatment groups.

The decrease in plasma glucose concentrations by the end of the study with Tugeo SoloStar® and insulin glargine 100 units/mL was similar, but with treatment with Tugeo SoloStar® the decrease was more gradual during the dose-fitting period.

Glycemic control, including improvement in HbAlc, was comparable when Tugeo SoloStar® was administered in the morning or evening, and changing the time of administration within 3 h before or 3 h after the patient’s usual time of administration had no effect on its effectiveness.

Patients treated with Tujeo SoloStar® showed an average weight change of less than 1 kg by the end of the 6-month therapy period.

The improvement in HbA1c was independent of gender, ethnicity, age, duration of diabetes (<10 and ≥10 years), HbAlc value at outcome (<8 or ≥8%), or BMI at outcome.

In patients with type 2 diabetes, clinical trial results have demonstrated a lower incidence of severe and/or confirmed hypoglycemia as well as documented hypoglycemia with clinical symptoms when treated with Tugeo SoloStar® compared to treatment with 100 units/mL insulin glargine.

The benefit of Tugeo SoloStar® over glargine 100 units/mL insulin in reducing the risk of severe and/or confirmed nocturnal hypoglycemia was shown in patients previously treated with oral hypoglycemic agents (23% risk reduction) or with insulin with meals (21% risk reduction) during the 9 weeks to end of study compared to treatment with glargine insulin 100 units/mL.

In the group of patients treated with Tujeo SoloStar® compared with patients treated with 100 U/mL insulin glargine, the reduction in risk of hypoglycemia was observed in both patients previously treated with insulin therapy and in patients not previously treated with insulin; the risk reduction was greater during the first 8 weeks of treatment (initial treatment period) and was independent of age, sex, race, BMI, and duration of diabetes (<10 and ≥10 years).

In patients with type 1 diabetes mellitus, the incidence of hypoglycemia during treatment with Tujeo SoloStar® was similar to that in patients treated with insulin glargine 100 units/ml. However, the incidence of nocturnal hypoglycemia (for all categories of hypoglycemia) during the initial treatment period was lower in patients treated with Tugeo SoloStar® compared to patients treated with 100 units/ml insulin glargine.

. In clinical trials, a single daily infusion of Tugeo SoloStar® in the evening, with a fixed infusion schedule (at the same time) or a flexible infusion schedule (at least twice weekly infusions were given 3 hours before or 3 hours after the usual infusion time, resulting in shortened intervals of up to 18 h or longer intervals of up to 30 h) had similar effects on HbA1c, fasting plasma glucose concentration (FPG), and mean preinjection plasma glucose concentration at self-determination. In addition, no differences in the incidence of hypoglycemia at any time of day or nocturnal hypoglycemia were observed when using Tugeo SoloStar® with fixed or flexible administration time schedules. Study results did not indicate any differences related to insulin antibody formation in efficacy, safety, or basal insulin dose between patients treated with Tugeo SoloStar® and insulin glargine 100 units/ml (see “Adverse Events”). The ORIGIN (Outcome Reduction with Initial Glargine Intervention) study was an international, multicenter, randomized study conducted in 12537 patients with impaired fasting glycemia (ADG), impaired glucose tolerance (IGT) or early stage type 2 diabetes and confirmed cardiovascular disease. Study participants were randomly allocated into groups – those receiving insulin glargine ≤100 units/mL (n=6264), which was titrated until reaching a GPA <5.3 mmol concentration, or standard treatment (n=6273). the mean follow-up period was approximately 6.2 years.

The median baseline HbA1c value was 6.4%. The median HbA1c during treatment ranged from 5.9-6.4% in the glargine insulin group and 6.2-6.6% in the standard treatment group over the entire follow-up period.

. The ORIGIN study showed that treatment with glargine insulin 100 units/ml, compared with standard hypoglycemic therapy, did not change the risk of cardiovascular complications (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke), risk of revascularization procedure (coronary, carotid or peripheral arteries) or hospitalization for the development of heart failure, the risk of developing microvascular complications (combined index of microvascular complications: laser photocoagulation or vitrectomy, vision loss due to diabetic retinopathy, progression of albuminuria or doubling of the blood creatinine concentration index, or occurrence of the need for dialysis therapy).

In a five-year follow-up study evaluating the effect of insulin glargine 100 units/ml on the development of diabetic retinopathy in patients with type 2 diabetes there was no significant difference in the progression of diabetic retinopathy with treatment with insulin glargine 100 units/ml compared to insulin isophane.

Particular patient groups

Gender and race. There were no differences in efficacy and safety between Tugeo SoloStar® and insulin glargine 100 units/ml based on patient gender and race.

Elderly age. In controlled clinical trials, 716 patients (23% of the safety assessment population) with type 1 and 2 diabetes were ≥65 years of age and 97 patients (3%) were ≥75 years of age. Overall, there were no differences in efficacy or safety between these patients and younger patients. In elderly patients with diabetes mellitus, to avoid hypoglycemic reactions, the starting and maintenance doses should be lower and dose increases should be slower. In elderly patients it may be difficult to recognize hypoglycemia. Close monitoring of blood glucose concentrations is recommended, and the insulin dose should be adjusted individually (see “Dosage and administration” and “Pharmacokinetics”).

Renal insufficiency. In controlled clinical trials, a subgroup analysis based on renal functional status (determined at outcome by GFR <60 or ≥60 ml/min/1.73 m2 body surface area) showed no difference in safety or efficacy between Tugeo SoloStar® and insulin glargine 100 units/mL. Close monitoring of blood glucose concentrations is recommended, and the insulin dose should be adjusted individually (see Administration and Doses and Pharmacokinetics).

Patients with obesity. In clinical trials, a subgroup analysis based on BMI (up to 63 kg/m2) showed no difference in efficacy and safety between Tugeo SoloStar® and insulin glargine 100 units/mL.

Children. There are no data on the use of Tugeo SoloStar® in children.

Pharmacokinetics

Absorption and distribution. Following p/k injection of Tujeo SoloStar® in healthy volunteers and diabetic patients, serum insulin concentrations indicate much slower and more prolonged absorption, resulting in a flatter AUC curve for up to 36 hours compared to insulin glargine 100 units/ml. The AUC curve of Tujeo SoloStar® was consistent with its pharmacodynamic activity curve. Css within the therapeutic concentration range was achieved after 3-4 days of daily use of Tugeo SoloStar®.

The variability in the same patient, defined as the coefficient of variation of systemic insulin exposure over 24 hours in the state of achieving Css, was low (17.4%) after a bpc injection of Tugeo SoloStar®.

Metabolism. In humans, insulin glargin is rapidly metabolized from the carboxyl end (C-end) of the β-chain to form two active metabolites M1 (21A-Gly insulin) and M2 (21A-Gly-des-30B-Thr-insulin) after p/c administration of Tugeo SoloStar®. Metabolite M1 predominantly circulates in blood plasma. Systemic exposure to M1 metabolite increases with increasing dose of Tujeo SoloStar®. Comparison of pharmacokinetic and pharmacodynamic data showed that the drug action is mainly due to systemic exposure of M1 metabolite. In the vast majority of patients, insulin glargine and M2 metabolite could not be detected in the systemic bloodstream. In cases where insulin glargin and metabolite M2 were detected in the blood, their concentrations were independent of the dose administered and the dosage form of insulin glargin.

Elimination. The T1/2 of metabolite M1, the quantitatively predominant metabolite of Tujeo SoloStar®, is 18-19 h after a p/k injection of the drug, regardless of the dose.

Particular patient groups

Gender and race. There is no information about the effect of race and gender on the pharmacokinetics of insulin glargine (see “Pharmacodynamics”).

Elderly age. The effect of age on the pharmacokinetics of Tujeo SoloStar® has not been studied at present. In elderly patients with diabetes mellitus, in order to avoid hypoglycemic reactions, the starting dose and maintenance dose should be lower and dose increases should be made more slowly (see “Pharmacodynamics” and “Dosage and administration”).

In children. In children, the pharmacokinetics of Tujeo SoloStar® have not been studied at this time.

Hepatic and renal insufficiency. The effect of renal and hepatic impairment on the pharmacokinetics of Tujeo SoloStar® has not been studied to date. However, some studies conducted with human insulin have shown increased insulin concentrations in patients with renal and hepatic impairment. Close monitoring of blood glucose concentrations and individual adjustment of insulin dose is recommended (see “Dosage and administration” and “Pharmacodynamics”).

Indications

Diabetes mellitus in adults requiring insulin treatment.

Active ingredient

Insulin glargine

Composition

1 ml of the solution contains:

the active ingredient:

insulin glargine 300 IU (10.91 mg);

excipients:

methacresol (m-cresol) – 2.70 mg,

zinc chloride – 0.19 mg (corresponding to 0.09 mg of zinc),

glycerol (85%) – 20 mg, <

Sodium hydroxide – to pH 4.0,

Hydrochloric acid – to pH 4.0,

Injection water – to 1.0 ml.

How to take, the dosage

General Guidelines

The units of Tugeo SoloStar® (insulin glargine 300 units/ml) refer only to Tugeo SoloStar® and are not equivalent to other units expressing the potency of other insulin analogues. Tugeo SoloStar® should be administered by injection once daily at any time of the day, preferably at the same time. Tujeo SoloStar® when administered once daily allows for a flexible injection schedule: if necessary, patients can have the injection within 3 hours before or 3 hours after their usual injection time.

The target values of blood glucose concentrations, doses and time of administration/injection of hypoglycemic drugs must be determined and adjusted individually.

Dose adjustments may also be necessary, for example, if the patient’s body weight or lifestyle changes, changes in the timing of insulin administration, or other conditions that may increase the predisposition to develop hypo- or hyperglycemia (see “Special Precautions”). Any changes in insulin dose should be made with caution and only under medical supervision. Tujeo SoloStar® is not the insulin of choice for the treatment of diabetic ketoacidosis. In this case, intravenous short-acting insulin should be preferred.

Blood glucose monitoring is recommended in all patients with diabetes mellitus.

The initiation of Tugeo SoloStar®

Patients with type 1 diabetes mellitus. Tugeo SoloStar® should be used once daily in combination with insulin administered with meals and requires individual dose adjustment.

Patients with type 2 diabetes mellitus. The recommended starting dose is 0.2 IU/kg once daily, with individual dose adjustment thereafter.

Transfer from the administration of 100 U/ml insulin glargine to Tugeo SoloStar® and vice versa from Tugeo SoloStar® to 100 U/ml insulin glargine

Isulin glargine 100 U/ml and Tugeo SoloStar® are not bioequivalent and are not directly interchangeable.

– Switching from 100 U/ml insulin glargine to Tugeo SoloStar® may be done on a unit per unit basis, but a higher dose of Tugeo SoloStar® may be required to achieve the target range of plasma glucose concentrations.

– When switching from Tujeo SoloStar® to 100 units/ml insulin glargine to reduce the risk of hypoglycemia, the dose should be reduced (approximately 20%), with subsequent dose adjustments if necessary.

We recommend careful metabolic monitoring during and for the first few weeks after switching from one of these drugs to the other.

The transition from other basal insulins to Tugeo SoloStar®

. When switching from a treatment regimen with intermediate and long-acting insulins to a treatment regimen with Tugeo SoloStar®, a change in basal insulin dose and correction of concurrent hypoglycemic therapy (change in doses and timing of administration of short-acting insulins or fast-acting insulin analogues, or doses of non-insulin hypoglycemic drugs) may be required.

– Transition from a single daily administration of basal insulins to a single daily administration of Tugeo SoloStar® may be made at the rate of one unit per unit of the previously administered dose of basal insulin.

– When switching from twice daily basal insulins to a single dose of Tugeo SoloStar®, the recommended starting dose of Tugeo SoloStar® is 80% of the total daily dose of basal insulin that is discontinued. Patients with high doses of insulin, due to their antibodies to human insulin, may have an improved response to Tugeo SoloStar®.

Careful metabolic monitoring is recommended during the transition to Tugeo SoloStar® and for several weeks thereafter.

With improvement in metabolic control and the resulting increase in insulin sensitivity, additional dosing adjustments may be required. Dosing adjustments may also be necessary, for example, if the patient’s body weight or lifestyle changes, if the timing of insulin dosing changes, or if there are other conditions that increase the predisposition to develop hypo- and hyperglycemia.

The transition from Tugeo SoloStar® to other basal insulins

Medical observation and close metabolic monitoring is recommended during the transition from Tugeo SoloStar® to other basal insulins and for several weeks thereafter.

It is recommended to refer to the instructions for use of the medication to which the patient is being switched.

Mixing and Dilution

Tugeo SoloStar® should not be mixed with any other insulin. Mixing leads to a change in the action profile of Tugeo SoloStar® over time and causes precipitation. Tugetio SoloStar® should not be diluted. Dilution may cause a change in the time course of action profile of Tugeo SoloStar®.

Particular patient groups

Children. The safety and efficacy of Tujeo SoloStar® in children and adolescents under 18 years of age has not yet been established (see “Pharmacokinetics”).

Elderly age. Tugeo SoloStar® may be used in elderly patients. Close monitoring of blood glucose concentration is recommended, and insulin dose should be adjusted individually. In elderly patients, progressive deterioration of renal function may result in permanently reduced insulin requirements (see “Special Precautions”, “Pharmacodynamics” and “Pharmacokinetics”).

Renal insufficiency. Tugeo SoloStar® may be used in patients with renal impairment. Close monitoring of blood glucose concentration is recommended, and the dose of insulin should be adjusted individually. In patients with renal insufficiency, insulin requirement may decrease due to slower insulin metabolism (see “Special Notes”, “Pharmacodynamics” and “Pharmacokinetics”).

Hepatic insufficiency. The drug Tugeo SoloStar® may be used in patients with hepatic impairment. Close monitoring of blood glucose concentration is recommended, and the dose of insulin should be adjusted individually. In patients with hepatic impairment, insulin requirement may decrease due to decreased gluconeogenesis and slower insulin metabolism (see “Pharmacodynamics”, “Pharmacokinetics” and “Special Precautions”).

How to use

Tugeo SoloStar® is injected into the subcutaneous fatty tissue of the abdomen, shoulders or thighs. The injection sites should alternate with each new injection within the recommended areas for administration of the product.

Tugeo SoloStar® is not indicated for intravenous administration. Prolonged action of insulin glargine is observed only when injected into the subcutaneous fatty tissue. IV administration of a normal p/k dose may cause severe hypoglycemia. Tujeo SoloStar® is not intended to be administered by insulin infusion pump.

Tugeo SoloStar® is a clear solution, not a suspension, so resuspension is not required before administration. The Tugeo SoloStar® syringe pen can be used to deliver doses from 1 to 80 IU per injection in increments of 1 IU:

The dose counter of the Tugeo SoloStar® syringe pen shows the number of IU of Tugeo SoloStar® to be delivered. The Tugeo SoloStar® syringe pen was specifically designed for Tugeo SoloStar®, so no additional dose counting is required;

– Tugeo SoloStar® should never be removed from the syringe pen cartridge into the syringe (see Special Instructions);

– Needles cannot be reused. A new sterile needle must be attached before each injection. Repeated use of needles increases the risk of needle blockage, which can lead to a lower dose or overdose. In addition, using a new sterile needle for each injection minimizes the risk of contamination and infection;

If the needle becomes clogged, the patient should follow the instructions in step 3 (see Tugeo SoloStar® Syringe Pen Instructions for Use).

In order to avoid possible transmission of blood-borne diseases, insulin syringe pens should not be used by more than one patient, even if the needle is changed.

For proper use of the Tugeo SoloStar® syringe pen, please refer to the Instructions for Use. Refer to the Instructions for Use for the Tugeo SoloStar® Syringe Pen. In order to eliminate the possibility of mistakenly (accidentally) injecting another type of insulin instead of Tugeo SoloStar®, always check the label on the syringe pen before each injection (the label on the Tugeo SoloStar® syringe pen has the “300 units/ml” concentration highlighted in a honey-gold background).

The shelf life of the drug in the Tugeo SoloStar® disposable syringe pen after the first use is 4 weeks, when stored in a light-protected place. It is recommended that the label on the syringe pen indicate the date of first use.

The Tujeo SoloStar® Syringe Pen Instructions for Use (Insulin Glargin 300 U/ml)

The Tujeo SoloStar® Syringe Pen contains 300 U/ml glargin insulin.

1. Never reuse the needle. If the needle is reused because the needle can become clogged, the patient may not get the dose they want (administering a smaller dose) or they may overdose (overdose).

2. Never use a syringe to remove insulin from the syringe pen. If you do, the patient may receive too large a dose of insulin. The scale on most insulin syringes is only for nonconcentrated insulin.

Important information

1. Do not use the same syringe pen at the same time as other people, even if the needle is changed. The patient could get a serious infection from other people, or pass on a serious blood-borne infection.

2. Never use the syringe pen if it is damaged or if the patient is unsure if it is working properly.

3. Always perform a safety test.

4. always carry a spare syringe pen and extra needles in case they get lost or become defective.

5 Before using a syringe pen, check with your healthcare provider about how to give an I.V. injection.

6 If the patient has vision problems, they may need the assistance of others who are able to follow all of the recommendations in these instructions for use of the Tujeo SoloStar® syringe pen.

The entire instruction manual should be read before using the syringe pen. If the patient does not follow all recommendations, they may receive either too much or too little insulin.

The patient also needs a new sterile needle (see Step 2), alcohol-soaked wipe, and a puncture-resistant container for used needles and syringes.

Interaction

A number of drugs affect glucose metabolism, which may require insulin dose adjustment and particularly close monitoring if used concomitantly with insulin.

The drugs that may increase the hypoglycemic effect of insulin and the tendency to develop hypoglycemia. Oral hypoglycemic agents, ACE inhibitors, salicylates, disopyramide; fibrates, fluoxetine, MAO inhibitors, pentoxifylline, propoxyphene, sulfonamide antibiotics. Concomitant administration of these drugs with insulin glargine may require adjustment of insulin dose.

The drugs that may weaken the hypoglycemic effect of insulin. GKS, danazol, diazoxide, diuretics, sympathomimetics (such as adrenaline, salbutamol, terbutaline); glucagon, isoniazid, phenothiazine derivatives, somatotropic hormone, thyroid hormones, estrogens and gestagens (for example, in hormonal contraceptives), protease inhibitors and atypical neuroleptics (such as olanzapine and clozapine). Concomitant use of these drugs with insulin glargine may require an adjustment of the insulin dose.

Beta-adrenoblockers, clonidine, lithium salts, and ethanol may increase or decrease the hypoglycemic effects of insulin.

Pentamidine in combination with insulin may cause hypoglycemia, which sometimes changes to hyperglycemia.

Sympatholytic drugs – Sympatholytic drugs such as beta-adrenoblockers, clonidine, guanethidine and reserpine may reduce or not show signs of adrenergic counter-regulation (activation of the sympathetic nervous system in response to the development of hypoglycemia).

Interaction with pioglitazone. When using pioglitazone in combination with insulin, cases of heart failure have been reported, especially in patients at risk of heart failure (see “Cautionary Note”). If cardiac symptoms appear or worsen, the use of pioglitazone should be discontinued.

Special Instructions

Patients should have the skills to self-monitor their diabetes, including monitoring blood glucose concentrations, as well as adhering to proper injection technique and being able to manage hypoglycemia and hyperglycemia. Insulin therapy requires constant alertness to the possibility of hyperglycemia or hypoglycemia.

If blood glucose control is inadequate or if there is a trend toward hypo- or hyperglycemia, accurate adherence to the prescribed dosing regimen, compliance with the site of administration, proper hypodermic injection technique and handling of the SoloStar® syringe, and all other factors that may contribute to this condition should be considered before initiating dosing adjustments.

Hypoglycemia

The timing of hypoglycemia depends on the profile of action of the insulins used and may thus vary with changes in the treatment regimen. Special caution should be exercised and monitoring of blood glucose concentrations should be intensified when using the drug in patients in whom episodes of hypoglycemia may have special clinical significance, such as patients with severe stenosis of coronary arteries or cerebral vessels (risk of cardiac and cerebral complications of hypoglycemia), and patients with proliferative retinopathy, especially if they are not treated with photocoagulation (risk of transient vision loss following hypoglycemia). As with any insulin, the precursor symptoms of hypoglycemia may change, become less pronounced or absent in some conditions.

These include:

– marked improvement in glycemic control;

– gradual development of hypoglycemia;

– older age;

– presence of autonomic neuropathy;

– long-term history of diabetes mellitus;

– presence of mental disorders;

– concomitant use of insulin glargine with some other drugs (see “Interactions. “Interactions”).

These situations can lead to severe hypoglycemia (with possible loss of consciousness) before the patient realizes that he/she is hypoglycemic.

It should be noted that the prolonged action of Tujeo SoloStar® when administered by injection may delay the patient’s recovery from hypoglycemia.

If normal or reduced glycosylated Hb values are noted, the possibility of recurrent unrecognized episodes of hypoglycemia (especially at night) should be considered.

Patient compliance with dosing and feeding regimens, proper insulin administration, and knowledge of hypoglycemic precursor symptoms all contribute to significantly reducing the risk of hypoglycemia.

Factors that increase the propensity for hypoglycemia that require particularly close monitoring and may require insulin dose adjustments:

– change in location of insulin administration;

– increased insulin sensitivity (e.g., when stressors are removed);

– Unusual, increased or prolonged physical activity;

– Intercurrent illness with vomiting, diarrhea;

– inadequate food intake;

– consumption of ethanol;

– certain uncompensated endocrine disorders (such as hypothyroidism, anterior pituitary gland or adrenal cortex insufficiency);

– simultaneous use of insulin glargine with certain other medications (see “Interactions “Interactions”).

In patients with renal insufficiency, the need for insulin may be reduced by slowing insulin metabolism (see “Pharmacodynamics”, “Pharmacokinetics” and “Dosage and administration”). In elderly patients, progressive deterioration of renal function may result in a sustained reduction of insulin requirement (see “Pharmacodynamics”, “Pharmacokinetics” and “Dosage and administration”).

In patients with severe hepatic impairment, insulin requirement may be reduced due to decreased gluconeogenesis capacity and slower insulin metabolism (see “Pharmacodynamics”, “Pharmacokinetics” and “Dosage and administration”).

Hypoglycemia in general can be corrected by immediate administration of rapidly digestible carbohydrates. Because initial action to correct hypoglycemia must be taken immediately, patients should always have at least 20 g of rapidly digestible carbohydrates with them.

Intercurrent illnesses

Intercurrent illnesses require more intensive monitoring of blood glucose concentrations. In many cases, urine ketone body testing is indicated, and adjustments to insulin dosing regimen are also often required. If intercurrent disease occurs, the need for insulin is often increased. Patients with type 1 diabetes should continue to receive carbohydrates on a regular basis, even if they are only able to eat in small portions or do not eat at all or if they develop vomiting; patients with type 1 diabetes should never completely skip an insulin injection.

The combination of insulin glargine with pioglitazone

In combination with insulin, pioglitazone has been reported to cause heart failure, especially in patients at risk for heart failure. This information should be taken into account when considering the use of a combination of pioglitazone with Tujeo SoloStar®. When using such a combination, patients should be monitored for signs and symptoms of heart failure, such as weight gain, edema. If cardiac symptoms appear or worsen, the use of pioglitazone should be discontinued.

Preventing mistakes when administering insulin preparations

To avoid confusing Tugeo SoloStar® with other insulins, the labeling on the syringe pen should always be checked before each injection. Cases have been reported where other insulins, particularly short-acting insulins, have been inadvertently injected instead of long-acting insulins.

In order to avoid dosing errors and possible overdose, patients should never use a syringe to remove Tugeo® from the SoloStar® pen syringe (see Administration and Doses, Overdose).

As with other insulin syringe pens, patients should visually check the number of units dispensed in the dose indicator window on the syringe pen. Blind or visually impaired patients should be assisted by others who have good vision and know how to use the Tugeo SoloStar® syringe pen.

Tugeo SoloStar® Syringe Pens Storage Recommendations

When storing Tugeo SoloStar® in the refrigerator (unopened/before use), care should be taken to ensure that the syringe pen packages do not come into direct contact with the freezer compartment or frozen foods, as the drug should not be frozen. If the insulin has been frozen, it should not be used and the syringe pen should be disposed of.

The SoloStar® syringe pens in use should be stored at a temperature not exceeding 30 °C, protected from light and heat.

Impact on the ability to drive vehicles and engage in other potentially dangerous activities. Patients’ ability to concentrate and quick psychomotor reactions may be impaired, e.g., by the development of hypoglycemia or hyperglycemia, as well as by visual impairment. This may pose a risk in situations where these abilities are particularly important (e.g., driving a car or working with other mechanisms). Patients are advised to take precautions to avoid developing hypoglycemia while driving. This is especially important for those patients who have little or no symptoms that are precursors of developing hypoglycemia, or for patients with frequent episodes of hypoglycemia. These patient characteristics should be considered when deciding whether the patient can drive.

Contraindications

hypersensitivity to insulin glargine or any of the drug excipients;

age under 18 years (due to the lack of clinical data confirming the effectiveness and safety of the drug in children and adolescents).

With caution: pregnant women (possible change in the need for insulin during pregnancy and after childbirth), elderly patients (see “Pharmacokinetics and Pharmacodynamics”, “Dosage method and “Special indications. “Pharmacokinetics”, “Pharmacodynamics”, “Dosage and administration” and “Special indications”); patients with uncompensated endocrine disorders (such as hypothyroidism, insufficiency of adenohypophysis and adrenal cortex); diseases accompanied by vomiting or diarrhea; severe stenosis of coronary arteries or cerebral vessels; proliferative retinopathy (especially if patients have not had photocoagulation); renal failure; severe hepatic failure (see “Special Indications”).

Side effects

The following adverse reactions (ARs) were observed during clinical trials conducted with Tugeo SoloStar® and during the clinical use of insulin glargine 100 units/ml. These HPs are presented by organ system (according to the MedDRA classification according to the following WHO recommended gradations of frequency of occurrence: Very common (≥10%); common (≥1; < 10%); infrequent (≥0.1; < 1%); rare (≥0.01; < 0.1%); very rare (< 0.01%), frequency unknown (it is not possible to determine the frequency of HPs from available data).

Metabolism and nutrition: hypoglycemia. Hypoglycemia, the most common adverse reaction during insulin therapy, may occur if the dose of insulin is too high compared to the need. As with other insulins, episodes of severe hypoglycemia, especially repeated episodes, can lead to neurological impairment.

Episodes of prolonged and severe hypoglycemia can be life threatening.

In many patients the signs and symptoms of neuroglycopenia (feeling of fatigue, inadequate fatigability or weakness, decreased ability to concentrate, drowsiness, visual disturbances, headache, nausea, confusion or loss of consciousness, seizure syndrome) are preceded by signs of adrenergic counter-regulation (sympathoadrenal system activation in response to hypoglycemia) – sense of hunger, irritability, nervous agitation or tremor, anxiety, pale skin, cold sweat, tachycardia, palpitations. Usually, the faster hypoglycemia develops and the more severe it is, the more pronounced are the symptoms of adrenergic counterregulation.

Visual side: significant improvement in glycemic control may cause temporary visual impairment due to temporary impairment of the turgor and refractive index of the lens of the eye.

Long-term improvement in glycemic control reduces the risk of progression of diabetic retinopathy. However, as with any insulin regimen, intensification of insulin therapy with dramatically improved glycemic control may be associated with a temporary worsening of the course of diabetic retinopathy.

In patients with proliferative retinopathy, especially those not treated with photocoagulation, episodes of severe hypoglycemia may result in transient vision loss.

Skin and subcutaneous tissues: As with treatment with any other insulin drugs, lipodystrophy may develop at the injection site, which may slow local absorption of insulin. With insulin therapy regimens including insulin glargine, lipodystrophy was observed in 1-2% of patients, and lipoatrophy was infrequently observed. Constant change of injection sites within the body areas recommended for p/c insulin administration may help to reduce the severity of this reaction or prevent its development.

Skeletal, muscular and connective tissue disorders: very rare – myalgia.

General disorders and disorders at the injection site: local allergic reactions at the injection site. As with any insulin therapy, these reactions include skin redness, pain, itching, urticaria, rash, edema and inflammation. In clinical studies in adult patients, the incidence of all injection site reactions in patients treated with Tugeo SoloStar® (2.5%) was similar to that in patients treated with insulin glargine 100 units/ml (2.8%). Most minor reactions at the site of insulin administration usually go away within a few days or a few weeks.

Immune system disorders: systemic allergic reactions. Allergic reactions of immediate type to insulin are rare. These reactions to insulin (including insulin glargine) or excipients may be accompanied by, for example, generalized skin reactions, angioedema (Quincke’s edema), bronchospasm, decreased blood pressure and shock and may be life-threatening.

Other reactions: the use of insulin may cause the formation of antibodies to it. In clinical studies comparing Tugeo SoloStar® and insulin glargine 100 units/ml, formation of insulin antibodies was observed with equal frequency in both treatment groups. As with other insulins, in rare cases the presence of such insulin antibodies may require a change in insulin dose to eliminate the tendency to develop hypoglycemia or hyperglycemia.

In rare cases, insulin may cause sodium retention and edema, particularly when previously inadequate metabolic control improves with intensified insulin therapy.

Children. A safety profile for children and adolescents younger than 18 years of age has not been established at this time.

Overdose

Symptoms: Insulin overdose (excess insulin relative to food intake, energy expenditure, or both) can lead to severe and sometimes prolonged and life-threatening hypoglycemia.

Treatment: episodes of moderate hypoglycemia are usually managed by oral administration of rapidly digestible carbohydrates. It may be necessary to change the dosing regimen of the drug, diet, or physical activity.

Episodes of more severe hypoglycemia manifested by coma, seizures or neurological disorders may be controlled by m/m or p/c administration of glucagon or by intravenous administration of concentrated dextrose (glucose) solution. Prolonged intake of carbohydrates and monitoring by a specialist may be required, since after visible clinical improvement, a relapse of hypoglycemia is possible.