Lantus Solostar solution for injection 100 U/ml cartridge 3 ml mounted in a syringe pen without needle No. 5

Instructions for Lantus Solostar solution for injection 100 U/ml cartridge 3 ml mounted in a syringe pen without needle No. 5

Composition

active ingredient: insulin glargine;

1 ml of solution for injection contains 3.6378 mg of insulin glargine, equivalent to 100 U of insulin glargine;

1 cartridge contains 3 ml of solution for injection, corresponding to 300 U of insulin glargine;

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

Dosage form

Solution for injection.

Main physicochemical properties: colorless or almost colorless transparent solution.

Pharmacotherapeutic group

Long-acting insulins and analogues for injection.

ATX code A10A E04.

Pharmacological properties

Pharmacodynamics.

Insulin glargine is designed as a human insulin analogue with low solubility in neutral medium. In Lantus® SoloStar®, it is completely soluble due to the acidic environment of the injection solution (pH 4). After injection into the subcutaneous tissue, the acidic solution is neutralized, which leads to the formation of microprecipitates from which a small amount of insulin glargine is constantly released, which provides a smooth (no peaks) and predictable profile of the concentration-time curve, as well as a longer duration of action of the drug.

Insulin glargine is metabolized to 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 that of human insulin.

Binding to the IGF-1 (insulin-like growth factor 1) receptor:

The affinity of insulin glargine 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 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 mechanism triggered by the IGF-1 receptor. Endogenous IGF-1 at physiological concentrations can activate the mitogenic-proliferative mechanism; however, therapeutic concentrations of insulin used in insulin therapy, including Lantus® SoloStar® insulin therapy, are significantly lower than the pharmacological concentrations required to activate the IGF-1-mediated mechanism.

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.

Clinical pharmacology studies have demonstrated equivalence of the same doses of insulin glargine and human insulin following intravenous administration. As with all insulins, the time course of action of insulin glargine may be influenced by physical activity and other factors.

Studies using the euglycemic state fixation method, which were conducted with the participation of healthy volunteers and patients with type 1 diabetes mellitus, demonstrated that, unlike NPH (neutral protamine Hagedorn) human insulin, the onset of action of insulin glargine after subcutaneous injection occurs later, the drug acts smoothly, without causing peaks in blood glucose concentration, and the duration of its action is prolonged.

The results of one of the studies among patients are shown in the graph below.

Activity profile in patients with type 1 diabetes.

Time (hours) elapsed after subcutaneous injection

End of observation period

* Defined as the amount of glucose administered to maintain a constant plasma glucose level (hourly average values).

The longer duration of action of subcutaneously administered insulin glargine is directly related to its slower absorption, allowing once-daily administration. The time course of action of insulin and its analogues, such as insulin glargine, can have significant inter- and intra-individual variability.

The effect of insulin glargine (administered once daily) on the progression of diabetic retinopathy was evaluated in a five-year, open-label, comparator-controlled trial of NPH insulin (administered twice daily) in 1,024 patients with type 2 diabetes mellitus who had progression of retinopathy of 3 or more points on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. Progression was assessed by fundus photography. There was no statistically significant difference in progression of diabetic retinopathy with Lantus® compared to NPH insulin.

The ORIGIN (Outcome Reduction with Initial Glargine INtervention) study was a multicenter, randomized, 2 x 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 agent (88% of participants). Participants were randomized (1:1) to receive either insulin glargine (n=6264), titrated to achieve a fasting plasma glucose of ≤95 mg/dL (5.3 mmol/L), or standard of care (n=6273).

The first measure in the composite primary endpoint was the time to the first occurrence of death from CV causes, non-fatal myocardial infarction (MI), or non-fatal stroke, and the second measure in the composite primary endpoint was the time to the first occurrence of any of these composite primary endpoint events or a revascularization procedure (coronary, carotid, or peripheral vessels), or hospitalization for heart failure.

Secondary endpoints included all-cause mortality and a composite endpoint of microvascular events.

Insulin glargine did not change the relative risk of CV disease and 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 composite endpoint including these adverse clinical outcomes; for all-cause mortality; or for the composite endpoint of microvascular events.

The mean dose of insulin glargine at the end of the study was 0.42 U/kg. At the start of the study, the mean HbA1c in participants was 6.4%, and on study treatment, HbA1c values ranged from 5.9 to 6.4% in the insulin glargine group and from 6.2 to 6.6% in the standard care group throughout the follow-up period.

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

At the last visit on study treatment, there was a mean increase in body weight from baseline of 1.4 kg in the insulin glargine group and a mean decrease of 0.8 kg in the standard therapy group.

Children and adolescents

A crossover study comparing insulin glargine plus insulin lispro and NPH insulin plus regular human insulin (each treatment was administered randomly for 16 weeks) was also conducted in 26 adolescents with type 2 diabetes aged 12 to 18 years. As in the pediatric study described above, the reduction in fasting blood glucose from baseline was greater in the insulin glargine group compared with the NPH/regular human insulin group. Changes from baseline in HbA1c were similar in both groups, but overnight glycemia was significantly higher in the insulin glargine/insulin lispro group than in the NPH/regular insulin group, with mean trough values of 5.4 mM and 4.1 mM, respectively. Accordingly, the incidence of nocturnal hypoglycemia was 32% in the insulin glargine/insulin lispro group and 52% in the NPH insulin/regular insulin group.

A 24-week, parallel-group study was conducted in 125 children with type 1 diabetes aged 2 to 6 years, comparing insulin glargine administered once daily in the morning with NPH insulin administered once or twice daily as basal insulin. Participants in both groups received bolus insulin injections before meals.

The main objective of the study – to demonstrate that NPH insulin has at least no advantages over insulin glargine with regard to the overall risk of hypoglycemia – was not achieved, and there was a trend towards an increase in the frequency of hypoglycemic events with insulin glargine [rate ratio in the insulin glargine: NPH groups (95% CI) = 1.18 (0.97─1.44)].

The changes in glycosylated hemoglobin and blood glucose levels were similar in both study groups. No new safety data were observed in this study.

Pharmacokinetics.

Comparison of serum insulin concentrations in healthy volunteers and diabetic patients indicated a slower and more prolonged absorption and showed the absence of a peak concentration after subcutaneous injection of insulin glargine compared to NPH human insulin. Thus, the obtained insulin glargine concentrations were fully consistent with the pharmacodynamic activity profile of the drug over time. The graph above shows the activity profile of insulin glargine and NPH insulin over time.

When insulin glargine is administered once daily, steady-state concentrations are reached within 2–4 days after the first injection.

When administered intravenously, the half-lives of insulin glargine and human insulin were quite comparable.

After subcutaneous injection of Lantus® SoloStar® in patients with diabetes mellitus, insulin glargine is rapidly metabolized at the carboxyl terminus of the beta chain to form two active metabolites, M1 (21A-glycine-insulin) and M2 (21A-glycine-des-30B-threonine-insulin). In plasma, metabolite M1 is the major circulating compound. Exposure to M1 increases in proportion to the administered dose of Lantus® SoloStar®. Pharmacokinetic and pharmacodynamic data indicate that the effect of subcutaneous injection of Lantus® SoloStar® is primarily due to exposure to M1. Insulin glargine and metabolite M2 were not detected in most subjects, and when their levels could be determined, their concentrations were independent of the administered dose of Lantus® SoloStar®.

In clinical studies, when analyzing subgroups based on age and gender, no differences in safety and efficacy were found between patients receiving insulin glargine and the overall study population.

Children and adolescents

The pharmacokinetics of the drug in children aged 2 to less than 6 years with type 1 diabetes mellitus were evaluated in one clinical study (see section "Pharmacodynamics"). In children receiving insulin glargine, trough levels of insulin glargine and its main metabolites (M1 and M2) in the blood plasma were determined. It was found that the patterns of changes in plasma concentrations were similar to those in adults, and no evidence was found for the accumulation of insulin glargine or its metabolites with prolonged use of the drug.

Preclinical safety data

Preclinical data obtained within the framework of standard studies on safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction revealed no special hazard for humans.

Indication

Treatment of diabetes mellitus in adults, adolescents and children aged 2 years and older.

Contraindication

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

Interaction with other medicinal products and other types of interactions

Substances that may enhance the hypoglycaemic effect of insulin and increase the susceptibility to hypoglycaemia include oral antidiabetic medicinal products, angiotensin converting enzyme (ACE) inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors, pentoxifylline, propoxyphene, salicylates and sulphonamide antimicrobials.

Substances that may reduce the hypoglycaemic effect of insulin include corticosteroids, danazol, diazoxide, diuretics, glucagon, isoniazid, oestrogens 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 potentiate or weaken the hypoglycaemic effect of insulin. Pentamidine may cause hypoglycaemia, sometimes followed by hyperglycaemia.

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

Lantus® SoloStar® is not the drug of choice for the treatment of diabetic ketoacidosis. Intravenous regular insulin is recommended instead.

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

Transferring a patient to another type or brand of insulin should be done under close medical supervision. Changes in strength, brand (manufacturer), type (regular, NPH, lente, long-acting, etc.), origin (animal, human, human insulin analogue), and/or method of manufacture may require a change in insulin dosage.

Insulin administration may induce the formation of insulin antibodies. In rare cases, the presence of insulin antibodies may necessitate dose adjustment to prevent hypo- or hyperglycemia (see section 4.8).

Patients should be advised to rotate injection sites to reduce the risk of lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsening glycemic control after insulin injections at sites of these reactions. Changing the injection site to an intact area of skin has been reported to result in hypoglycemia. It is recommended that blood glucose levels be monitored after changing injection sites and that dosage adjustments of antidiabetic medications be considered.

Hypoglycemia

The time it takes for hypoglycemia to develop depends on the action profile of the insulins used and may therefore change when the treatment regimen is changed. Due to the more stable basal insulin delivery with Lantus®, hypoglycemia is expected to be less likely to occur at night, while hypoglycemia is more likely in the early morning hours.

Particular caution and increased blood glucose monitoring are necessary in patients in whom hypoglycemic attacks 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 patients with proliferative retinopathy 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 (vegetative) 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) can occur before the patient realizes that their blood glucose level has dropped.

Since insulin glargine has a prolonged duration of action when administered subcutaneously, this may result in a longer time required to normalize glycemic control.

To reduce the risk of hypoglycemia, it is very important for the patient to adhere to the drug dose, diet, correct insulin administration, and 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. These include:

changing the site of insulin injection,

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

unusual, excessive or prolonged physical exertion,

concomitant illness (e.g. vomiting, diarrhea),

unhealthy diet,

skipping meals,

alcohol consumption,

some endocrine system disorders (thyroid dysfunction, adenohypophysis or adrenal cortex insufficiency) in the decompensation stage,

simultaneous use of certain other medications.

Comorbidities

The presence of a comorbid condition requires increased metabolic monitoring. In many cases, urine ketone testing is indicated and insulin dosage adjustment is often necessary. Insulin requirements may often increase. Patients with type 1 diabetes should continue to consume at least a small amount of carbohydrates regularly, even if they are able to eat little or no food, or if they are vomiting. They should never stop using insulin completely.

Insulin antibodies

Insulin administration may result in the formation of insulin antibodies. In rare cases, the presence of insulin antibodies may necessitate dose adjustment to prevent hypo- or hyperglycemia (see section 5.1).

Using a syringe pen

Before using the SoloStar® pen, you should carefully read the instructions for use. SoloStar® should be used in accordance with the recommendations contained in this instruction manual (see section “Instructions for use of the Lantus® SoloStar® pen”).

Mistaken administration of another drug

There have been reports of medication errors where other insulins, including short-acting insulins, have been accidentally injected instead of insulin glargine. The insulin label should be checked before each injection to avoid the mistaken administration of other insulins instead of insulin glargine.

Combination of Lantus® SoloStar® with pioglitazone

Cases of heart failure have been reported with pioglitazone in combination with insulin, particularly in patients at risk for heart failure. This should be taken into account when considering the combination of pioglitazone and Lantus® SoloStar®. Patients should be monitored for signs and symptoms of heart failure, weight gain and oedema when using this combination. Pioglitazone should be discontinued if any worsening of cardiac symptoms occurs.

Excipients

This medicine contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially sodium-free.

Use during pregnancy or breastfeeding

Pregnancy. There are no clinical data from controlled clinical studies on the use of insulin glargine during pregnancy. A large amount of data on pregnant women (more than 1000 pregnancy outcomes) from post-marketing experience indicate that insulin glargine has no harmful effects on pregnancy and does not cause malformations or toxicity to the fetus/newborn. Studies in laboratory animals have not shown reproductive toxicity. Lantus® SoloStar® can be used during pregnancy if necessary.

In patients with pre-existing diabetes and in patients with gestational diabetes, it is important to maintain adequate metabolic control throughout pregnancy to prevent the development of adverse clinical outcomes associated with hyperglycemia. Insulin requirements may decrease during the first trimester of pregnancy and increase during the second and third trimesters. Immediately after delivery, insulin requirements decrease rapidly (increasing the 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 to occur in the newborn/infant due to the passage of insulin glargine through breast milk, as insulin glargine is a peptide that is broken down to amino acids in the human gastrointestinal tract. However, breast-feeding women may require dose and dietary adjustments.

Reproductive function.

Studies in laboratory animals have not revealed direct harmful effects on reproductive function.

Ability to influence reaction speed when driving or using other mechanisms

The patient's ability to concentrate and react may be impaired due to hypoglycemia or hyperglycemia or, for example, due to visual disturbances. This may be dangerous in situations where these qualities are particularly important (when driving vehicles or operating machinery).

Patients should be advised to take the necessary precautions to avoid hypoglycemia while driving. This is especially important for those patients in whom the first signs of hypoglycemia are weak or absent, as well as for those patients in whom hypoglycemia occurs quite often. Careful consideration should be given to whether to drive or operate machinery in this condition.

Method of administration and doses

Dosage

Lantus® SoloStar® contains insulin glargine, a long-acting insulin analogue. The drug is administered once a day at any time of the day, but at the same time each time.

The dosage regimen of Lantus® SoloStar® (dose and time of administration) should be selected individually. In patients with type 2 diabetes, Lantus® SoloStar® can also be used simultaneously with oral antidiabetic drugs. The potency of this drug is expressed in units. These units are used exclusively for Lantus® SoloStar® and differ from the IU or units in which the potency of other insulin analogues is expressed (see section "Pharmacological properties").

Children and adolescents

The safety and efficacy of Lantus® SoloStar® have been demonstrated in adolescents and children aged 2 years and older (see section 5.1). Lantus® SoloStar® has not been studied in children under 2 years of age.

Elderly patients (over 65 years of age)

In elderly patients, age-related progressive deterioration of renal function may cause a permanent decrease in insulin requirements.

Kidney failure

In patients with renal insufficiency, insulin requirements may be reduced due to impaired insulin metabolism.

Liver failure

In patients with hepatic insufficiency, insulin requirements may be reduced due to reduced capacity for gluconeogenesis and slower insulin metabolism.

Switching from other insulins to Lantus® SoloStar®

When switching from treatment regimens with intermediate-acting or long-acting insulins to a treatment regimen with Lantus® SoloStar®, there may be a need to change the dose of basal insulin, as well as to correct concomitant antidiabetic therapy (doses and timing of administration of additionally used regular insulins or rapid-acting insulin analogues or doses of oral antidiabetic drugs).

Switching from twice daily NPH insulin (neutral protamine Hagedorn) to Lantus® SoloStar®

To reduce the risk of nocturnal or early morning hypoglycemia, patients who change their basal insulin regimen from twice daily NPH insulin to once daily Lantus® SoloStar® should reduce their basal insulin dose by 20–30% during the first weeks of treatment.

Switching from insulin glargine 300 U/ml to Lantus® SoloStar®

Lantus® SoloStar® and Toujeo SoloStar (insulin glargine 300 U/mL) are not bioequivalent and cannot be used interchangeably. To reduce the risk of hypoglycemia, patients who switch from a single-dose basal insulin regimen (insulin glargine 300 U/mL) to a single-dose Lantus® SoloStar® should reduce their basal insulin dose by approximately 20%.

During this period, the dose reduction should be at least partially compensated by an increase in the dose of meal-related insulin. After this period, the dosage regimen should be adjusted individually.

When switching to another drug and during the first weeks thereafter, it is recommended to carefully monitor metabolic parameters.

Improvement in metabolic control and the associated increase in insulin sensitivity may require additional adjustment of the dosage regimen. Dose adjustment may also be necessary, for example, if the patient's weight or lifestyle changes, changes in the time of day when insulin is administered, or other factors that increase the susceptibility to hypo- or hyperglycemia occur (see section "Special instructions").

In patients receiving high doses of insulin due to the presence of antibodies to human insulin, switching to Lantus® SoloStar® may improve the body's response to insulin administration.

Method of administration

Lantus® SoloStar® should be administered subcutaneously by injection into the abdominal wall, thigh, upper arm, deltoid or gluteal region. Injection sites should always be rotated within the same area to reduce the risk of lipodystrophy and cutaneous amyloidosis (see sections “Special instructions” and “Adverse reactions”).

There is no clinically significant difference in plasma insulin or glucose levels after administration of Lantus® SoloStar® into the abdominal, deltoid, or thigh areas. The injection site should be rotated within the recommended body area for insulin administration with each subsequent injection.

Lantus® SoloStar® should not be mixed with any other insulin or diluted. Mixing or diluting may change the time course of action of the drug. In addition, mixing with other insulins may result in precipitation.

Before using the SoloStar® pen, carefully read the “Instructions for using the Lantus® SoloStar® pen” section.

Before first use, the pen should be kept at room temperature for 1-2 hours. Inspect the cartridge before use. It should only be used if the solution is clear, colorless, free of visible particles, and has the consistency of water. Since Lantus® SoloStar® is a solution, it does not require resuspension before use.

Empty pens cannot be reused and must be disposed of properly.

To prevent infection, each syringe pen should only be used by one person.

Before each injection, the insulin label should be checked to avoid mistakenly injecting other insulins instead of insulin glargine (see section "Special instructions").

Overdose

Symptoms

An overdose of insulin can lead to severe and sometimes prolonged hypoglycemia, which can be life-threatening.

Treatment

Mild cases of hypoglycemia can usually be corrected by oral administration of carbohydrates. Dosage adjustments of medications and changes in diet or physical activity may also be necessary.

More severe episodes of hypoglycemia, accompanied by coma, seizures or neurological disorders, require intramuscular/subcutaneous administration of glucagon or intravenous administration of concentrated glucose solution. Since hypoglycemia may recur even after apparent improvement in the patient's clinical condition, prolonged carbohydrate intake and patient observation are necessary measures.

Side effects

General overview of the safety profile of the drug

Hypoglycaemia (very common) is generally the most common adverse reaction observed during insulin therapy. It occurs when the dose of insulin administered is significantly higher than the insulin requirement (see section 4.4).

Tabulated list of adverse reactions

Adverse drug reactions observed during clinical trials are listed below by system organ class in order of decreasing frequency (very common (≥ 1/10); common (≥ 1/100 - < 1/10); uncommon (≥ 1/1,000 - < 1/100); rare (≥ 1/10,000 - < 1/1,000); very rare (< 1/10,000), frequency unknown (cannot be estimated from the available data).

Within each of these groups, adverse reactions are presented in order of decreasing seriousness.

Description of selected adverse reactions

Metabolic and nutritional disorders

Severe episodes of hypoglycemia, especially if they occur repeatedly, can cause damage to the nervous system. Prolonged or severe hypoglycemia can be life-threatening.

In many patients, the appearance of symptoms indicating insufficient glucose supply to brain tissue (neuroglycopenia) is preceded by signs of adrenergic counterregulation. As a rule, the more and faster the decrease in glucose