Sultofail solution for subcutaneous use 100 Edlyaml+3.6mg/ml 3ml cartridges in syringe pens, 5pcs

Composition

1 ml contains: Active ingredients: insulin degludec 100 units (3.66 mg), liraglutide 3.6 mg. Auxiliary substances: glycerol, phenol, zinc (in the form of zinc acetate), hydrochloric acid/sodium hydroxide (for pH correction), water for injection, pH of the solution 8.15.

Pharmacological action

Sultofay is a combination drug that consists of insulin degludec and liraglutide (produced by recombinant DNA biotechnology using the Saccharomyces cerevisiae strain), which have complementary mechanisms of action to improve glycemic control.

Insulin degludec is a basal insulin that, after subcutaneous use, forms soluble multihexamers that form a depot in the subcutaneous adipose tissue, from where continuous and slow absorption of insulin into the bloodstream occurs, providing an ultra-long, flat and stable hypoglycemic effect of the drug with low daily variability. Insulin degludec specifically binds to the human insulin receptor, providing the same pharmacological effect as human insulin.

The hypoglycemic effect of insulin degludec is due to an increase in glucose utilization by tissues after binding of insulin to muscle and fat cell receptors and simultaneous inhibition of glucose intake from the liver.

Liraglutide is an analog of human glucagon-like peptide-1 (GLP-1) with 97% homology to human endogenous GLP-1, which binds to and activates the GLP-1 receptor. The long-term action profile of liraglutide during subcutaneous use is provided by three mechanisms: self-association, which results in delayed absorption of the drug; binding to albumin; higher resistance to dipeptidyl peptidase-4 (DPP-4) and neutral endopeptidase (NEP), which leads to an increase in T 1/2 of the drug from blood plasma.

Liraglutide acts by specifically interacting with GLP-1 receptors and improving glycemic control by reducing fasting and post-meal blood glucose concentrations. Liraglutide stimulates insulin secretion and reduces excessively high glucagon secretion in a glucose-dependent manner. When the concentration of blood glucose increases, insulin secretion is stimulated and glucagon secretion is inhibited.

Conversely, during hypoglycemia, liraglutide reduces insulin secretion and does not interfere with glucagon secretion. The mechanism of lowering blood glucose concentration is also associated with a slight delay in gastric emptying. Liraglutide reduces body weight and reduces adipose tissue mass by mechanisms that cause a decrease in hunger and a decrease in energy consumption.

GLP-1 is a physiological regulator of appetite and calorie intake, and GLP-1 receptors are located in several brain regions involved in appetite regulation.

In animal studies, peripheral use of liraglutide led to drug uptake in specific areas of the brain, including the hypothalamus, where liraglutide, through specific activation of GLP-1 receptors, increased satiety signals and weakened hunger signals, thereby leading to a decrease in body weight.

The drug has a stable pharmacodynamic profile with a duration of action reflecting the combination of individual profiles of action of insulin degludec and liraglutide, which allows the drug to be administered 1 time / day at any time, regardless of food intake. The drug improves glycemic control by permanently reducing the concentration of fasting blood glucose and after meals.

A decrease in postprandial glucose concentration was confirmed in a 4-hour sub-study with a standard breakfast, which included patients with poor glycemic control on the background of metformin monotherapy or on the background of metformin therapy in combination with pioglitazone.

The drug improves the function of pancreatic beta cells, as shown in the homeostatic model for assessing the function of pancreatic beta cells (NOMA-beta).

Indications

Sultofay is indicated for achieving glycemic control in adults with type 2 diabetes mellitus in combination with oral hypoglycemic medications.

Contraindications

Type 1 diabetes mellitus, diabetic ketoacidosis; NYHA class III-IV chronic heart failure; hepatic impairment; severe renal impairment; inflammatory bowel diseases and diabetic gastroparesis; age up to 18 years; pregnancy, lactation; hypersensitivity to insulin degludec, liraglutide or any of the auxiliary components of the drug. The drug should be used with caution in patients with NYHA class I-II chronic heart failure, thyroid diseases, as well as in patients with a history of chronic pancreatitis.

Side effects

In the program of clinical trials of the drug, there was no increase in the frequency of specific adverse reactions compared to the individual components of the drug: insulin degludec and liraglutide. Hypoglycemia and gastrointestinal disorders were the most frequently reported adverse reactions during drug therapy.

Adverse reactions associated with the use of the drug are listed below in accordance with the classification of organ systems and frequency of occurrence. The frequency categories are defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (

Allergic reactions:  infrequently – urticaria, hypersensitivity; frequency unknown – anaphylactic reactions.

From the side of metabolism:  very often – hypoglycemia; infrequently-dehydration.

From the digestive system:  often-decreased appetite, nausea, diarrhea, vomiting, constipation, dyspepsia, gastritis, abdominal pain, gastroesophageal reflux, bloating; infrequently-belching, flatulence, cholelithiasis, cholecystitis; frequency unknown-pancreatitis (including necrotizing pancreatitis).

Skin and subcutaneous tissue disorders:  infrequently – rash, pruritus, acquired lipodystrophy.

Other services:  often – reactions at the injection site; infrequently-increased heart rate; frequency unknown-peripheral edema (caused by the introduction of insulin).

Description of individual adverse reactions

Hypoglycemia

Hypoglycemia may develop if the dose of the drug exceeds the required one. Severe hypoglycemia can lead to loss of consciousness and/or seizures, temporary or permanent impairment of brain function, or even death. Symptoms of hypoglycemia usually develop suddenly. These may include cold sweats, pale skin, increased fatigue, irritability or tremors, feelings of anxiety, unusual tiredness or weakness, confusion, difficulty concentrating, drowsiness, severe hunger, visual disturbances, headache, nausea, and palpitations.

Allergic reactions

Allergic reactions (with signs and symptoms such as hives, rash, itching, and/or swelling of the face) have been reported with the drug. Several cases of anaphylactic reactions with additional symptoms such as hypotension, palpitation, dyspnea, and peripheral edema have been reported with post-marketing use of liraglutide. Anaphylactic reactions can potentially be life-threatening.

Adverse reactions from the gastrointestinal tract

Adverse gastrointestinal events were reported in patients treated with the drug, including nausea, diarrhea, vomiting, constipation, dyspepsia, gastritis, abdominal pain, gastroesophageal reflux, bloating, belching, flatulence and decreased appetite. These adverse events may occur more frequently at the start of therapy with the drug and usually decrease within a few days or weeks with continued therapy.

Pancreatic enzymes

The use of the drug is associated with an increase in the activity of pancreatic enzymes, lipase and amylase, by an average of 43% and 18%, respectively, relative to the initial value. In the absence of other signs and symptoms of acute pancreatitis, increased activity of pancreatic enzymes is not a prognostic factor for the development of acute pancreatitis.

Injection site reactions

Injection site reactions (including injection site hematoma, pain, hemorrhage, erythema, nodules, swelling, discoloration of the skin, pruritus, hyperemia, and compaction at the injection site) were noted in patients receiving the drug. These reactions were usually mild and transient, and in most cases resolved during continued therapy.

Lipodystrophy

Lipodystrophy (including lipohypertrophy, lipoatrophy) may develop at the injection site. Following the rule of changing the injection site within one anatomical area can help reduce the risk of developing this reaction.

Increased heart rate

In clinical studies, when using the drug, an increase in heart rate compared to the initial one was noted by an average of 2-3 beats/min. No long-term clinical effects of increased heart rate were found

Interaction

A number of substances affect glucose metabolism and may require dose adjustment.

The need for the drug is reduced by hypoglycemic drugs, MAO inhibitors, non-selective beta-blockers, ACE inhibitors, salicylates, anabolic steroids and sulfonamides.

The need for the drug is increased by oral hormonal contraceptives, thiazides, corticosteroids, thyroid hormone preparations, sympathomimetics, somatropin and danazol.

Beta-blockers can mask the symptoms of hypoglycemia.

Octreotide/lanreotide can both increase or decrease the need for the drug.

Ethanol and ethanol-containing drugs can both enhance and reduce the hypoglycemic effect of the drug.

Liraglutide showed a very low ability to interact pharmacokinetically with other active substances in relation to cytochrome P450 (CYP) metabolism and binding to plasma proteins.

A slight delay in gastric emptying when using liraglugide may affect the absorption of concomitant oral medications. Drug interaction studies have not shown any clinically significant slowing of the absorption of these drugs.

A clinically significant interaction with active substances with low solubility or with a narrow therapeutic index, such as warfarin, cannot be excluded. After starting combination therapy, more frequent monitoring of INR is recommended in patients receiving warfarin or other coumarin derivatives.

Liraglutide did not alter the overall exposure of paracetamol after a single 1000 mg dose. C_{max of} paracetamol was reduced by 31%, and the median tmax was increased by 15 minutes. No dose adjustment is required for concomitant use of paracetamol.

Liraglutide did not change the overall exposure of atorvastatin to a clinically significant extent after a single dose of atorvastatin 40 mg. Therefore, dose adjustment of atorvastatin when used in combination with liraglutide is not required. With liraglutide C_{, the max of} atorvastatin was reduced by 38%, and the median tmax was increased from 1 h to 3 h.

Liraglutide did not alter the overall griseofulvin exposure after a single 500 mg dose. C_{max of} griseofulvin was increased by 37%, while the median Tmax did not change. Dose adjustment of griseofulvin and other compounds with low solubility and high penetration capacity is not required.

A single use of digoxin at a dose of 1 mg in combination with liraglutide resulted in a decrease in digoxin AUC by 16% and a decrease in cmax by 31%. The median time to reach_cmax was increased from 1 h to 1.5 h. Based on these results, no dose adjustment of digoxin is required.

A single 20 mg dose of lisinopril combined with liraglutide resulted in a 15% decrease in lisinopril AUC and a 27% decrease in cmax. The median T_max of lisinopril was increased from 6 h to 8 h. Taking into account these results, no dose adjustment of lisinopril is required.

After a single oral contraceptive, liraglutide resulted in a 12% and 13% decrease in the cmax of ethinyl estradiol and levonorgestrel, respectively. T_max Both compounds were increased by 1.5 h with liraglutide. There was no clinically significant effect on the systemic exposure of ethinyl estradiol or levonorgestrel. Thus, no effect on the contraceptive effect is expected with the combined use of oral hormonal contraceptives and liraglutide.

Substances added to the combined preparation can cause the destruction of active substances. The drug should not be added to infusion solutions or mixed with other medications.

How to take, course of use and dosage

The drug is intended for subcutaneous use only.

The drug is administered 1 time/day, at any time of the day, preferably at the same time.

The drug should be administered in the hip, shoulder, or abdominal area. You should constantly change the injection sites within the same anatomical area to reduce the risk of developing lipodystrophy.

The dose of the drug is set in accordance with the individual needs of the patient. To optimize glycemic control, it is recommended to select the dose based on the fasting plasma glucose concentration.

The maximum daily dose of the drug is 50 units of insulin degludec and 1.8 mg of liraglutide.

When the drug is added to oral hypoglycemic drugs, the recommended initial dose of the drug is 10 units of insulin degludec and 0.36 mg of liraglutide.

When switching from GLP-1 receptor agonist therapy, the recommended starting dose is 16 units of insulin degludec and 0.6 mg of liraglutide.

When switching from basal insulin therapy, the recommended initial dose of the drug is 16 units of insulin degludec and 0.6 mg of liraglutide.

During the transfer and in the following weeks, careful monitoring of glycemia is recommended.

No dose adjustment is required in patients with mild or moderate renal insufficiency (creatinine clearance 60-90 ml / min and 30-59 ml / min). The use of the drug in patients with severe renal impairment, including patients with end-stage renal failure, is contraindicated.

The use of the drug in patients with impaired liver function is contraindicated.

The drug can be used in elderly patients. Enhanced glycemic control and individual dose adjustment are required.

The use of the drug in children and adolescents under 18 years of age is contraindicated due to the lack of data on safety and efficacy

Special instructions

Hypoglycemia can occur if the dose of the drug is too large in relation to the patient’s needs. Hypoglycemia can be caused by skipping meals or unplanned active physical activity. When combined with a sulfonylurea preparation, the risk of hypoglycemia can be reduced by reducing the dose of the sulfonylurea preparation. Concomitant diseases of the kidneys, liver, or diseases involving the adrenal, thyroid, or pituitary glands may require a change in the dose of the drug. Patients with a significant improvement in glycemic control (e. g., with intensive therapy) may experience a change in the usual symptoms that are harbingers of hypoglycemia, and they should be informed accordingly. In patients with long-term diabetes mellitus, the usual symptoms-harbingers of hypoglycemia-may disappear. As with all drugs containing basal insulin, the prolonged effect of the combined drug may lead to a delayed recovery from hypoglycemia.

use of inadequate doses and / or discontinuation of hypoglycemic therapy may lead to the development of hyperglycemia and possibly to the development of ketoacidotic coma. In case of discontinuation of therapy with the drug, follow the instructions for starting alternative hypoglycemic therapy. In addition, concomitant diseases, especially infectious diseases, can lead to the development of hyperglycemia, and thus cause an increase in the need for hypoglycemic therapy.

Usually, the first symptoms of hyperglycemia develop gradually, over several hours or days. These include thirst, frequent urination, nausea, vomiting, drowsiness, flushing and dry skin, dry mouth, loss of appetite, and the smell of acetone in the exhaled air. In a situation of severe hyperglycemia, short-acting insulin should be administered. If left untreated, hyperglycemia eventually leads to the development of hyperosmolar coma/diabetic ketoacidosis, which can lead to death.

Cases of chronic heart failure have been reported when patients are treated with thiazolidinediones in combination with insulin preparations, especially when these patients have risk factors for developing chronic heart failure. This fact should be taken into account when prescribing combination therapy with thiazolidinediones and a combination drug to patients. When prescribing such combination therapy, it is necessary to conduct a medical examination of patients for signs and symptoms of chronic heart failure, weight gain, and the presence of peripheral edema. If the symptoms of heart failure worsen in patients, treatment with thiazolidinediones should be discontinued.

Intensification of insulin therapy (a component of the drug) with a sharp improvement in glycemic control may be accompanied by a temporary deterioration in the manifestations of diabetic retinopathy, while long-term improvement in glycemic control reduces the risk of progression of diabetic retinopathy.

use of the drug may lead to the formation of antibodies to insulin degludec and / or liraglutide. In rare cases, when antibodies are formed, it may be necessary to adjust the dose of the drug to prevent the development of hyperglycemia or hypoglycemia. In a very small number of patients, therapy with the drug can cause the formation of specific antibodies to insulin degludec, antibodies that cross-react with human insulin, or antibodies to liraglutide. The formation of antibodies is not associated with a decrease in the effectiveness of the drug.

The use of GLP-1 receptor agonists was associated with the risk of acute pancreatitis. Acute pancreatitis has been reported in clinical trials and post-marketing use with liraglutide, a component of the drug. Patients should be informed about the characteristic symptoms of acute pancreatitis.

If pancreatitis is suspected, the drug should be discontinued; if acute pancreatitis is confirmed, therapy with the drug should not be resumed. Caution should be exercised when using the drug in patients with a history of pancreatitis.In the absence of other signs and symptoms of acute pancreatitis, increased activity of pancreatic enzymes is not a prognostic factor for the development of acute pancreatitis.

In clinical studies using GLP-1 receptor agonists, including liraglutide, adverse thyroid reactions have been reported, including increased blood calcitonin concentrations, goiter, and thyroid neoplasm, especially in patients with pre-existing thyroid disease. In this regard, the drug should be used with caution in such patients.

There is no experience of using the drug in patients with inflammatory bowel diseases and diabetic gastroparesis. In this regard, the use of the drug in such patients is contraindicated.

Signs and symptoms of dehydration, including impaired renal function and acute renal failure, have been reported in clinical trials in patients treated with GLP-1 receptor agonists, including liraglutide. Patients receiving the combination drug should be informed of the potential risk of dehydration associated with gastrointestinal side effects, and should take precautions to prevent hypovolemia.

Patients should be advised to always check the label on the syringe handle before injecting to avoid accidentally injecting another injectable diabetes drug instead of the drug.

The effect of liraglutide on myocardial repolarization was studied in a study with the determination of the QT interval_c. Liraglutide at steady-state concentrations when administered in daily doses up to 1.8 mg did not lead to prolongation of the QTC interval. With regard to insulin degludec, there was no statistically significant difference between insulin degludec and the reference drug in terms of changes in the duration of the QT interval_c compared to the baseline value based on ECG analysis in a 12-month clinical study.

Influence on the ability to drive motor vehicles and manage mechanisms

When hypoglycemia occurs, patients ‘ ability to concentrate and reaction speed may be impaired. This can be dangerous in situations where these abilities are particularly necessary (for example, when driving vehicles or working with mechanisms). Patients should be advised to take measures to prevent the development of hypoglycemia when driving vehicles or working with mechanisms. This is especially important for patients with the absence or decrease in the severity of symptoms that are harbingers of hypoglycemia or with frequent episodes of hypoglycemia. In these cases, you should consider the feasibility of driving a vehicle or performing similar work.

Active ingredient

Insulin degludec, Liraglutide

Conditions of release from pharmacies

By prescription

Dosage form

solution for injection