Sultofay^® (Solution) Instructions for Use

Marketing Authorization Holder

Novo Nordisk A/S (Denmark)

ATC Code

A10AE56 (Insulin degludec and Liraglutide)

Active Substances

Liraglutide (Rec.INN registered by WHO)

Insulin degludec (Rec.INN registered by WHO)

Dosage Form

Sultofay®

Solution for subcutaneous administration 100 IU/ml+3.6 mg/ml: cartridge in a pen-injector 3 ml 5 pcs.

Dosage Form, Packaging, and Composition

Solution for subcutaneous administration colorless or almost colorless, transparent.

Solution pH 8.15.
1 unit (IU) of insulin degludec is equivalent to 0.0366 mg of anhydrous salt-free insulin degludec.
1 pre-filled pen contains 3 ml of solution, which corresponds to 300 IU of insulin degludec and 10.8 mg of liraglutide.

Excipients: glycerol, phenol, zinc (as zinc acetate), hydrochloric acid/sodium hydroxide (for pH adjustment), water for injections.

3 ml – glass cartridges (1) – polypropylene multi-dose disposable pen-injectors for multiple injections (5) – cardboard packs.

Clinical-Pharmacological Group

Combined hypoglycemic drug

Pharmacotherapeutic Group

Hypoglycemic agent – long-acting insulin analog

Pharmacological Action

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

Insulin degludec is a basal insulin that, after subcutaneous administration, forms soluble multihexamers, creating a depot in the subcutaneous adipose tissue, from which continuous and slow absorption of insulin into the bloodstream occurs, providing an ultra-long, flat and stable hypoglycemic effect of the drug with low day-to-day 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 increased glucose utilization by tissues after insulin binds to receptors on muscle and fat cells and simultaneous inhibition of glucose output from the liver.

Liraglutide is an analog of human glucagon-like peptide-1 (GLP-1) with 97% homology to endogenous human GLP-1, which binds to and activates the GLP-1 receptor. The long-acting profile of liraglutide after subcutaneous administration is provided by three mechanisms: self-association, which results in delayed absorption of the drug; binding to albumin; and higher resistance to dipeptidyl peptidase-4 (DPP-4) and neutral endopeptidase (NEP), leading to an increased T_1/2 of the drug from plasma. The action of liraglutide is mediated by specific interaction with GLP-1 receptors and improves glycemic control by reducing fasting and postprandial blood glucose concentrations. Liraglutide stimulates insulin secretion and reduces excess glucagon secretion in a glucose-dependent manner. When blood glucose concentration increases, insulin secretion is stimulated and glucagon secretion is inhibited. Conversely, during hypoglycemia, Liraglutide reduces insulin secretion and does not inhibit glucagon secretion. The mechanism of blood glucose reduction is also associated with a slight delay in gastric emptying. Liraglutide reduces body weight and adipose tissue mass through mechanisms that reduce hunger and decrease energy intake.

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

In animal studies, peripheral administration of liraglutide resulted in uptake of the drug in specific areas of the brain, including the hypothalamus, where Liraglutide, through specific activation of GLP-1 receptors, enhanced satiety signals and attenuated hunger signals, thereby leading to weight loss.

The drug has a stable pharmacodynamic profile with a duration of action reflecting the combination of the individual action profiles of insulin degludec and liraglutide, allowing the drug to be administered once daily at any time, independent of meals. The drug improves glycemic control through sustained reduction of fasting and postprandial blood glucose concentrations.

Reduction in postprandial glucose concentration was confirmed in a 4-hour sub-study with a standard breakfast, which included patients with inadequate glycemic control on metformin monotherapy or on metformin therapy in combination with pioglitazone.

The drug improves pancreatic β-cell function, as shown in the homeostatic model assessment of β-cell function (HOMA-β).

Pharmacokinetics

Overall, the pharmacokinetics of insulin degludec and liraglutide upon administration of the drug were not clinically significantly changed compared to separate injections of insulin degludec and liraglutide.

The overall exposure of insulin degludec was the same after administration of the combined drug and insulin degludec alone, while C_max was 12% higher. The overall exposure of liraglutide was the same after administration of the combined drug and liraglutide alone, while C_max was 23% lower. The difference was considered clinically insignificant since the initial dose of the drug and dose adjustment depend on the target glucose concentration for the specific patient. Based on the results of population pharmacokinetic analysis, the exposure of insulin degludec and liraglutide increased proportionally to the drug dose across the entire dose range.

C_ss of insulin degludec and liraglutide is reached after 2-3 days of daily administration. Insulin degludec and Liraglutide are largely bound to plasma proteins (>99% and >98%, respectively).

The degradation of insulin degludec is similar to that of human insulin; all metabolites formed are inactive. Throughout 24 hours after administration of a single dose of [³H]-liraglutide to healthy volunteers, the main component in plasma remained unchanged Liraglutide. Two metabolites were detected (<9% and <5% of the total radioactivity level in plasma). Liraglutide is metabolized endogenously, similar to large proteins, without the involvement of any specific organ as the main route of elimination.

T_1/2 of insulin degludec is approximately 25 hours, of liraglutide – approximately 13 hours.

Pharmacokinetics in special patient groups

Age, sex, ethnicity did not have a clinically significant effect on the pharmacokinetics of the drug.

No clinically significant differences in the pharmacokinetics of insulin degludec were found between patients with renal impairment and healthy individuals. Renal impairment did not have any clinically significant effect on the pharmacokinetics of liraglutide.

No clinically significant differences in the pharmacokinetics of insulin degludec were found between patients with hepatic impairment and healthy individuals. Hepatic impairment did not have any clinically significant effect on the pharmacokinetics of liraglutide.

Indications

To improve glycemic control in adults with type 2 diabetes mellitus in combination with oral hypoglycemic drugs.

ICD codes

Dosage Regimen

The drug is intended for subcutaneous administration only.

The drug is administered once daily, at any time of day, preferably at the same time.

The drug should be injected into the thigh, shoulder, or abdominal area. Injection sites should be rotated within the same anatomical area to reduce the risk of lipodystrophy.

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

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

When adding the drug to oral hypoglycemic drugs, the recommended starting dose of the drug is 10 IU of insulin degludec and 0.36 mg of liraglutide.

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

When switching from therapy with a basal insulin, the recommended starting dose of the drug is 16 IU of insulin degludec and 0.6 mg of liraglutide.

Careful glycemic monitoring is recommended during the switch and in the following weeks.

No dose adjustment is required in patients with mild or moderate renal impairment (CrCl 60-90 ml/min and 30-59 ml/min). Use of the drug in patients with severe renal impairment, including patients with end-stage renal disease, is contraindicated.

Use of the drug in patients with hepatic impairment is contraindicated.

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

Use of the drug in children and adolescents under 18 years of age is contraindicated due to lack of safety and efficacy data.

Adverse Reactions

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

Adverse reactions associated with the use of the drug are listed below according to the system organ class and frequency of occurrence. Frequency categories are defined as follows: very common (≥1/10); common (from ≥1/100 to <1/10); uncommon (from ≥1/1000 to <1/100); rare (from ≥1/10,000 to <1/1000); very rare (<1/10,000) and frequency not known (frequency cannot be estimated from the available data).

Allergic reactions uncommon – urticaria, hypersensitivity; frequency not known – anaphylactic reactions.

Metabolism and nutrition disorders very common – hypoglycemia; uncommon – dehydration.

Gastrointestinal disorders common – decreased appetite, nausea, diarrhea, vomiting, constipation, dyspepsia, gastritis, abdominal pain, gastroesophageal reflux, abdominal distension; uncommon – belching, flatulence, cholelithiasis, cholecystitis; frequency not known – pancreatitis (including necrotizing pancreatitis).

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

General disorders and administration site conditions common – injection site reactions; uncommon – increased heart rate; frequency not known – peripheral edema (caused by insulin administration).

Description of selected adverse reactions

Hypoglycemia

Hypoglycemia may occur if the dose of the drug is excessive relative to the patient’s needs. Severe hypoglycemia may lead to unconsciousness and/or convulsions, temporary or permanent impairment of brain function, or even death. Symptoms of hypoglycemia usually occur suddenly. They may include cold sweat, pale skin, increased fatigue, nervousness or tremor, anxiety, unusual tiredness or weakness, confusion, difficulty concentrating, drowsiness, excessive hunger, visual disturbances, headache, nausea, and palpitations.

Allergic reactions

Allergic reactions (manifested by signs and symptoms such as urticaria, rash, itching and/or facial swelling) have been observed with the use of the drug. Several cases of anaphylactic reactions with additional symptoms such as arterial hypotension, palpitations, dyspnea, and peripheral edema have been reported during post-marketing use of liraglutide. Anaphylactic reactions can potentially be life-threatening.

Gastrointestinal adverse reactions

Patients receiving the drug experienced gastrointestinal adverse events, including nausea, diarrhea, vomiting, constipation, dyspepsia, gastritis, abdominal pain, gastroesophageal reflux, abdominal distension, belching, flatulence, and decreased appetite. These adverse events may occur more frequently during the initiation of therapy with the drug and usually decrease within a few days or weeks with continued therapy.

Pancreatic enzymes

Use of the drug is associated with an increase in the activity of pancreatic enzymes, lipase and amylase, on average by 43% and 18%, respectively, from baseline. In the absence of other signs and symptoms of acute pancreatitis, an increase in pancreatic enzyme activity is not a predictive factor for the development of acute pancreatitis.

Injection site reactions

Patients receiving the drug experienced injection site reactions (including injection site hematoma, pain, hemorrhage, erythema, nodules, swelling, skin discoloration, itching, hyperemia, and induration at the injection site). These reactions were generally mild and transient and resolved in most cases during continued therapy.

Lipodystrophy

Lipodystrophy (including lipohypertrophy, lipoatrophy) may develop at the injection site. Adherence to the rule of rotating injection sites within the same anatomical area may help reduce the risk of this reaction.

Increased heart rate

In clinical studies, an increase in heart rate compared to baseline by an average of 2-3 beats/min was observed with the use of the drug. No long-term clinical effects of the increased heart rate were established.

Contraindications

Type 1 diabetes mellitus, diabetic ketoacidosis; chronic heart failure NYHA class III-IV; hepatic impairment; severe renal impairment; inflammatory bowel disease and diabetic gastroparesis; age under 18 years; pregnancy, lactation; hypersensitivity to insulin degludec, liraglutide or any of the excipients of the drug.

With caution, the drug should be used in patients with chronic heart failure NYHA class I-II, thyroid diseases, as well as in patients with a history of chronic pancreatitis.

Use in Pregnancy and Lactation

In reproductive function studies in animals, no differences were found between insulin degludec and human insulin in terms of embryotoxicity and teratogenicity. In animal studies of liraglutide, reproductive toxicity was demonstrated. The potential risk to humans is unknown. Use of the drug during pregnancy is contraindicated. If pregnancy occurs, therapy with the drug must be discontinued.

Due to insufficient experience with the use of the drug during pregnancy, women of childbearing potential should discontinue treatment with the drug if they are planning a pregnancy.

It is not known whether Liraglutide or Insulin degludec are excreted in human breast milk. In rats, Insulin degludec passes into breast milk; the concentration of the drug in breast milk was lower than in plasma. Animal studies have demonstrated that the passage of liraglutide and structurally related metabolites into breast milk is low. Due to the lack of experience, the drug is contraindicated during breastfeeding.

No adverse effects of insulin degludec on fertility were found in animal studies. Except for a small reduction in the number of live implants, no evidence of adverse effects of liraglutide on fertility was obtained in animal studies.

Use in Hepatic Impairment

Use of the drug is contraindicated in hepatic impairment.

Use in Renal Impairment

Use of the drug is contraindicated in severe renal impairment.

No dose adjustment is required in patients with mild or moderate renal impairment (CrCl 60-90 ml/min and 30-59 ml/min).

Pediatric Use

Use of the drug in children and adolescents under 18 years of age is contraindicated due to lack of safety and efficacy data.

Geriatric Use

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

Special Precautions

Hypoglycemia may occur if a dose of the drug that is too large relative to the patient’s need is administered. Hypoglycemia can be caused by missed meals or unplanned strenuous physical exertion. When combined with a sulfonylurea drug, the risk of hypoglycemia may be reduced by lowering the dose of the sulfonylurea drug. Concomitant kidney disease, liver disease, or diseases affecting the adrenal glands, thyroid, or pituitary may require a change in the dose of the drug. Patients with significant improvement in glycemic control (e.g., during intensified therapy) may experience a change in their usual warning symptoms of hypoglycemia, about which they should be appropriately informed. In patients with long-standing diabetes, the usual warning symptoms of hypoglycemia may disappear. As with all drugs containing basal insulin, the prolonged effect of the combined drug may lead to delayed recovery from hypoglycemia.

Administration of inadequate doses and/or discontinuation of hypoglycemic therapy may lead to the development of hyperglycemia and possibly the development of ketoacidotic coma. In case of discontinuation of therapy with the drug, instructions for initiating alternative hypoglycemic therapy should be ensured. In addition, concomitant diseases, especially infectious ones, can lead to the development of hyperglycemia and thus cause an increased 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, flushed and dry skin, dry mouth, loss of appetite, and acetone odor on the breath. In a situation of severe hyperglycemia, short-acting insulin should be administered. If left untreated, hyperglycemia will eventually lead to the development of hyperosmolar coma/diabetic ketoacidosis, which can be fatal.

Cases of chronic heart failure development have been reported during treatment of patients with thiazolidinediones in combination with insulin preparations, especially in patients with risk factors for chronic heart failure. This fact should be taken into account when prescribing combined therapy with thiazolidinediones and the combination drug to patients. When prescribing such combination therapy, patients should undergo medical examination to identify signs and symptoms of chronic heart failure, weight gain, and the presence of peripheral edema. If patients experience worsening symptoms of heart failure, 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 worsening of diabetic retinopathy manifestations; however, long-term improvement in glycemic control reduces the risk of diabetic retinopathy progression.

Administration of the drug may lead to the formation of antibodies to insulin degludec and/or liraglutide. In rare cases, antibody formation may require dose adjustment of the drug to prevent the development of hyperglycemia or hypoglycemia. In a very small number of patients, therapy with the drug may cause the formation of specific antibodies to insulin degludec, antibodies cross-reacting with human insulin, or antibodies to liraglutide. Antibody formation is not associated with a reduction in the drug’s efficacy.

The use of GLP-1 receptor agonists has been associated with the risk of acute pancreatitis. Reports of acute pancreatitis events have been received from 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, use of 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, an increase in pancreatic enzyme activity is not a predictive factor for the development of acute pancreatitis.

In clinical trials with GLP-1 receptor agonists, including liraglutide, adverse reactions related to the thyroid gland were observed, including increased blood calcitonin concentration, goiter, and thyroid neoplasia, especially in patients with pre-existing thyroid disease. Therefore, the drug should be used with caution in such patients.

There is no experience with the use of the drug in patients with inflammatory bowel disease and diabetic gastroparesis. Therefore, the use of the drug in such patients is contraindicated.

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

Patients should be informed to always check the label on the pen-injector before injection to avoid accidental administration of another injectable diabetes medication instead of the drug.

The effect of liraglutide on myocardial repolarization was studied in a QTc interval assessment trial. Liraglutide at steady-state concentration when used in daily doses up to 1.8 mg did not lead to QTc interval prolongation. Regarding insulin degludec, no statistically significant difference was noted between insulin degludec and the comparator drug in terms of change from baseline in QTc interval duration based on ECG analysis in a 12-month clinical trial.

Effect on Ability to Drive and Use Machines

During hypoglycemia, patients’ ability to concentrate and reaction speed may be impaired. This may pose a danger in situations where these abilities are especially necessary (e.g., when driving vehicles or operating machinery). Patients should be advised to take measures to prevent the development of hypoglycemia while driving or operating machinery. This is particularly important for patients with absent or reduced awareness of hypoglycemia or with frequent episodes of hypoglycemia. In these cases, the advisability of driving or performing such work should be considered.

Drug Interactions

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

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

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

Beta-blockers may mask the symptoms of hypoglycemia.

Octreotide/lanreotide may either increase or decrease the requirement for the drug.

Ethanol and ethanol-containing medicinal products may either enhance or reduce the hypoglycemic effect of the drug.

Liraglutide has shown a very low potential for pharmacokinetic interaction with other active substances regarding cytochrome P450 (CYP) metabolism and plasma protein binding.

A slight delay in gastric emptying with liraglutide use may affect the absorption of concomitant oral medications. Drug interaction studies have not shown any clinically significant delay in the absorption of these drugs.

Clinically significant interaction with active substances with low solubility or a narrow therapeutic index, such as warfarin, cannot be excluded. After initiation of therapy with the combination drug, 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. The C_max of paracetamol was reduced by 31%, and the median T_max was increased by 15 min. No dose adjustment is required for concomitant use of paracetamol.

Liraglutide did not alter the overall exposure of atorvastatin in a clinically significant manner after a single 40 mg dose of atorvastatin. Therefore, no dose adjustment of atorvastatin is required when used in combination with liraglutide. With liraglutide use, the C_max of atorvastatin was reduced by 38%, and the median T_max was increased from 1 h to 3 h.

Liraglutide did not alter the overall exposure of griseofulvin after a single 500 mg dose. The C_max of griseofulvin was increased by 37%, while the median T_max was unchanged. No dose adjustment for griseofulvin and other compounds with low solubility and high permeability is required.

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

Single administration of lisinopril at a dose of 20 mg in combination with liraglutide resulted in a 15% decrease in lisinopril AUC and a 27% decrease in C_max. The median T_max of lisinopril was increased from 6 h to 8 h. Based on these results, no dose adjustment of lisinopril is required.

After single administration of an oral contraceptive, liraglutide led to a decrease in the C_max of ethinyl estradiol and levonorgestrel by 12% and 13%, respectively. The T_max of both compounds during liraglutide use was increased by 1.5 h. No clinically significant effect on the systemic exposure of ethinyl estradiol or levonorgestrel was noted. Thus, no effect on the contraceptive effect is expected with the concomitant use of oral hormonal contraceptives and liraglutide.

Substances added to the combination drug may cause degradation of the active substances. The drug must not be added to infusion solutions or mixed with other medicinal products.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.