Saxenda solution for subcutaneous injection of 6mg/ml 3ml syringe pen №5

Mechanism of action

Hypoglycemic agent. Lyraglutide is an analogue of human glucagon-like peptide-1 (GLP-1), produced by recombinant DNA biotechnology using the Saccharomyces cerevisiae strain, having 97% homology with human GLP-1, which binds and activates the GLP-1 receptors in humans. The GLP-1 receptor serves as a target for native GLP-1, an endogenous hormone incretin, which stimulates glucose-dependent insulin secretion in pancreatic beta cells. Unlike native GLP-1, the pharmacokinetic and pharmacodynamic profiles of liraglutide allow it to be administered to patients daily 1 time per day.

The long-acting profile of liraglutide in a s / c injection is provided by three mechanisms: self-association, as a result of which a slow absorption of the drug occurs; binding with albumin and a higher level of enzymatic stability with respect to dipeptidyl peptidase-4 (DPP-4) and the enzyme neutral endopeptidase (NEP), which ensures a long half-life of the drug from plasma. The action of liraglutide is due to the interaction with specific GLP-1 receptors, as a result of which the level of cyclic adenosine monophosphate cAMP increases. Under the action of liraglutide, glucose-dependent stimulation of insulin secretion occurs.At the same time, liraglutide suppresses the excessively high glucose-dependent secretion of glucagon. Thus, with an increase in blood glucose concentration, insulin secretion is stimulated and glucagon secretion is suppressed. On the other hand, during hypoglycemia, liraglutide decreases insulin secretion, but does not inhibit glucagon secretion. The mechanism of reducing blood glucose levels also includes a slight delay in gastric emptying. Lyraglutide reduces body weight and reduces adipose tissue of the body through mechanisms that reduce hunger and reduce energy consumption.

Liraglutide has a long 24-hour action and improves glycemic control by reducing fasting blood glucose concentrations and after eating in patients with type 2 diabetes.

With an increase in blood glucose concentration, liraglutide increases insulin secretion. With the use of phased glucose infusion, insulin secretion after administration of a single dose of liraglutide in patients with type 2 diabetes increases to a level comparable to that in healthy subjects.

As part of a combination therapy with Metformin, Glimepiride, or a combination of metformin with rosiglitazone, lyraglutide for 26 weeks caused a statistically significant (p <0.0001) and prolonged decrease in HbA_1ccompared with the same indicator in patients who received therapy with placebo.

With monotherapy with liraglutide for 52 weeks, a statistically significant (p <0.0014) and prolongedHbA decline_1c compared with the same indicator in patients receiving glimepiride therapy. At the same time, a marked decrease in HbA_1cbelow the level of 7% persisted for 12 months. The number of patients who reached the level of HbA_1c<7%, statistically significantly increased (p≤0.0007) compared with the number of patients receiving glimepiride. During the 52-week treatment with liraglutide in patients with type 2 diabetes mellitus, improvement of the first and second phases of insulin secretion was observed (n = 29). At the same time, sustained weight loss was observed.

At week 26 of using liraglutide in combination with metformin, sulfonylurea derivatives, or a combination of metformin with thiazolidinedione, the number of patients reaching HbA_1c≤6.5%, statistically significant (p≤0.0001) increased in relation to the number of patients who received therapy alone, without the addition of liraglutide, with hypoglycemic drugs. At the same time managed to reach the level of HbA_1c<7% in a larger number of patients who received the drug in the form of combination therapy, compared with the number of patients who received it in the form of substitution therapy.

The fasting glucose level decreased by 13-43.5 mg% (0.72-2.42 mmol / l) in patients receiving liraglutide as monotherapy, and in combination with one or two oral hypoglycemic agents. This decrease was observed during the first 2 weeks from the start of treatment.

The use of liraglutide within 3 days of ingestion of standard food contributed to the reduction of postprandial glucose concentration by 31–49 mg% (1.68–2.71 mmol / l).

Sustained weight loss was also observed with liraglutide in combination with metformin and in combination with combinations of metformin with glimepiride or metformin with rosiglitazone.

The greatest weight loss was observed in patients who had an increased body mass index (BMI) at the starting point of the study.

A decrease in body weight was observed in all patients treated with liraglutide, regardless of whether or not they experienced an adverse reaction in the form of nausea.

As part of combination therapy with metformin, Liraglutide reduced the volume of subcutaneous fat by 13-17%.

During all clinical trials, patients treated with liraglutide showed a decrease in systolic blood pressure by an average of 2.3-6.7 mm Hg. relative to baseline numbers at the beginning of the study, compared with those in patients who received active comparator drugs, in which the reduction was from 1.9 to 4.5 mm Hg. A decrease in systolic blood pressure was observed before the onset of weight loss.

Pharmacokinetics

Liraglutide absorption after sc injection is slow, T_maxin plasma - 8-12 hours. C_max plasma liraglutide after s / c injection in a single dose of 600 µg is 9.4 nmol / l. With the introduction of liraglutide in a dose of 1.8 mg, the average of its C_ss in plasma reaches approximately 34 nmol / l. The exposure of liraglutid increases in proportion to the dose administered. After the introduction of liraglutide in a single dose, the intrapopulation coefficient of variation of AUC is 11%. The absolute bioavailability of liraglutide after sc injection is approximately 55%.

Seeming v_dliraglutida in tissues after s / c injection is 11-17 liters. Medium V_dliraglutida after the on / in the introduction of 0.07 l / kg. Lyraglutide is largely bound to plasma proteins (> 98%).

For 24 hours after administration to a healthy volunteer of a single dose labeled with a radioactive isotope [³H] -liraglutide unchanged liraglutide remained the main component of plasma. Two plasma metabolites were detected (≤ 9% and ≤ 5% of the total radioactivity level in the blood plasma). Lyraglutide is metabolized endogenously, like large proteins.

After a dose [³H] lraglutide, unchanged liraglutide was not detected in urine or feces. Only an insignificant part of the administered radioactivity in the form of metabolites bound to liraglutide (6% and 5%, respectively) was excreted by the kidneys or through the intestines. Radioactive substances are excreted by the kidneys or through the intestines, mainly during the first 6-8 days after a dose, and are three metabolites. The average clearance from the body after s / to the introduction of liraglutide in a single dose is approximately 1.2 l / h with an elimination half-life of approximately 13 hours.

Data from pharmacokinetic studies in a group of healthy volunteers and analysis of pharmacokinetic data obtained in a population of patients (from 18 to 80 years old) indicate that age does not have a clinically significant effect on the pharmacokinetic properties of liraglutide.

A population pharmacokinetic analysis of data obtained in a study of the effect of liraglutide in patients with white, black, Asian and Latin American racial groups suggests that ethnicity does not have a clinically significant effect on the pharmacokinetic properties of liraglutide.

Liraglutide exposure in patients with mild and moderate liver failure was reduced by 13–23% compared with that in the group of healthy subjects. In patients with severe hepatic impairment (according to Child-Pugh classification, the severity of the disease is> 9 points), the exposure of liraglutide was significantly lower (by 44%).

In patients with renal insufficiency, the exposure of liraglutide was reduced compared to that in patients with normal renal function. The exposure of liraglutide was reduced by 33%, 14%, 27% and 28%, respectively, in patients with mild (CK 50-80 ml / min), moderate (CK 30-50 ml / min) and severe (CK <30 ml / min) the degree of renal failure and end-stage renal failure in patients on dialysis.

Indications

As an aid against diet and exercise to achieve glycemic control in patients with type 2 diabetes.

To achieve glycemic control in combination therapy with metformin or sulfonylurea derivatives in patients with insufficient glycemic control, despite the maximum tolerated doses of metformin or derivativessulfonylureas in monotherapy; with metformin and sulfonylurea derivatives or metformin and thiazolidinediones in patients with insufficient glycemic control, despite the combination therapy with two drugs.

Dosing regimen

Enter s / c 1 time / day in the abdomen, thigh or shoulder. Place and time of injection can be changed without dose adjustment. However, it is preferable to administer at about the same time of day, at the time most convenient for the patient.

Do not enter in / in or in / m.

The initial dose is 0.6 mg / day. After applying for at least one week, the dose should be increased to 1.2 mg. There is evidence that in some patients the effectiveness of treatment increases with an increase in the dose of the drug from 1.2 mg to 1.8 mg. In order to achieve the best glycemic control in a patient and taking into account the clinical efficacy, the dose can be increased to 1.8 mg after applying it in a dose of 1.2 mg for at least one week. Use in a daily dose of more than 1.8 mg is not recommended.

It is recommended to apply in addition to the existing therapy with metformin or combination therapy with metformin with thiazolidinedione. Therapy with metformin and thiazolidinedione can be continued in previous doses.

Lyraglutide is recommended to be added to the ongoing therapy with sulfonylurea derivatives or to combination therapy with metformin with sulfonylurea derivatives. When liraglutide is added to sulfonylurea therapy, a reduction in the dose of sulfonylurea derivatives should be considered in order to minimize the risk of unwanted hypoglycemia.

Side effect

Metabolism: often - hypoglycemia (especially when combined with sulfonylurea derivatives), anorexia, loss of appetite.

From the nervous system:often - a headache.

From the digestive system: very often - nausea, diarrhea; often - vomiting, dyspepsia, pain in the upper abdomen, constipation, gastritis, flatulence, abdominal distention, gastroesophageal reflux, belching.

Infections: very often - upper respiratory tract infections.

Allergic reactions: in some cases (0.05%) - angioedema.

Other: less than 1% - reactions from the thyroid gland; 8.6% - formation of antibodies to liraglutide (did not cause a decrease in efficacy).

Contraindications

Type 1 diabetes; diabetic ketoacidosis; pregnancy; lactation period (breastfeeding); severe renal impairment; abnormal liver function; heart failure III and IV functional class according to the NYHA classification; inflammatory bowel disease; paresis of the stomach; children and adolescents up to 18 years; hypersensitivity to liraglutide.

Use during pregnancy and lactation

Contraindicated use during pregnancy and lactation (breastfeeding).

special instructions

To be used with care in patients with heart failure of the I and II functional class according to the NYHA classification; impaired renal function of moderate severity; aged 75 and over.

If pancreatitis is suspected, treatment with liraglutide and other potentially suspected drugs should be discontinued immediately.

During clinical trials, side effects were reported from the thyroid gland, incl. about an increased level of calcitonin in the serum, goiter and thyroid neoplasms, especially in patients with already existing thyroid diseases.

Influence on ability to drive motor transport and control mechanisms

Patients should be warned that they should take precautions to prevent them from developing a state of hypoglycemia while driving and when working with mechanisms, especially if liraglutide is taken as part of combination therapy with sulfonylurea derivatives.

Drug interaction

A slight delay in gastric emptying due to liraglutide may have an effect on the absorption of concomitant medications for oral administration.

Diarrhea, which sometimes occurs when taking liraglutide, can affect the absorption of oral medications, which are used simultaneously.

At the beginning of treatment with liraglutide in patients receiving Warfarin, it is recommended to monitor MHO more often.