Lysumia - instructions for use, dose, side effects, contraindications

Active substanceLixisenatideLixisenatide

Similar drugsTo uncover

solution PC

Dosage form: & nbsphypodermic solution

Composition:

	A solution of 0.05 mg / ml (10 μg / dose)		A solution of 0.1 mg / ml (20 μg / dose)
Components	Content in 1 ml	Content in 1 dose	Content in 1 ml	Content in 1 dose
Active substance
Lixisenatide	0.05 mg	0.01 mg	0.1 mg	0.02 mg
Excipients
Glycerol 85%	18.0 mg	3.6 mg	18.0 mg	3.6 mg
Sodium acetate	3.5 mg	0.70 mg	3.5 mg	0.70 mg
trihydrate
Methionine	3.0 mg	0.60 mg	3.0 mg	0.60 mg
Metacresol	2.7 mg	0.54 mg	2.7 mg	0.54 mg
1 M solution of hydrochloric acid or 1 M sodium hydroxide solution	up to pH 4.5	up to pH 4.5	up to pH 4.5	up to pH 4.5
Water for injections	up to 1 ml	up to 0.2 ml	up to 1.0 ml	up to 0.2 ml

Description:

Transparent colorless liquid.

Pharmacotherapeutic group:A hypoglycemic agent, a glucagon-like receptor polypeptide, an agonist

ATX: & nbsp

A.10.B.X.10 Lixisenatide

Pharmacodynamics:

Mechanism of action

Lixisenatide is a potent and selective glucagon-like peptide-1 receptor agonist-1 (GLP-1). The GLP-1 receptor is the target for native GLP-1, the endogenous hormone of internal secretion, which potentiates the glucose-dependent secretion of insulin by beta cells of pancreatic islets. The action of lixisenatide is associated with its specific interaction with receptors GLP-1, leading to an increase in the intracellular content of cyclic adenosine monophosphate (cAMP). Lixisenatide stimulates secretion of insulin beta cells by pancreatic islets in response to hyperglycemia. With a decrease in the concentration of glucose in the blood to normal values, stimulation of insulin secretion stops, which reduces the risk of developing hypoglycemia. With hyperglycemia lixisenatide simultaneously suppresses the secretion of glucagon, but it still preserves the protective reaction of glucagon secretion in response to hypoglycemia.

A trend towards insulinotropic activity lixisenatide, including an increase in insulin biosynthesis and stimulation of pancreatic beta cells islets in animals. Lixisenatide slows down emptying the stomach, thereby reducing the rate of increase blood glucose concentrations after eating. Influence at gastric emptying can also contribute to weight loss body.

Pharmacodynamic effects

When administered once a day, patients with type 2 diabetes mellitus lixisenatide improves glycemic control by rapidly developing after its introduction and a continuous decrease in the concentration of glucose in the blood after eating and on an empty stomach.This effect of lixisenatide on the concentration of glucose in the blood after a meal was confirmed in a 4-week study comparing the use of lixisenatide in combination with metformin with liraglutide 1.8 mg once daily in combination with metformin.

Lixisenatide at a dose of 20 mcg once a day showed a greater decrease in area under the blood glucose concentration curve after a standard meal (standard thick breakfast), compared with the use of liraglutide 1.8 mg once a day. These observations also were confirmed in an 8-week study comparing the use of lixisenatide with liraglutide, when administered before breakfast, in combination with insulin glargine in combination or without combination with metformin. In this study, the decrease from the original value AUC_0:30-4-30h The concentration of glucose in the blood after a sample with standard food load (standard thick breakfast) was: in group of lixisenatide -13.33 h * mmol / L (-240.15 h * mg / dl), in the group of liraglutide 1.2 mg-7.32 h * mmol / l (-131.82 h * mg / dl) and in the group of liraglutide in a dose of 1.8 mg - 8.72 h * mmol / l (-157 h * mg / dL).

Clinical efficacy and safety

The effect of the drug Lixumia® on glycemic control was studied in six randomized, double-blind, placebo-controlled clinical trials and one randomized, open, controlled active drug (exenatide) a study in which, in total, included 3825 patients with type 2 diabetes mellitus (lixisenatide was used in 2445 patients (48.2% of men and 51.8 % women). 768 patients (447 patients were randomized to receive lixisenatide) were aged ≥65 years and 103 patients (57 patients were randomized to receive lyxisenatide) were ≥75 years of age.

Completed clinical Phase III studies showed that 90% of patients continued treatment with Lycumia® at a maintenance dose of 20 μg once a day at the end of the 24-week treatment period.

Influence on glycemic control

When using the drug Lysymy ® has a greater, compared with placebo, reduction in the glycosylated hemoglobin (HbA_1C) in the blood (regardless of concomitant treatment). In addition, the drug Lixumia ® with a single administration during the day showed no less decrease in the HbA_1Cthan exenatide when administered twice a day.This effect on the decrease in the HbA_1C remained in long-term studies up to 2 years.

Decrease in HbA_1C was reliable with daily single administration of the drug Lixumia®, both in the morning and in the evening.

Adding lixisenatide to treatment with oral hypoglycemic drugs

The preparation Lixumia® in combination with metformin, oral hypoglycemic drug of the sulfonylurea group, or with combinations of these drugs in end of the 24-week treatment period, compared with placebo, showed clinically and a statistically significant decrease in HbA_1C, the concentration of glucose in the blood on an empty stomach and 2 hours after a meal (sample with standard food load).

Adding lixisenatide to monotherapy with metformin

In placebo-controlled addition studies lixisenatide to metformin led to a decrease in the HbA_1C by 0.83% and a decrease of 0.42% with the addition of a placebo. Percentage of patients who achieved a decrease in HbA_1C up to <7%, was 43% in the lyxisenatide group and 24% in the placebo group.

In a controlled active drug (exenatide) study at the end of the main 24-week treatment period, once-a-day administration of the drug LYXOEMIA® showed no less decrease indicator HbA_1C, compared with twice during the day by the administration of exenatide (respectively, 0.79% and 0.96%, respectively); At the same time, almost the same percentage of patients who achieved a reduction in the indicator HbA_1C to <7%: 48.5% in the lixisenatide group and 49.8% in the exenatide group.

Adding lixisenatide to treatment with one of the oral hypoglycemic drugs of the sulfonylurea group in monotherapy and in combination with metformin

The addition of lixisenatide to treatment with one of the oral hypoglycemic drugs of the sulfonylurea group in monotherapy and in combination with metformin resulted in a decrease in the index HbA_1C by 0.85% compared with that of a placebo supplement of -0.10%. Percentage of patients who achieved a reduction in the indicator HbA_1C to <7%, was 36.4% with the addition of lixisenatide and 13.5% with the addition of placebo.

The addition of lixisenatide to a combined therapy, including basal insulin

The drug Lixumia® when used together with basal insulin in monotherapy, or with a combination of basal insulin with metformin,or with a combination of basal insulin with an oral hypoglycemic drug of the sulfonylurea group caused a statistically significant decrease in the index HbA_1C and glucose concentrations 2 hours after a standard meal compared with placebo. At the end of the main 24-week treatment period, the decrease in the daily dose of insulin was significantly higher in the LYCUMSIA® group compared to the placebo group, compared to its doses before the addition of LYXYMY® to the treatment.

When lixisenatide was added to basal insulin therapy in monotherapy or in combination with metformin, a decrease was observed HbA_1C by 0.74% against -0.38% with the addition of placebo, and with the addition of lixisenatide to basal insulin therapy in monotherapy or in combination with the oral hypoglycemic drug of the sulfonylurea group, a decrease was observed HbA_1C by 0.77% against -0.11% with the addition of a placebo.

Influence on the concentration of glucose in blood plasma on an empty stomach

In placebo-controlled studies, the mean values of the decrease in fasting plasma glucose concentration achieved with LYXOXYUM® by the end of the 24-week treatment period were in the range of 0.42 mmol / l to -1.19 mmol / l.

Effect on postprandial (after eating) blood glucose concentration

Treatment with the drug Lixumia®, regardless of concomitant therapy, resulted in a statistically superior placebo effect in reducing 2-hour postprandial (determined 2 hours after a standard meal) of blood glucose. By the end of the 24-week treatment period, in all studies in which the determination was made postprandial glucose concentration in the blood, ego reduction of 2- hour postprandial blood glucose concentrations were in the range of 4.51 mmol / L to -7.96 mmol / L (compared to 2-hour postprandial blood glucose concentrations prior to the use of LYXYMUM®); 26.2% -46.8% of patients had 2- hour postprandial blood glucose concentrations below 7.8 mmol / L.

Effect on body weight

In all controlled trials, treatment with Lysumia® in combination with metformin, basal insulin, and / or the oral hypoglycemic drug of the sulfonylurea group at the end of the main 24-week treatment period resulted in an average weight loss of up to-2.96 kg, which persisted in long-term studies to 2 years.

The decrease in body weight did not depend on the occurrence of nausea and vomiting.

Effect on the function of beta cells of pancreatic islets

The preparation Lixumia® improves the function of beta cells of pancreatic islets, determined using a homeostatic model for the evaluation of beta-cell function (HOMA-β).

In patients with diabetes mellitus 2 type (n= 20) after a single injection of the drug Lysumia® was demonstrated restoration of the first phase of insulin secretion and improvement of the second phase of insulin secretion in response to intravenous bolus administration of glucose.

Effect on heart rate (heart rate)

In placebo-controlled clinical studies of the III phase did not show an increase in mean heart rate.

In a 4-week clinical study, compared with liraglutide in group lixisenatide (20 mcg once a day), heart rate decreased by an average of 3.6 beats per minute, and in the group of liraglutide (1.8 mg once a day) the heart rate decreased by 5.3 beats per minute.

Influence on blood pressure (BP)

In placebo-controlled Phase III studies a decrease in the average values of systolic and diastolic blood pressure by 2.1 mm Hg. Art. and by 1.5 mm Hg. art., respectively.

Pharmacokinetics:

Absorption

After subcutaneous administration of lixisenatide to patients with type 2 diabetes mellitus, the rate of its absorption is high and does not depend on the administered dose. Regardless of the dose and whether the lixisenatide once or daily repeatedly, in patients with type 2 diabetes mellitus, the median time to reach the maximum concentration of lyxisenatide in the blood (t_max) is 1-3.5 hours. There are no clinically significant differences in the rate of absorption of lixisenatide when it is administered subcutaneously to the abdominal region, thigh area or shoulder area.

Distribution

Lixisenatide has a moderate degree of association with human blood proteins (55%). Regardless of the dose administered, the volume of distribution after subcutaneous administration of lixisenatide in patients with type 2 diabetes mellitus is 90-140 L after a single injection and 90-120 L with repeated administration (in the state of achieving an equilibrium concentration of lyxisenatide in the blood).

Metabolism

As a peptide, lixisenatide is derived by glomerular filtration, followed by tubular reabsorption and metabolic degradation, resulting in the formation of smaller peptides and amino acids that are re-involved in protein metabolism.

Excretion

After repeated administration to patients with type 2 diabetes mellitus, the mean value of the half-life (t_1/2) was usually in the range of 1.5-4.5 h, and the average clearance value was in the range of 20-67 l / h (in the state of reaching the equilibrium concentration of lyxisenatide in the blood).

Special patient groups

Gender identity

According to the analysis of population pharmacokinetic data, gender does not affect the pharmacokinetics of lixisenatide.

Elderly patients

According to the analysis of population pharmacokinetic parameters in patients with type 2 diabetes and analysis of pharmacokinetic studies performed in elderly patients without diabetes mellitus, age does not have a clinically significant effect on the pharmacokinetics of lixisenatide.

Ethnicity

According to pharmacokinetic studies conducted among Caucasians, Japanese and Chinese, ethnicity does not have a clinically significant effect on the pharmacokinetics of lixisenatide.

Patients with hepatic insufficiency

As lixisenatide is mainly excreted by the kidneys, no pharmacokinetic studies have been performed in patients with acute or chronic liver dysfunction. It is not expected that a violation of the function of the liver can affect the pharmacokinetics of lixisenatide.

Patients with renal insufficiency

There were no significant differences in mean values of clearance, the maximum concentration in the blood (C_m_Oh) and the area under the pharmacokinetic curve "concentration-time" (AUC) lixisenatide with normal renal function and mild renal insufficiency. With an increase in the severity of the failure, the mean C_m_Oh and AUC increased.

Indications:

Diabetes mellitus type 2 in adults to achieve glycemic control in patients whose diabetes mellitus is not controlled by hypoglycemic therapy.

The drug Lixumia® is indicated in combination with the following oral hypoglycemic drugs:

- metformin,

- oral hypoglycemic drug of the sulfonylurea group,

- combination of these medicines.

The drug Lixumia® is shown in combination with basal insulin:

- in monotherapy,

- in combination with metformin,

- in combination with an oral hypoglycemic drug of the sulfonylurea group.

Contraindications:

- Hypersensitivity to the active substance or any of the excipients of the drug.

- Pregnancy.

- Breastfeeding period.

- Diabetes mellitus type 1.

- Diabetic ketoacidosis.

- Severe diseases of the gastrointestinal tract, including gastroparesis.

- Severe renal insufficiency (creatinine clearance less than 30 ml / min).

- Children and adolescents under 18 years.

Carefully:

At a pancreatitis in the anamnesis.

Pregnancy and lactation:

Pregnancy

There is a lack of sufficient data on the use of the drug Lixumia® in pregnant women. Studies carried out in animals demonstrated embryo and fetotoxic effects. The potential risk of using LYXOXYUM® during pregnancy is unknown in humans. The use of the drug LYXOEMIA® during pregnancy is contraindicated. During pregnancy, the use of insulin is recommended. If the patient is planning a pregnancy or has a pregnancy diagnosed, treatment with Lysyme ® should be discontinued.

Breastfeeding period

It is not known whether the lixisenatide in breast milk. The use of the drug LYXOEMIA® is contraindicated during the period of breastfeeding (due to the lack of experience of use).

Dosing and Administration:

Doses

The initial dose is 10 μg of the drug Lixumia® once a day for 14 days.

Then the dose of the drug Lixumia® should be increased to 20 mcg once a day. This dose is supportive.

When the drug Lixumia ® is added to the already administered metformin therapy, metformin may be continued without changing its dose.

When the preparation Lixumia® is added to the already administered oral hypoglycemic drug of the sulfonylurea group or to combination therapy with an oral hypoglycemic drug of the sulfonylurea group and basal insulin, a reduction in the dose of the oral hypoglycemic drug of the sulfonylurea group or basal insulin can be considered to reduce the risk of hypoglycemia (see section "Special instructions").

The use of the drug Lyssumia® does not require special monitoring of the concentration of glucose in the blood.However, when used in combination with an oral hypoglycemic drug of the sulfonylurea group or basal insulin, it may be necessary to monitor blood glucose concentration or self-monitoring (patient control) of blood glucose concentration to correct the dose of the oral hypoglycemic drug of the sulfonylurea group or basal insulin.

Special patient groups

Children and teenagers under the age of 18

At present, the safety and effectiveness of the use of the drug LYXOEMIA® in patients under the age of 18 years has not been studied.

Elderly people

No dosage adjustment is required depending on the age of the patient.

Patients with hepatic insufficiency

No dose adjustment is required in patients with hepatic insufficiency.

Patients with renal insufficiency

No dose adjustment is required in patients with mild renal insufficiency (creatinine clearance 50-80 ml / min) and moderate renal insufficiency (creatinine clearance 30-50 ml / min).

There is no therapeutic experience with the use of Lixumia® in patients with severe renal insufficiency (creatinine clearance less than 30 ml / min) or with terminal stage of renal failure,in connection with which the use of the drug Lixumia ® in this group of patients is contraindicated.

Mode of application

The drug Lixumia® is administered 1 time per day within 1 h to the first during the day of food intake or within 1 h before the evening meal. If you miss the introduction of the next dose, it should be introduced within 1 hour before the next meal.

The drug LYCLUMIA® is injected subcutaneously into the thigh, abdominal wall or shoulder area. The drug Lixumia ® can not be administered intravenously and intramuscularly.

Prior to use, the syringe pen should be stored in the refrigerator at 2-8 ° C in its packaging in order to protect it from exposure to light. After first use, the lyxyme® syringe pen should be stored at a temperature not exceeding 30 ° C. After each use, the lyxyme® syringe pen should be capped to protect it from exposure to light. The syringe-pen Lycsumia® should not be stored with the attached needle. Do not use the lyxyme® pen if it has been frozen.

The syringe-pen Lixumia® is to be disposed of after 14 days.

For more information on injecting using the Liksumia® penstick,below in the section "Description of the Lycsmy® syringe pens and instructions for their use".

Side effects:

Frequency of occurrence of undesirable reactions (HP) was defined as follows: very often: ≥ 10%; often: ≥ 1% - <10%; infrequently: ≥ 10% - <1%; rarely: ≥ 0.01% - <0.1%; very rarely: <0.01%.

In 8 major placebo-controlled and active phase III clinical trials, more than 2,600 patients received the LYXOXY® preparation in monotherapy or in combination with metformin, an oral hypoglycemic drug of the sulfonylurea group (in combination with metformin or without combination with metformin) or basal insulin (in combination with metformin, or without combination with metformin, or in combination with an oral hypoglycemic drug of the sulfonylurea group, or without combination with oral hypoglyca Sulfonylurea group).

The most frequent HP, which were reported in clinical studies, were nausea and vomiting. These reactions were mainly mild and transitory.

Below are the HP, reports about which came from placebo-controlled and controlled by the active drug phase III clinical trials, which for the entire treatment period (including the period,exceeding the main 24-week treatment period in studies in which treatment was given for a total of ≥ 76 weeks) occurred with a frequency of> 5% (if their frequency was higher in patients taking Lysxymia ® than in patients taking all other drugs comparisons, including placebo); as well as with a frequency ≥ 1% in patients in the LYCLUSMY® group, if their frequency is more than 2 times higher than the frequency of this HP in patients who received any of the reference drugs (including placebo).

Infectious and parasitic diseases

Often
Influenza, upper respiratory tract infection.

Disorders of metabolism and nutrition

Often
Hypoglycemia, which proceeds with clinical symptoms (when the drug Lixumia® is used in combination with an oral hypoglycemic drug of the sulfonylurea group and / or basal insulin).

Disturbances from the nervous system

Often
Headache.
Often
Dizziness.

Disorders from the gastrointestinal tract

Often
Nausea, vomiting, diarrhea.
Often
Dyspepsia.

Disturbances from musculoskeletal and connective tissue

Often
Back pain.

Hypoglycaemia

In patients receiving the preparation of LYXOXYUM in monotherapy or in combination with metformin, hypoglycemia with clinical manifestations developed frequently, and its frequency in patients who received the drug LYXOEMIA® was similar to that of placebo during the entire treatment period.

In patients who received the drug Lixumia ® in combination with an oral hypoglycemic drug of the sulfonylurea group or basal insulin, the incidence of hypoglycemia developing with clinical symptoms was very frequent.

During the entire period of treatment with the drug Lixumia, the incidence of symptomatic hypoglycemia was slightly higher than with placebo, when the drug Lixumia® was used in combination:

- with an oral hypoglycemic drug of the sulfonylurea group and metformin,

- with monotherapy of basal insulin,

- with a combination of basal insulin and metformin.

During the entire treatment period, when the drug Lixumia® was used in combination with monotherapy with the oral hypoglycemic drug of the sulfonylurea group,hypoglycemia with clinical manifestations arose in 22.7% of patients treated with the drug Lixumia®, and 15.2% in patients receiving placebo. When the drug Lixumia® was used in triple combination with the oral hypoglycemic drug of the sulfonylurea group and basal insulin, hypoglycemia with clinical manifestations occurred in 47.2% of patients treated with lixisenatide and in 21.6% of patients receiving placebo.

In general, during the entire period of drug administration in controlled phase III clinical trials, the incidence of severe hypoglycemia with clinical manifestations was in accordance with the gradation of "infrequently" (0.4% in patients receiving the LYXYMY® preparation and 0.2% in patients receiving placebo ).

Disorders from the gastrointestinal tract

Nausea and vomiting were the most common HP, which were reported during the main 24-week treatment period. The incidence of nausea was higher in patients treated with LYXOEMIA (26.1%) than in patients receiving placebo (6.2%). The incidence of vomiting was also higher in patients treated with LYksumia® (10.5%) than in patients receiving placebo (1.8%). These HP were mainly mild and transient and occurred within the first 3 weeks after the start of treatment. During the following weeks they gradually decreased.

In patients treated with Lyscmia®, the incidence of nausea was lower (24.5%) than in patients treated with exenatide twice daily (35.1%), and the incidence of other HP The gastrointestinal tract in both treatment groups was the same.

Reactions at the site of administration

Reactions at the site of administration during the 24-week treatment period were observed in 3.9 % of the patients receiving the drug LYXUMIA®, while in the patients receiving the placebo, they were observed at a frequency of 1.4%. Most of the reactions were mild in intensity and usually did not lead to discontinuation of treatment.

Immunogenicity

In connection with the potentially immunogenic properties of drugs containing proteins or peptides, antibodies to lixisenatide may be formed in patients after treatment with Lysumia®. At the end of the 24-week treatment period in placebo-controlled trials, 69.4% of patients treated with lixisenatide had positive results for antibodies to lixisenatide. However, change in the indicator HbA₁_C, compared with that before the use of lixisenatide, was the same, regardless of the positive or negative test result for antibodies to lixisenatide. Of patients who received lixisenatide treatment, HbA₁_C, 79.3% had a negative test for antibodies to lixisenatide or the titer of antibodies to lixisenatide was below the lower limit of the possibility of its quantitative determination, while the remaining 20.7% of patients had quantitatively detectable titers of antibodies to lixisenatide.

There was no difference in the overall safety profile in patients, depending on the status of antibodies to lixisenatide, except for an increase in the frequency of reactions at the site of administration in antibody-positive patients. Most of the reactions at the site of administration were mild, regardless of the presence or absence of antibodies to lixisenatide.

There was no cross immunological reactivity with native glucagon or endogenous GLP-1.

Allergic reactions

Allergic reactions, possibly associated with the use of lixisenatide (such as anaphylactic reactions,angioneurotic edema and urticaria) during the main 24-week treatment period were observed in 0.4% of the patients receiving the LYXOEMY® preparation, compared with less than 0.1% of patients in the placebo group.

Premature termination of the drug

The frequency of cessation of treatment with the drug due to the occurrence of undesired reactions was 7.4% in the group of the drug Lixumia® and 3.2% in the placebo group. The most frequent HP, leading to withdrawal of treatment in the group of the drug LYXUMIA®, were nausea (3.1%) and vomiting (1.2%).

Overdose:

Overdose Symptoms

During a 13-week clinical trial, patients with type 2 diabetes mellitus received doses of lixisenatide up to 30 μg twice a day. These doses were well tolerated, only an increase in the frequency of occurrence of disorders from the gastrointestinal tract was observed.

Treatment

In case of an overdose, depending on the clinical manifestations and symptoms in the patient, appropriate supportive treatment should be given, and the dose of the drug LYCLUSMY® should be reduced to the prescribed dose.

Interaction:

Lixisenatide is a peptide and is not metabolized by cytochrome P450 isoenzymes. AT in vitro studies conducted in humans, lixisenatide did not violate the activity of the tested cytochrome P450 isoenzymes or transports. The delay in emptying the stomach with the use of lixisenatide may affect the rate of absorption of drugs taken orally. For oral medications whose effectiveness is particularly dependent on threshold concentrations, patients should be advised to take these medications at least 1 hour before or 11 hours after the injection of lyxisenatide.

Paracetamol

After a single dose of paracetamol in a dose of 1000 mg, AUC and t_l_/2paracetamol did not change, regardless of the time it was taken (before or after the injection of lixisenatide). When administered at 1 h or 4 h after injection, 10 μg of lyxisenatide C_max paracetamol decreased by 29% and 31%, respectively, and the median t_max increased by 4.5 h and 2 h, respectively. Based on these data, there is no need for correction of the dose of paracetamol when it is used in conjunction with lixisenatide.

Oral contraceptive medicines

After a single oral ingestion of oral contraceptive drug (ethinyl estradiol 0.03 mg / levonorgestrel 0.15 mg) 1 hour before or 11 hours after subcutaneous injection of lixisenatide C_max, AUC, t_l_/2and t_max Ethinyl estradiol and levonorgestrel did not change. Ingestion of ethinyl estradiol and levonorgestrel 1 h or 4 h after subcutaneous injection of lixisenatide had no effect on their AUC and t_l_/2, while C_m_Oh ethinyl estradiol was reduced by 52% (after 1 hour) and 39% (when taken after 4 hours), and C_m_Oh Levonogestrel decreased by 46% (when taken after 1 h) and 20% (when taken after 4 hours), as well as the median t_max increased by 2-4 hours.

Decrease in C_m_Oh has limited clinical significance, and no dose adjustment for oral contraceptives is required.

Atorvastatin

With the simultaneous use in the morning of lixisenatide and atorvastatin in a dose of 40 mg, the systemic exposure of atorvastatin did not change, its C_m_Oh slightly decreased, and t_max increased by 1.5-4 h.

If atorvastatin was taken in the evening, and lixisenatide in the morning, there was no increase t_max, but AUC and C_m_Oh increased by 27% and 66%, respectively.

These changes were not clinically significant, and therefore do not require dose adjustment atorvastatin when combined with lixisenatide.

Warfarin

After simultaneous application of warfarin 25 mg and lixisenatide there was no effect on AUC or INR (international normalized attitude), while t_max increased to 7 hours.

Based on these data, there is no need for correction of the dose of warfarin when it is combined with lixisenatide.

Digoxin

After simultaneous use of lixisenatide and digoxin in a dose of 0.25 mg AUC digoxin did not change, t_max increased by 1.5 h and C_m_Oh decreased by 26%.

Based on these data, there is no need to adjust the dose of digoxin when it is used together with lixisenatide.

Ramipril

After simultaneous use of lixisenatide and ramipril in a dose of 5 mg for 7 days AUC ramipril increased by 21%, while C_m_Oh decreased by 63%. AUC and C_m_Oh active metabolite (ramiprilata) did not change. t_max ramipril and ramiprilate increased by approximately 2.5 h.

Based on these data, there is no need for correction of the dose of ramipril when it is combined with lixisenatide.

Special instructions:

Application for type 1 diabetes mellitus

There is no therapeutic experience with the use of the drug LYXUMIA® in patients with type 1 diabetes mellitus, and its use in such patients is contraindicated.The use of the drug Lixumia ® in diabetic ketoacidosis is contraindicated.

Risk of pancreatitis

The use of GLP-1 receptor agonists was associated with a risk of developing acute pancreatitis. A characteristic symptom of acute pancreatitis is long-lasting strong abdominal pain. If suspected development of pancreatitis, discontinue treatment with Lyscmy®; When confirming the diagnosis of acute pancreatitis, resume treatment with the drug LYCLUSMY® can not. It should be used with caution in patients with pancreatitis in the anamnesis.

Application in severe gastroparesis

The use of GLP-1 receptor agonists can be associated with adverse gastrointestinal reactions. The use of the drug Lixumia in patients with severe gastrointestinal diseases, including gastroparesis, has not been studied to date, and therefore, in such patients, the use of the drug LYCLUSMA® is contraindicated.

The risk of developing hypoglycemia

Patients receiving treatment with Lysumia® in combination with an oral hypoglycemic drug of the sulfonylurea group or with a combination of basal insulin and oral hypoglycemicof the sulfonylurea group may have an increased risk of developing hypoglycemia. To reduce the risk of hypoglycemia, the question of reducing the dose of an oral hypoglycemic drug of the sulfonylurea group or basal insulin may be considered.

Effect on the ability to drive transp. cf. and fur:

There have been no studies on the effect of the drug on the ability to drive vehicles and engage in other potentially hazardous activities.

When the drug is used in combination with an oral hypoglycemic drug of the sulfonylurea group or basal insulin, patients should be informed of the need to take precautions to prevent hypoglycemia during driving or other potentially hazardous activities.

Form release / dosage:

The solution for subcutaneous administration was 0.05 mg / ml (10 μg / dose) and 0.1 mg / ml (20 μg / dose).

Packaging:

3 ml of the drug in a cartridge of colorless glass (type I). The cartridge is sealed on one side with a stopper (synthetic rubber isoprene rubber laminate and bromobutyl rubber), crimped with an aluminum cap,on the other hand it is closed with a ground piston made of bromobutyl rubber. The cartridge is mounted in a disposable syringe pen.

For a solution of 0.05 mg / ml (10 μg / dose): on 1 syringe-pen together with the instruction on application in a cardboard pack, equipped with a fixative.

For a solution of 0.1 mg / ml (20 μg / dose): 1, 2 or 6 syringe pens together with instructions for use in a cardboard pack equipped with a lock.

Set: 1 handle with a solution of 0.05 mg / ml (10 μg / dose) and 1 syringe pen with a solution of 0.1 mg / ml (20 μg / dose) together with instructions for use in a cardboard pack equipped with a fixer.

Storage conditions:

Store in a dark place at a temperature of 2 ° C to 8 ° C.

Do not freeze.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002737

Date of registration:02.12.2014

The owner of the registration certificate:Sanofi-aventis groupSanofi-aventis group France

Manufacturer: & nbsp