Byeta solution of subcutaneous injection enter 250mkg ml 2.4ml N1
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Active ingredients
Release form
Pharmacological effect
Exenatide (exendin-4) is a receptor agonist of a glucagon-like polypeptide and is a 39-amino acid amidopeptide. Incretins, such as glucagon-like peptide-1 (GLP-1), increase glucose-dependent insulin secretion, improve β-cell function, suppress inadequately increased glucagon secretion, and slow down gastric emptying after they enter the bloodstream from the intestine.
Exenatide is a potent incretin mimetic, which causes an increase in glucose-dependent insulin secretion and has other hypoglycemic effects inherent to incretin, which allows for improved glycemic control in patients with type 2 diabetes.
The amino acid sequence of exenatide partially corresponds to the sequence of human GLP-1, as a result of which it binds and activates GLP-1 receptors in humans, which leads to increased glucose-dependent synthesis and insulin secretion from β-cells of the pancreas with the participation of cyclic AMP and / or other intracellular signal ways. Exenatide stimulates insulin release from β-cells in the presence of elevated glucose concentrations.
In terms of chemical structure and pharmacological action, exenatide differs from insulin, sulfonylurea derivatives, D-phenylalanine derivatives and meglitinides, biguanides, thiazolidinediones and alpha-glucosidase inhibitors.
Exenatide improves glycemic control in patients with type 2 diabetes due to the following mechanisms.
Glucose-dependent insulin secretion: in hyperglycemic conditions, exenatide enhances glucose-dependent insulin secretion from β-cells of the pancreas. This insulin secretion stops as the concentration of glucose in the blood decreases and approaches its normality, thereby reducing the potential risk of hypoglycemia.
The first phase of the insulin response: insulin secretion during the first 10 minutes, known as the “first phase of the insulin response,” is specifically absent in patients with type 2 diabetes. In addition, the loss of the first phase of the insulin response is an early dysfunction of β-cells in type 2 diabetes.
The administration of exenatide restores or significantly enhances both the first and second phase of the insulin response in patients with type 2 diabetes.
Secretion of glucagon: in patients with type 2 diabetes with hyperglycemia, administration of exenatide suppresses excessive secretion of glucagon. However, exenatide does not interfere with the normal glucagon response to hypoglycemia.
Food consumption: the introduction of exenatide leads to a decrease in appetite and a decrease in food intake; inhibits gastric motility, which leads to a slowdown in its emptying.
Gastric emptying: introduction of exenatide has been shown to inhibit gastric motility, which leads to a slowdown in its emptying. In patients with type 2 diabetes, treatment with exenatide in combination with metformin, thiazolidinedione and / or sulfonylurea drugs leads to a decrease in fasting blood glucose, postprandial blood glucose, and HbA1c, thereby improving glycemic control in these patients.
Pharmacokinetics
Suction
After s / c administration in patients with type 2 diabetes, exenatide is rapidly absorbed and reaches a mean C max after 2.1 hours. The average C max is 211 pg / ml, AUCo-inf is 1036 pg × h / ml after a s / c dose of 10 mcg exenatide. When exposed to exenatide, AUC increases in proportion to the dose increase from 5 μg to 10 μg, while there is no proportional increase in Cmax. The same effect was observed when s / c the introduction of exenatide in the abdomen, thigh or shoulder.
Distribution
Vd exenatide after s / c injection is 28.3 liters.
Metabolism and excretion
Exenatide is predominantly excreted by glomerular filtration followed by proteolytic disintegration. Exenatide clearance is 9.1 l / h. The final T1 / 2 is 2.4 hours. These pharmacokinetic characteristics of exenatide are not dose dependent.
Measured concentrations of exenatide are determined for approximately 10 hours after a dose.
Special patient groups
Patients with impaired renal function
In patients with mild or moderate renal impairment (CC 30-80 ml / min), exenatide clearance is not significantly different from clearance in patients with normal renal function; therefore, a dose adjustment of the drug is not required.However, in patients with end-stage renal disease on dialysis, the average clearance is reduced to 0.9 l / h (compared to 9.1 l / h in healthy patients).
Patients with impaired liver function
Since exenatide is mainly excreted by the kidneys, it is believed that an abnormal liver function does not alter the concentration of exenatide in the blood.
Elderly
Age does not affect the pharmacokinetic characteristics of exenatide. Therefore, elderly patients are not required to carry out dose adjustment.
Children
The pharmacokinetics of exenatide in children has not been studied.
Teenagers (12 to 16 years old)
In a pharmacokinetic study involving patients with type 2 diabetes in the age group of 12 to 16 years, the administration of exenatide at a dose of 5 μg was accompanied by pharmacokinetic parameters similar to those observed in the adult population.
Floor
There are no clinically significant differences in the pharmacokinetics of exenatide between men and women.
Race
Race has no significant effect on exenatide pharmacokinetics. Dose adjustment based on ethnic origin is not required.
Obese patients
There is no marked correlation between BMI and exenatide pharmacokinetics.
Dose adjustment based on BMI is not required.
Indications
Monotherapy
- type 2 diabetes as monotherapy in addition to diet and exercise to achieve adequate glycemic control.
Combination therapy
- Type 2 diabetes mellitus as an additional therapy to metformin, a sulfonylurea derivative, thiazolidinedione, a combination of metformin and a sulfonylurea derivative, or metformin and thiazolindione in case of failure to achieve adequate glycemic control;
- Type 2 diabetes mellitus as an additional therapy to a combination of basal insulin and metformin preparations to improve glycemic control.
Contraindications
- hypersensitivity to exenatide or excipients that are part of the drug;
- Type 1 diabetes mellitus or the presence of diabetic ketoacidosis;
- severe degree of renal failure (CC <30 ml / min);
- the presence of severe gastrointestinal diseases with concomitant paresis of the stomach;
- pregnancy;
- lactation period (breastfeeding);
- children's age up to 18 years (safety and efficacy of the drug in children has not been established);
- acute pancreatitis.
Carefully: pancreatitis in history.
Precautionary measures
Use during pregnancy and lactation
Application for violations of kidney function
In patients with mild or moderate renal impairment (CC 30-80 ml / min), exenatide clearance is not significantly different from clearance in patients with normal renal function; therefore, a dose adjustment of the drug is not required.
The drug is contraindicated in severe renal failure (CC <30 ml / min).
Use in children
Contraindicated use of the drug in children and adolescents under the age of 18 years.
Use in elderly patients
The drug Byetha® is injected sf into the region of the thigh, abdomen or shoulder.
The initial dose is 5 micrograms, which is administered 2 times / day at any time during the 60-minute period before the morning and evening meals. Do not administer the drug after a meal. In case of missing an injection, treatment continues without changing the dose.
1 month after the start of treatment, the dose of Byetha® can be increased to 10 mcg 2 times / day.
When a joint appointment of the drug Byetha® with metformin, thiazolidinedione or with a combination of these drugs, the initial dose of metformin and / or thiazolidinedione may not change. In the case of a combination of the drug Byeta® with sulfonylurea derivatives, it may be necessary to reduce the dose of the sulfonylurea derivative in order to reduce the risk of hypoglycemia.
In the case of a combination of Byetha® with an insulin preparation, it may be necessary to lower the dose of the insulin preparation in order to reduce the risk of hypoglycemia.
Side effects
Monotherapy
Adverse reactions occurring more often than in isolated cases are listed according to the following gradation: very often (≥10%), often (≥1%, <10%), infrequently (> 0.1%, <1%), rarely ( > 0.01%, <0.1%), very rarely (<0.01%).
Often - skin reaction at the injection site (itching).
Often - nausea, vomiting, diarrhea, dyspepsia, loss of appetite, dizziness.
Seldom - skin reactions at the injection site (rash, redness).
When using the drug Byetha® as monotherapy, the incidence of cases of hypoglycemia was 5% compared with 1% placebo.
Most episodes of hypoglycemia were mild or moderate in intensity.
Combination therapy
Adverse reactions occurring more often than in isolated cases are listed according to the following gradation: very often (≥10%), often (≥1%, <10%), infrequently (> 0.1%, <1%), rarely ( > 0.01%, <0.1%), very rarely (<0.01%).
Often - nausea, vomiting, diarrhea, hypoglycemia (in combination with a sulfonylurea derivative), skin reaction at the injection site (itching).
Often - dyspepsia, trembling, dizziness, headache, loss of appetite, weakness, gastroesophageal reflux.
Infrequently - abdominal pain, bloating, belching, constipation, a violation of taste, flatulence.
Seldom - drowsiness, skin reactions at the injection site (rash, redness), dehydration (in most cases associated with nausea, vomiting and / or diarrhea), angioedema, acute pancreatitis, impaired renal function (including acute renal failure, aggravation of chronic renal failure , increased serum creatinine concentration).
Very rarely - Anaphylactic reaction.
A few cases of increased clotting time have been reported with simultaneous use of warfarin and exenatide, which is infrequently accompanied by bleeding.
Since the frequency of hypoglycemia increases with co-administration of Byetta® with a sulfonylurea derivative; it is necessary to provide for a reduction in the dose of the sulfonylurea derivative with an increased risk of hypoglycemia. Most episodes of hypoglycemia in intensity were mild or moderate and were stopped by oral carbohydrate intake.
In general, the intensity side effects were mild or moderate and did not lead to the abolition of treatment. Most commonly recorded nausea of weak or moderate intensity was dose-dependent and decreased over time without interfering with daily activity.
Spontaneous (post-marketing) messages
On the part of the immune system: very rarely - an anaphylactic reaction.
Malnutrition and Metabolism: dehydration, usually associated with nausea, vomiting and / or diarrhea, weight loss.
From the nervous system: dysgeusia, drowsiness.
From the digestive system: belching, constipation, flatulence; rarely (including, in very rare cases - necrotizing or hemorrhagic) - acute pancreatitis.
From the urinary system:change in renal function, incl. acute renal failure, exacerbation of chronic renal failure, impaired renal function, increased serum creatinine concentration.
From the skin and subcutaneous tissue: maculosis skin rashes, papular skin rashes, pruritus, urticaria, angioedema, alopecia.
Abnormalities identified in laboratory studies: increased INR (when combined with warfarin), in some cases associated with the development of bleeding. in some cases associated with the development of bleeding.
Overdose
In case of overdose (the dose is 10 times higher than the maximum recommended dose), the following were observed.symptoms: severe nausea and vomiting, as well as a rapid decrease in the concentration of glucose in the blood (hypoglycemia).
Treatment: symptomatic, including in / in the introduction of the solution of dextrose in case of severe hypoglycemia.
Interaction with other drugs
Byaeta® drug should be used with caution in patients who ingest drugs that require rapid absorption from the gastrointestinal tract, because Byetta® may cause a delay in gastric emptying.
Patients should be advised to take oral medications, the effect of which depends on their threshold concentration (for example, antibiotics), not less than 1 hour before the administration of exenatide. If such drugs must be taken with food, then they should be taken during those meals when Byetha® is not administered.
Digoxin
With simultaneous administration of digoxin (0.25 mg 1 time / day) with the drug Byetha®, Cmax of digoxin decreases by 17%, and Tmax increases by 2.5 hours. However, the AUC in an equilibrium state does not change.
Lovastatin
On the background of the administration of the drug Byeta® AUC and Cmax of lovastatin, decreased by approximately 40% and 28%, respectively, and Tmax increased by approximately 4 hours. The co-administration of Byeta® with HMG-CoA reductase inhibitors was not accompanied by changes in the blood lipid composition (HDL-cholesterol , LDL-cholesterol, total cholesterol and TG).
Lisinopril
In patients with mild or moderate arterial hypertension, stabilized by lisinopril (5–20 mg / day), Byetta® did not change the AUC and Cmax of lisinopril at equilibrium. In equilibrium, the rate of lisinopril increased by 2 hours. There were no changes in the average daily systolic and diastolic BP values.
Warfarin
It was noted that with the introduction of warfarin 35 minutes after the drug Byetta®Tmax increased by about 2 hours. There was no clinically significant change in Cmax or AUC.
Other hypoglycemic drugs
Use of the drug Bytata® in combination with derivatives of D-phenylalanine, meglitinides or alpha-glucosidase inhibitors has not been studied.
special instructions
The drug Byetha® should not be administered after meals. Not recommended in / in or in / m the introduction of the drug.
Byate® should not be used if particles are detected in the solution or if the solution is cloudy or has staining.
Due to the potential immunogenicity of drugs containing proteins and peptides, during therapy with the drug Byetha®, the production of antibodies to exenatide is possible. In the majority of patients in whom the production of such antibodies was noted, their titer decreased as therapy continued and remained low for 82 weeks. The presence of antibodies does not affect the frequency and types of reported side effects.
Patients should be informed that treatment with Byetta® can lead to a decrease in appetite and / or body weight, and that due to these effects there is no need to change the dosage regimen.
In preclinical studies in mice and rats, no carcinogenic effect of exenatide was found. When a dose was applied in rats, 128 times the dose in humans, a numerical increase in C-cell thyroid adenomas was noted without any signs of malignancy, which was associated with an increase in the life expectancy of experimental animals receiving exenatide.
Rare cases of impaired renal function have been reported, including elevated serum creatinine levels, development of renal failure, exacerbation of chronic and acute renal failure; sometimes hemodialysis was required. Some of these phenomena were observed in patients who received one or more pharmacological drugs that affect renal function / water metabolism and / or against the background of other adverse events that contribute to impaired hydration, such as nausea, vomiting and / or diarrhea.Related drugs included ACE inhibitors, NSAIDs, diuretic drugs. In the appointment of symptomatic therapy and the abolition of the drug, allegedly the cause of pathological changes, impaired renal function was restored. When conducting preclinical and clinical studies of exenatide, no evidence of its direct nephrotoxicity was found.
Rare cases of acute pancreatitis have been reported with the administration of the drug Byetta®. Patients should be informed about the characteristic symptoms of acute pancreatitis: persistent severe abdominal pain. When prescribing symptomatic therapy, resolution of acute pancreatitis was observed.
Patients before starting treatment with Byetha® should familiarize themselves with the “Manual on the use of syringe pens” attached to the preparation.
Storage conditions
The drug should be kept out of the reach of children, protected from light, not frozen, at a temperature of 2 ° to 8 ° C. Shelf life - 3 years.
A used drug in a pen should be stored at a temperature not higher than 25 ° C for no more than 30 days.