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

Active substanceExenatideExenatide

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Baeta®

solution PC

AstraZeneca UK Ltd United Kingdom

Baeta® Long

powder PC

AstraZeneca UK Ltd United Kingdom

Dosage form: & nbsphypodermic solution

Composition:

1 ml of the solution contains:

active substance: exenatide 250 mcg;

Excipients: sodium acetate three hydrate, acetic acid icy, mannitol, metarecil, water for injection.

Description:

Colorless transparent solution.

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

ATX: & nbsp

A.10.B.X.04 Exenatide

Pharmacodynamics:

Exenatide (exendin-4) is a glucagon-like polypeptide receptor agonist and is a 39 amino acid amide peptide. Increcines, such as glucagon-like peptide-1 (GLP-1), enhance glucose-dependent insulin secretion, improve beta cell function, suppress inadequately increased secretion of glucagon and slow the emptying of the stomach after they enter the total bloodstream from the intestine.

Exenatide is a potent mimetic of incretin, which causes an increase in glucose-dependent insulin secretion and has other hypoglycemic effects inherent in incretins, which improves glycemic control in patients with type 2 diabetes mellitus.

The amino acid sequence of exenatide partially corresponds to the sequence of human GLP-1, as a result of which it binds and activates human GLP-1 receptors, which leads to an increase in glucose-dependent synthesis and insulin secretion from pancreatic beta cells involving cyclic AMP and / or other intracellular signaling ways. Exenatide stimulates the release of insulin from beta cells in the presence of increased glucose concentration.

On 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 by the following mechanisms.

Glucose-dependent secretion of insulin: in hyperglycemic states exenatide enhances the glucose-dependent secretion of insulin from the beta cells of the pancreas. This secretion of insulin ceases as the concentration of glucose in the blood decreases and approaches it to normal, thereby reducing the potential risk of hypoglycemia.

The first phase of the insulin response: the secretion of insulin during the first 10 minutes, known as the "first phase of an insulin response," is absent in patients with type 2 diabetes mellitus. In addition, the loss of the first phase of the insulin response is an early disruption of the function of beta cells in type 2 diabetes mellitus.

The administration of exenatide restores or significantly enhances both the first and second phase of the insulin response in patients with type 2 diabetes mellitus.

Glucagon secretion: in patients with type 2 diabetes mellitus on the background of hyperglycemia, the administration of exenatide suppresses the excessive secretion of glucagon. But, exenatide does not violate the normal glucagon response to hypoglycemia.

Food consumption: The administration of exenatide leads to a decrease in appetite and a decrease in food intake.

Emptying the stomach: it was shown that the administration of exenatide suppresses gastric motility, which leads to a slowdown in its emptying. In patients with type 2 diabetes mellitus, exenatide therapy in monotherapy and in combination with metformin and / or sulfonylureas leads to a decrease in fasting blood glucose, postprandial blood glucose concentration,as well as the index of HbAlc, thereby improving glycemic control in these patients

Pharmacokinetics:

Suction

After subcutaneous administration to patients with type 2 diabetes mellitus exenatide is rapidly absorbed and reaches average maximum plasma concentrations in 2.1 hours. The mean maximum concentration (C max) is 211 pg / ml and the total area under the concentration-time curve (AUC0-int) is 1036 pg / hr / ml after subcutaneous administration of a dose of 10 mcg exenatide. Under the influence of exenatide, the AUC increases proportionally to an increase in the dose from 5 μg to 10 μg, and there is no proportional increase in Cmax. The same effect was observed with subcutaneous administration of exenatide in the abdomen, hip or shoulder region.

Distribution

The volume of exenatide distribution after subcutaneous administration is 28.3 liters. Metabolism and excretion Exenatide mainly excreted by glomerular filtration followed by proteolytic decay. The clearance of exenatide is 9.1 l / h and the final elimination half-life is 2.4 hours. These pharmacokinetic characteristics of exenatide are dose independent.

The measured concentrations of exenatide are determined approximately 10 hours after dosing.

Special patient groups

Patients with impaired renal function

In patients with mild or moderate impairment of renal function (creatinine clearance 30-80 ml / min), exenatide clearance does not significantly differ from clearance in subjects with normal renal function; therefore, correction of the dose of the drug is not required. However, in patients with terminal stage of renal failure who are on dialysis, the average clearance is reduced to 0.9 l / h (compared to 9.1 l / h in healthy subjects).

Patients with impaired hepatic function

Because the exenatide mainly excreted by the kidneys, it is believed that a violation of the liver function does not change the concentration of exenatide in the blood.

Elderly

Age does not affect the pharmacokinetic characteristics of exenatide. Therefore, elderly patients do not need to adjust the dose.

Children

The pharmacokinetics of exenatide in children has not been studied.

Adolescents (12 to 16 years of age)

In the pharmacokinetic study, conducted with the participation of patients with type 2 diabetes mellitus in the age group from 12 to 16 years, the appointment of exenatide at a dose of 5 μg was accompanied by pharmacokinetic parameters similar to those observed in the adult population.

Floor

Between men and women clinically significant differences in the pharmacokinetics of exenatide are not observed.

Race

The race has no appreciable effect on the pharmacokinetics of exenatide. Correction of dose taking into account ethnic origin is not required.

Patients with obesity

There is no significant correlation between the body mass index (BMI) and the pharmacokinetics of exenatide.

Correction of the dose in view of the BMI is not required.

Indications:

Monotherapy

Diabetes mellitus type 2 as a monotherapy in addition to diet and exercise to achieve adequate glycemic control.

Combination Therapy

Type 2 diabetes mellitus as an adjunct to metformin, a sulfonylurea derivative, thiazolidinedione, a combination of metformin and a sulfonylurea derivative or metformin and thiazolidinedione in the absence of adequate glycemic control.

Type 2 diabetes mellitus as an adjunct to the combination of basal insulin and metformin preparations to improve glycemic control.

Contraindications:

· Hypersensitivity to exenatide or excipients included in the preparation

· Type 1 diabetes mellitus or the presence of diabetic ketoacidosis

· Severe renal failure (creatinine clearance <30 mL / min)

· The presence of severe diseases of the gastrointestinal tract with concomitant paresis of the stomach

· Pregnancy and breastfeeding

· Children under 18 years of age (safety and efficacy of BEAET ® in children is not established)

· Acute pancreatitis

Carefully:

Pancreatitis in the anamnesis.

Dosing and Administration:

The preparation BETA ® is administered subcutaneously in the area of the thigh, abdomen or shoulder.

The initial dose is 5 μg, which is administered twice a day at any time during the 60-minute period of time before the morning and evening meals. Do not administer the drug after eating. In the case of missed injection of the drug treatment continues without changing the dose.

1 month after the start of treatment, the dose of BETA ® can be increased to 10 μg twice a day.

With the joint administration of BETA ® with metformin, thiazolidinedione or a combination of these drugs, the initial dose of metformin and / or thiazolidinedione may not change. In the case of a combination of BETA® with a sulfonylurea derivative, a dose reduction of the sulfonylurea derivative may be required to reduce the risk of hypoglycemia.

In the case of a combination of BETA® with an insulin preparation, a reduction in the dose of insulin may be required to reduce the risk of hypoglycemia.

Side effects:

Monotherapy

Adverse reactions occurring more often than in single cases are listed according to the following gradation: 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, decreased appetite, dizziness;

Rarely - skin reactions at the injection site (rash, redness).

With the use of BATEA® as monotherapy, the incidence of hypoglycemia was 5% compared to 1% placebo. Most episodes of hypoglycemia were weak or moderate in intensity.

Combination Therapy

Often - nausea, vomiting, diarrhea, hypoglycemia (in combination with the sulfonylurea derivative), skin reaction at the injection site (itching);

Often - indigestion.trembling, dizziness, headache, decreased appetite, weakness, gastroesophageal reflux;

Infrequently - abdominal pain, bloating, eructation, constipation, a violation of taste sensations, flatulence;

Rarely - drowsiness, skin reactions at the injection site (rash, redness), dehydration (mostly associated with nausea, vomiting and / or diarrhea), angioedema, acute pancreatitis, impaired renal function (including acute renal failure, worsening of chronic renal failure , increased serum creatinine concentration);

Rarely anaphylactic reaction. Several cases of increased coagulation time have been reported with simultaneous use of warfarin and exenatide, infrequently accompanied by bleeding.

Since the frequency of hypoglycemia increases with the co-administration of the drug BETA® with the sulfonylurea derivative, it is necessary to provide a reduction in the dose of the sulfonylurea derivative with an increased risk of hypoglycemia. Most episodes of hypoglycemia were weak or moderate in intensity and were stopped by oral intake of carbohydrates.

Overall, the intensity side effects were mild or moderate and did not lead to withdrawal of treatment. The most frequently reported nausea of mild or moderate intensity was dose-dependent and decreased over time, without interfering with daily activities.

Spontaneous post-marketing messages

Immune system disorders: anaphylactic reaction (very rarely).

Disorders of nutrition and metabolism: dehydration, usually associated with nausea, vomiting and / or diarrhea, weight loss.

Disturbances from the nervous system: dysgeusia, drowsiness.

Disorders from the digestive system: eructation, constipation, flatulence, acute pancreatitis (rarely, including, in very rare cases, necrotizing or hemorrhagic).

Disorders from the urinary system: changes in kidney function, including acute renal failure, aggravation of chronic renal failure, impaired renal function, increased serum creatinine concentration.

Disorders from the skin and popliteal fiber: macular skin rashes, papular skin rashes, itching, hives, angioedema, alopecia.

Deviations from the norm, revealed in laboratory studies: an increase in the international normalized relationship (when combined with warfarin), in some cases associated with the development of bleeding.

Overdose:

In case of an overdose (a dose 10 times higher than the maximum recommended dose), the following symptoms were observed: severe nausea and vomiting, as well as a rapid decrease in glucose concentrations in the blood (hypoglycemia).

Treatment: symptomatic, including parenteral administration of glucose in the case of severe hypoglycemia.

Interaction:

BETA® preparation should be used with caution in patients taking oral medications that require rapid absorption in the gastrointestinal tract, since BATEA can cause a delay in gastric emptying.

Patients should be advised to take oral medications, the action of which depends on their threshold concentration (eg, antibiotics), at least 1 hour before the administration of exenatide. If such drugs should be taken with food, you should take them during those meals, when BATE is not being administered.

Digoxin

With concomitant administration of digoxin (0.25 mg once daily) with BETA®, C decreasesmah digoxin by 17%, and Tmax increased by 2.5 hours. However, the overall pharmacokinetic effect in the equilibrium state (AUC) does not change.

Lovastatin

Against the background of the introduction of the drug BATE AUC and Cmax, lovastatin decreased by approximately 40% and 28%, respectively, and Tmax increased by approximately 4 hours. The simultaneous administration of BETA® with HMG-CoA reductase inhibitors was not accompanied by changes in the lipid composition (HDL-cholesterol, LDL-cholesterol, total cholesterol and triglycerides).

Lisinopril

In patients with mild or moderate arterial hypertension, stabilized with lisinopril (5-20 mg / day), the BETA® preparation did not change the AUC and Cmax of lisinopril in the equilibrium state.

Tmax of lisinopril in the equilibrium state was increased by 2 hours. No changes in the mean daily systolic and diastolic blood pressure were observed.

Warfarin

It was noted that with the introduction of warfarin 35 minutes after the preparation BETA® Tmax increased by about 2 hours. There was no clinically significant effect on Cmax or AUC.

Other hypoglycemic drugs The use of BETA® in combination with D-phenylalanine derivatives, meglitinides or alpha-glucosidase inhibitors has not been studied.

Special instructions:

BETA® should not be taken after meals. It is not recommended intravenous or intramuscular injection of the drug.

The BETA® preparation should not be used if particles are found in the solution if the solution is cloudy or has a staining.

In view of the potential immunogenicity of drugs containing proteins and peptides, the development of antibodies to exenatide is possible against the background of therapy with the drug BATE. In most patients who have seen the production of such antibodies, their titer decreased as the 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 BATEA® can lead to a decrease in appetite and / or body weight, and that, because of these effects, there is no need to change the dosage regimen.

Pre-clinical studies in mice and rats showed no carcinogenic effects of exenatide. When a dose 128 times higher than the human dose was applied in rats, a numerical increase in C-cell adenomas of the thyroid gland was noted without any signs of malignancy, which was associated with an increase in the survival of experimental animals receiving exenatide.

There have been reports of rare cases of renal dysfunction, including increased serum creatinine levels, development of renal failure, worsening of chronic and acute renal failure; sometimes hemodialysis was required. Some of these phenomena have been observed in patients receiving one or more pharmacological agents that affect renal function / water metabolism and / or against other undesirable effects contributing to the disruption of hydration, such as nausea, vomiting and / or diarrhea. Concomitant medications included angiotensin-converting enzyme inhibitors, non-steroidal anti-inflammatory drugs, diuretics. With the appointment of symptomatic therapy and the abolition of the drug, presumably caused by pathological changes, the impaired renal function was restored. In pre-clinical and clinical studies, exenatide data, indicating its immediate nephrotoxicity, was not detected.

It was reported that there were rare cases of acute pancreatitis against the background of taking BATEA®.Patients should be informed of the characteristic symptoms of acute pancreatitis: persistent severe pain in the abdomen. With the appointment of symptomatic therapy, resolution of acute pancreatitis was observed. Patients should be familiarized with the "Manual on the use of the syringe-pen" attached to the preparation before starting the treatment with BETA®.

Form release / dosage:

A solution for subcutaneous administration of 250 μg / ml

Packaging:

In the syringe pen, 1.2 ml or 2.4 ml. One syringe-pen together with the instruction on the use of the drug and the manual on the use of a syringe-pen in a pack of cardboard.

Storage conditions:

At a temperature of 2-8 ° C. The drug in use in a syringe-pen should be stored at a temperature of no higher than 25 ° C for not more than 30 days. Do not freeze. Protect from light. Keep out of the reach of children.

Shelf life:

3 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LS-002221

Date of registration:09.06.2011 / 01.06.2016

Expiration Date:Unlimited

The owner of the registration certificate:AstraZeneca UK LtdAstraZeneca UK Ltd United Kingdom

Manufacturer: & nbsp

BAXTER PHARMACEUTICAL SOLUTIONS, LLC USA

Representation: & nbspELI LILLY EAST SA ELI LILLY EAST SA Switzerland

Information update date: & nbsp13.01.17

Illustrated instructions

Instructions

Baeta® (Byetta®)