Universal reference book for medicines
Product name: BEAUT ® (BYETTA)

Active substance: exenatide

Type: Hypoglycemic drug.
A glucagon-like peptide receptor agonist
Manufacturer: ASTRAZENECA UK (United Kingdom) manufactured by BAXTER PHARMACEUTICAL SOLUTIONS (USA)
Composition, form of production and packaging
The solution for the sc administration is
colorless, transparent.

1 ml

exenatide 250 mcg

Excipients: sodium acetate trihydrate - 1.59 mg, acetic acid - 1.1 mg, mannitol - 43 mg, metarecil - 2.2 mg, water q / and - qs to 1 ml.

1.2 ml - cartridges (1) - syringe-pens (1) - packs cardboard.

2.4 ml - cartridges (1) - syringe-pens (1) - packs of cardboard.

INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2016.

PHARMACHOLOGIC EFFECT

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) increase glucose-dependent secretion of insulin, improve the function of β-cells, 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 the human GLP-1 receptors, which leads to an increase in glucose-dependent synthesis and insulin secretion from pancreatic β -cells involving cyclic AMP and / or other intracellular signaling ways.
Exenatide stimulates the release of insulin from β-cells in the presence of elevated glucose concentrations.
The chemical structure and pharmacological effect of 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 secretion of insulin: in hyperglycemic states, exenatid enhances glucose-dependent insulin secretion from the β-cells of the pancreas.
This secretion of insulin ceases as the glucose levels in the blood decrease and approach it to normal, thereby reducing the potential risk of hypoglycemia.
The first phase of the insulin response: insulin secretion during the first 10 min, 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 disruption of the function of? -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 a background of hyperglycemia, the administration of exenatide suppresses the excessive secretion of glucagon.
However, exenatide does not violate the normal glucagon response to hypoglycemia.
Food intake: the administration of exenatide leads to a decrease in appetite and a decrease in food intake;
suppresses the motility of the stomach, which leads to a slowdown in its emptying.
Emptying the stomach: it has been shown that the administration of exenatide suppresses the gastric motility, which leads to a slowdown in its emptying.
In patients with type 2 diabetes, exenatide therapy in combination with metformin, thiazolidinedione and / or sulfonylureas leads to a decrease in fasting blood glucose, postprandial blood glucose, and HbA 1c , thereby improving glycemic control in these patients.
PHARMACOKINETICS

Suction

After SC administration to patients with type 2 diabetes mellitus, exenatide is rapidly absorbed and reaches a mean of C max in 2.1 hours. The average C max is 211 pg / ml, AUC o-inf is 1036 pg / ml after a 10-dose dose of 10 mkg of 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 C max . The same effect was observed with n / k introduction exenatide in the abdomen, hip or shoulder area.
Distribution

V d of exenatide after SC administration is 28.3 liters.

Metabolism and excretion

Exenatide is mainly excreted by glomerular filtration followed by proteolytic decay.
The clearance of exenatide is 9.1 l / h. The final T 1/2 is 2.4 h. These pharmacokinetic characteristics of exenatide are dose independent.
The measured concentrations of exenatide are determined approximately 10 hours after dose administration.

Special patient groups

Patients with impaired renal function

In patients with mild to moderate renal dysfunction (CK 30-80 ml / min), exenatide clearance is not significantly different from clearance in patients 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 patients).
Patients with impaired hepatic function

Since exenatide is mainly excreted by the kidneys, it is believed that a violation of 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 a 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 indices 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 BMI and the pharmacokinetics of exenatide.

Correction of dose taking into account the BMI is not required.

INDICATIONS

Monotherapy

- Type 2 diabetes mellitus 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 thiazoldinedione in the case of failure to achieve adequate glycemic control;

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

DOSING MODE

The preparation of Baeta ® is injected s / c into the region of the thigh, abdomen or shoulder

The initial dose is 5 μg, 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 eating. In the case of missed injection of the drug treatment continues without changing the dose.
In 1 month after the start of treatment, the dose of Baeta ® can be increased to 10 μg 2 times / day.

When co-prescribing Baeta ® 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 Baeta ® with sulfonylureas, a dose reduction of the sulfonylurea derivative may be required to reduce the risk of hypoglycemia.
In the case of a combination of Baeta ® with an insulin preparation, you may need to reduce the dose of insulin to reduce the risk of hypoglycemia.

SIDE EFFECT

Monotherapy

Adverse reactions occurring more often than in single 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%).

Very often - a 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 the preparation Baeta ® as monotherapy, the incidence 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 single 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%).

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

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

Infrequently - abdominal pain, bloating, belching, constipation, a violation of taste sensations, flatulence.

Rarely , 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, worsening of chronic renal disease insufficiency, increased serum creatinine concentration).

Very rarely - anaphylactic reaction.

There have been reports of several cases of increased coagulation time with concomitant use of warfarin and exenatide, infrequently accompanied by bleeding.

Because
the frequency of hypoglycemia increases with the co-administration of Baeta ® 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

From the side of the immune system: very rarely - anaphylactic reaction.

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

From the nervous system: dysgeusia, drowsiness.

From the digestive system: eructation, constipation, flatulence;
rarely (including, in very rare cases - necrotizing or hemorrhagic) - acute pancreatitis.
From the side of the urinary system: a change in kidney function, incl.
acute renal failure, aggravation of chronic renal failure, impaired renal function, increased serum creatinine concentration.
From the skin and subcutaneous tissue: macular skin rashes, papular skin rashes, itching, hives, angioedema, alopecia.

Abnormalities detected 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.
CONTRAINDICATIONS

- hypersensitivity to exenatide or excipients included in the preparation;

- Type 1 diabetes mellitus or the presence of diabetic ketoacidosis;

- severe degree of renal failure (CK <30 ml / min);

- the presence of severe diseases of the gastrointestinal tract with concomitant paresis of the stomach;

- Pregnancy;

- lactation period (breastfeeding);

- Children under 18 years of age (safety and efficacy of the drug in children is not established);

acute pancreatitis.

With caution: pancreatitis in the anamnesis.

PREGNANCY AND LACTATION

The drug is contraindicated in pregnancy and lactation (breastfeeding).

APPLICATION FOR FUNCTIONS OF THE LIVER

In patients with mild to moderate renal dysfunction (CK 30-80 ml / min), exenatide clearance is not significantly different from clearance in patients with normal renal function;
therefore, correction of the dose of the drug is not required.
The drug is contraindicated in patients with severe renal insufficiency (CC <30 ml / min).

APPLICATION FOR CHILDREN

Contraindicated in children and adolescents under the age of 18 years.

APPLICATION IN ELDERLY PATIENTS

It is not necessary to adjust the dose to elderly patients.

SPECIAL INSTRUCTIONS

The preparation of Baeta ® should not be administered after a meal.
Not recommended IV or IM injection.
The preparation of Baeta ® should not be used if particles are found in the solution or if the solution is cloudy or has a staining.

In view of the potential immunogenicity of drugs containing proteins and peptides, against the background of therapy with the preparation of Baeta ®, antibodies to exenatide are possible.
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 Baeta ® 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 of 128 times the dose in humans was used 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 an increase in serum creatinine, the development of renal failure, aggravation 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 other undesirable events that contribute to hydration disorders such as nausea, vomiting and / or diarrhea.Concomitant medications included ACE inhibitors, NSAIDs, 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 direct nephrotoxicity, was not detected.
It has been reported that there are rare cases of acute pancreatitis with the use of Baeta ® .
Patients should be informed of the characteristic symptoms of acute pancreatitis: persistent severe abdominal pain. 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 treatment with Baete ® .

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, and a rapid decrease in blood glucose (hypoglycemia).

Treatment: symptomatic, including intravenous administration of r-dextrose in case of severe hypoglycemia.

DRUG INTERACTION

The preparation of Baeta ® should be used with caution in patients taking oral preparations that require rapid absorption from the digestive tract,
Baeta ® can cause a delay in the emptying of the stomach.
Patients should be advised to take oral medications, the action of which depends on their threshold concentration (eg, antibiotics), at least 1 hour prior to administration of exenatide.
If such drugs must be taken with food, then they should be taken during those meals when Baeta ® is not administered.
Digoxin

With the simultaneous administration of digoxin (0.25 mg 1 time / day) with the preparation of Baeta ®, C max of digoxin decreases by 17%, and T max increases by 2.5 h. However, the AUC does not change in the equilibrium state.

Lovastatin

Against the background of the introduction of the preparation Baeta ® AUC and C max lovastatin decreased by approximately 40% and 28%, respectively, and T maxincreased by approximately 4 hours. The co-administration of the Baeta ® preparation with HMG-CoA reductase inhibitors was not accompanied by changes in the lipid composition of the blood (HDL -cholesterol, LDL-cholesterol, total cholesterol and TG).

Lisinopril

In patients with mild or moderate arterial hypertension, stabilized with lisinopril (5-20 mg / day), the preparation of Baeta ® did not change the AUC and C max oflisinopril in the equilibrium state.
T max of lisinopril in the equilibrium state was increased by 2 h. No changes in the mean daily systolic and diastolic BP were observed.
Warfarin

It was noted that with the introduction of warfarin 35 min after the preparation of Baeta ® T max it was increased by about 2 hours. There was no clinically significant change in C max or AUC.

Other hypoglycemic drugs

Use of the drug Byetta ® in combination with D-phenylalanine derivatives, meglitinides, or alpha-glucosidase inhibitors have not been studied.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The drug should be stored in reach of children, protected from light, do not freeze at a temperature from 2 ° to 8 ° C. Shelf life - 3 years.
Currently in use in drug injection pen must be stored at a temperature not higher than 25 ° C
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