Galvus Met pills coated 50mg + 500mg №30

Dosage form

Pills

Composition

1 coated pill contains: Vildagliptin 50 mg., Metformin hydrochloride 500 mg.

Auxiliary substances: Hyprolosis, Magnesium stearate, hypromellose, titanium dioxide (E171), macrogol 4000, talc, iron oxide yellow (E172).

Packaging

In the blister of 10 tablets. In a carton 3 blisters.

Mechanism of action

The preparation Galvus Met consists of two hypoglycemic agents with different mechanisms of action: vildagliptin, belonging to the class of inhibitors of dipeptidyl peptidase-4, and metformin (in the form of hydrochloride), a representative of the class of biguanides. The combination of these components allows you to more effectively control the blood glucose level in patients with type 2 diabetes within 24 hours.

- Vildagliptin Vildagliptin is a member of the pancreatic islet apparatus stimulator class that selectively inhibits the enzyme dipeptidyl peptidase-4 (DPP-4), which destroys glucagon-like peptide type 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (HIP). Rapid and complete inhibition of the activity of DPP-4 causes an increase in both basal and food-stimulated secretion of GLP-1 and HIP from the intestine into the systemic circulation throughout the day.Increasing levels of GLP-1 and HIP, vildagliptin causes an increase in the sensitivity of β-cells of the pancreas to glucose, which leads to an improvement in glucose-dependent insulin secretion. The degree of improvement in the function of β-cells depends on the degree of their initial damage; so in non-diabetic individuals (with normal plasma glucose levels), vildagliptin does not stimulate insulin secretion and does not decrease glucose levels. By increasing levels of endogenous GLP-1, vildagliptin increases the sensitivity of β-cells to glucose, which leads to an improvement in glucose-dependent regulation of glucagon secretion. A decrease in the level of excess glucagon during a meal, in turn, causes a decrease in insulin resistance. An increase in the insulin / glucagon ratio due to hyperglycemia due to increased levels of GLP-1 and HIP causes a decrease in glucose production by the liver both during and after meals, which leads to a decrease in plasma glucose levels. In addition, against the background of vildagliptin, there was a decrease in the level of lipids in the blood plasma after a meal, however, this effect is not associated with its effect on GLP-1 or HIP and an improvement in the function of pancreatic islet cells. It is known that an increase in the level of GLP-1 may lead to a slower gastric emptying, but this effect is not observed when using vildagliptin. When using vildagliptin in 5759 patients with type 2 diabetes mellitus for 52 weeks as monotherapy or in combination with metformin, sulfonylurea derivatives, thiazolidinedione,or insulin showed a significant long-term decrease in the concentration of glycated hemoglobin (HbA 1c) and fasting blood glucose.

- Metformin Metformin improves glucose tolerance in patients with type 2 diabetes, reducing plasma glucose levels both before and after meals. Metformin reduces the production of glucose by the liver, reduces the absorption of glucose in the intestine, and reduces insulin resistance by increasing glucose uptake and utilization of peripheral tissues. Unlike sulfonylurea derivatives, metformin does not cause hypoglycemia in patients with type 2 diabetes or in healthy subjects (except in special cases). Drug therapy does not lead to the development of hyperinsulinemia. When using metformin, insulin secretion does not change, while insulin plasma levels on an empty stomach and during the day may decrease. Metformin induces intracellular glycogen synthesis, acting on glycogen synthase, and enhances glucose transport by certain membrane glucose transfer proteins (GLUT-1 and GLUT-4). When using metformin, there is a favorable effect on lipoprotein metabolism: a decrease in the level of total cholesterol, low density lipoprotein cholesterol and triglycerides, which is not associated with the effect of the drug on plasma glucose concentration.

- vildagliptin + metformin When using combination therapy with vildagliptin / metformin in daily doses of 1500 -3000 mg of metformin and 50 mg of vildagliptin for 1 year, a statistically significant persistent decrease in the blood glucose concentration (determined by a decrease in HbA 1c) and an increase in the proportion of patients was observedin which the decrease in the level of HbA 1c was not less than 0.6-0.7% (compared with the group of patients who continued to receive only metformin). In patients receiving the combination of vildagliptin and metformin, there was no statistically significant change in body weight compared with the initial state. 24 weeks after the start of treatment in groups of patients who received vildagliptin in combination with metformin, there was a decrease in systolic and diastolic blood pressure compared with the initial state.

Indications and usage

- Diabetes mellitus type 2 (in combination with diet therapy and exercise):
- With insufficient effectiveness of monotherapy with vildagliptin or metformin.
- In patients previously receiving the combination therapy with vildagliptin and metformin in the form of monodrugs.

Contraindications

- Hypersensitivity to vildagliptin or metformin or any other components of the drug.
- Renal failure.
- Impaired renal function (when serum creatinine level is 1.5 mg% (> 135 μmol / L) for men and 1.4 mg% (> 110 μmol / L) for women).
- Acute conditions occurring at risk of developing renal dysfunction:
- Dehydration (with diarrhea, vomiting).
- Fever.
- Severe infectious diseases.
- Conditions of hypoxia:
- Shock.
- Sepsis.
- Renal infections.
- Bronchopulmonary diseases.

- Including diabetic ketoacidosis, with or without coma.
- Lactic acidosis (including, and in the anamnesis).

- Surgical operations.
- Radioisotope, X-ray studies with the introduction of contrast media and within 2 days after their conduct.

- Patients over 60 years old.
- When performing heavy physical work due to the increased risk of lactic acidosis.

Pregnancy and Breastfeeding

In experimental studies when prescribing vildagliptin in doses 200 times higher than recommended, the drug did not cause impairment of fertility and early embryonic development and did not have a teratogenic effect on the fetus. When prescribing vildagliptin in combination with metformin at a ratio of 1:10, no teratogenic effect on the fetus was also detected.

Since there are no sufficient data on the use of Galvus Met in pregnant women, the drug should not be used during pregnancy.

When violations of glucose metabolism in pregnant women there is an increase in the risk of developing congenital anomalies, as well as the frequency of neonatal morbidity and mortality. To normalize blood glucose levels during pregnancy, insulin monotherapy is recommended.

Since it is not known whether vildagliptin or metformin is excreted in human breast milk, Galvus Met should not be used during lactation.

Dosage and administration

The drug is used inside.

Dosing regimen Galvus Met should be selected individually depending on the effectiveness and tolerability.

When using Galvus Met, do not exceed the recommended maximum daily dose of vildagliptin (100 mg). The recommended initial dose of Galvus Met should be selected, taking into account the treatment regimens of vildagliptin and / or metformin already used in the patient. To reduce the severity of side effects from the digestive system, characteristic of metformin, Galvus Met take during meals.

- The initial dose of Galvus Met with the ineffectiveness of monotherapy with vildagliptin. Treatment with Galvus Met can be started with one pill 2 times a day, and after evaluating the therapeutic effect, the dose can be gradually increased.

- The initial dose of Galvus Met with the ineffectiveness of monotherapy with metformin Depending on the dose of metformin already taken, treatment with Galvus Met can be started with one pill of Galvus Met table. 50 mg / 850 mg pack. 30 Novartis Pharma AG or Galvus Met. Table. 50 mg / 1000 mg pack. 30 Novartis Pharma AG 2 times a day.

- The initial dose of Galvus Met in patients previously receiving the combination therapy with vildagliptin and metformin as separate tablets Depending on the doses already taken with vildagliptin or metformin, treatment with Galus Met should be started with a pill as close as possible in dosage to the existing treatment with Galvus Met. 50 mg / 850 mg pack. 30 Novartis Pharma AG or Galvus Met. Table. 50 mg / 1000 mg pack. 30 Novartis Pharma AG and titrated by effect.

- Patients with impaired renal function Galvus Met should not be used in patients with renal insufficiency or with impaired renal function,when serum creatinine level is 51.5 mg% (> 135 mmol / L) for men and 51.4 mg% (> 110 mmol / L) for women.

- Use in patients aged? 65 years old Metformin excreted by the kidneys. Since in patients over 65 years of age, there is often a decrease in renal function, Galvus Met is prescribed a minimal dose of this category of patients, ensuring normalization of glucose levels, only after determining CC to confirm normal kidney function. When using the drug in patients over 65, it is necessary to regularly monitor renal function.

- Use in patients aged? 18 years Since the safety and efficacy of Galvus Met in children and adolescents under 18 years of age has not been studied, the drug is not recommended for use in this category of patients.

To assess the incidence of adverse events, the following criteria were used:

- Very often (> 1/10).
- Often (> 1/100, - Sometimes (> 1/1000, - Rarely (> 1/10 000, - Very rarely (

In combination therapy with vildagliptin and metformin: The adverse reactions possibly associated with the use of combination therapy with vildagliptin and metformin (the incidence of which in the group of vildagliptin + metformin differed from that compared with placebo and metformin by more than 2%) are presented below.

On the part of the nervous system: Often - headache, dizziness, tremor.

On the part of the endocrine system: When using vildagliptin in combination with metformin in various doses, hypoglycemia was observed in 0.9% of cases (compared to the placebo group in combination with metformin - in 0.4%).

On the part of the digestive system: Against the background of combination therapy, vildagliptin + metformin was 12.9%. When using metformin, such adverse events were observed in 18.1% of patients. In groups of patients who received Metformin in combination with vildagliptin, gastrointestinal disturbances were observed with a frequency of 10% —15%, and in the group of patients who received Metformin in combination with placebo, with a frequency of 18%.

When using vildagliptin as monotherapy: Long-term clinical studies of up to 2 years did not reveal any additional deviations in the safety profile or unforeseen risks when using vildagliptin as monotherapy.

On the part of the nervous system: Often - dizziness, headache.

Of the digestive system: Often - constipation.

Dermatological reactions: Sometimes - a skin rash.

From the musculoskeletal system: Often - arthralgia.

Other: Sometimes - peripheral edema.

Changes in laboratory parameters: When using vildagliptin at a dose of 50 mg 1 time per day or 100 mg per day (in 1 or 2 doses) for 1 year, the frequency of increase in the activity of alaninamine transferase (AlAt) and aspartate aminotransferase (AsAt) is more than 3 times compared with the upper limit of normal, was 0.3% and 0.9%, respectively (0.3% in the placebo group). Increased activity of AlAt and AsAt, as a rule, was asymptomatic, did not increase and was not accompanied by cholestasis or jaundice.

When using combination therapy with vildagliptin + metformin, there was no clinically significant increase in the incidence of the above adverse events reported with vildagliptin.

Against monotherapy with vildagliptin or metformin, the incidence of hypoglycemia was 0.4%.

Vildagliptin monotherapy and vildagliptin + metformin combination therapy had no effect on patient weight. Long-term clinical studies of up to 2 years did not reveal any additional deviations of the safety profile or unforeseen risks when using vildagliptin as monotherapy.

- Postmarketing Studies The following adverse reactions were identified during postmarketing studies: Frequency unknown - urticaria.

- When using metformin as monotherapy
- Disorders of metabolism Very rarely - reduced absorption of vitamin B 12, lactic acidosis.

- Of the digestive system. Very often - nausea, vomiting, diarrhea, abdominal pain, loss of appetite. Often - metallic taste in the mouth.

- From the side of the liver and biliary tract. Very rarely - violations of the biochemical parameters of liver function.

- On the part of the skin and subcutaneous tissue. Very rarely - skin reactions (in particular, erythema, pruritus, urticaria).

Since a decrease in the absorption of vitamin B 12 and a decrease in its serum concentration against the background of metformin was noted very rarely in patients who received the drug for a long time, this undesirable phenomenon has no clinical significance.Consider the possibility of a decrease in the absorption of vitamin B 12 should only be in patients with megaloblastic anemia.

Individual cases of impaired biochemical parameters of liver function or hepatitis, which were observed during the use of metformin, were resolved after discontinuation of metformin.

The efficacy and safety of the drug in children under 18 years of age has not been established. Since in some cases lactic acidosis has been noted in patients with impaired liver function, which may be one of the side effects of metformin, Galvus Met should not be used in patients with liver diseases or impaired hepatic biochemical parameters.

In patients receiving insulin, Galus Meth cannot replace insulin.

Vildagliptin
Liver dysfunction: Since the use of vildagliptin increased activity of aminotransferases (usually without clinical manifestations) was noted somewhat more often than in the control group, before the appointment of Galvus Met, and regularly during treatment with the drug, it is recommended to determine the biochemical indicators of liver function. If a patient has an increased activity of aminotransferases, this result should be confirmed by repeated research, and then the determination of biochemical indicators of liver function should be carried out regularly until they normalize. If the excess of AST or ALT activity 3 or more times higher than the upper limit of the norm is confirmed by repeated examination, it is recommended to cancel the drug.

Metformin
Lactic acidosis: Lactic acidosis is a very rare but severe metabolic complication that occurs when metformin accumulates in the body. Lactic acidosis against the use of metformin was observed mainly in diabetic patients with high-grade renal failure. The risk of developing lactic acidosis is increased in patients with diabetes mellitus that is difficult to treat, with ketoacidosis, prolonged fasting, prolonged alcohol abuse, liver failure and diseases causing hypoxia. With the development of lactic acidosis, shortness of breath, abdominal pain and hypothermia, followed by coma. The following laboratory parameters are of diagnostic value: a decrease in blood pH, a serum lactate concentration above 5 nmol / l, as well as an increased anion interval and an increased lactate / pyruvate ratio. If metabolic acidosis is suspected, the drug should be discontinued, and the patient should be hospitalized immediately.

Control of renal function: Since metformin is largely excreted by the kidneys, the risk of its accumulation and the development of lactic acidosis is the higher, the more renal function is impaired. When using Galvus Met, you should regularly evaluate your kidney function, especially in the following conditions that contribute to its violation: the initial phase of treatment with antihypertensive drugs, hypoglycemic agents or NSAIDs .As a rule, kidney function should be assessed before starting treatment with Galvus Met, and then at least 1 time per year for patients with normal renal function and at least 2–4 times per year for patients with serum creatinine above the upper limit of normal. In patients with a high risk of impaired renal function, it should be monitored more than 2-4 times a year. If signs of deterioration in kidney function appear, Galvus Met should be abolished.

Use of iodine-containing radiopaque agents for intravascular administration: When conducting x-ray examinations requiring intravascular administration of iodine-containing radiocontrast agents, Galvus Met should be temporarily canceled (during the study, or directly in front of it, and also within 48 hours after the study), since intravascular administration of iodine-containing radiopaque agents can lead to a sharp deterioration in renal function and increase the risk of developing lactic acidosis. You can resume Galvus Met only after re-evaluating kidney function.

Hypoxia: In acute cardiovascular insufficiency (shock), acute heart failure , acute myocardial infarction, and other conditions characterized by hypoxia, lactic acidosis and prerenal acute renal failure may develop. When the above conditions occur, the drug should be immediately canceled.

Surgical interventions: At the time of surgical interventions (except for small operations not related to restriction of food and fluid intake), Galvus Met should be canceled. You can resume taking the drug after the patient begins to eat on his own and it is shown that his kidney function is not impaired.

Alcohol use: Alcohol has been found to increase the effect of metformin on lactate metabolism. Patients should be warned about the inadmissibility of alcohol abuse during the use of Galvus Met.

Vitamin B12 content: Metformin has been found in about 7% of cases to cause an asymptomatic decrease in the serum concentration of vitamin B 12. Such a decrease in very rare cases leads to the development of anemia. Apparently, after the abolition of metformin and / or vitamin replacement therapy, the serum concentration of vitamin B 12 is quickly normalized. Patients receiving Galvus Met are advised to perform a complete blood count at least once a year and, if any irregularities are detected, determine their cause and take appropriate measures. Apparently, some patients (for example, patients with inadequate intake or impaired absorption of vitamin B 12 or calcium) have a predisposition to reduce the serum concentration of vitamin B 12. In such cases, it may be recommended to determine the serum concentration of vitamin B 12 at least once every 2-3 years.

Deterioration of patients with type 2 diabetes mellitus who previously responded to therapy: If a patient with type 2 diabetes mellitus who has previously responded to therapy has signs of deterioration (changes in laboratory parameters or clinical manifestations), and the symptoms are not clearly expressed, it should be immediately analyzed for the detection of ketoacidosis and / or lactic acidosis. If acidosis is confirmed in one form or another, you should immediately cancel Galus Met and take appropriate measures.

Hypoglycemia: Typically, patients who receive only Galvus Met have no hypoglycemia, but it can occur on the background of a low-calorie diet (when intense exercise is not compensated by caloric intake), or on the background of alcohol. Hypoglycemia is most likely in elderly, debilitated or debilitated patients, as well as on the background of hypopituitarism, adrenal insufficiency or alcohol intoxication. In elderly patients and in those receiving beta-blockers, the diagnosis of hypoglycemia may be difficult.

Reducing the effectiveness of hypoglycemic agents: With stress (fever, trauma, infection, surgery, etc.) that has arisen in a patient receiving hypoglycemic agents by a stable scheme, a sharp decrease in the effectiveness of the latter is possible for some time. In this case, it may be necessary to cancel Galvus Met and prescribe insulin.You can resume treatment with Galvus Met after the end of the acute period.

Influence on ability to drive motor transport and control mechanisms: The influence of Galvus Met on the ability to drive and operate machinery has not been studied. With the development of dizziness during the use of the drug should refrain from driving and working with mechanisms.

Vildagliptin + Metformin: With simultaneous use of vildagliptin (100 mg 1 time / day) and metformin (1000 mg 1 time / day), there were no clinically significant pharmacokinetic interactions between them. Neither during clinical trials, nor during the wide clinical use of Galvus Met in patients who received other concomitant drugs and substances, unforeseen interactions have been identified.

Vildagliptin: Vildagliptin has a low potential for drug interaction. Since vildagliptin is not a substrate of cytochrome P 450 isoenzymes, nor does it inhibit or induce these isoenzymes, its interaction with drugs that are substrates, inhibitors or inducers of P 450 is unlikely. With simultaneous use of vildagliptin does not affect the metabolic rate of drugs that are enzyme substrates: CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 / 5. Clinically significant interaction of vildagliptin with drugs most commonly used in the treatment of diabetesType 2 (glibenclamide, pioglitazone, metformin) or with a narrow therapeutic range (amlodipine, Digoxin , Ramipril , Simvastatin , valsartan, warfarin) is not installed.

Metformin: Furosemide increases C max and AUC of metformin, but does not affect its renal clearance. Metformin reduces C max and AUC of furosemide and does not affect its renal clearance. Nifedipine increases the absorption, C max and AUC of metformin; in addition, it increases its excretion in the urine. Metformin has virtually no effect on the pharmacokinetic parameters of nifedipine. Glibenclamide does not affect the pharmacokinetic / pharmacodynamic parameters of metformin. Metformin generally reduces g max and AUC of glibenclamide, but the magnitude of the effect varies greatly. For this reason, the clinical significance of such an interaction remains unclear. Organic cations, such as amiloride, digoxin, morphine, procainamide, quinidine, quinine, Ranitidine , triamterene, trimethoprim, Vancomycin , etc., are excreted by the kidney by tubular secretion, theoretically they can interact with metformin, since they compete for common renal tubular transport systems. Cimetidine increases both plasma / blood metformin concentration and its AUC by 60% and 40%, respectively. Metformin does not affect the pharmacokinetic parameters of cimetidine. Care must be taken when using Galvus Met with drugs that affect kidney function or the distribution of metformin in the body.Some drugs can cause hyperglycemia and help reduce the effectiveness of hypoglycemic agents, such drugs include thiazides and other diuretics, GCS, phenothiazines, thyroid hormones, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, Calcium antagonists and isoniazid. When prescribing such concomitant medications or, on the contrary, in the event of their withdrawal, it is recommended to carefully monitor the effectiveness of metformin (its hypoglycemic effect) and, if necessary, adjust the dose of the drug. It is not recommended to take danazol at the same time to avoid the hyperglycemic action of the latter. If necessary, treatment with danazol and after discontinuation of the latter requires a dose adjustment of metformin under the control of glucose levels. Chlorpromazine, when taken in high doses (100 mg per day), increases blood glucose levels, reducing insulin release. When treating neuroleptics and after discontinuation of the latter, a dose adjustment of the drug is required under the control of glucose level. Radiological study with the use of iodine-containing radiopaque agents can cause the development of lactic acidosis in patients with diabetes mellitus on the background of functional renal failure. Injectable? 2-sympathomimetics increase glycemia due to stimulation of? 2 receptors. In this case, glycemia control is necessary. If necessary, the appointment of insulin is recommended.With simultaneous use of metformin with sulfonylurea derivatives, insulin, acarbose, salicylates, hypoglycemic action may be enhanced. Since the use of metformin in patients with acute alcohol intoxication increases the risk of lactic acidosis (especially during fasting, exhaustion, or liver failure), during treatment with Galusus Meth one should refrain from the use of alcohol and drugs containing ethanol.

Vildagliptin

Symptoms: vildagliptin is well tolerated at a dose of up to 200 mg / day. When using the drug at a dose of 400 mg / day, muscle pain may occur, rarely - light and transient paresthesias, fever, edema and a transient increase in lipase concentration (2 times higher than the upper limit of normal). By increasing the dose of vildagliptin to 600 mg / day, it is possible to develop edema of the extremities, accompanied by paresthesias, and an increase in the concentration of CPK, AST, C-reactive protein and myoglobin.
Treatment: all symptoms of overdose and changes in laboratory parameters disappear after discontinuation of the drug. Removal of the drug from the body through dialysis is unlikely. However, the main hydrolytic metabolite of vildagliptin (LAY151) can be removed from the body by hemodialysis.

Metformin

There have been several cases of overdose of metformin, including as a result of ingestion of the drug in an amount of more than 50 g
Symptoms: in overdose of metformin, hypoglycemia was observed in approximately 10% of cases (however, its connection with the administration of the drug has not been established); in 32% of cases - lactacidosis was noted. Early symptoms of lactic acidosis are nausea, vomiting, diarrhea, decrease in body temperature, abdominal pain, muscle pain, and there may be an increase in breathing, dizziness, impaired consciousness, and coma.
Treatment: Metformin is eliminated from the blood by hemodialysis (with clearance up to 170 ml / min) without the development of hemodynamic disturbances. Thus, hemodialysis can be used to remove metformin from the blood during an overdose of the drug. In the case of overdose, it is necessary to carry out appropriate symptomatic treatment, based on the patient's condition and clinical manifestations.

Store in a dry place at a temperature not exceeding 30 ° C.

18 months.