Instructions Diaformin film-coated tablets 1000 mg blister No. 60
Composition
active ingredient: metformin hydrochloride;
1 film-coated tablet of 1000 mg contains 1000 mg of metformin hydrochloride;
excipients: sodium starch glycolate (type A), povidone (K-30), corn starch, colloidal anhydrous silicon dioxide, magnesium stearate;
film coating Opadry White 04 G58897: hypromellose, talc, titanium dioxide (E 171), macrogol 6000, propylene glycol.
Dosage form
Film-coated tablets.
Main physicochemical properties: oval-shaped tablets with a biconvex surface, film-coated, white or almost white in color, with a deep dividing line on one side and a score on the other side.
Pharmacotherapeutic group
Oral hypoglycemic agents, except insulins. Biguanides. ATC code A10B A02.
Pharmacological properties
Pharmacodynamics
Metformin is a biguanide with antihyperglycemic effects. It reduces both baseline and postprandial plasma glucose levels. It does not stimulate insulin secretion and does not cause hypoglycemic effects mediated by this mechanism.
Metformin works in three ways:
leads to a decrease in glucose production in the liver by inhibiting gluconeogenesis and glycogenolysis; improves insulin sensitivity in muscles, which leads to improved peripheral glucose uptake and utilization; delays glucose absorption in the intestine.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthetase. It increases the transport capacity of all known types of membrane glucose transporters (GLUT).
Regardless of its effect on glycemia, metformin has a positive effect on lipid metabolism: it reduces total cholesterol, low-density lipoproteins, and triglycerides.
During metformin use, patients' body weight remained stable or decreased moderately.
Pharmacokinetics
Absorption. After oral administration of metformin, the time to maximum concentration (Tmax) is approximately 2.5 hours. Absolute bioavailability is approximately 50–60%. After oral administration, the fraction that is not absorbed and is excreted in the feces is 20–30%.
After oral administration, the absorption of metformin is saturable and incomplete.
The pharmacokinetics of metformin absorption are expected to be non-linear. At recommended metformin doses and dosing regimens, steady-state plasma concentrations are achieved within 24–48 hours and are less than 1 μg/ml. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 5 μg/ml even at maximum doses.
When taken with food, the absorption of metformin is reduced and slowed down.
Distribution. Plasma protein binding is negligible. Metformin penetrates into erythrocytes. Peak blood concentrations are lower than peak plasma concentrations and are reached at approximately the same time. Erythrocytes are likely to be the second distribution compartment. The mean volume of distribution (Vd) ranges from 63 to 276 L.
Metabolism: Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination: Renal clearance of metformin is > 400 mL/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. After an oral dose, the elimination half-life is approximately 6.5 hours. In cases of impaired renal function, renal clearance is reduced in proportion to creatinine clearance and therefore the elimination half-life is increased, leading to increased metformin plasma levels.
Indication
Type 2 diabetes mellitus with ineffective diet therapy and exercise regimen, especially in patients with excess body weight;
as monotherapy or combination therapy in combination with other oral hypoglycemic agents, or in combination with insulin for the treatment of adults; as monotherapy or combination therapy with insulin for the treatment of children aged 10 years and older and adolescents.
To reduce the complications of diabetes in adult patients with type 2 diabetes mellitus and overweight as a first-line drug after ineffective diet therapy.
Contraindication
Hypersensitivity to metformin or any other component of the drug; diabetic ketoacidosis, diabetic precoma; moderate (stage IIIb) and severe renal failure or impaired renal function (creatinine clearance < 45 ml/min or GFR < 45 ml/min/1.73 m2); acute conditions with a risk of developing renal dysfunction, such as: dehydration, severe infectious diseases, shock; diseases that may lead to the development of tissue hypoxia (especially acute diseases or exacerbation of chronic diseases): decompensated heart failure, respiratory failure, recent myocardial infarction, shock; liver failure, acute alcohol poisoning, alcoholism.
Interaction with other medicinal products and other types of interactions
Acute alcohol intoxication is associated with an increased risk of lactic acidosis, especially in cases of fasting or low-calorie diet, as well as in liver failure. During treatment with Diaformin®, alcohol and alcohol-containing medications should be avoided.
Iodinated radiocontrast agents: Intravenous use of iodinated radiocontrast agents may lead to renal failure and, as a result, to metformin accumulation and an increased risk of lactic acidosis.
In patients with GFR > 60 ml/min/1.73 m2, metformin should be discontinued prior to or at the time of the test and not resumed until 48 hours after the test, only after re-evaluation of renal function and confirmation of no further deterioration of renal function (see section 4.4).
In patients with moderate renal impairment (GFR 45–60 mL/min/1.73 m2), metformin should be discontinued 48 hours prior to the administration of iodinated contrast media and not resumed until 48 hours after the procedure, and only after re-evaluation of renal function and confirmation of no further deterioration of renal function.
Combinations that should be used with caution.
Drugs with hyperglycemic effects (systemic and local glucocorticosteroids, sympathomimetics). Blood glucose levels should be monitored more frequently, especially at the beginning of treatment. During and after discontinuation of such concomitant therapy, the dose of Diaformin® should be adjusted under glycemic control.
Diuretics, especially loop diuretics, may increase the risk of lactic acidosis due to possible decreased renal function.
Application features
Lactic acidosis is a rare but serious metabolic complication (high mortality rate in the absence of urgent treatment) that may occur as a result of metformin accumulation. Cases of lactic acidosis have been reported in patients with diabetes mellitus, renal failure or acute deterioration of renal function. Caution should be exercised in cases where renal function may be impaired, for example in case of dehydration (severe diarrhea or vomiting) or at the beginning of treatment with antihypertensive agents, diuretics and at the beginning of therapy with nonsteroidal anti-inflammatory drugs (NSAIDs). In the event of these exacerbations, metformin should be temporarily discontinued.
Other risk factors for lactic acidosis should be considered: poorly controlled diabetes mellitus, ketosis, prolonged fasting, alcohol abuse, hepatic insufficiency or any condition associated with hypoxia (decompensated heart failure, acute myocardial infarction) (see section "Contraindications").
Lactic acidosis may present with muscle cramps, indigestion, abdominal pain and severe asthenia. Patients should be advised to report these reactions to their doctor immediately, especially if they have previously tolerated metformin well. In such cases, metformin should be temporarily discontinued until the situation is resolved. Metformin therapy should be resumed after an individual benefit/risk assessment and assessment of renal function.
Diagnostics. Lactic acidosis is characterized by acidotic dyspnea, abdominal pain and hypothermia, and coma may develop later. Diagnostic indicators: laboratory decrease in blood pH, increase in serum lactate concentration above 5 mmol/l, increase in anion gap and lactate/pyruvate ratio. In case of development of lactic acidosis, the patient should be hospitalized immediately (see section "Overdose"). The doctor should warn patients about the risk of developing symptoms of lactic acidosis.
Renal failure. Since metformin is excreted by the kidneys, creatinine levels (can be estimated from plasma creatinine levels using the Cockcroft-Golte formula) or GFR should be checked before starting and regularly during treatment with Diaformin®:
patients with normal kidney function – at least once a year; patients with creatinine clearance at the lower limit of normal and elderly patients – at least 2–4 times a year.
If creatinine clearance < 45 ml/min (GFR < 45 ml/min/1.73 m2), metformin is contraindicated (see section "Contraindications").
Decreased renal function is common in the elderly and is asymptomatic. Caution should be exercised in situations where renal function may be impaired, such as dehydration or at the beginning of treatment with antihypertensive agents, diuretics and at the beginning of therapy with non-steroidal anti-inflammatory drugs. In such cases, it is also recommended to check renal function before starting treatment with metformin.
Iodinated radiocontrast agents. Intravenous administration of radiocontrast agents for radiological examinations may cause renal failure and, as a result, lead to metformin accumulation and an increased risk of lactic acidosis. In patients with a GFR > 60 ml/min/1.73 m2, metformin should be discontinued prior to or at the time of the examination and not resumed until 48 hours after the examination and only after re-evaluation of renal function and confirmation of no further deterioration of renal function (see section 4.5).
In patients with moderate renal impairment (GFR 45-60 ml/min/1.73 m2), metformin should be discontinued 48 hours before the administration of iodinated radiocontrast agents and not resumed until 48 hours after the examination and only after re-evaluation of renal function and confirmation of no further deterioration of renal function (see section 4.5).
Surgical interventions. Diaformin® should be discontinued 48 hours before elective surgery performed under general, spinal or epidural anesthesia and not resumed earlier than 48 hours after surgery or resumption of oral nutrition and only if renal function is normal.
Children. Before starting treatment with metformin, the diagnosis of type 2 diabetes mellitus should be confirmed. Clinical studies have not revealed any effect of metformin on growth and puberty in children. However, there is no data on the effect of metformin on growth and puberty with long-term use of Diaformin®, therefore, the drug should be used with extreme caution in children during puberty, especially between the ages of 10 and 12.
Other precautions: Patients should follow a diet with a balanced carbohydrate intake throughout the day. Overweight patients should continue to follow a low-calorie diet. Patients' carbohydrate metabolism should be monitored regularly.
Metformin monotherapy does not cause hypoglycemia. When Diaformin® is used simultaneously with insulin or other oral hypoglycemic agents (e.g. sulfonylurea derivatives or meglitinides), an increase in the hypoglycemic effect is possible.
Ability to influence reaction speed when driving vehicles or other mechanisms
Diaformin® does not affect the speed of reactions when driving vehicles and working with other mechanisms, since monotherapy with the drug does not cause hypoglycemia.
However, caution should be exercised when metformin is used in combination with other hypoglycemic agents (sulfonylureas, insulin, or meglitinides) due to the risk of hypoglycemia.
Use during pregnancy or breastfeeding
Pregnancy. Uncontrolled diabetes during pregnancy (gestational or permanent) increases the risk of congenital anomalies and perinatal mortality. There are limited data from the use of metformin in pregnant women, which do not indicate an increased risk of congenital anomalies. Preclinical studies have not shown any negative effects on pregnancy, embryonic development, childbirth and postnatal development. In case of planning pregnancy, as well as in case of pregnancy, metformin therapy should be discontinued, the doctor should be informed and insulin therapy should be prescribed to maintain blood glucose levels as close to normal as possible, in order to reduce the risk of fetal malformations.
Lactation. Metformin is excreted in breast milk. No adverse effects have been observed in newborns/infants. Due to insufficient safety data, breastfeeding is not recommended during therapy with Diaformin®. A decision on whether to discontinue breastfeeding should be made taking into account the benefit of the drug to the mother and the potential risk to the child.
Fertility: Metformin had no effect on animal fertility at doses of 600 mg/kg/day, which is almost three times the maximum recommended daily human dose based on body surface area.
Method of administration and doses
Adults.
Monotherapy or combination therapy compatible with other oral hypoglycemic agents.
The usual starting dose is 500 mg or 850 mg 2–3 times daily during or after meals.
After 10–15 days of treatment, the dose should be adjusted according to the results of serum glucose measurements.
Slowly increasing the dose helps reduce side effects from the digestive tract.
The maximum recommended dose is 3000 mg per day in 3 divided doses.
When treating high doses, Diaformin®, film-coated tablets, 1000 mg, is used.
When switching to treatment with Diaformin®, it is necessary to stop taking another antidiabetic agent.
Combination therapy is compatible with insulin.
To achieve better blood glucose control, metformin and insulin can be used as combination therapy. The usual starting dose is 500 mg or 850 mg of Diaformin® 2–3 times daily, while the insulin dose is adjusted according to blood glucose measurements.
Monotherapy or combination therapy compatible with insulin.
Diaformin® is used in children aged 10 years and older and adolescents. The usual starting dose is 500 mg or 850 mg of Diaformin® once daily with or after meals. After 10–15 days of treatment, the dose should be adjusted according to the results of serum glucose measurements.
Slowly increasing the dose helps reduce side effects from the digestive tract.
The maximum recommended dose is 2000 mg per day in 2–3 doses.
Elderly patients may have decreased renal function, therefore the dose of metformin should be selected based on assessment of renal function, which should be performed regularly (see section "Special warnings and precautions for use").
Patients with renal insufficiency. Diaformin® can be used in patients with moderate renal insufficiency, stage IIIa (creatinine clearance 45–59 ml/min or GFR 45–59 ml/min/1.73 m2), only in the absence of other conditions that may increase the risk of lactic acidosis, and with subsequent dose adjustment: the initial dose is 500 mg or 850 mg of metformin hydrochloride 1 time per day. The maximum dose is 1000 mg per day and should be divided into 2 doses. Careful monitoring of renal function should be carried out (every 3–6 months).
If creatinine clearance or GFR decreases to < 45 mL/min or 45 mL/min/1.73 m2, respectively, metformin should be discontinued immediately.
Children
The drug Diaformin® can be used in children aged 10 years and older.
Overdose
When using the drug in a dose of 85 g, hypoglycemia was not observed. However, in this case, the development of lactic acidosis was observed. A significant excess of the metformin dose or concomitant risk factors can lead to the occurrence of lactic acidosis. Lactic acidosis is an emergency and should be treated in a hospital. The most effective measure for removing lactate and metformin from the body is hemodialysis.
Adverse reactions
The most common adverse reactions, especially at the beginning of treatment, are nausea, vomiting, diarrhea, abdominal pain, lack of appetite. These symptoms usually resolve on their own. To prevent side effects from the digestive tract, it is recommended to slowly increase the dosage and use the drug 2–3 times a day during or after meals.
Metabolism: lactic acidosis.
With prolonged use of the drug, the absorption of vitamin B12 may decrease, which is accompanied by a decrease in its level in the blood serum. This has been observed when metformin is prescribed to patients with megaloblastic anemia.
From the nervous system: taste disturbance.
From the digestive tract: digestive tract disorders such as nausea, vomiting, diarrhea, abdominal pain, lack of appetite. Most often, these side effects occur at the beginning of treatment and, as a rule, disappear spontaneously. To prevent the occurrence of side effects from the digestive system, it is recommended to slowly increase the dosage and use the daily dose of the drug in 2-3 doses during or after meals.
On the part of the hepatobiliary system: liver function tests or hepatitis, which completely disappear after metformin withdrawal.
Skin and subcutaneous tissue disorders: skin reactions including erythema, pruritus, urticaria.
Expiration date
3 years.
Do not use the drug after the expiration date indicated on the package.
Storage conditions
Store at a temperature not exceeding 25 ºС.
Keep out of reach of children.
Packaging
10 tablets in a blister; 6 blisters in a pack.
Vacation category
According to the recipe.
Producer
PJSC "Farmak".
Location of the manufacturer and its business address
Ukraine, 04080, Kyiv, Frunze St., 74.
