Instructions Diaformin SR prolonged-release tablets 1000 mg blister No. 60
Composition
active ingredient: metformin;
1 tablet contains metformin hydrochloride 1000 mg;
excipients: stearic acid, shellac, povidone (K-30), colloidal anhydrous silicon dioxide, magnesium stearate; film coating composition: hypromellose, hydroxypropylcellulose, titanium dioxide (E 171), propylene glycol, macrogol 6000, talc.
Dosage form
Extended-release tablets.
Main physicochemical properties:
1000 mg prolonged-release tablets: oval-shaped tablets with a biconvex surface, film-coated, almost white in color, with a score on one side and smooth on the other side.
Pharmacotherapeutic group
Oral hypoglycemic agents, except insulins.
Biguanides. ATX code A10B A02.
Pharmacological properties
Pharmacodynamics
Metformin is a biguanide with antihyperglycemic effect. It reduces both the initial and postprandial glucose levels in the blood plasma. It does not stimulate insulin secretion and does not cause a hypoglycemic effect.
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 by improving peripheral glucose uptake and utilization; delays glucose absorption in the intestine.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthetase.
Increases the transport capacity of all types of membrane glucose transporters (GLUT). Clinical studies have shown that the main effect of metformin is stabilization or slight loss of body weight.
Independently of its effect on glycemia, metformin immediate-release tablets have a positive effect on lipid metabolism. This effect has been demonstrated at therapeutic doses in controlled medium- or long-term clinical trials: metformin immediate-release tablets reduce total cholesterol, low-density lipoproteins and triglycerides. A similar effect was not observed with the prolonged-release tablets, probably due to the
using the drug in the evening. This may also cause an increase in triglycerides.
Pharmacokinetics
Absorption. After oral administration of Diaformin® SR prolonged-release tablets, the absorption of metformin is significantly slower compared to immediate-release metformin tablets. The time to reach maximum plasma concentration (Tmax) is 7 hours (Tmax for immediate-release tablets is 2.5 hours). At steady state, as with immediate-release tablets, the maximum concentration (Cmax) and the area under the AUC curve increase disproportionately with the administered oral dose. The AUC after a single oral dose of 2000 mg metformin prolonged-release tablets is similar to the AUC observed after taking 1000 mg metformin immediate-release tablets twice daily.
The variation in Cmax and AUC in individual subjects with metformin extended-release tablets was comparable to that observed with metformin immediate-release tablets. A 30% decrease in AUC was observed after administration of the extended-release tablets in the fasted state (Cmax and Tmax remained unchanged).
The absorption of metformin from prolonged-release tablets is not affected by food. No accumulation is observed with multiple doses of up to 2000 mg of metformin prolonged-release tablets.
Distribution: Binding to plasma proteins is negligible. Metformin penetrates into erythrocytes.
The maximum concentration in the blood is lower than the maximum concentration in the blood plasma and is reached after approximately the same time. The erythrocytes most likely represent the second distribution chamber. The mean volume of distribution (Vd) ranges from 63 to 276 liters.
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 renal impairment, renal clearance decreases in proportion to creatinine clearance and therefore the elimination half-life increases, leading to increased metformin plasma levels.
Special patient groups
Kidney failure
Limited data are available in patients with moderate renal impairment, so it is not possible to accurately estimate the systemic exposure of metformin in this patient group compared to patients with normal renal function. Therefore, dose adjustment is necessary according to clinical efficacy/tolerability (see section 4.2).
Indication
Type 2 diabetes mellitus (non-insulin-dependent) in adults (especially in overweight patients) when diet therapy and exercise are ineffective, as monotherapy or in combination with other oral antidiabetic agents, or in combination with insulin.
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
Combinations that are not recommended for use
Alcohol
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® SR, alcohol and alcohol-containing medications should be avoided.
Iodine-containing radiopaque agents
Intravascular use of iodinated contrast agents may lead to functional renal failure, and as a result, 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 radiocontrast agents and not resumed until 48 hours after the examination, only after re-evaluation of renal function and confirmation of no further deterioration of renal function.
Combinations to be used with caution
Drugs that have a hyperglycemic effect (glucocorticosteroids of systemic and local action, sympathomimetics, chlorpromazine). It is necessary to monitor the blood glucose level more often, especially at the beginning of treatment. During and after discontinuation of such concomitant therapy, it is necessary to adjust the dose of Diaformin® SR under the control of the glycemia level. ACE inhibitors may lower the blood glucose level. If necessary, the dosage of the drug should be adjusted during concomitant therapy. Diuretics, especially loop diuretics, may increase the risk of lactic acidosis due to a possible decrease in 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 diabetic patients with renal failure or acute deterioration in renal function. Caution should be exercised in cases where renal function may be impaired, for example, in cases 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, excessive alcohol consumption, hepatic insufficiency or any condition associated with hypoxia (decompensated heart failure, acute myocardial infarction) (see section "Contraindications").
Lactic acidosis may present with non-specific symptoms such as 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 assessment of the benefit/risk ratio in the individual case and after 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 development and 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-Gault formula) or GFR should be checked before starting and regularly during treatment with Diaformin® SR:
In case of creatinine clearance < 45 ml/min (GFR < 45 ml/min/1.73 m2), the use of 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 (NSAIDs). In such cases, it is also recommended to check renal function before starting treatment with metformin.
Cardiac function. Patients with heart failure are at increased risk of hypoxia and renal failure. Metformin may be used in patients with stable chronic heart failure with regular monitoring of cardiac and renal function. Metformin is contraindicated in patients with acute and unstable heart failure (see section 4.3).
Iodinated radiocontrast agents. Intravascular administration of radiocontrast agents for radiological examinations may cause renal failure, and consequently 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, 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 earlier than 48 hours after the examination, only after re-evaluation of renal function and confirmation of the absence of further deterioration of renal function (see section "Interaction with other medicinal products and other forms of interaction"). Surgical interventions. Diaformin® SR 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 normal renal function has been established.
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. Laboratory blood glucose levels should be monitored regularly.
Metformin monotherapy does not cause hypoglycemia. When Diaformin® SR is used simultaneously with insulin or other oral hypoglycemic agents (e.g. sulfonylurea derivatives or meglitinides), the hypoglycemic effect may be enhanced. Tablet shell fragments may be present in the feces. This is normal and does not
has clinical significance.
Ability to influence reaction speed when driving vehicles or other mechanisms
Diaformin® SR does not affect the speed of reactions when driving or 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, 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 that do not indicate an increased risk of congenital anomalies.
Preclinical studies have not revealed any negative effects on pregnancy, embryonal or foetal development, labour and postnatal development. If pregnancy is planned or if pregnancy occurs, 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 to reduce the risk of foetal malformations.
Breastfeeding. Metformin is excreted in human milk, but no adverse effects have been observed in breastfed newborns/infants. However, due to insufficient data on the safety of the drug, breastfeeding is not recommended during therapy with Diaformin® SR. The decision to discontinue breastfeeding should be made taking into account the benefits of breastfeeding and the potential risk of adverse effects for 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
The tablets should be swallowed whole, without chewing.
The recommended initial dose is 500 mg per day. After 10-15 days of treatment, the dose should be adjusted according to the results of serum glucose measurements. A slow increase in the dose helps to reduce side effects from the digestive tract. The maximum recommended dose is 2000 mg per day.
The dose of the drug should be taken once a day during the evening meal, increasing by 500 mg every 10-15 days to 2000 mg. If the required glycemia level cannot be achieved when using Diaformin® SR in the maximum dose of 2000 mg, which the patient takes 1 time per day, this dose can be divided into 2 doses per day (1 time in the morning and 1 time in the evening during meals). If the required glycemia level is not achieved, Diaformin® SR can be used in the maximum recommended dose of 3000 mg per day.
For patients already treated with metformin, the initial dose of Diaformin® SR prolonged-release tablets should be equivalent to the daily dose of immediate-release tablets. Patients receiving metformin therapy at a dose higher than 2000 mg per day are not recommended to switch to Diaformin® SR therapy.
When switching to Diaformin® SR prolonged-release tablets, it is necessary to discontinue the other oral antidiabetic drug.
Combination therapy in combination with insulin
To achieve better blood glucose control, metformin and insulin can be used as combination therapy. The usual starting dose of Diaformin® SR is 500 mg per day with the evening meal, while the insulin dose should be adjusted according to blood glucose measurements.
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 impairment. Metformin can be used in patients with moderate renal impairment, 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, with the following dose adjustment: the initial dose is 500 mg or 750 mg of metformin hydrochloride 1 time per day. The maximum dose is 1000 mg per day. Careful monitoring of renal function (every 3 - 6 months) should be carried out.
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 should not be used in children, as there are no clinical data regarding this age group of patients.
Overdose
When using the drug at a dose of 85 g, hypoglycemia was not observed, however, the development of lactic acidosis was observed. A significant excess of the metformin dose or concomitant risk factors may cause the occurrence of lactic acidosis. Lactic acidosis is an emergency. In the event of lactic acidosis, treatment with Diaformin® SR must be discontinued and the patient urgently hospitalized. 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, and loss of appetite. These symptoms usually resolve on their own.
Metabolic and nutritional disorders: lactic acidosis (see section "Special warnings and precautions for use"). With prolonged use of the drug in patients with megaloblastic anemia, vitamin B12 absorption may decrease, which is accompanied by a decrease in its level in the blood serum.
From the nervous system: taste disturbance.
On the part of the digestive tract: nausea, vomiting, diarrhea, abdominal pain, lack of appetite.
These side effects most often occur at the beginning of treatment and usually disappear spontaneously. To prevent the occurrence of side effects from the digestive tract, it is recommended to slowly increase the dose of the drug.
On the part of the hepatobiliary system: liver function tests or hepatitis, which completely disappear after metformin withdrawal.
Skin and subcutaneous tissue disorders: allergic 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 30 ° C. Keep out of the 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, st. Frunze, 74.
