Metformin Zentiva - instructions for use, dose, side effects, contraindications

Composition:1 tablet contains:
active substance: metformin hydrochloride is 500/850/1000 mg. auxiliary substances: core: sodium carboxymethyl starch - 20,0 / 34,0 / 40,0 mg, povidone 40 - 40,0 / 68,0 / 80,0 mg, silicon dioxide colloid - 7,0 / 11,9 / 14,0 mg, corn starch - 10.0 / 17.0 / 20.0 mg, magnesium stearate 3.0 / 5.1 / 6.0 mg; film sheath: sepiphilm 752 white (hypromellose 35.00-45.00%, microcrystalline cellulose 27.00-37.00%, macrogol stearate 6.00-10.00%, titanium dioxide 18.00-22.00%) - 10.648 / 17,33 / 20,0 mg, macrogol 6000 - 0,122 / 0,2 / 0,23 mg.

Description:Film-coated tablets, 500 mg:
Round biconvex tablets, covered with a film coating of white color.
Film-coated tablets, 850 mg:
Oblong biconvex tablets covered with a white film membrane, with a risk for division on one side.
Tablets, film-coated, 1000 mg:
Oblong biconvex tablets, coated with a white film coating, with a risk for division from two sides.

Pharmacotherapeutic group:Hypoglycemic agent for oral administration of the biguanide group.

ATX: & nbsp

A.10.B.A.02 Metformin

Pharmacodynamics:Mechanism of action
Metformin is a biguanide with a hypoglycemic property that reduces basal (fasting) and postprandial (2 hours after the start of food intake) glucose concentration in the blood plasma. In contrast to the sulfonylurea derivatives, metformin does not stimulate the secretion of insulin with beta cells of the pancreas and does not create the danger of developing hypoglycemia.
Increases the sensitivity of peripheral receptors to insulin and the utilization of glucose by cells. Reduces the production of glucose by the liver by inhibiting gluconeogenesis and glycogenolysis. Delays the absorption of glucose in the intestine. Metformin stimulates the synthesis of intracellular glycogen, affecting glycogen synthase.Increases the transport capacity of all types of membrane glucose transporters.
Metformin has a beneficial effect on lipid metabolism: it reduces the content of total cholesterol, low-density lipoproteins and triglycerides.
On the background of taking metformin, the patient's body weight either remains stable or moderately decreases.
Pediatric population.
In patients aged 10-16 years who were treated with metformin for 1 year, the glycemic control parameters were comparable with those of the adult population.

Pharmacokinetics:Absorption
After oral administration metformin absorbed in the gastrointestinal tract. The maximum concentration in the blood plasma (C_max) is achieved 2.5 hours after ingestion. Bioavailability for dosages of 500 and 850 mg in healthy people is 50-60%. Absorption of metformin upon ingestion is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption is nonlinear. When metformin is used at recommended doses and according to the recommended scheme, the equilibrium concentration in the blood plasma is reached within 24-48 hours and is usually less than 1 μg / ml. C_max metformin does not exceed 5 mcg / ml, even when the drug is used in maximum doses.
Eating lowers the degree and somewhat slows the absorption of metformin. After ingestion of 850 mg tablet, a decrease in C_max by 40%, a decrease in the AUC (area under the concentration-time curve) by 25% and an increase by 35 minutes reaching the C_max
Distribution
Metformin is rapidly distributed in tissues, practically does not bind to blood plasma proteins. Metformin penetrates into the red blood cells. The maximum concentration in the blood is lower than the maximum concentration in the blood plasma, and is achieved approximately simultaneously. Erythrocytes, in all probability, represent a secondary distribution depot. The average volume of distribution (Vd) is in the range of 63-276 liters. Biotransformation
Metformin is excreted by the kidneys unchanged, undergoes very little metabolism, no metabolites were detected.
Excretion
After taking the drug inside through the intestine, 20-30% of the unabsorbed substance is excreted. The renal clearance of metformin is more than 400 ml / min, which indicates the excretion of metformin by active glomerular filtration and tubular secretion. After oral administration, the elimination half-life (T_1/2) is about 6.5 hours.If the kidney function is disturbed, cumulation of the drug is possible, which leads to an increase in the concentration of metformin in the blood plasma.
Special patient groups
Patients with impaired renal function
The available data obtained in patients with moderate renal insufficiency are few and do not allow a reliable assessment of the systemic effects of metformin in this subgroup, as can be done in individuals with normal renal function.
Patients of childhood
- After a single application of metformin in a dosage of 500 mg, a pharmacokinetic profile similar to the profile observed in healthy adults was revealed in pediatric patients.
- After repeated use of metformin at a dosage of 500 mg twice a day for 7 days in patients of childhood C_max and AUCo-t were reduced by approximately 33% and 40%, respectively, compared with the values of these parameters in adult patients with diabetes mellitus who received metformin in a dosage of 500 mg twice a day for 14 days. Since the dose of the drug is selected individually depending on the level of glycemia, these data have limited clinical significance.

Indications:Diabetes mellitus type 2 (especially in obese patients) with ineffective diet and exercise:
- in adults as a monotherapy or in combination with other oral hypoglycemic agents or with insulin;
- in children from 10 years as a monotherapy and in combination with insulin.

Contraindications:- Hypersensitivity to metformin or any auxiliary substance included in the preparation;
- diabetic ketoacidosis, diabetic precoma, coma;
- renal failure of moderate to severe severity or renal dysfunction (creatinine clearance [CC] <45 ml / min, glomerular filtration rate [GFR] <45 ml / min / 1.73 m² body surface);
- acute conditions, taking place with the risk of developing a violation of kidney function: dehydration (with diarrhea, vomiting), fever, severe infectious diseases, shock;
- acute and chronic diseases that can lead to the development of tissue hypoxia (such as acute myocardial infarction, shock, heart failure with unstable hemodynamics, respiratory failure, etc.);
- extensive surgery and trauma (against which background insulin therapy is indicated);
- impaired liver function;
- chronic alcoholism, acute alcohol intoxication;
- Pregnancy;
- lactic acidosis (including in the anamnesis);
- use for less than 48 hours before and within 48 hours after radioisotope or X-ray studies with intravenous administration of iodine-containing radiopaque substance;
- compliance with the hypocaloric diet (less than 1000 kcal / day).

Carefully:Use the drug in people over 60 years of age who perform heavy physical work, which is associated with an increased risk of developing lactic acidosis; in patients with impaired renal function (CK 45-59 mmol / L, GFR 45-59 ml / min / 1.73 m² body surface); in the period of breastfeeding.

Pregnancy and lactation:Pregnancy
Uncontrolled diabetes mellitus during pregnancy is associated with an increased risk of congenital malformations and perinatal mortality. A limited amount of evidence suggests that taking metformin in pregnant women does not increase the risk of developing congenital malformations of the fetus.Animal studies have not shown adverse effects on pregnancy, development of the embryo or fetus, delivery and postnatal development.
When planning pregnancy, as well as in case of pregnancy on the background of taking metformin, the drug should be canceled and insulin therapy prescribed. It is necessary to maintain the level of glucose in the blood plasma at the level closest to normal, in order to reduce the risk of developmental malformations in the fetus.
Breast-feeding
Metformin penetrates into breast milk. Side effects in newborns / infants against metformin were not observed. However, due to the limited data, the use of the drug during breastfeeding is not recommended. The decision to stop breastfeeding should be taken in consideration of the benefits of breastfeeding and the potential risk of side effects in the child.

Dosing and Administration:Tablets should be taken orally, wholly during or immediately after a meal, with a small amount of liquid.
The drug Metformin Zentiva should be taken daily, without interruption.In the event of discontinuation of treatment, the patient should inform the physician about this.
Adults
Monotherapy and combination therapy in combination with other oral hypoglycemic agents
- The usual initial dose is 500 mg or 850 mg 2-3 times per day after or during meals. A further gradual increase in the dose is possible depending on the concentration of glucose in the blood.
- After 10-15 days of use, the dose should be adjusted taking into account the results of measuring the concentration of glucose in the blood plasma. A slow increase in the dose may help improve gastrointestinal tolerance.
- The maintenance dose is usually 1500-2000 mg per day. To reduce side effects from the gastrointestinal tract, the daily dose should be divided into 2-3 doses. The maximum dose is 3000 mg per day, divided into three doses.
- Patients receiving metformin in doses of 2000-3000 mg per day, can be transferred from taking metformin tablets at a dosage of 500 mg to taking metformin tablets at a dosage of 1000 mg. The maximum recommended dose is 3000 mg per day, divided into 3 doses.
In case of planning the transition from taking another hypoglycemic agent: it is necessary to stop taking another medication and start taking Metformin Zentiva in the dose indicated above.
Combination with insulin
To achieve better control of blood glucose metformin and insulin can be used as a combination therapy. The usual initial dose of Metformin Zentiva is 500 mg or 850 mg 2-3 times a day, while the insulin dose is selected based on the glucose concentration in the blood.
Patients with impaired renal function
Metformin can be used in patients with impaired renal function of moderate severity (CK 45-59 ml / min., GFR 45-59 ml / min / 1.73 m² body surface) only in the absence of other conditions that may increase the risk of lactic acidosis, and under the following dose adjustment conditions:
- the initial dose is 500 mg or 850 mg of Metformin Zentiva once a day. The maximum dose is 1000 mg in the bluish, divided into 2 doses. Careful monitoring of kidney function is necessary (every 3-6 months).
If the SC <45 ml / min or GFR <45 ml / min / 1.73 m² the surface of the body, the drug Metformin Zentiva should be immediately canceled.
Elderly patients
Due to a possible decrease in renal function, the dose of Metformin Zentiva in elderly patients should be selected under regular monitoring of renal function (to determine the concentration of serum creatinine at least 2-4 times a year).
Children and teens
In children from the age of 10, the drug Megformin Zentiva can be used both in monotherapy and in combination with insulin. The usual initial dose is 500 mg or 850 mg once a day after or during a meal. After 10-15 days the dose should be adjusted based on the glucose concentration in the blood. The maximum daily dose is 2000 mg, divided into 2-3 doses.

Side effects:When metformin is used, the following side effects can occur, which are divided into system-organ classes according to the classification of the Medical Dictionary of Regulatory Activities (MedDRA). The WHO classification was used to indicate the incidence of adverse events: very often (≥ 10%); often (≥ 1% and <10%); infrequently (≥ 0.1% and <1%); rarely (≥ 0.01% and <0.1%); very rarely (<0.01%); the frequency is unknown (it is not possible to determine the incidence of side effects from the available data).
Violations from the blood and lymphatic system: frequency unknown - hemolytic anemia.
Disorders from the metabolism and nutrition: very rarely - lactic acidosis, decreased absorption of vitamin B12 in patients with megaloblastic anemia; frequency unknown -pheripheral neuropathy in patients with vitamin B12 deficiency.
Impaired nervous system: often - distortion of taste sensations; frequency is unknown - encephalopathy.
Disorders from the gastrointestinal tract: very often - nausea, vomiting, diarrhea, abdominal pain, loss of appetite. These undesirable effects most often occur during the initiation of therapy and in most cases are resolved independently. To prevent their occurrence, it is recommended to take a daily dose of metformin for 2 or 3 doses during or after a meal. A slow increase in the dose of the drug may improve the tolerance of the gastrointestinal tract. Disturbances from the skin and subcutaneous tissues: very rarely - erythema, pruritus, hives: frequency unknown - photosensitivity.
Disorders from the liver and sting ducts: very rarely - an increase in the activity of "hepatic" granaminases or hepatitis that disappear after the drug is withdrawn.
Influence on the results of laboratory and instrumental studies: the frequency is unknown - a decrease in the concentration of thyroid-stimulating hormone (TSH) in blood plasma in patients with hypothyroidism, hypomagnesemia against diarrhea.
Children and teens
Published data, post-registration data, as well as the results of controlled clinical trials in a limited children's population in the 10-16 age group who received metformin for 1 year, show that adverse events in children of a nature and severity are similar to those in adults patients.

Overdose:Symptoms
When applied at a dose of 85 g (42.5 times the maximum daily dose), the development of hypoglycemia was not observed. With an overdose of metformin, the development of lactic acidosis is possible. Lactic acidosis is an emergency and requires inpatient treatment. The cause of the development of lactic acidosis may also be cumulation of the drug due to impaired renal function.
The early symptoms of lactic acidosis are nausea, vomiting, diarrhea,lowering body temperature, abdominal pain, muscle pain, there may be more rapid breathing, dizziness, impaired consciousness and coma development.
Against the background of an overdose of metformin, the occurrence of pancreatitis may occur.
Treatment
In case of signs of lactic acidosis, metformin treatment should be stopped immediately, the patient urgently needs to be hospitalized, the concentration of lactic acid in the blood plasma should be confirmed and the diagnosis confirmed. The most effective measure for excretion of lactic acid and metformin from the body is hemodialysis. Conduct also symptomatic treatment.

Interaction:Contraindicated combinations:
Iodine-containing radiopaque agents
Intravascular injection of iodine-containing radiocontrast agents can lead to the development of functional renal failure, thereby increasing the cumulation of metformin and the risk of lactic acidosis.
In patients with GFR> 60 mL / min / 1.73 m² of the body surface area, it is necessary to stop the use of metformin before or during the X-ray examination and not to resume within 48 hours after its end, subject to confirmation of normal kidney function.
In patients with impaired renal function of moderate severity (GFR 45-60 ml / min / 1.73 m² on the body surface area) the use of metformin should be discontinued 48 hours before iodine-containing contrast medium and should be resumed no earlier than 48 hours after the end of the study and only after a reassessment of kidney function in the absence of signs of its deterioration.
Uncommon combinations:
Alcohol
In acute alcohol intoxication, the risk of developing lactic acidosis increases, especially in case of fasting or malnutrition, low-calorie diet or liver failure. When taking the drug, avoid drinking alcohol and medications containing ethanol.
Combinations requiring caution:
Danazol
It is not recommended simultaneous reception of danazol in order to avoid hyperglycemic action of the latter. If it is necessary to treat danazol and after stopping the latter, a dose adjustment of metformin is required under the control of the glucose concentration in the blood.
Chlorpromazine
When taken in high doses (100 mg per day) increases the concentration of glucose in the blood, reducing the release of insulin.When treating with antipsychotics and after stopping their intake, a dose adjustment of metformin is required under the control of blood glucose concentration.
Glucocorticosteroids (GCS)
SCS systemic and topical action reduces glucose tolerance, increases the concentration of glucose in the blood, sometimes causing ketosis. In the treatment of GCS and after discontinuation of their admission, a dose adjustment of metformin is required under the control of the glucose concentration in the blood.
Diuretics (especially "loop")
Simultaneous reception of "loop" diuretics can lead to the development of lactic acidosis due to possible functional renal failure. Do not assign metformin patients, if the SC is below 60 ml / min.
Beta₂-adrenomimetics in the form of injections
Beta₂-adrenomimetiki increase the concentration of glucose in the blood due to stimulation of beta₂adrenoreceptors. In this case, it is advisable to carry out regular monitoring of the concentration of glucose in the blood. If necessary, the appointment of insulin is recommended. With the simultaneous use of the above drugs, the dose of metformin can be adjusted during treatment or after its termination.Hypotensive drugs, with the exception of angiotensin-converting enzyme inhibitors, can alter the concentration of glucose in the blood. If necessary, the dose of metformin should be adjusted.
Derivatives of sulfonylureas, insulin and acarbose
With simultaneous use with metformin possible development of hypoglycemia.
Salicylates
With simultaneous use with metformin possible development of hypoglycemia.
Nifedipine
Increases absorption and increases C_max metformin.
Cationic drugs
Amyloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim and vancomycin, excreted by the renal tubules, compete with metformin over the tubular transport systems and can lead to an increase in C_max TO 60%.
The hypoglycemic effect of metformin can reduce phenothiazines, glucagon, estrogens, including in the composition of oral contraceptives, phenytoin, sympathomimetics, a nicotinic acid, isoniazid, blockers of "slow" calcium channels.
Levothyroxine may reduce the hypoglycemic effect of metformin.It is recommended to monitor the concentration of glucose in the blood, especially when starting or stopping thyroid hormone therapy, and if necessary, the dose of metformin should be adjusted.
With the simultaneous use of metformin with non-steroidal anti-inflammatory drugs (NSAIDs), monoamine oxidase inhibitors, oxytetracycline, fibrolic acid derivatives, cyclophosphamide, probenecid, chloramphenicol, sulfanilamide antimicrobials, hypoglycemic effects of metformin may be enhanced.
Propranolol, ibuprofen
In healthy volunteers, studies of a single dose of metformin and propranolol, as well as metformin and ibuprofen, showed no change in their pharmacokinetic performance.
Metformin can help reduce the therapeutic effect of the anticoagulant fenprokumona. When combined, careful monitoring of the International Normalized Relationship (INR) is recommended.

Special instructions:Lactic acidosis
Lactic acidosis is rare but severe (high mortality in the absence of immediate treatment), a metabolic complication that may arise from metformin cumulation.There are reports of cases of lactic acidosis on the background of metformin therapy in patients with diabetes mellitus and with severe renal failure or acute impairment of renal function. Special attention should be given to situations in which there may be impairment of kidney function, for example, in case of dehydration (with severe diarrhea or vomiting) or at the onset of antihypertensive therapy or diuretic therapy (especially looping), and also at the beginning of NSAID therapy. The acute conditions of therapy with the drug Metformin Zentiva should be temporarily discontinued.
Other associated risk factors, such as decompensated diabetes mellitus, ketosis, prolonged fasting, excessive alcohol consumption, liver failure and any condition associated with severe hypoxia (for example, heart failure with unstable hemodynamics, respiratory failure, acute myocardial infarction, etc.) (see the section "Contraindications").
The risk of developing lactic acidosis should be considered when non-specific signs appear, such as muscle cramps, dyspeptic disorders, abdominal pain and severe asthenia.Patients should be instructed to immediately notify their physician of the onset of these symptoms, especially if the patient has previously tolerated metformin therapy. In this case, it is necessary to stop the therapy with Metformin Zentiva, at least temporarily, until the situation is clarified. The issue of resumption of therapy must be addressed individually, taking into account the benefit / risk ratio, and also taking into account the state of kidney function in this patient.
Diagnostics
Lactic acidosis is characterized by acidotic dyspnea, abdominal pain, hypothermia followed by coma. Laboratory indicators include: a decrease in blood pH (less than 7.25), a concentration of lactic acid in the blood plasma above 5 mmol / l, and an increased anion gap and a lactate / pyruvate ratio. If there is a suspicion of metabolic acidosis, it is necessary to stop taking metformin and immediately hospitalize the patient.
Doctors should inform patients about the risk of lactic acidosis and its symptoms.
Surgical operations
Metformin Zentiva should be stopped 48 hours before the planned surgical intervention under general anesthesia, spinal or epidural anesthesia.The therapy can be resumed no earlier than 48 hours after the operation or after the restoration of the reception of the poor and only under the condition of normal kidney function. Kidney function
As metformin is excreted by the kidneys, the QC value should be monitored before the start of therapy and then regularly:
- at least once a year in patients with normal renal function;
- at least 2-4 times a year in patients with a CK value at the lower limit of the norm and in elderly patients.
At a CC level <45 mL / min (GFR <45 mL / min / 1.73 m² surface of the body) Metformin Zentiva is contraindicated (see section "Contraindications"). Impairment of kidney function in elderly patients is often asymptomatic. Special caution should be exercised in case of possible renal dysfunction in the case of dehydration or with the simultaneous use of antihypertensive drugs, diuretics (especially "loop") or NSAIDs. In these cases, it is also recommended to check the status of kidney function before starting therapy with Metformin Zentiva.
Heart failure
Patients with heart failure have a higher risk of developing hypoxia and kidney failure.In patients with stable chronic heart failure, Metformin Zentiva can be used with regular monitoring of heart function and kidney function.
The use of the drug Metformin Zentiva is contraindicated in patients with acute or chronic heart failure with unstable hemodynamic parameters (see section "Contraindications").
Reproductive function
Metformin did not affect the reproductive function of male or female rats when administered at doses up to 600 mg / kg / day, which is approximately three times the maximum recommended daily dose in humans based on the results of comparison based on body surface area.
Children and teens
The diagnosis of Type 2 diabetes mellitus should be confirmed before the beginning of therapy with Metformin Zentiva.
In controlled clinical trials, the duration of one year of metformin exposure to the growth and puberty of children was not detected. However, due to the lack of long-term data, it is recommended that careful monitoring of the subsequent effect of metformin on these parameters in children taking the Metformin Zentiva drug is recommended, especially in children aged 10-12 years.
Other Precautions
- Patients should adhere to a diet with regular intake of carbohydrates throughout the day. Patients with excessive body weight should continue to adhere to a low-calorie diet (but not less than 1000 kcal per day).
- Regularly standard laboratory tests should be performed to control diabetes mellitus.
- Metformin when monotherapy does not cause hypoglycemia, nevertheless it is advisable to use caution when using it in combination with insulin or other hypoglycemic agents (for example, sulfonylureas, repaglinide etc.).
- Long-term therapy with metformin is accompanied by a decrease in the concentration of vitamin B₁₂ in the blood plasma, which can cause peripheral neuropathy. It is recommended to monitor the concentration of vitamin B regularly₁₂ in the blood plasma.

Effect on the ability to drive transp. cf. and fur:The use of Metformin Zentiva in monotherapy does not affect the ability to drive vehicles and mechanisms.
When the drug Metformin Zentiva with other hypoglycemic agents (derivatives of sulfonylureas, insulin,meglitinids, etc.), it is necessary to warn patients about the possibility of developing hypoglycemic conditions, in which the ability to drive vehicles and engage in other potentially dangerous activities that require increased attention and rapid psychomotor reactions deteriorates.

Form release / dosage:Tablets, film-coated, 500 mg, 850 mg and 1000 mg.

Packaging:For 10 tablets in a blister of PVC / PVDC / A1.
Tablets, 500 mg and 850 mg: For 3, 6 or 9 blisters in a cardboard pack together with instructions for use.
Tablets, 1000 mg: For 1, 3, 6 or 9 blisters in a cardboard pack together with instructions for use.

Storage conditions:Does not require special storage conditions.
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:LSR-003625/10

Date of registration:30.04.2010 / 31.03.2014

Expiration Date:Unlimited

The owner of the registration certificate:Zentiva as.Zentiva as. Czech Republic

Manufacturer: & nbsp

Saneca Pharmaceuticals a.s. The Slovak Republic

Representation: & nbspSanofi Aventis GroupSanofi Aventis Group

Information update date: & nbsp2016-09-26

Illustrated instructions

Instructions

Metformin Zentiva (Metformin-Zentiva)