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METAMIN tablets


This information is intended for medical professionals only

APPROVED
Order of Ministry of
Healthcare of Ukraine
14.11.11 № 787
Registration certificate
№ UA/11506/02/01
№ UA/11506/02/02
№ UA/11506/02/03

INSTRUCTION
for medical use

METAMIN®



Composition:

active substance: metformin hydrochloride;
1 tablet contains metformin hydrochloride 500 mg, 850 mg, 1000 mg;
excipients: povidone, magnesium stearate, colloidal anhydrous silica, hydroxypropyl methyl cellulose.

Pharmaceutical form.
Coated tablets.

Pharmacotherapeutic group
.
Oral hypoglycemic agents, excluding insulins. Code АТС А10В А02.

Clinical characteristics.
Indications.
Type 2 diabetes mellitus (insulin-independent) in case of ineffective diet therapy,
– in adults as monotherapy or in combination with other oral hypoglycemic drugs or insulin;
– in children older than 10 years as monotherapy or in combination with insulin.

Contraindications.
Hypersensitivity to the active substance or any other component of the drug;
– diabetic keto-acidosis, diabetic precoma, diabetic coma;
– impaired renal function;
– acute diseases, which increase the risk of impaired renal function, dehydration (in case of diarrhea, vomiting), fever, severe infectious diseases, hypoxic conditions (shock, sepsis, renal infection, bronchopulmonary disease);
– severe clinical manifestations of acute and chronic diseases, which can cause tissue hypoxia (cardiac or respiratory failure, acute myocardial infarction, etc.);
– serious surgical operations and severe trauma (when insulin therapy is appropriate);
– impaired hepatic function;
– chronic alcoholism, acute alcohol intoxication;
– lactic acidosis (incl. in past history);
– administration no less than 2 days prior and 2 days after radioisotope and x-ray examinations with injection of iodine-containing contrast agent;
– hypocaloric diet therapy (less than 1000 cal./day).
The drug is not recommended in patients over 60 years old engaged in heavy physical labour, which is associated with increased risk of lactic acidosis.

Dosage and administration.

Monotherapy and combined therapy with other oral hypoglycemic agents.

Adults. The usual initial dose is 500 mg or 850 mg (Metamin®, coated tablets, 500 mg or 850 mg) 2-3 times per day during or after meal.
After 10-15 days of treatment, the dose should be adjusted according to the results of measuring serum glucose level.
Slow increase of the dosage helps minimize adverse effects on the gastrointestinal tract.
Maximum recommended dose is 3000 mg per day, divided in 3 doses.
For treatment with high doses, Metamin® coated tablets 1000 mg are used.
When changing to Metamin® other antidiabetic drug should be stopped.
Combination with insulin.
To achieve a better glucose level control, metformin and insulin should be used as a combined therapy. The usual initial dose is 500 mg or 850 mg of Metamin ® 2-3 times per day, while the dose of insulin is adjusted individually according to serum glucose level.
Monotherapy or combined therapy with insulin.
Children. The drug Metamin® is used in children older than 10 years. The usual initial dose is 500 mg or 850 mg of Metamin® 1 time per day after meal. After 10-15 days of treatment, the dose should be adjusted according to serum glucose level.
Slow increase of the dosage helps minimize adverse effects on the gastrointestinal tract.
Maximum recommended dose is 2000 mg per day, divided in 2-3 doses.
In elderly patients renal function impairment is possible, therefore, the dose of metformin should be adjusted according to assessment of renal function, which should be held regularly (see “Peculiarities of use”).

Adverse reactions.

Frequency of adverse reactions: very common (> 1/10),  common  (> 1/100, < 1/10),  uncommon  (> 1/1000,  < 1/100), rare (> 1/1000, < 1/100), very rare (< 1/10 000), unknown (cannot be estimated from available data).
Gastrointestinal tract: very common (especially at the beginning of treatment) – nausea, vomiting, “metallic” taste, anorexia, flatulence, diarrhea, abdominal pain. Slow increase of the dosage helps minimize adverse effects on the gastrointestinal tract.
The symptoms, as a rule, disappear. Antacids, atropine derivatives or spasmolytics help decrease these symptoms. To avoid adverse effects, it is recommended to use the drug during or after meal 2-3 times per day.
Metabolic disorders: very rare (in case of long-term therapy) – lactic acidosis (the treatment should be stopped).
Malabsorption of vitamin В12 is accompanied by a decrease in its serum level.
Nervous system: common – dysgeusia.
Hepatobiliary system: in isolated cases – impaired liver functions or drug-induced hepatitis, which disappear after withdrawal of metformin
Skin and subcutaneous tissue: very rare – rash, itching, urticaria.
In some conditions, the drug increases the risk of lactic acidosis. The risk of lactic acidosis may increase in case of overdose.

Overdose.
Hypoglycemia was not observed when using metformin at a dose of 85 g. But in this case lactic acidosis was observed. Hypoglycemia was not observed when using metformin at a dose of 85 g; breath holding, dizziness, mental disorders and coma nay develop further.
Treatment. At the first signs of lactic acidosis, metformin therapy should be stopped, the patient should be hospitalized immediately; determine the concentration of lactate and clarify the diagnosis. The most effective method to remove lactate and metformin from the organism is hemodialysis.
Symptomatic therapy is recommended.

Pregnancy and lactation.
When planning pregnancy or during pregnancy, the drug should be stopped and insulin therapy is recommended. During metformin therapy, the patient should inform the physician in case of becoming pregnant. The mother and the newborn are suspect to monitoring, as there is no data on excretion of metformin in breast milk. This drug is contraindicated during breast-feeding.
If the drug therapy is necessary during lactation, breast-feeding should be stopped.

Children.
The drug is used in children older than 10 years.

Peculiarities of use.
Lactic acidosis is a rare and severe metabolic complication caused by accumulation of metformin hydrochloride. There are cases of lactic acidosis in patients with diabetes mellitus and severe hepatic failure. Risk factors for lactic acidosis are: uncontrolled diabetes, ketonemia, fast, alcohol abuse, hepatic failure and hypoxia-related conditions.
Lactic acidosis is characterized by muscle convulsions, acidotic dyspnea, abdominal pain and hypothermia, coma is possible. At assumption of lactic acidosis, stop metformin immediately and seek medical attention.
The diagnosis is confirmed by such laboratory parameters as low blood pH value, plasma lactate level > 5 mmol/L, increase in lactate/pyruvate ratio. At assumption of lactic acidosis, stop metformin immediately and seek medical attention.
Hepatic failure. As metformin is renally excreted, serum creatinine levels should be determined before initiating treatment and regularly thereafter, especially in patients with impaired renal function and in elderly patients.
Caution should be exercised in case of possible impairment of renal function, e.g. at the beginning of treatment with antihypertensive agents or diuretics, during therapy with nonsteroidal anti-inflammatory drugs.
Radiocontrast iodine-containing products. When performing x-ray examinations with radiocontrast iodine-containing products, metformin should be discontinued 48 hours before the examination, and restarted not earlier than in 48hours, after the x-ray examination and evaluation of renal function.
Surgical interventions. The drug should be discontinued 48 hours before the planned surgical intervention, performed with general, spinal or epidural anesthesia, and restarted not earlier than in 48 hours, after reforming the operation and evaluation of renal function.
Children. The clinical trials have revealed no effect of metformin on growth and pubertal development in children. However, there are no data of the effect of metformin on growth and pubertal development in case of long-term use of Metamin, therefore, special caution should be exercised when using the drug in children during puberty, especially in children aged 10 to 12 years.
The patients should keep a diet and control the laboratory parameters. In co-administration with insulin or sulfonylurea derivatives, hypoglycemic action may increase.


Effects on ability to drive and operate machinery.
Monotherapy with metformin does not provoke hypoglycemia and does not affect the ability to drive transport and operate mechanisms which requires concentration and increased attention. But the patient should be informed that the risk of hypoglycemia exists when using metformin with other antidiabetic drugs (sulfonylurea derivatives, repaglinide).

Drug interactions and other kinds of interactions.
To avoid hypoglycemic effect of danazol, its co-administration is not recommended. In case of necessity of treatment with danazol, and after its stopping, the dose of Metamin® should be adjusted in accordance with the level of glycemia.
Alcohol increases the risk of lactic acidosis when acute alcohol intoxication, especially in case of fasting or hypocaloric diet, and hepatic failure. During the drug therapy, avoid using alcohol or any alcohol containing drugs.
Radiocontrast iodine-containing products. X-ray examinations with radiocontrast iodine-containing products may provoke lactic acidosis in patients with diabetes mellitus at the background of functional renal failure. Metamin® should be stopped 48 hours before the examination, and restarted not earlier than in 48hours, after the x-ray examination with radiocontrast iodine-containing products.
Combinations requiring precaution.
Chlorpromazine. When used in large doses (100 mg per day), it increases glycemia and decreases insulin release. Metamin® dosage adjustment and glycemic level control is required during and after treatment with neuroleptic agents.
Systemic and topical glucocorticosteroids (GCS) decrease glucose tolerance, increase glycemia, sometimes provoke ketosis. When using GCS and after stopping them, the dose of metformin should be adjusted according to glycemic level.
Diuretics. Co-administration with loop diuretics may lead to lactic acidosis due to possible renal failure. Metamin® is not recommended in case if blood creatinine level exceeds 135 µmol/L in men and 110 µmol/L in women.
Injections of β2-sympathomimetic agents. Increase glycemia due to stimulation of beta-2 receptors. In this case, control of glycemia is necessary. Insulin is recommended in case of necessity.
Hypoglycemic effect of metformin may be induced by co-administration with sulfonylurea derivatives, insulin, acarbose, salicylates.
Angiotensin-converting enzyme inhibitors (ACE inhibitors).  ACE inhibitors may decrease blood glucose level; therefore, their use is possible only with caution. If necessary, the dosage of antidiabetic drug should be adjusted during and after using these drugs.

Pharmacological properties.

Pharmacodynamics. Metformin decreases hyperglycemia, does not provoke hypoglycemia. Unlike sulphonylurea, it does not stimulate insulin secretion, and has no hypoglycemic effect in healthy volunteers.
Decreases baseline plasma glucose and plasma glucose after meal.
Metformin acts in 3 ways:
– decreases the production of glucose in the liver by inhibiting gluconeogenesis and glycogenolysis;
– improves the capture and utilization of peripheral glucose in muscles by increasing insulin sensitivity;
– slows down the intestinal absorption of glucose.
Metformin stimulates intracellular glycogen synthesis by affecting glycogen synthetase.
Increases transport capacity of all types of membrane glucose transporters (GLUT).
Regardless of its effect on glycemia, metformin shows positive effect on lipid metabolism: reduces total cholesterol, low density lipoproteins, and triglycerides.
Pharmacokinetics.
Absorption. After oral administration, metformin is almost completely absorbed in gastrointestinal tract; 20-30 % is excreted in faeces. Time to reach maximum concentration (Тmax) is 2.5 hours. Absolute bioavailability is 50-60%.
When used along with meal, the rate of metformin absorption is reduced and slowed.
Distribution. Plasma protein binding is negligible. Metformin penetrates into erythrocytes. Cmax in blood is lower than Cmax in plasma, and is reached approximately in the same time. Erythrocytes most likely represent a secondary compartment of distribution. The mean distribution volume is 63-276 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. This indicates that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent half-life is approximately 6.5 hours. In case of impaired renal function, renal clearance is decreased in proportion to that of creatinine, and thus the elimination half-life is prolonged, leading to increased levels of metformin in plasma.     

Pharmaceutical characteristics.
Main physico-chemical properties:

tablets 500 mg, 850 mg: round biconvex coated white to off-white tablets, smooth on both sides;
tablets 1000 mg: oval biconvex coated white to off-white tablets, smooth on both sides.

Shelf life.

3 years.

Storage conditions.

Store at ≤ 25 °С in a dry place. Protect from sunlight.
Keep out of reach of children.

Package.
Tablets 500 mg, 850 mg: 10 tablets in a blister. 3 or 10 blisters in a carton.
Tablets 1000 mg: 15 tablets in a blister. 2 or 6 blisters in a carton.

Conditions of supply
. On prescription.

Manufacturer. 

LLC “KUSUM PHARM”.

Address.
54 Skryabina St., Sumy 40030, Ukraine.

Last revision date.

Information given on this site should not be used for self-diagnosis and treatment and can't be a replacement of doctor's advice.