Metadiene

General characteristics. Structure:

Active ingredient: 500 mg of Metforminum of a hydrochloride.

Excipients: cellulose microcrystallic, magnesium stearate, karmelloza of sodium, gipromelloz (M K-100), gelatin, povidone middlemolecular.

Pharmacological properties:

Pharmacodynamics. Metforminum brakes a gluconeogenesis in a liver, reduces absorption of glucose from intestines, strengthens peripheral utilization of glucose, and also increases sensitivity of fabrics to insulin. At the same time has  no effect on insulin secretion by pancreas beta cells, does not cause hypoglycemic reactions.

Pharmacokinetics. Absorption. After oral administration of a tablet of the prolonged action, Metforminum absorption in a slowed-up way in comparison with a tablet with usual release of Metforminum. Time of achievement of the maximum concentration (TCmax) makes 7 hours. Fluctuations of the maximum concentration of Metforminum (Cmax) and the area under a curve "concentration – time" are comparable (AUC) at certain patients in case of reception of Metforminum in the form of tablets of the prolonged action with the same indicators, as well as in case of reception of tablets with a usual profile of release.

Distribution. Communication with proteins of plasma is insignificant. Metforminum partially contacts erythrocytes. Cmax in blood below Cmax in plasma, is also reached approximately through the same time. At usual therapeutic doses of cumulation of Metforminum in plasma it is not observed, except for cases of a renal failure. The average volume of distribution fluctuates in the range of 63-276 l.

Metabolism. Metforminum is metabolized in an untied form. Metabolites are not revealed.

Removal. Metformin is removed in not changed look by kidneys. The renal clearance of Metforminum makes> 400 ml/min. that indicates that metformin is removed due to glomerular filtering and canalicular secretion. After oral administration the elimination half-life makes: about 6,5 hours from a blood plasma and about 17,5 hours from blood erythrocytes.

At an impaired renal function the clearance of Metforminum decreases in proportion to clearance of creatinine, the elimination half-life increases that can lead to increase in concentration of Metforminum in plasma.

Indications to use:

Treatment of a diabetes mellitus 2 types at adults at inefficiency of a dietotherapy (especially at the patients having obesity) as monotherapy, or in combination with other peroral hypoglycemic means, or with insulin.

Route of administration and doses:

The metadiene is appointed inside. Tablets are swallowed, without chewing, during a dinner (once a day) or during a breakfast and a dinner (2 times a day). A pill should be taken only during food.

The dose of drug is defined, proceeding from the content of glucose in a blood plasma.

Monotherapy and combination therapy in combination with other hypoglycemic means. Usual initial dose: 1 tablet once a day during a dinner. Upon transition from drug Metforminum with usual release of active component the initial dose of drug of Metadiyen has to be to an equal daily dose of Metforminum with usual release of active component. Titration of a dose. Depending on the content of glucose in a blood plasma, every 10-15 days the dose is slowly increased by 500 mg to the maximum daily dose.

Maximum daily dose: 4 tablets once a day during a dinner. If control of content of glucose is not reached at the maximum daily dose accepted once a day, then it is possible to consider the possibility of division of this dose into several receptions in day according to the following scheme: 2 tablets during a breakfast and 2 tablets during a dinner.

Combination with insulin. At drug use Metadiyen together with insulin the usual initial dose of drug makes 1 tablet once a day, and the dose of insulin is selected, proceeding from results of measurement of content of glucose in a blood plasma.

Treatment duration. The metadiene should be accepted daily, without interruption. In case of the treatment termination the patient has to report about it to the doctor.

Admission of a dose. In case of the admission of the next dose the following dose should be accepted in usual time. It is impossible to double a drug dose.

Elderly patients and patients with reduced function of kidneys. To elderly patients and patients with reduced function of kidneys the dose is adjusted on the basis of assessment of renal function which it is necessary to carry out regularly not less than 2 times a year.

Features of use:

Use during pregnancy and during breastfeeding. When planning pregnancy, and also in case of approach of pregnancy against the background of Metforminum reception, drug has to be cancelled, and an insulin therapy is appointed. The patient has to inform the doctor on approach of pregnancy against the background of Metforminum administration of drug.

As there are no data on penetration of Metforminum into breast milk, this drug is contraindicated when breastfeeding.

In need of use of drug in the period of a lactation, breastfeeding should be stopped.

Lactoacidosis is extremely rare, but serious (high mortality in the absence of urgent treatment) a complication which can arise because of Metforminum cumulation. Lactoacidosis cases at the patients receiving Metforminum arose generally at patients with a diabetes mellitus with the expressed renal failure.

It is necessary to consider also other interfaced risk factors, such as badly controlled diabetes, ketosis, long starvation, alcohol overconsumption, liver failure and any state connected with the expressed hypoxia. It can help to reduce the frequency of cases of developing of lactoacidosis.

It is necessary to consider risk of development of lactoacidosis at emergence of nonspecific signs, such as the muscular pains, spasms which are followed by dispepsichesky frustration, an abdominal pain, the general weakness and a strong indisposition. In this case the patient needs to stop administration of drug and to see immediately a doctor.

Use of Metforminum has to be stopped in 48 hours prior to carrying out planned surgeries and can be continued not earlier than in 48 hours later provided that during inspection function of kidneys was recognized as normal. Purpose of drug Metadiyen should be cancelled in 48 hours prior to and not to renew before 2 days after X-ray inspection with use of iodinated X-ray contrast means provided that during inspection function of kidneys was recognized as normal.

As metformin is removed by kidneys, before an initiation of treatment, and is regular in the subsequent, it is necessary to determine the content and/or the clearance of creatinine (CC) in blood serum: at least once a year patients with normal function of kidneys, and 2-4 times a year at elderly patients, and also at patients with KK on the lower bound have norms. Drug Metadiyen is recommended to begin therapy after assessment of function of kidneys. At decrease in KK it is necessary to control function of kidneys at least 2-4 times a year.

It is necessary to show extra care at possible disturbance of functions of kidneys at elderly patients, at simultaneous use of hypotensive drugs, diuretics or NPVP.

The patient has to report to the doctor about emergence of a bronchopulmonary infection or  infectious disease of urinogenital bodies.

It is regularly necessary to carry out standard laboratory analyses for control of a diabetes mellitus.

During administration of drug it is necessary to avoid the alcohol intake and medicines containing ethanol.

Influence on ability to manage avtotrasporty and to work with mechanisms. Monotherapy by drug Metadiyen does not cause a hypoglycemia and therefore does not influence ability to manage motor transport and to work with mechanisms.

At Metadiyen's use with other hypoglycemic means (sulphonylurea derivatives, insulin, etc.) development of hypoglycemic states at which ability to control of motor transport and occupation other potentially dangerous types of activity requiring special attention and bystry psychomotor reactions worsens is possible.

Side effects:

Frequency of side effects of drug is regarded as follows:

 Very frequent: ³ 1/10

Frequent: ³ 1/100, < 1/10         

Infrequent: ³ 1/1000, < 1/100

Rare: ³ 1/10 000, < 1/1000

Very rare: < 1/10 000

Single: cannot be estimated at the available data.

Side effect is presented as decrease in the importance:

Nervous system. Often: taste disturbance (metal smack in a mouth).

Gastrointestinal disturbances. Very often: nausea, vomiting, diarrhea, abdominal pains and lack of appetite.

Most often they arise during an initial stage of treatment and in most cases spontaneously pass. For prevention of symptoms it is recommended to accept Metforminum in time or after meal, having divided a daily dose into 2 receptions a day. Slow increase in a dose can improve gastrointestinal portability. At long preservation of symptoms it is necessary to stop administration of drug and to see behind consultation a doctor.

Skin and hypodermic cellulose. Very seldom: skin reactions such as erythema, itch, urticaria.

Disbolism. Very seldom: lactoacidosis (See. "Special instructions").

Gepato-biliarnye frustration. There are single messages on disturbance of indicators of function of a liver or development of hepatitis; after Metforminum cancellation the undesirable phenomena completely disappear.

If dispeptic symptoms do not disappear, treatment by Metforminum should be stopped.

Others: At the patients receiving treatment by Metforminum a long time the decrease in absorption of B12 vitamin which was followed by decrease in its concentration in blood serum can be observed. At detection of megaloblastny anemia it is necessary to consider a possibility of such etiology.

Interaction with other medicines:

Contraindicated combinations. Iodinated X-ray contrast means: against the background of a functional renal failure the radiological research using iodinated X-ray contrast means can cause development of lactoacidosis in patients with a diabetes mellitus

Not recommended combinations. Alcohol intake increases risk of development of lactoacidosis during an acute drunkenness, especially in a case:

• hyponutrient, observance of a low-calorie diet
• liver failure.
During administration of drug it is necessary to avoid the alcohol intake and medicines containing ethanol.

The combinations demanding extra care. Danazol: the concomitant use of a danazol in order to avoid hyper glycemic action of the last is not recommended. In need of treatment danazoly and after the termination of reception of the last dose adjustment of Metforminum under control of content of glucose is required.

Chlorpromazinum: at reception in high doses (100 mg a day) raises a glycemia, reducing insulin release. At treatment by neuroleptics and after the termination of reception of the last dose adjustment of drug under control of level of a glycemia is required.

Glucocorticosteroids (GKS) of systemic and local action reduce tolerance to glucose, raise a glycemia, sometimes causing a ketosis. At treatment of GKS, and after the termination of reception of the last, dose adjustment of Metforminum under control of level of a glycemia is required.

Diuretics: the concomitant use of loopback diuretics can lead to development of lactoacidosis because of a possible functional renal failure. It is not necessary to appoint Metforminum if the clearance of creatinine is lower than 60 ml/min.

The sympathomimetics appointed in the form of injections beta-2: raise a glycemia owing to stimulation beta 2 - receptors. In this case control of a glycemia is necessary. If necessary purpose of insulin is recommended.

At simultaneous use of above-mentioned medicines more frequent control of content of glucose in blood, especially in an initiation of treatment can be required. If necessary the dose of Metforminum can be corrected in the course of treatment and after its termination.

Inhibitors of an angiotensin-converting enzyme and other anti-hypertensive medicines can reduce the content of glucose in blood. If necessary it is necessary to correct Metforminum dose.

At simultaneous use of Metforminum with sulphonylurea derivatives, insulin, acarbose, salicylates strengthening of hypoglycemic action is possible.

Loopback diuretics and non-steroidal anti-inflammatory drugs (NPVP) increase risk of depression of function of kidneys. In this case it is necessary to be careful at Metforminum use.

Contraindications:

• hypersensitivity to Metforminum to a hydrochloride or to any excipient;
• diabetic ketoacidosis, diabetic prekoma, coma;
• renal failure or renal failure (clearance of creatinine less than 60 ml/min.);
• the acute states proceeding with risk of development of renal failures:

- dehydration (at diarrhea, vomiting), fever, serious infectious diseases,

- conditions of a hypoxia (shock, sepsis, renal infections, bronchopulmonary diseases);

• clinically expressed displays of acute and chronic diseases which can lead to development of a fabric hypoxia (including, heart or respiratory failure, an acute myocardial infarction);
• extensive surgeries and injuries when performing insulin therapy is shown (see the section "Special Instructions");
• liver failure, abnormal liver function;
• alcoholism, acute alcoholic poisoning;
• pregnancy, breastfeeding period;
• lactoacidosis (including and in the anamnesis);
• use within not less than 2 days to and within 2 days after carrying out radio isotope or X-ray inspections with administration of iodinated contrast medium (see the section "Interaction with Other Medicines");
• observance of a hypocaloric diet (less than 1000 kal/days);
• children's age up to 18 years.

With care. To use drug at persons 60 years performing hard physical activity that is connected with the increased risk of development of lactoacidosis at them are more senior.

Overdose:

At use of Metforminum in a dose of 85 g (by 42,5 times exceeding the maximum daily dose) development of a hypoglycemia was not observed. However in this case  development of lactoacidosis was observed.  Early  symptoms of lactoacidosis are nausea, vomiting, diarrhea, decrease in body temperature, an abdominal pain, muscle pain, breath increase, dizziness, disturbance of consciousness and development of a coma can be noted further.

Treatment:    In case of  symptoms of lactoacidosis treatment by drug needs to be stopped immediately, urgently to hospitalize the patient and, having defined concentration of a lactate, to specify the diagnosis. The most effective action for removal from an organism of a lactate and Metforminum is the hemodialysis. Carry out also symptomatic treatment.

Storage conditions:

List B. To store in the dry, protected from light place at a temperature not above 25 °C. To store in the place, unavailable to children. A period of validity - 2 years. Not to use after a period of validity.

Issue conditions:

According to the recipe

Packaging:

Tablets of the prolonged action of 500 mg. On 10 tablets in the aluminum blister. 10 blisters in a cardboard pack together with the application instruction.