Metformin film-coated tablets 500 mg or 1000 mg

Metformin film-coated tablets 500 mg or 1000 mg

International nonproprietary name

Metformin

Pharmacological group

Гипогликемические средства

Composition

Active substance:
Metformin hydrochloride
(equivalent to 100% substance)                             - 500 mg     - 1000 mg
Excipients of the core:
povidone (К 30)                                                     - 36 mg          - 48.6 mg
copovidone (kollidon VA 64)                                  - 12 mg
silicium dioxide colloidal (aerosil)                          - 6 mg           - 10.7 mg
calcium stearate                                                    - 6 mg           - 10.7 mg
microcrystalline cellulose                                      - 40 mg         - 40 mg
Excipients of the coating:
hypromellose                                                        - 18 mg           - 32.1 mg
titanium dioxide                                                    - 2.88 mg        - 5.14 mg
polysorbate 80 (tween 80)                                    - 3.6 mg         - 6.42 mg
magnesium hydroxide (talc)                                 - 1.44 mg        - 2.57 mg
lactose monohydrate (lactobiose)                         - 4.032 mg      - 3.684 mg
azorubine (acid red 2S)                                         - 0.048 mg       - 0.086 mg

Pharmacological action

Metformin reduces hyperglycemia without causing hypoglycemia. Unlike derivatives of sulfonylurea the drug does not stimulate insulin secretion and does not have a hypoglycemic effect in healthy persons. The drug increases sensitivity of peripheral receptors to insulin and utilization of glucose by cells. Metformin reduces production of glucose by the liver by inhibiting gluconeogenesis and glycogenolysis. The drug delays absorption of glucose in the intestine.
Metformin stimulates the synthesis of glycogen, affecting glycogen synthase. The drug increases the transport capacity of all types of glucose transporters.
In addition, Metformin has a beneficial effect on lipid metabolism: it reduces the content of total cholesterol, low-density lipoproteins and triglycerides.
After administration of metformin the patient's body weight either remains stable or moderately decreases.

Pharmacokinetics

Absorption and distribution
After oral administration, metformin is absorbed from the gastrointestinal tract quite in full. Absolute bioavailability is 50 - 60%. The maximum plasma concentration (approximately 2 μg/ml or 15 μmol) is achieved after 2.5 hours. In case of simultaneous intake of food, absorption of metformin is reduced and delayed. Metformin is rapidly distributed in tissues, practically does not bind to the plasma proteins.
Metabolism and excretion
Metabolism of the drug is very weak and the drug is excreted by the kidneys. The clearance of metformin in healthy persons is 400 ml/min (4 times more than the creatinine clearance), which indicates the presence of active canaliculia secretion. Half-life is about 6.5 hours. It increases in patients with renal failure with the risk of the drug cummulation.

Indications for Use

Diabetes mellitus type 2 in adults, especially in patients with obesity, when diet and exercises are ineffective:
- in adults as a monotherapy or in combination with other oral hypoglycemic agents or insulin;
- in children from 10 years old as a monotherapy or in combination with insulin.

Contraindications

- increased sensation to metformin or to any excipients;
- diabetic ketoacidosis, diabetic precoma, coma;
- renal failure or renal dysfunction (creatinine clearance less than 45 mL /min);
- acute conditions associated with the risk of renal dysfunction: dehydration (associated with diarrhea, vomiting), severe infectious diseases, shock;
- significant symptoms of acute or chronic diseases causing tissue hypoxia (including acute cardiac failure or chronic heart failure with instable haemodinamics indicators, acute respiratory failure, acute myocardial infarction);
- extensive surgery and trauma, when insulin therapy is administered (see section "Precautions");
- hepatic failure, liver dysfunction;
- chronic alcoholism, acute alcohol poisoning;
- pregnancy;
- pediatric use (age to 10 years old);
- lactoacidosis (including in the past medical history);
- administration within less than 48 hours before and within 48 hours after radioisotope or X-ray examinations with introduction of iodine-containing contrast medium (see section "Interaction with other drugs");
- hypocaloric diet (less than 1000 kcal/day).
With care
Administration of the drug in persons over 60 years old performing heavy physical work, which is associated with increased risk of lactic acidosis; in patients with renal failure (creatinine clearance 45 - 59 ml/min); during the lactation period.
 

Cautions

Lactic acidosis

Lactic acidosis is rare but serious (high mortality in case of lack of  emergency treatment) complication, which can be caused by cumulation of metformin. Cases of lactic acidosis caused by administration of metformin were developed mainly in patients with diabetes mellitus with severe renal failure.
Other associated risk factors, such as decompensated diabetes mellitus, ketosis, prolonged fasting, alcoholism, liver failure and any condition associated with severe hypoxia, shall be considered. This can help to reduce the incidence of lactic acidosis.
The risk of lactic acidosis in case of nonspecific signs appear, such as muscle cramps associated with dyspeptic disorders, abdominal pain and severe asthenia shall be considered. Lactic acidosis symptoms include acidotic dyspnea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory indicators include decreased blood pH (less than 7.25), the plasma concentration of lactate exceeding 5 mmol/l, increased anion gap and the lactate / pyruvate ratio. In case of suspected lactic acidosis, discontinue administration of the drug and consult a doctor immediately.
Surgical operations
Administration of metformin shall be discontinued 48 hours before planned surgery and can be continued no earlier than 48 hours after it, provided that during the examination the renal function is considered as normal.
Kidney function
Since metformin is excreted by the kidneys, before starting the treatment and regularly later on, creatinine clearance shall be determined: at least once per year in patients with normal renal function and 2 - 4 times per year in elderly patients, as well as in patients with creatinine clearance at the lower limit.
Special care shall be taken in cases of possible renal dysfunction in elderly patients in case of simultaneous administration of antihypertensive drugs, diuretics or non-steroidal anti-inflammatory drugs.
Heart failure
Patients with heart failure have a higher risk of hypoxia and renal failure. Patients with chronic heart failure shall regularly monitor cardiac function and kidney function during the treatment with metformin.
Administration of metformin in patients with acute heart failure and chronic heart failure with unstable hemodynamics is contraindicated.
Children and young men
The diagnosis of 2 diabetes mellitus type shall be confirmed before the start of the treatment with metformin.
The results of the 1 year clinical studies showed that metformin does not affect growth and puberty. However, due to the lack of long-term treatment data, careful monitoring of the subsequent influence of metformin on these parameters is recommended in children, especially during puberty period.
The most careful monitoring is required for children at the age from 10 to 12 years old.
Other precautions
Patients are recommended to continue keeping a diet with even intake of carbohydrates throughout the day. Patients with excessive body weight shall continue keeping hypocaloric diet (but not less than 1000 kcal/day).
Regular laboratory testing is recommended to be conducted on a regular basis to control diabetes mellitus.
Metformin does not cause hypoglycemia in patients receiving monotherapy, but care shall be taken for administration in combination with insulin or other oral hypoglycemic agents (for example, sulfonylureas or repaglinide derivatives, etc.).
Effects on ability to drive and use machines
Monotherapy with the drug Metformin does not cause hypoglycemia, therefore does not affect the ability to drive vehicles and mechanisms.
Nevertheless, the patients shall be warned about the risk of hypoglycemia after administration of metformin in combination with other hypoglycemic drugs (sulfonylureas, insulin, repaglinide, etc.).

Dosing and Administration

Oral administration.

Adults:
Monotherapy and combined therapy together with other hypoglycemic agents:
- the usual initial dose is 500 mg or 850 mg 2 - 3 times per day after or during meals.
Every 10 -15 days, it is recommended to adjust the dose based on the results of measuring the concentration of glucose in the blood.
Slow dose increase may improve gastrointestinal tolerance.
- the supporting dose of the drug is usually 1500 - 2000 mg/day. To reduce the adverse gastrointestinal tract effects, the daily dose shall be divided into 2 - 3 administrations. The maximum dose is 3000 mg/day divided into 3 administrations.
- the patients receiving metformin at doses 2000 - 3000 mg/day can be transferred to the therapy with metformin at dose 1000 mg. The maximum dose is 3000 mg/day divided into 3 administrations.
In the case of planning transition from administration of another hypoglycemic agent:
discontinue administration of another drug and start administration of metformin at dose indicated above.
Combination with insulin
To achieve better glycemic control, metformin and insulin can be used as a combined therapy. The usual initial dose of the drug is 500 mg or 850 mg 2-3 times per day, while the insulin dose is selected based on the results of measuring the blood glucose concentration.
Children and young men
In children from 10 years old metformin can be administered both in monotherapy and in combination with insulin. The usual initial dose is 500 mg or 850 mg once per day after or during a meal. After 10 to 15 days, the dose shall be adjusted based on the blood glucose concentration. The maximum daily dose is 2000 mg divided into 2 - 3 administrations.
Patients with renal failure:
Metformin can be administered in patients with moderate renal failure (creatinine clearance 45 - 59 ml/min) only in the absence of conditions that can increase the risk of lactic acidosis.
In patients with CC 45 - 59 ml/min: the initial dose is 500 mg or 850 mg once per day. The maximum dose is 1000 mg per day divided into 2 administrations. The renal function should be carefully monitored every 3 to 6 months.
If the creatinine clearance is less than 45 ml/min, the drug shall be immediately withdrawn.
Elderly patients
Because of the risk of renal dysfunction, the dose of metformin shall be selected under regular monitoring of the renal function (determine the concentration of serum creatinine at least 2 - 4 times per year).
Duration of the treatment
Metformin shall be administered on a daily basis, without interruption. In case of discontinuation of the treatment, the patient shall inform the physician about this.

Side effect

The frequency of adverse effects of the drug is classified as follows:

Very common: ≥ 1/10
Common (frequent): ≥ 1/10,000, < 1/10
Uncommon (infrequent): ≥ 1/10,000, < 1/100
Rare: ≥ 1/10,000, < 1/1000
Very rare: < 1/10 000
Adverse effects are listed in order of decreasing importance.
Adverse metabolism and digestive  effects:
very rare - lactic acidosis (see "Precautions").
Long-term administration of metformin can decrease absorption of vitamin B12. In case of diagnosed megaloblastic anemia,consider the possibility of such etiology.
Adverse nervous system effects:
common (frequent) - taste disorders.
Adverse gastrointestinal effects:
very common - nausea, vomiting, diarrhea, abdominal pain and lack of appetite.
Most often they occur during the initial period of treatment and in most cases pass spontaneously. To prevent symptoms, it is recommended to administer metformin 2 or 3 times per day during or after a meal.
 Slow dose increase may improve gastrointestinal tolerance.
Adverse skin and subdermal tissue effects:
very rare - skin reactions such as erythema (redness of the skin), itching, rash.
Adverse liver and biliary tract effects:
very rare: liver dysfunction and hepatitis; after withdrawal of metformin, these adverse events disappear completely.
The published data, post authorization data, and controlled clinical studies with limited child population at the age of 10-16 years old show that the adverse effects in children are similar in nature and severity to those in adult patients.
Overdose
Administration of metformin at dose 85 g (42.5 times maximum daily dose) does not cause development of hypoglycemia observed. However, lactoacidosis was observed in this case. Significant overdose or associated risk factors can cause lactic acidosis (see "Precautions").
Treatment: in case of signs of lactic acidosis the treatment with the drug shall be discontinued immediately, the patient shall be urgently hospitalized and, after determination of the lactate content, clarify the diagnosis. The most effective measure for elimination of lactate and metformin from the body is hemodialysis. Expectant treatment is also conducted.
 

Interaction with other medicines

Condradicted combinations

Iodine-containing radiopaque means in patients with functional renal failure associated with diabetes mellitus, a radiological examination using iodine-containing radiocontrast agents can cause lactic acidosis. The treatment with Metformin shall be terminated based on the renal function 48 hours prior to or at the time of radiologic examination using iodine-containing radiopaque means and renewed no earlier than 48 hours after, provided that during the examination the renal function was found to be normal.
Unrecommended combinations
Alcohol: acute alcohol intoxication increases the risk of lactic acidosis, especially in case of:
- malnutrition, low-calorie diet;
- hepatic failure.
During the treatment with the drug avoid drinking alcohol and administering the drugs containing ethanol.
Combinations requiring caution
Danazol: simultaneous administration of danazol is not recommended to avoid hyperglycemic effect of the latter. If treatment with danazol is required and after withdrawal of the latter, correction of the dose of metformin is required with monitoring the concentration of glucose 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. Treatment with neuroleptics and after discontinuation of the latter, correction of the dose of metformin is required with monitoring the concentration of glucose in the blood.
Glucocorticosteroids of systemic and local effect reduce glucose tolerance, increase the concentration of glucose in the blood, sometimes causing ketosis. Treatment with glucocorticosteroids and after discontinuation of the latter, correction of the dose of metformin is required with monitoring the concentration of glucose in the blood.
Diuretics: simultaneous administration of loop diuretics can cause lactic acidosis because of possible functional renal failure. Do not administer Metformin if the creatinine clearance is less than 60 mL/min.
Beta2-adrenomimetics administered as injections increase the concentration of glucose in the blood due to stimulation of beta2-adrenoreceptors. In this case monitoring the concentration of glucose in the blood is required. Administration of insulin is recommended if required.
Simultaneous administration of the above drugs can require more frequent monitoring of glucose concentration in the blood, especially at the beginning of the treatment. If required, the dose of the drug Metformin can be adjusted during the treatment and after its termination.
Hypotensive drugs except for angiotensin-converting enzyme inhibitors can reduce the concentration of glucose in the blood. If required, the dose of the drug Metformin can be adjusted.
Simultaneous administration of the drug Metformin with derivatives of sulfonylurea, insulin, acarbose, salicylates can cause hypoglycemia.
Nifedipine increases absorption and maximum concentration of metformin.
Cationic drugs (amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim and vancomycin) secreted in the renal tubules compete with metformin over the tubular transport systems and can increase its maximum concentration.
 

Form release

Storage conditions

In a dark place at temperature maximum 25 °С.

Expiration date

3 years