Formetin Long, 500 mg 60 pcs.

Pharmacotherapeutic group:

Hypoglycemic agent for oral use of the group of biguanides

ATC:

A.10.B.A.02 Metformin

Pharmacodynamics:

Metformin is a biguanide with hypoglycemic action, reducing both basal and postprandial plasma glucose concentrations. It does not stimulate insulin secretion and therefore does not cause hypoglycemia. Increases the sensitivity of peripheral receptors to insulin and glucose utilization by cells. Reduces glucose production by the liver by inhibiting gluconeogenesis and glycogenolysis. Delays the absorption of glucose in the intestine. Metformin stimulates glycogen synthesis by acting on glycogen synthase. Increases the transport capacity of all types of membrane glucose transporters. Against the background of metformin administration, the patient’s body weight either remains stable or decreases moderately.

Metformin has a favorable effect on lipid metabolism: it reduces total cholesterol, low-density lipoproteins and triglycerides.

Pharmacokinetics:

Intake

After oral administration of the drug in the form of sustained-release tablets, metformin absorption is delayed compared to tablets with normal metformin release.

The time to reach the maximum Cmax concentration at the average value is 5-7 hours (range from 4 to 12 hours). At the same time, the TCmax for the tablet with normal release is 2.5 hours.

In the equilibrium state, identical to the equilibrium state of metformin with normal release, the maximum concentration (Cmax) and the area under the curve “concentration-time” (AUC) increase not in proportion to the dose taken. After a single oral dose of 2000 mg of metformin in the form of sustained release tablets, the AUC is similar to that observed after taking 1000 mg of metformin in the form of normally-released tablets twice daily. Intraindividual variability of Cmax and AUC after administration of metformin in the form of sustained release tablets is similar to that observed after administration of metformin in the form of normally-released tablets.

The absorption of metformin from sustained release tablets does not vary with food intake. No cumulation is observed with repeated administration of up to 2000 mg of metformin in the form of sustained release tablets.

Distribution

The binding to plasma proteins is insignificant. Cmax in blood is lower than Cmax in plasma and is reached after approximately the same time. Mean volume of distribution (Vd) ranges from 63-276 L.

Metabolism

Metabolites have not been detected in humans.

Elimination

Metformin is excreted unchanged by the kidneys.

The renal clearance of metformin is > 400 ml/min, indicating that metformin is excreted by glomerular filtration and tubular secretion. After oral administration, the elimination half-life is approximately 6.5 hours. In impaired renal function, metformin clearance decreases in proportion to creatinine clearance, the elimination half-life increases, which may lead to increased plasma concentrations of metformin.

Indications

Type 2 diabetes mellitus in adults, especially in obese patients, when diet therapy and physical activity are ineffective:

– as monotherapy;

– in combination with other oral hypoglycemic agents or with insulin.

Active ingredient

Composition

On one tablet:

The active ingredient:

metformin hydrochloride – 500.00 mg, 750.00 mg, 850.00 mg, 1000.0 mg.

Auxiliary substances:

Hypromellose (200,000 cPs hydroxypropyl methylcellulose) – 248.00 mg,

330.00 mg, 374.00 mg, 294.00 mg;

Hyprolose (hydroxypropyl cellulose) – 40.0 mg, 60.00 mg, 68.00 mg, 70.00 mg;

Magnesium stearate – 4.00 mg, 6.00 mg, 6.80 mg, 7.00 mg;

colloidal silica (aerosil) – 4.00 mg, 6.00 mg, 6.80 mg, 7.00 mg;

Lactose monohydrate – 4.00 mg, 48.00 mg, 54.40 mg, 22.00 mg.

Shell:

VIVACOAT® RA-1P-000 [hypromellose (hydroxypropyl methylcellulose 6 cPs) – 9.36 mg, 14.04 mg, 15.99 mg, 16.38 mg; titanium dioxide – 7.20 mg, 10.80 mg, 12.30 mg, 12.60 mg; polydextrose, 3.60 mg, 5.40 mg, 6.15 mg, 6.30 mg; talc, 2.40 mg, 3.60 mg, 4.10 mg, 4.20 mg; polyethylene glycol 3350 (macrogol-3350), 1.44 mg, 2.16 mg, 2.46 mg, 2.52 mg], 24.00 mg, 36.00 mg, 41.00 mg, 42.00 mg.

How to take, the dosage

The drug Formetin® Long, sustained release film-coated tablets, 500 mg, 750 mg, 850 mg, 1000 mg are taken orally. The tablets are swallowed whole, without chewing, with small amount of liquid, once a day with dinner.

The dose of the medication is adjusted by the physician individually for each patient based on the results of blood glucose measurements.

Monotherapy and combination therapy in combination with other hypoglycemic agents

For patients not taking metformin, the recommended starting dose of Formetin® Long, film-coated sustained release tablets is 500 mg, 750 mg or 850 mg once daily with dinner. It is recommended that the dose be adjusted every 10-15 days, depending on plasma glucose concentrations. Slow dose increases help to reduce gastrointestinal side effects;

– For patients already receiving metformin treatment, the starting dose of Formetin® Long should be equivalent to the daily dose of normally-released tablets;

– patients taking metformin in the form of normal-release tablets with an active ingredient dose greater than 2,000 mg should not be recommended to switch to Formetin® Long. – if a switch from another hypoglycemic drug is planned, the dose should be adjusted as described above, starting with Formetin® Long at a dose of 500 mg, 750 mg, or 850 mg, with possible subsequent switching to Formetin® Long 1000 mg.

Combination with insulin

To achieve better control of blood glucose concentrations, metformin and insulin can be used as combination therapy. Usual starting dose of Formetin® Long is one tablet of 500 mg, 750 mg or 850 mg once daily at supper time, while insulin dose is chosen on the basis of blood glucose concentration measurement results. Further switching to Formetin® Long 1000 mg is possible.

The daily dose

The maximum recommended dose of Formetin® Long, 500 mg and 1000 mg film-coated sustained release tablets is 4 500 mg (2000 mg) or 2 1000 mg (2000 mg) tablets daily, respectively. If the maximum recommended dose of Formetin® Long 500 mg or 1000 mg once daily fails to achieve adequate glycemic control, the maximum dose may be divided into two doses: 2 tablets 500 mg at breakfast and 2 tablets 500 mg at supper, or one tablet 1000 mg at breakfast and one tablet 1000 mg at supper.

The recommended dose of Formetin® Long, 750 mg and 850 mg film-coated sustained release tablets is 2 750 mg (1500 mg) or 2 850 mg (1700 mg) tablets, respectively, once daily. If at administration of recommended dose of Formetin® Long 750 mg or 850 mg it is not achieved the adequate glycemic control, it is possible to increase the dose to maximum – respectively, 3 tablets of 750 mg (2250 mg) or 3 tablets of 850 mg (2550 mg) of Formetin® Long once daily. In order to reduce the gastrointestinal side effects the daily dose of the preparation Formetin® Long 750 mg or 850 mg can be divided into 2 doses.

If the adequate glycemic control is not achieved by taking the maximum recommended dose of Formetin® Long, switching to metformin with standard active ingredient release (for example, Formetin® tablets 0.5 g, 0.85 g, 1.0 g) with maximum daily dose of 3000 mg is possible.

The use of the drug in patients with renal insufficiency

Metformin can be used in patients with moderate renal insufficiency (creatinine clearance 45-59 ml/min) only in the absence of conditions that may increase the risk of lactacidosis.

The starting dose is 500 mg or 750 mg once daily. The maximum dose is 1000 mg daily. Renal function should be monitored closely every 3-6 months. If creatinine clearance is lower than 45 ml/min, the drug should be discontinued.

The use of the drug in elderly patients

In elderly patients, the dose of metformin is adjusted based on renal function assessment, which should be performed regularly but at least twice a year (See “Special Precautions”).

The duration of treatment

Formetin® Long should be taken daily, without interruption. If treatment is discontinued, the patient should inform the physician.

Dose skipping

If a dose is missed, the patient should take the next dose at the usual time. A double dose of Formetin® Long should not be taken.

Interaction

Contraindicated combinations

Iodine-containing radiopaque agents: against the background of functional renal insufficiency in patients with diabetes mellitus, radiological examination with iodine-containing radiopaque agents may cause development of lactocidosis. Formetin® Long should be discontinued depending on renal function 48 hours before or during radiological examination with iodine containing radiological contrast agents and should be renewed not earlier than 48 hours after, on condition that during the examination the renal function was acknowledged normal.

Unrecommended combinations

Alcohol: acute alcohol intoxication increases the risk of lactoacidosis, especially if:

– inadequate diet, adherence to a low-calorie diet;

– hepatic insufficiency.

When taking the drug, alcohol and medicinal products containing ethanol should be avoided.

Combinations requiring caution

Drugs with indirect hyperglycemic effects (e.g., glucocorticosteroids (GCS) and tetracosactide (systemic and topical), beta2-adrenomimetics, danazol, chlorpromazine when taken in high doses (100 mg daily) and diuretics: More frequent monitoring of blood glucose concentrations may be required, especially at the beginning of treatment. If necessary, the dose of Formetin® Long may be adjusted during treatment and after discontinuation of treatment, based on the level of glycemia.

Diuretics: concomitant administration of “loop” diuretics may lead to development of lactoacidosis due to possible functional renal failure. Formetin® Long should not be administered if creatinine clearance is less than 45 ml/min.

Per concomitant administration of Formetin® Long with sulfonylurea derivatives, insulin, acarbose, salicylates may cause hypoglycemia.

Nifedipine increases absorption and Cmax of metformin.

Cationic drugs (amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim and vancomycin) that are secreted in the renal tubules compete with metformin for tubular transport systems and may increase its Cmax.

Colecevelam, when used concomitantly with metformin in sustained release tablet form, increases plasma metformin concentrations (increased AUC without significantly increasing Cmax).

Special Instructions

Lactoacidosis

Lactoacidosis is a rare but serious (high mortality if not treated urgently) complication that can occur due to metformin cumulation. Cases of lactoacidosis when taking metformin have occurred mainly in patients with diabetes mellitus with severe renal insufficiency.

Contraindications

– Hypersensitivity to metformin or any excipient;

– diabetic ketoacidosis, diabetic precoma, coma;

– renal insufficiency or impaired renal function (creatinine clearance less than 45 ml/min);

– acute conditions with risk of renal impairment: dehydration (with chronic or severe diarrhea, repeated bouts of vomiting), severe infectious diseases (e.g., respiratory tract infections, urinary tract infections), shock;

– clinically expressed manifestations of acute or chronic diseases that may lead to the development of tissue hypoxia (including cardiac or respiratory failure, acute myocardial infarction);

– major surgical operations and injuries when insulin therapy is indicated (see

– hepatic insufficiency, liver dysfunction;

– chronic alcoholism, acute alcohol poisoning;

– pregnancy;

– lactoacidosis (including

– use less than 48 hours before and 48 hours after radioisotopic or radiology studies with iodine contrast media (e.g., internal urography, angiography).

– compliance with a hypocaloric diet (less than 1000 calories/day);

– Lactose intolerance, lactase deficiency, glucose-galactose malabsorption;

– childhood under 18 years of age due to lack of data on its use.

With caution:

Prevent use of the drug:

– in persons over 60 years of age who perform heavy physical work, due to the increased risk of lactoacidosis in them;

– in patients with renal impairment (creatinine clearance 45-59 ml/min)

– during breastfeeding.

Side effects

The frequency of side effects of the drug is rated as follows:

Very frequent: ≥ 1/10.

Frequent: ≥ 1/100, < 1/10.

Infrequent: ≥ 1/1000, < 1/100.

Rare: ≥ 1/10,000, < 1/1000.

Very rare:

Metabolic and nutritional disorders:

Very rare: lactoacidosis (see Special Instructions).

In long-term administration of metformin, decreased absorption of vitamin B12 may be observed. If megaloblastic anemia is detected, the possibility of this etiology should be considered.

Nervous system disorders:

Often: impaired taste (metallic taste in the mouth).

Gastrointestinal disorders:

very often: nausea, vomiting, diarrhea, abdominal pain and lack of appetite.

These are most common during the initial period of treatment and go away spontaneously in most cases. It is recommended that metformin be taken with meals to prevent the symptoms. Slowly increasing the dose may improve gastrointestinal tolerance.

Hepatic and biliary tract disorders:

Very rare: impaired liver function and hepatitis; these adverse events disappear completely after withdrawal of metformin.

Skin and subcutaneous tissue disorders:

Very rare: skin reactions such as erythema (redness of the skin), itching, urticaria.

If any of the side effects listed in the instructions worsen, or if any other side effects not listed in the instructions have been noticed, you should tell your doctor.

Overdose

When using metformin at a dose of 85 g (42.5 times the maximum daily dose) the development of hypoglycemia was not observed. However, in this case the development of lactoacidosis was observed. Significant overdose or concomitant risk factors may lead to the development of lactoacidosis (see “Cautionary Note”).

Treatment: In case of signs of lactocidosis the drug treatment should be stopped immediately, the patient should be urgently hospitalized and after determination of lactate concentration the diagnosis should be specified. The most effective measure for lactate and metformin elimination from the body is hemodialysis. Symptomatic treatment is also carried out.

Similarities