Metformin-Teva (Tablets) Instructions for Use

Marketing Authorization Holder

Teva Pharmaceutical Industries, Ltd. (Israel)

Manufactured By

Teva Czech Industries, s.r.o. (Czech Republic)

Packaging and Quality Control Release

R-PHARM NOVOSELKI, LLC (Russia)

Or

TEVA Pharmaceutical Works, Private Limited Company (Hungary)

ATC Code

A10BA02 (Metformin)

Active Substance

Metformin (Rec.INN registered by WHO)

Dosage Forms

	Metformin-Teva	Film-coated tablets, 500 mg: 30 or 60 pcs.
		Film-coated tablets, 850 mg: 30 or 60 pcs.
		Film-coated tablets, 1000 mg: 30 or 60 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, oval, with a score on both sides, with an engraving “9” to the left of the score and “3” to the right of the score on one side, and “72” to the left of the score and “14” to the right of the score on the other.

Excipients : povidone K30 – 31.6 mg, povidone K90 – 22.6 mg, colloidal silicon dioxide – 2.4 mg, magnesium stearate – 5.4 mg.

Shell composition Opadry white Y-1-7000H (hypromellose (E464) – 20 mg, titanium dioxide (E171) – 10 mg, macrogol 400 – 2 mg).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.

Film-coated tablets white or almost white, oval, with an engraving “93” on one side and “48” on the other.

Excipients : povidone K30 – 13.8 mg, povidone K90 – 13.3 mg, colloidal silicon dioxide – 1.2 mg, magnesium stearate – 2.7 mg.

Shell composition Opadry white Y-1-7000H (hypromellose (E464) – 10 mg, titanium dioxide (E171) – 5 mg, macrogol 400 – 1 mg).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.

Film-coated tablets white or almost white, oval, with an engraving “93” on one side and “49” on the other.

Excipients : povidone K30 – 23.5 mg, povidone K90 – 22.6 mg, colloidal silicon dioxide – 2 mg, magnesium stearate – 4.6 mg.

Shell composition Opadry white Y-1-7000H (hypromellose (E464) – 16.9 mg, titanium dioxide (E171) – 8.4 mg, macrogol 400 – 1.7 mg).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.

Clinical-Pharmacological Group

Oral hypoglycemic drug

Pharmacotherapeutic Group

Oral hypoglycemic agent of the biguanide group

Pharmacological Action

Metformin is an oral hypoglycemic agent from the biguanide group.

In patients with diabetes mellitus, it reduces blood glucose concentration by inhibiting gluconeogenesis in the liver, reducing glucose absorption from the gastrointestinal tract, and increasing its utilization in tissues by increasing their sensitivity to insulin (primarily in striated muscle, to a lesser extent in adipose tissue).

It does not stimulate insulin secretion and does not cause hypoglycemic reactions.

It affects lipid metabolism by reducing the concentration of triglycerides, cholesterol, and low-density lipoproteins in the blood serum.

It stimulates intracellular glycogenesis by activating glycogen synthase.

Pharmacokinetics

Absorption

After oral administration, Metformin is sufficiently completely absorbed from the gastrointestinal tract.

The absolute bioavailability is 50-60%.

The maximum concentration (C_max) in plasma is approximately 2 µg/ml or 15 µmol/l and is reached after 2.5 hours.

After 7 hours, absorption from the gastrointestinal tract ends, and the concentration of metformin in plasma gradually decreases.

When taken simultaneously with food, the absorption of metformin is reduced and slowed down.

Distribution

Metformin practically does not bind to plasma proteins and is rapidly distributed into body tissues.

It penetrates into erythrocytes.

It accumulates in the salivary glands, liver, and kidneys.

The apparent volume of distribution is 63-276 l.

Metabolism and excretion

It is excreted by the kidneys unchanged.

The clearance of metformin in healthy individuals is 400 ml/min, which indicates active glomerular filtration and tubular secretion.

The elimination half-life (T_1/2) is approximately 6.5 hours.

Pharmacokinetics in special clinical cases

In patients with renal failure, the renal clearance of metformin decreases in proportion to the decrease in creatinine clearance, T_1/2 increases, which leads to an increase in the concentration of metformin in the blood.

Accumulation is possible.

Indications

• Type 2 diabetes mellitus in adults (especially in patients with obesity) when diet and physical exercise are ineffective, as monotherapy or in combination with other oral hypoglycemic agents or insulin.

ICD codes

Dosage Regimen

Orally, during or immediately after meals.

Monotherapy and combination therapy with other oral hypoglycemic agents

Initial dose: 500-1000 mg once a day in the evening.

After 7-15 days, in the absence of adverse effects from the gastrointestinal tract, 500-1000 mg is prescribed twice a day in the morning and evening.

A further gradual increase in dose is possible depending on the blood glucose concentration.

Maintenance dose: 1500-2000 mg/day.

To reduce gastrointestinal side effects, the dose should be divided into 2-3 doses.

Maximum dose: 3000 mg/day in 3 doses.

A slow increase in dose may help improve gastrointestinal tolerance of the drug.

Patients taking Metformin at doses of 2000-3000 mg/day can be switched to a dose of 1000 mg.

The maximum recommended dose: 3000 mg/day in 3 doses.

When switching to therapy from another hypoglycemic agent, the other agent should be discontinued and Metformin-Teva should be started at the dose indicated above.

Combinations with insulin

Metformin-Teva and insulin can be used in combination therapy to achieve better glycemic control.

Metformin-Teva is prescribed at the usual initial dose of 500 mg or 850 mg 2-3 times a day.

The insulin dose is selected based on blood glucose measurement results.

After 10-15 days, the dose is adjusted depending on the blood glucose concentration.

The maximum dose of metformin in combination therapy: 2 g/day in 2-3 doses.

In elderly patients the daily dose should not exceed 1000 mg/day.

Adverse Reactions

Side effects are classified according to the following frequency: very common – not less than 10%; common – not less than 1%, but less than 10%; uncommon – not less than 0.1%, but less than 1%; rare – not less than 0.01%, but less than 0.1%; very rare – less than 0.01%, including isolated cases.

From the central nervous system common – taste disturbance (metallic taste in the mouth).

From the digestive system very common – nausea, vomiting, abdominal pain, loss of appetite, occurring at the initial stage of treatment and in most cases resolving spontaneously; isolated cases – impaired liver function tests or hepatitis, completely disappearing after drug withdrawal.

Allergic reactions very rare – erythema, skin itching, rash.

From the metabolism very common – lactic acidosis (requires drug withdrawal).

Other very rare – with prolonged use, vitamin B₁₂ deficiency develops.

Contraindications

• Hypersensitivity to metformin or any excipient of the drug;
• Diabetic ketoacidosis, diabetic precoma, coma;
• Renal failure or impaired renal function (creatinine clearance less than 60 ml/min);
• Acute conditions with a risk of impaired renal function;
• Dehydration (due to diarrhea, vomiting), fever, severe infectious diseases;
• Conditions of hypoxia (shock, sepsis, renal infections, bronchopulmonary diseases);
• Clinically pronounced manifestations of acute and chronic diseases that can lead to the development of tissue hypoxia (including cardiac or respiratory failure, acute myocardial infarction);
• Extensive surgical operations and injuries when insulin therapy is indicated;
• Hepatic failure, impaired liver function;
• Chronic alcoholism, acute alcohol poisoning;
• Lactic acidosis (including in history);
• Use for at least 48 hours before and within 48 hours after radioisotope or X-ray studies with the administration of iodine-containing contrast agent;
• Period of at least 48 hours before and within 48 hours after surgical interventions under general anesthesia, spinal or epidural anesthesia;
• Adherence to a hypocaloric diet (less than 1000 kcal/day);
• Children under 18 years of age.

With caution in persons over 60 years of age performing heavy physical work (increased risk of lactic acidosis).

Use in Pregnancy and Lactation

The drug is contraindicated for use during pregnancy and breastfeeding.

When planning or during pregnancy, Metformin-Teva should be discontinued and insulin therapy prescribed.

The patient should be warned about the need to inform the doctor in case of pregnancy.

The mother and child should be monitored.

It is not known whether Metformin is excreted in breast milk.

If it is necessary to use the drug during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

Contraindicated in hepatic failure, impaired liver function.

Use in Renal Impairment

Contraindicated in renal failure or impaired renal function (creatinine clearance less than 60 ml/min).

Pediatric Use

Contraindicated in children under 18 years of age.

Geriatric Use

Use the drug with caution in persons over 60 years of age performing heavy physical work (increased risk of lactic acidosis).

In elderly patients, the daily dose should not exceed 1000 mg/day.

Special Precautions

During treatment with Metformin-Teva, it is necessary to regularly monitor blood glucose concentration on an empty stomach and after meals.

The patient should be warned about the need to stop taking the drug and consult a doctor if vomiting, abdominal pain, muscle pain, general weakness, and severe malaise appear.

These symptoms may be signs of incipient lactic acidosis.

Metformin-Teva should be discontinued 48 hours before and within 48 hours after an X-ray examination (including urography, intravenous angiography) using X-ray contrast agents.

Metformin-Teva should be discontinued 48 hours before and within 48 hours after surgical interventions under general anesthesia, spinal or epidural anesthesia.

Since Metformin is excreted by the kidneys, creatinine clearance should be determined before starting treatment and regularly thereafter: in patients with preserved renal function once a year, in patients with reduced creatinine clearance and in elderly patients 2-4 times a year.

Special caution should be exercised in case of impaired renal function, for example, during the initial period of therapy with antihypertensive agents, diuretics, NSAIDs.

The patient should be informed about the need to consult a doctor if symptoms of bronchopulmonary infection or infectious disease of the genitourinary organs appear.

While using Metformin-Teva, alcohol consumption should be avoided due to the increased risk of hypoglycemia and a disulfiram-like effect.

Vitamin B₁₂ deficiency when taking Metformin-Teva is due to impaired absorption of vitamin B₁₂ and is reversible.

After discontinuation of Metformin-Teva, signs of vitamin B₁₂ deficiency quickly disappear.

Effect on ability to drive vehicles and operate machinery

Monotherapy with Metformin-Teva does not cause hypoglycemia and therefore does not affect the ability to drive a car and work with machinery.

When using Metformin-Teva with other hypoglycemic agents (sulfonylurea derivatives, insulin, etc.), the development of hypoglycemic conditions is possible, in which the ability to drive a vehicle and engage in other potentially hazardous activities requiring increased attention and rapid psychomotor reactions is impaired.

Overdose

Symptoms

When metformin was used at a dose of 85 g, hypoglycemia was not observed, but lactic acidosis developed.

Early symptoms of lactic acidosis are nausea, vomiting, diarrhea, decreased body temperature, abdominal pain, muscle pain; later, rapid breathing, dizziness, impaired consciousness, and coma may occur.

Treatment

If signs of lactic acidosis appear, treatment with the drug must be immediately discontinued, the patient urgently hospitalized and, after determining the lactate concentration, the diagnosis clarified.

The most effective measure for removing lactate and metformin from the body is hemodialysis.

Symptomatic treatment is also carried out.

Drug Interactions

Not recommended combinations

When metformin is used concomitantly with danazol, a hyperglycemic effect may develop.

If treatment with danazol is necessary and after its discontinuation, adjustment of the metformin dose under glycemic control is required.

When metformin is used concomitantly with alcohol and ethanol-containing drugs, the risk of lactic acidosis increases during acute alcohol intoxication, especially during fasting or adherence to a low-calorie diet, as well as in hepatic failure.

Combinations requiring special caution

Chlorpromazine in high doses (100 mg/day) reduces insulin release and increases blood glucose concentration.

When used concomitantly with antipsychotics and after their discontinuation, adjustment of the metformin dose under glycemic control is required.

Glucocorticosteroids (GCS) reduce glucose tolerance and increase blood glucose concentration, in some cases causing ketosis.

If such a combination is necessary and after discontinuation of GCS, adjustment of the metformin dose under glycemic control is required.

When “loop” diuretics and metformin are used concomitantly, there is a risk of lactic acidosis due to the possible occurrence of functional renal failure.

Radiological examination using iodine-containing X-ray contrast agents can cause the development of lactic acidosis in patients with diabetes mellitus against the background of functional renal failure.

The use of metformin should be discontinued 48 hours before and not resumed earlier than 48 hours after an X-ray examination using X-ray contrast agents.

Administration of beta2-adrenomimetics by injection reduces the hypoglycemic effect of metformin due to stimulation of beta2-adrenergic receptors.

In this case, blood glucose concentration should be monitored and, if necessary, insulin should be prescribed.

Angiotensin-converting enzyme inhibitors and other antihypertensive drugs may reduce blood glucose concentration.

If necessary, the dose of metformin should be adjusted.

When metformin is used concomitantly with sulfonylurea derivatives, insulin, acarbose, and salicylates, the hypoglycemic effect may be enhanced.

“Loop” diuretics and NSAIDs increase the risk of decreased renal function.

In this case, caution should be exercised when using metformin.

Storage Conditions

At a temperature not exceeding 25°C (77°F).

Keep out of reach of children.

Shelf Life

The shelf life is 3 years.

Dispensing Status

By prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.