Siofor 500, 60 pcs

Pharmacodynamics

Hypoglycemic drug of the biguanide group. It provides reduction of both basal and postprandial blood glucose concentrations. It does not stimulate insulin secretion and therefore does not lead to hypoglycemia. The action of metformin is probably based on the following mechanisms:

• reduction of glucose production in the liver due to inhibition of gluconeogenesis and glycogenolysis;
• increased muscle sensitivity to insulin and thus improved peripheral glucose uptake and utilization;
• inhibition of glucose absorption in the gut.

Metformin through its action on glycogen synthetase stimulates intracellular glycogen synthesis. Increases the transport capacity of all hitherto known membrane glucose transport proteins.

Independently of the effect on blood glucose levels, it has a favorable effect on lipid metabolism and leads to a decrease in total cholesterol, low-density cholesterol and triglycerides.

Pharmacokinetics

Intake

After oral administration, Cmax in plasma is reached after about 2.5 h and at maximum dosage does not exceed 4 mcg/ml. With food, absorption decreases and slows down slightly. Absolute bioavailability in healthy patients is approximately 50-60%.

Distribution

It is practically not bound to plasma proteins. The average Vd is 63-276 L. It accumulates in salivary glands, muscles, liver and kidneys. It penetrates the erythrocytes.

Elimination

Extracted by the kidneys in unchanged form. Renal clearance is >400 ml/min. T1/2 is about 6.5 h.

Pharmacokinetics in special clinical cases

In decreased renal function, metformin clearance decreases in proportion to creatinine clearance. Thus, the T1/2 is prolonged and the plasma concentration of metformin is increased.

Indications

Type 2 diabetes mellitus, especially in patients with excessive body weight with ineffectiveness of diet therapy and physical activity.

It is possible to use as monotherapy or in combination with other oral hypoglycemic drugs and insulin.

Active ingredient

Composition

Active ingredients:

metformin hydrochloride 500 mg.

Auxiliary substances:

Hypromellose – 17.6 mg,

Povidone – 26.5 mg,

Magnesium stearate – 2.9 mg.

Composition of the shell:

Hypromellose – 6.5 mg,

Macrogol 6000 – 1.3 mg,

Titanium dioxide (E171) – 5.2 mg.

How to take, the dosage

The drug should be taken orally with or after meals. The dose and regimen of the drug, as well as the duration of treatment are determined by the attending physician depending on the blood glucose level.

Adults

Monotherapy

The recommended starting dose is 500 mg (1 tablet of Siofor® 500 or 1/2 tablet of Siofor® 1000) 1-2 times daily or 850 mg (1 tablet of Siofor® 850) once daily.

In 10-15 days after the beginning of therapy further gradual dose increase is possible, depending on blood glucose level, up to medium daily dose: 3-4 tablets of Siofor® 500 or 2-3 tablets of Siofor® 850 or 2 tablets of Siofor® 1000. Gradual increase of the dose reduces the number of unwanted effects from the gastrointestinal tract.

The maximum dose is 3000 mg/day in 3 doses (6 tablets of Siofor® 500 or 3 tablets of Siofor® 1000).

For patients who are prescribed high doses (2000-3000 mg/day) it is possible to replace 2 tablets of Siofor® 500 with 1 tablet of Siofor® 1000.

If a patient is switched to therapy with Siofor® from therapy with another antidiabetic drug, the latter should be discontinued and Siofor® should be started at the above doses.

Combined use with insulin

Siofor® and insulin may be combined to improve glycemic control. The standard starting dose is 500 mg (1 tablet of Siofor® 500 or 1/2 tablet of Siofor® 1000) 1 to 2 times daily or 850 mg (1 tablet of Siofor® 850) once daily, with gradual dose increase at approximately one week intervals to mean daily dose of 3 to 4 tablets of Siofor® 500 or 2 tablets of Siofor® 1000 or 2-3 tablets of Siofor® 850; the insulin dose is determined on the basis of blood glucose concentration.

The maximum dose is 3000 mg/day in 3 doses.

Because of possible renal dysfunction in elderly patients, the dose of Siofor® is adjusted with regard to creatinine concentration in plasma. Regular assessment of renal function is necessary.

Children 10 to 18 years of age

Monotherapy and combined use with insulin

The standard starting dose is 500 mg (1 tablet). Siofor® 500 or 1/2 tablet of Siofor® 1000) once daily or 850 mg (1 tablet of Siofor® 850) once daily.

In 10-15 days after initiation of the drug, further gradual increase of the dose is possible, depending on the blood glucose level. Gradual increase of the dose reduces the number of undesirable effects on the gastrointestinal tract.

The maximum dose for children is 2000 mg/day (4 tablets of Siofor® 500 or 2 tablets of Siofor® 1000) in 2-3 doses.

The dose of insulin is determined on the basis of blood glucose levels.

Interaction

Contraindicated combinations

In intravascular administration of iodine-containing contrast agents in patients with diabetes mellitus may be complicated by renal impairment, whereby metformin cumulates and the risk of lactacidosis increases. The use of Sioformin® should be discontinued 48 hours prior to X-ray examination with iodine-containing contrast agents provided that serum creatinine concentration is normal.

Unrecommended combinations

The risk of lactacidosis increases with acute alcohol intoxication or concomitant use with ethanol-containing medications, especially with dietary or nutritional disorders and liver failure.

Combinations requiring caution

The concomitant use of metformin with danazolol may lead to the development of hyperglycemic effects. Dose adjustment of metformin under control of blood glucose concentrations is required if treatment with danazololol is necessary and after discontinuation of danazolol.

In concomitant use with oral contraceptive drugs, epinephrine, glucagon, thyroid hormones, phenothiazine derivatives, nicotinic acid may increase blood glucose concentrations.

Nifedipine increases absorption, Cmax in plasma metformin, prolongs its excretion.

The cationic drugs (amiloride, morphine, procainamide, quinidine, ranitidine, triamterene, vancomycin) that are secreted in the tubules compete for tubular transport systems and with prolonged therapy may increase plasma Cmax of metformin.

Cimetidine slows drug excretion, which increases the risk of lactacidosis.

Metformin decreases Cmax and T1/2 of furosemide.

Metformin may decrease the effect of indirect anticoagulants.

Glucocorticoids (systemic and topical), beta-adrenomimetics and diuretics have hyperglycemic activity. Blood glucose concentration should be monitored more carefully, especially at the beginning of treatment. If necessary, the dose of metformin should be adjusted for the period of concomitant use and after withdrawal of these drugs.

ACE inhibitors and other antihypertensive drugs may decrease blood glucose. If necessary, the dose of metformin may be adjusted.

In concomitant use of Siofor® with sulfonylurea derivatives, insulin, acarbose, salicylates may increase the hypoglycemic effect.

Special Instructions

Lactacidosis is a serious pathological condition that is extremely rare and is associated with the accumulation of lactic acid in the blood, which can be caused by metformin cumulation. The described cases of lactacidosis in patients receiving metformin were observed mainly in patients with diabetes mellitus with severe renal insufficiency. Prevention of lactacidosis involves the identification of all associated risk factors, such as decompensated diabetes, ketosis, prolonged fasting, excessive alcohol consumption, liver failure and any condition associated with hypoxia. If lactacidosis is suspected, immediate withdrawal of the drug and emergency hospitalization is recommended.

Because metformin is excreted by the kidneys, plasma creatinine concentration should be determined before starting treatment, and then regularly thereafter. Particular caution should be exercised when there is a risk of impaired renal function, such as at the beginning of therapy with antihypertensive drugs, diuretics or NSAIDs.

The treatment with Siofor® should be temporarily changed to other hypoglycemic agents (e.g., insulin) 48 hours before and 48 hours after radiologic investigation with intravenous infusion of iodine contrast agents.

The use of Siofor® preparation should be discontinued 48 hours prior to elective surgery under general anesthesia, with spinal or epidural anesthesia. The therapy should be continued after resumption of oral nutrition or not earlier than 48 hours after surgical intervention on condition of confirmation of normal renal function.

Sioform® is not a substitute for diet and daily exercise – these therapies should be combined in accordance with the physician’s recommendations. During treatment with Siofor® all patients should follow a dietary diet with equal intake of carbohydrates during the day. Patients with excessive body weight should follow a low-calorie diet.

The standard laboratory tests for diabetic patients should be performed regularly.

The diagnosis of type 2 diabetes mellitus must be confirmed before using Siofor® in children aged 10 to 18 years.

In one-year controlled clinical trials of metformin effect on growth and development as well as puberty in children were not observed, data on these parameters with longer duration of use are not available. In this regard, it is recommended to closely monitor the relevant parameters in children receiving metformin, especially in the prepubertal period (10-12 years).

Monotherapy with Sioform® does not cause hypoglycemia, but caution is recommended when concomitant use of the drug with insulin or sulfonylurea derivatives.

Impact on the ability to drive vehicles and other mechanisms requiring high concentration

The use of Siofor® does not cause hypoglycemia, so it does not affect the ability to drive vehicles and operate mechanisms.

When using Siofor® concomitantly with other hypoglycemic agents (sulfonylurea derivatives, insulin, repaglinide) hypoglycemic states may develop, therefore caution must be exercised while driving vehicles and performing other potentially dangerous activities that require concentration and quick psychomotor reactions.

Contraindications

Side effects

Possible side effects when using the drug are listed according to the frequency of occurrence:

Nervous system disorders: often – taste disorder.

Digestive system disorders: nausea, vomiting, “metallic” taste in the mouth, lack of appetite, diarrhea, abdominal pain. These undesirable effects often occur at the beginning of therapy and in most cases disappear spontaneously. To prevent the occurrence of symptoms, it is recommended to distribute the drug dose into 2-3 doses during or after meals. Gradually increasing the dose reduces the likelihood of gastrointestinal undesirable effects.

Allergic reactions: very rare – skin reactions (e.g., hyperemia, itching, urticaria).

Metabolic disorders: very rare: – lactacidosis (requires discontinuation of treatment). With prolonged use decrease of absorption of vitamin B12 and decrease of its concentration in blood plasma is observed. This should be taken into account if a patient has megaloblastic anemia.

Hepatic and biliary tract disorders: some reports – reversible liver function abnormalities manifested by increased liver transaminase activity, or hepatitis that disappear after discontinuation of metformin.

Overdose

Hypoglycemia was not observed when using metformin in doses up to 85 g.

Symptoms:In significant overdose, lactacidosis may develop, with symptoms such as marked weakness, respiratory disorders, drowsiness, nausea, vomiting, diarrhea, abdominal pain, hypothermia, BP decrease, reflex bradyarrhea. Muscle pain, confusion and loss of consciousness may occur.

Treatment: Immediate withdrawal of the drug and emergency hospitalization is recommended. The most effective method of removing lactate and metformin from the body is hemodialysis.

Pregnancy use

The drug is contraindicated in pregnancy and during lactation (breastfeeding).

The patient should be warned to inform the physician if she becomes pregnant. If the patient with type 2 diabetes plans or becomes pregnant, the drug should be withdrawn and the blood glucose level should be normalized or brought as close to normal as possible with insulin therapy to reduce the risk of fetal defects due to the pathological effects of hyperglycemia.

Metformin penetrates the milk of laboratory animals. Similar data in humans are not available, therefore a decision should be made to discontinue breastfeeding or to discontinue Sioformin®, taking into account the necessity of using the drug in the mother.

Similarities