Siofor XR 1000 prolonged-release tablets 1000 mg blister No. 120

Instructions for Siofor XR 1000 prolonged-release tablets 1000 mg blister No. 120

Composition

active ingredient: metformin hydrochloride;

1 prolonged-release tablet contains 1000 mg of metformin hydrochloride;

excipients: magnesium stearate, colloidal anhydrous silicon dioxide, carmellose sodium,

hypromellose (viscosity type – 100,000 mPa·s, substitution type – 2208), purified water.

Dosage form

Extended-release tablets.

Main physicochemical properties: oval-shaped tablets from white to almost white color with embossing "SR 1000" on one side and smooth on the other side.

Pharmacotherapeutic group

Hypoglycemic agents except insulins. Biguanides.

ATX code A10B A02.

Pharmacological properties

Pharmacodynamics

Metformin is a biguanide with antihyperglycemic effect. It reduces the level of glucose in the blood plasma both on an empty stomach and after eating. It does not stimulate insulin secretion and does not exhibit a hypoglycemic effect mediated by this mechanism.

Metformin works in three ways:

– leads to a decrease in glucose production in the liver due to inhibition of gluconeogenesis and glycogenolysis;

– improves insulin sensitivity in muscles, which leads to improved peripheral glucose uptake and utilization;

– delays the absorption of glucose in the intestine.

Metformin hydrochloride stimulates intracellular glycogen synthesis by acting on glycogen synthetase. It increases the transport capacity of all known types of membrane glucose transporters (GLUT).

Pharmacodynamic effects

Clinical studies have shown that the main effect of metformin, in addition to hypoglycemic, is stabilization or slight loss of body weight.

Independently of its effect on glycaemia, metformin immediate-release tablets have a positive effect on lipid metabolism. This effect has been demonstrated at therapeutic doses in controlled medium- or long-term clinical trials: metformin immediate-release tablets reduce total cholesterol, low-density lipoproteins and triglycerides. A similar effect was not observed with the prolonged-release tablets, probably due to the evening administration of the drug. This may also lead to an increase in triglycerides.

Clinical efficacy

Reducing the risk or delaying the onset of type 2 diabetes

The Diabetes Prevention Program (DPP) in Adults was a multicenter, randomized, controlled clinical trial that evaluated the effectiveness of an active lifestyle or metformin in preventing or delaying the development of type 2 diabetes. Inclusion criteria were age ≥ 25 years, body mass index (BMI) ≥ 24 kg/m2 (≥ 22 kg/m2 for Asian Americans), and impaired glucose tolerance plus a fasting glucose level of 95–125 mg/dL (or ≤ 125 mg/dL for American Indians). Patients were assigned to an active lifestyle, 2×850 mg metformin plus standard lifestyle changes, or placebo plus standard lifestyle changes.

Mean baseline values for DPP participants (n = 3,234 for 2.8 years): age 50.6 ± 10.7 years, fasting plasma glucose 106.5 ± 8.3 mg/dL, two-hour oral glucose plasma glucose 164.6 ± 17.0 mg/dL, and BMI 34.0 ± 6.7 kg/m2. Implementing an active lifestyle in combination with metformin may reduce the risk of developing diabetes compared with placebo by 58% (95% CI 48-66%) and 31% (95% CI 17-43%), respectively.

The benefit of implementing lifestyle changes over metformin was greater in elderly patients.

Patients who benefited most from metformin treatment were those aged 45 years or older with a BMI ≥ 35 kg/m2, a baseline 2-hour glucose level of 9.6-11.0 mmol/L, a baseline HbA1C ≥ 6.0%, or patients with gestational diabetes.

For the prevention of one development of diabetes over three years in the DPP group, 6.9 patients were in the active lifestyle group and 13.9 patients were in the metformin group. The point at which the cumulative incidence of diabetes of 50% was reached was delayed by approximately three years in the metformin group compared with placebo.

Among DPPOS participants (n = 2776), the cumulative incidence of diabetes at 15 years was 62% in the placebo group, 56% in the metformin group, and 55% in the active lifestyle group. The overall rates were 7.0, 5.7, and 5.2 cases of diabetes per 100 patient-years in the placebo, metformin, and active lifestyle groups, respectively. Compared with placebo, the risk of diabetes was reduced by 18% in the metformin group (hazard ratio (HR) 0.82, 95% CI 0.72-0.93; p = 0.001) and by 27% (HR 0.73, 95% CI 0.65-0.83; p 0.0001) in the active lifestyle group. For the composite microvascular endpoint of nephropathy, retinopathy, and neuropathy, results did not differ significantly between groups, but for participants who did not develop diabetes during DPP/DPPOS, the prevalence of microvascular complications was 28% lower than in those who developed diabetes (HR 0.72, 95% CI 0.63-0.83; p 0.0001). There are no comparative data on the effect of metformin on macrovascular complications in patients with impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) and/or elevated HbA1c.

Published risk factors for type 2 diabetes include: Mongoloid or Negroid origin, age over 40 years, dyslipidemia, hypertension, obesity or overweight, age, family history (1st degree relative with diabetes mellitus, history of gestational diabetes mellitus, and polycystic ovary syndrome (PCOS).

Treatment of type 2 diabetes

A prospective randomised (UKPDS) trial demonstrated the benefit of intensive blood glucose control in overweight patients with type 2 diabetes treated with immediate-release metformin hydrochloride as first-line therapy after diet failure. Analysis of the outcomes of overweight patients treated with metformin hydrochloride after diet failure showed:

· a significant reduction in the absolute risk of any diabetes-related complication in the metformin hydrochloride group (29.8 events/1000 patient-years) compared with the diet group (43.3 events/1000 patient-years), p = 0.0023, and compared with the sulfonylurea combination therapy and insulin monotherapy groups (40.1 events/1000 patient-years), p = 0.0034;

· significant reduction in the absolute risk of diabetes-related mortality: metformin hydrochloride 7.5 cases/1000 patient-years, diet alone – 12.7 cases/1000 patient-years (p = 0.017);

· a significant reduction in the absolute risk of all-cause mortality: in the metformin hydrochloride group 13.5 cases/1000 patient-years compared to 20.6 cases/1000 patient-years (p = 0.011), in the diet group, and compared to the combination therapy with sulfonylurea and insulin monotherapy group; 18.9 cases/1000 patient-years (p = 0.021);

· significant reduction in the absolute risk of myocardial infarction: metformin hydrochloride 11 cases/1000 patient-years, diet alone – 18 cases/1000 patient-years (p = 0.01).

For metformin hydrochloride used as second-line therapy, no clinical outcome advantage has been shown in combination with a sulfonylurea.

In type 1 diabetes, the combination of metformin hydrochloride and insulin has been used in selected patients, but the clinical benefit of this combination has not been formally established.

Pharmacokinetics

Absorption

After oral administration of 1 tablet of the drug SIOFOR® XR 1000 by patients after eating and fasting, the maximum plasma concentration is 1214 ng/ml and is reached on average in 5 hours (from 4 to 10 hours).

The maximum concentration (Cmax) and the area under the pharmacokinetic concentration-time curve (AUC) of SIOFOR® XR 1000 are bioequivalent to a 1000 mg dose of SIOFOR® XR 500 in healthy volunteers both after food and in the fasted state.

A bioequivalent drug has the following properties.

At steady state, as with the immediate-release tablets, the maximum concentration (Cmax) and AUC increase disproportionately with the administered oral dose. The AUC after a single oral dose of 2000 mg metformin hydrochloride prolonged-release tablets is similar to the AUC observed after 1000 mg metformin hydrochloride immediate-release tablets twice daily.

The variations in Cmax and AUC in individual patients with metformin hydrochloride extended-release tablets are comparable to those observed with metformin hydrochloride immediate-release tablets.

Following administration of the 1000 mg prolonged-release tablets with food, a 77% increase in AUC was observed (Cmax increased by 26% and Tmax was prolonged to 1 hour).

The absorption of metformin hydrochloride from prolonged-release tablets is not affected by food intake. No accumulation is observed after multiple doses of up to 2000 mg of metformin hydrochloride prolonged-release tablets.

Distribution

Binding to plasma proteins is negligible. Metformin penetrates into erythrocytes. The maximum concentration in the blood is lower than the maximum concentration in plasma and is reached after approximately the same time. Erythrocytes most likely represent a second distribution chamber. The mean volume of distribution (Vd) ranges from 63 to 276 liters.

Metabolism

Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.

Renal clearance of metformin is > 400 ml/min. This indicates that metformin is eliminated by glomerular filtration and tubular secretion. After oral dosing, the elimination half-life is approximately 6.5 hours. In cases of renal impairment, renal clearance decreases in proportion to creatinine clearance, so the elimination half-life increases, leading to increased metformin plasma levels.

Special patient groups

Kidney failure

Limited data are available in patients with moderate renal impairment, so it is not possible to accurately estimate the systemic exposure of metformin in this patient group compared to patients with normal renal function. Therefore, dose adjustment is necessary according to clinical efficacy/tolerability (see section 4.2).

Preclinical safety data

Preclinical data revealed no specific hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction.

Indication

· Reducing the risk or delaying the onset of type 2 diabetes in overweight adult patients with PTH* and/or PGH* and/or elevated HbA1C who have:

- high risk of developing overt (manifest) type 2 diabetes mellitus (see section "Pharmacodynamics");

- progressive disorders of carbohydrate metabolism, despite modification of an active lifestyle for 3 to 6 months.

Treatment with SIOFOR® XR 1000 should be based on a risk assessment, including appropriate glycemic control measures and evidence of high cardiovascular risk.

Lifestyle changes should be continued while starting metformin, except in cases where the patient is unable to make such changes for medical reasons.

*IGT: Impaired glucose tolerance; FPG: Impaired fasting glycemia.

Treatment of type 2 diabetes mellitus in adults, especially in overweight patients, when diet and exercise alone do not provide adequate glycaemic control.

The drug SIOFOR® XR 1000 can be used as monotherapy or in combination with other oral antidiabetic agents, or in combination with insulin.

Contraindication

– Hypersensitivity to metformin or any other component of the drug;

– any type of acute metabolic acidosis (e.g. lactic acidosis, diabetic ketoacidosis);

– diabetic precoma;

– severe renal failure (glomerular filtration rate (GFR)

ml/min);

– acute condition with a risk of developing kidney dysfunction: dehydration, severe infectious diseases, shock;

– diseases that can lead to the development of tissue hypoxia (especially acute diseases or exacerbation of a chronic disease): decompensated heart failure, respiratory failure, recent myocardial infarction, shock;

– liver failure, acute alcohol poisoning, alcoholism.

Interaction with other medicinal products and other types of interactions

Combinations that are not recommended for use

Alcohol

Alcohol intoxication is associated with an increased risk of lactic acidosis, especially in cases of fasting or low-calorie dieting, as well as in liver failure.

Iodine-containing radiopaque agents

Patients should discontinue metformin prior to or at the time of the test and resume no earlier than 48 hours after the test, provided that renal function is normal (see sections 4.2 and 4.4).

Combinations to be used with caution

Some medicinal products, such as non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase (COX) II inhibitors, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists and diuretics, especially loop diuretics, may adversely affect renal function, which may increase the risk of lactic acidosis. When initiating treatment with the above medicinal products or when used in combination with metformin, careful monitoring of renal function is necessary.

Drugs that have a hyperglycemic effect (glucocorticosteroids of systemic and local action, sympathomimetics)

Blood glucose levels should be monitored more frequently, especially at the beginning of treatment. The dose of SIOFOR® XR 1000 should be adjusted during and after discontinuation of such concomitant therapy.

Organic cation transporters (OCT)

Metformin is a substrate of both OCT1 and OCT2 transporters.

Concomitant use of metformin with:

- OCT1 inhibitors (such as verapamil) may reduce the effectiveness of metformin;

- OCT1 inducers (such as rifampicin) may increase gastrointestinal absorption and efficacy of metformin;

- OCT2 inhibitors (such as cimetidine, dolutegravir, ranolazine, trimethoprim, vandetanib, isavuconazole) may reduce the renal excretion of metformin with a subsequent increase in metformin plasma concentrations;

Therefore, special caution is recommended when these drugs are used concomitantly with metformin, especially in patients with renal impairment, as metformin plasma concentrations may increase. If necessary, metformin dose adjustment should be considered, as OCT inhibitors/inducers may affect the efficacy of metformin.

Application features

Lactic acidosis

Lactic acidosis is a very rare but serious metabolic complication that most often occurs in the setting of acute renal failure, cardiopulmonary disease, or sepsis. In acute renal failure, metformin accumulates, increasing the risk of lactic acidosis.

In case of dehydration (severe diarrhea or vomiting, fever, or decreased fluid intake), it is recommended to temporarily discontinue metformin and seek medical attention.

If a patient is receiving metformin, caution should be exercised when initiating medicinal products that may acutely impair renal function (e.g. antihypertensives, diuretics and NSAIDs). Other risk factors for lactic acidosis include excessive alcohol consumption, hepatic insufficiency, poorly controlled diabetes mellitus, ketosis, prolonged fasting and any condition associated with hypoxia, as well as concomitant use of medicinal products that may lead to lactic acidosis (see sections 4.3 and 4.5).

Patients and/or caregivers should be informed of the risk of lactic acidosis. Characteristic signs of lactic acidosis are acidotic dyspnea, abdominal pain, muscle cramps, asthenia and hypothermia, which may progress to coma. If any symptom of lactic acidosis occurs, the patient should discontinue metformin and seek medical attention immediately.

Diagnostic laboratory results include a decrease in blood pH (5 mmol/L) and an increase in the anion gap and lactate/pyruvate ratio.

Kidney failure

GFR should be assessed before starting treatment and regularly thereafter (see section 4.2). Metformin is contraindicated in patients with renal impairment (see section 4.3).

Heart function

Patients with heart failure are at increased risk of hypoxia and renal failure. Metformin may be used in patients with stable chronic heart failure with regular monitoring of cardiac and renal function. Metformin is contraindicated in patients with acute and unstable heart failure (see section 4.3).

Elderly patients

Due to limited data on the therapeutic efficacy of reducing the risk of developing type 2 diabetes or delaying its onset in patients aged 75 years and older, metformin is not recommended for such patients.

Iodine-containing radiopaque agents

Intravascular administration of iodinated contrast media may cause contrast-induced nephropathy, leading to metformin accumulation and an increased risk of lactic acidosis. Patients should discontinue metformin prior to or at the time of the procedure and not resume treatment until 48 hours after the procedure and only after renal function has been re-evaluated and found to be normal (see sections 4.2 and 4.5).

Surgical interventions

Metformin should be discontinued during surgery performed under general, spinal or epidural anesthesia and should not be resumed until 48 hours after surgery or resumption of oral nutrition and only after renal function has been assessed and found to be normal.

Other precautions

Patients should follow a diet with a balanced intake of carbohydrates throughout the day. Overweight patients should continue to follow a low-calorie diet. Laboratory blood glucose levels should be monitored regularly.

Metformin may decrease serum vitamin B12 levels. The risk of low vitamin B12 levels increases with increasing metformin dose, duration of treatment and/or in patients with risk factors known to predispose to vitamin B12 deficiency. Serum vitamin B12 levels should be monitored if vitamin B12 deficiency is suspected (e.g. anaemia or neuropathy). Patients with risk factors for vitamin B12 deficiency may require periodic monitoring of vitamin B12. Metformin therapy should be continued as long as tolerated and not contraindicated, and appropriate corrective treatment for vitamin B12 deficiency is provided in accordance with current clinical guidelines.

Metformin monotherapy does not cause hypoglycemia, but caution should be exercised when metformin is used concomitantly with insulin or other oral hypoglycemic agents (e.g., sulfonylureas or meglitinides). Tablet shell fragments may be present in the feces. This is normal and has no clinical significance.

This medicinal product contains less than 1 mmol (23 mg) sodium/dose, i.e. essentially 'sodium-free'.

Use during pregnancy or breastfeeding

Pregnancy

Uncontrolled hyperglycemia in the periconceptional phase and during pregnancy is associated with an increased risk of congenital anomalies, pregnancy loss, pregnancy-induced hypertension, preeclampsia, and perinatal mortality. It is important to maintain blood glucose levels as close to normal as possible throughout pregnancy to reduce the risk of adverse consequences of hyperglycemia for the mother and her baby.

Metformin crosses the placenta at levels that may be as high as maternal concentrations.

A large amount of data on pregnant women (more than 1000 exposure outcomes) from a registry-based cohort study and published data (meta-analyses, clinical trials and registries) indicate no increased risk of congenital anomalies or foetal/neonatal toxicity following periconceptional and/or pregnancy exposure to metformin.

There are limited and inconclusive data on the effects of metformin on long-term weight outcomes in children exposed in utero. Metformin does not appear to affect motor and social development in children under 4 years of age exposed during pregnancy, although data on long-term outcomes are limited.

If clinically necessary, metformin may be considered during pregnancy and the periconceptional period as an adjunct to or alternative to insulin.

Breastfeeding period

Metformin is excreted in human milk, but no adverse effects have been observed in breastfed newborns/infants. However, due to insufficient data on the safety of the drug, breastfeeding is not recommended during metformin therapy. A decision on whether to discontinue breastfeeding should be made taking into account the benefits of breastfeeding and the potential risk of adverse effects to the child.

Fertility

Metformin did not affect animal fertility at doses of 600 mg/kg/day, which is almost 3 times the maximum recommended daily human dose based on body surface area.

Ability to influence reaction speed when driving vehicles or other mechanisms

The drug SIOFOR® XR 1000 does not affect the reaction speed when driving or working with other mechanisms, since monotherapy with the drug does not cause hypoglycemia.

However, caution should be exercised when metformin is used in combination with other hypoglycemic agents (sulfonylureas, insulin, meglitinides) due to the risk of hypoglycemia.

Method of administration and doses

The tablets should be swallowed whole with water. They should not be chewed or crushed.

Adult patients with normal renal function (GFR ≥ 90 mL/min)

Reducing the risk or delaying the onset of type 2 diabetes

Metformin should only be prescribed when lifestyle changes within 3–6 months do not provide adequate glycemic control.

• Treatment should begin with one tablet of SIOFOR® XR 500 once daily with an evening meal.
• After 10-15 days of treatment, the dose should be adjusted according to the results of blood glucose measurements (OGTT (oral glucose tolerance test) and/or fasting plasma glucose and/or HbA1c should be normal). A slow increase in dose may improve gastrointestinal tolerability. The maximum recommended dose of SIOFOR® XR 1000 is 2 tablets (2000 mg) once daily with an evening meal.

It is recommended to regularly monitor (every 3–6 months) glycemic status (OGTT value and/or fasting plasma glucose and/or HbA1c), as well as risk factors to decide on the need to continue, change or discontinue treatment.

· Treatment should also be re-evaluated if the patient subsequently implements improved nutrition and/or exercise or if changes in the patient's health status allow for lifestyle changes.

Monotherapy or combination therapy in combination with other oral hypoglycemic agents

SIOFOR® XR 1000 should be taken once daily with an evening meal. The maximum recommended dose is 2 tablets per day.

SIOFOR® XR 1000 should be used as maintenance therapy for patients already treated with metformin hydrochloride 1000 mg or 2000 mg. When switching, the daily dose of SIOFOR® XR 1000 should be equivalent to the current daily dose of metformin hydrochloride.

Patients treated with metformin hydrochloride at a dosage of more than 2000 mg per day are not recommended to switch to therapy with SIOFOR® XR 1000.

Patients treated with SIOFOR® XR 1000 should not exceed a dosage of 2000 mg per day.

For patients starting treatment, the usual starting dose of SIOFOR® XR is 500 mg once daily with the evening meal. After 10–15 days of treatment, the dose should be adjusted according to blood glucose measurements. A slow increase in dose helps to reduce gastrointestinal side effects.

SIOFOR® XR 1000 in a maximum dose of 2000 mg, taken once a day, this dose can be divided into 2 doses per day (once in the morning and once in the evening, during meals).

If the required glycemia level remains unattained, SIOFOR® film-coated tablets can be used at the maximum recommended dose of 3000 mg per day.

When switching from therapy with another antidiabetic drug to SIOFOR® XR 1000, titrate the dose and start with SIOFOR® XR 500.

Combination therapy with insulin

Metformin and insulin can be used as combination therapy to achieve better blood glucose control. The usual starting dose of SIOFOR® XR is 500 mg once daily with the evening meal, with insulin dose titrated based on blood glucose measurements.

The drug SIOFOR® XR 1000 can be used after titration of the drug dose.

Elderly patients

Elderly patients may have impaired renal function, therefore the dose of metformin should be selected based on the assessment of renal function, which should be carried out regularly (see section "Special instructions").

The benefit of reducing the risk of developing type 2 diabetes or delaying its onset has not been established in patients aged 75 years and older (see section 5.1), therefore metformin is not recommended for use in such patients (see section 4.2).

Kidney failure

GFR should be assessed before starting metformin-containing medicinal products and at least annually thereafter. In patients at increased risk of further progression of renal failure and in elderly patients, renal function should be monitored more frequently, e.g. every 3-6 months.

Children.

The drug should not be used in children, as there are no clinical data on this age group of patients.

Overdose

When using the drug in a dose of 85 g, hypoglycemia was not observed. However, in this case, the development of lactic acidosis was observed. A significant excess of the metformin dose or concomitant risk factors can cause the occurrence of lactic acidosis. Lactic acidosis is an emergency. In the event of lactic acidosis, the use of the drug SIOFOR® XR 1000 must be discontinued and the patient urgently hospitalized. The most effective measure for removing lactate and metformin from the body is hemodialysis.

Adverse reactions

According to post-marketing and controlled clinical studies, adverse reactions in patients using SIOFOR® XR 1000 were similar in nature and severity to those in patients using SIOFOR® (immediate release).

The most common side effects at the beginning of treatment are nausea, vomiting, diarrhea, abdominal pain, and loss of appetite. These symptoms usually resolve on their own.

Adverse reactions are classified according to the frequency of occurrence into the following categories:

very common (> 1/10), common (> 1/100 and > 1/1000 and > 1/10000 and

Metabolic disorders

Common: Vitamin B12 deficiency/decrease (see section "Special warnings and precautions for use").

Very rare: lactic acidosis (see section "Special warnings and precautions for use").

From the nervous system

Common: taste disturbance.

From the digestive system

Very common: digestive system disorders: nausea, vomiting, diarrhea, abdominal pain, loss of appetite. Most often, these adverse reactions occur at the beginning of treatment and in most cases disappear spontaneously. To prevent the occurrence of adverse reactions from the digestive system, a slow increase in the dose of the drug is recommended.

Hepatobiliary system

Very rare: isolated reports of abnormal liver function tests or hepatitis, which completely resolved after metformin discontinuation.

Skin and subcutaneous tissue disorders

Very rare: allergic skin reactions, including erythema, pruritus, urticaria.

Reporting possible adverse reactions

Reporting of adverse reactions after the registration of a medicinal product is important. This allows monitoring of the benefit/risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should be informed of all cases of suspected adverse reactions and

lack of effectiveness of the medicinal product through the Automated Pharmacovigilance Information System at the link: https://aisf.dec.gov.ua or through the company's website https://www.berlin-chemie.ua.

Expiration date

3 years.

Storage conditions

No special storage conditions are required. Keep out of the reach of children.

Packaging

15 tablets in a blister; 2, 4 or 8 blisters in a cardboard box.

Vacation category

According to the recipe.

Producer

BERLIN-CHEMI AG.

Location of the manufacturer and address of its place of business

Glienicker Weg 125, 12489 Berlin, Germany.

Applicant

BERLIN-CHEMI AG.

Applicant's location

Glienicker Weg 125, 12489 Berlin, Germany.