DIAFORMIN® SR

Composition:

Active ingredient: metformin;

1 tablet contains 500 mg or 1000 mg of metformin hydrochloride;

Excipients: stearic acid, shellac, povidone (K-30), silica colloidal anhydrous, magnesium stearate;

composition of film coating: hypromellose, hydroxypropylcellulose, titanium dioxide (E 171), propylene glycol, macrogol 6000, talc.

Pharmaceutical form

Prolonged-release tablets.

Basic physical and chemical properties:

Prolonged-release tablets 500 mg: off-white, oval, biconvex, plain on both sides, film-coated tablets;

Prolonged-release tablets 1000 mg: off-white, oval, biconvex, scored on one side and plain on another side, film-coated tablets;

Pharmacotherapeutic group

Oral blood glucose lowering drugs, excl. insulins. Biguanides. ATC Code А10В А02.

Pharmacological properties

Pharmacodynamics

Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and post-prandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.

Metformin may act via 3 mechanisms:

– reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis;

– in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilisation;

– delay of intestinal glucose absorption.

Metformin hydrochloride stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin increases the transport capacity of all types of membrane glucose transporters (GLUTs) known to date.

Pharmacodynamic effects

In clinical studies, the main non-glycemic effect of metformin was associated with either a stable body weight or modest weight loss.

Independently of its action on glycaemia, immediate release metformin tablets have favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: immediate release metformin reduces total cholesterol, LDL cholesterol and triglyceride levels. A similar action has not been demonstrated with the prolonged release formulation, possibly due to the evening administration, and an increase in triglycerides may occur.

Clinical efficacy

Reduction in the risk or delay of type 2 diabetes mellitus

The Diabetes Prevention Program (DPP) was a multicenter randomised controlled clinical trial in adults assessing the efficacy of an intensive lifestyle intervention or metformin to prevent or delay the development of type 2 diabetes mellitus. Inclusion criteria were age ≥25 years, BMI ≥24 kg/m² (≥22 kg/m² for Asian-Americans), and impaired glucose tolerance plus a fasting plasma glucose of 95 – 125 mg/dl (or ≤125 mg/dl for American Indians). Patients were either treated with intensive lifestyle intervention, 2 x 850 mg metformin plus standard lifestyle change, or placebo plus standard lifestyle change.

The mean baseline values of the DPP participants (n=3,234 for 2.8 years) were age 50.6±10.7 years, 106.5±8.3 mg/dl fasted plasma glucose, 164.6±17.0 mg/dl plasma glucose two hours after an oral glucose load, and 34.0±6.7 kg/m² BMI. Intensive lifestyle intervention as well as metformin significantly reduced the risk of developing overt diabetes compared to placebo, 58% (95% CI 48-66%) and 31% (95% CI 17-43%), respectively.

The advantage of the lifestyle intervention over metformin was greater in older persons.

The patients who benefited most from the metformin treatment were aged below 45 years, with a BMI equal or above 35 kg/m², a baseline glucose 2 h value of 9.6-11.0 mmol/l, a baseline HbA1C equal or above 6.0% or with a history of gestational diabetes. To prevent one case of overt diabetes during the three years in the whole population of the DPP, 6.9 patients had to participate in the intensive lifestyle group and 13.9 in the metformin group. The point of reaching a cumulative incidence of diabetes equal to 50% was delayed by about three years in the metformin group compared to placebo.

The Diabetes Prevention Program Outcomes Study (DPPOS) is the long-term follow-up study of the DPP including more than 87% of the original DPP population for long-term follow up.

Among the DPPOS participants (n=2776), the cumulative incidence of diabetes at year 15 is 62% in the placebo group, 56% in the metformin group, and 55% in the intensive lifestyle intervention group.  Crude rates of diabetes are 7.0, 5.7 and 5.2 cases per 100 person‐years among the placebo, metformin, and intensive lifestyle participants, respectively.  Reductions in the diabetes risk were of 18% (hazard ratio (HR) 0.82, 95% CI 0.72–0.93; p=0.001) for the metformin group and 27% (HR 0.73, 95% CI 0.65–0.83; p<0.0001) for the intensive lifestyle intervention group, when compared with the placebo group. For an aggregate microvascular endpoint of nephropathy, retinopathy and neuropathy, the outcome was not significantly different between the treatment groups, but among the participants who had not developed diabetes during DPP/DPPOS, the prevalence of the aggregate microvascular outcome was 28% lower compared with those who had developed diabetes (Risk Ratio 0.72, 95% CI 0.63–0.83; p<0.0001). No prospective comparative data for metformin on macrovascular outcomes in patients with IGT and/or IFG and/or increased HbA1C are available.

Published risk factors for type 2 diabetes include: Asian or black ethnic background, age above 40, dyslipidaemia, hypertension, obesity or being overweight, age, 1st degree family history of diabetes, history of gestational diabetes mellitus, and polycystic ovary syndrome (PCOS).

Treatment of type 2 diabetes mellitus

The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood glucose control in overweight type 2 diabetic patients treated with immediate release metformin as first-line therapy after diet failure. Analysis of the results showed:

• a significant reduction of the absolute risk of any diabetes-related complication in the metformin group (29.8 events/1000 patient-years) versus diet alone (43.3 events/1000 patient-years), p=0.0023, and versus the combined sulphonylurea and insulin monotherapy groups (40.1 events/1000 patient-years), p=0.0034.
• a significant reduction of the absolute risk of diabetes-related mortality: metformin5 events/1000 patient-years, diet alone 12.7 events/1000 patient-years, p=0.017;
• a significant reduction of the absolute risk of overall mortality: metformin5 events/1000 patient-years versus diet alone 20.6 events/1000 patient-years (p=0.011), and versus the combined sulphonylurea and insulin monotherapy groups 18.9 events/1000 patient-years (p=0.021);
• a significant reduction in the absolute risk of myocardial infarction: metformin 11 events/1000 patient-years, diet alone 18 events/1000 patient-years (p=0.01)

For metformin used as second-line therapy, in combination with a sulphonylurea, benefit regarding clinical outcome has not been shown.

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

Pharmacokinetics

Absorption

After an oral dose of prolonged release tablet, metformin absorption is significantly delayed compared to the immediate release tablet.

Following a single oral administration in the fed state of one tablet of Metformin 1000 mg prolonged release tablets, a mean peak plasma concentration of 1214 ng/ml is achieved with a median time of 5 hours (range of 4 to 10 hours).

At steady state, similar to the immediate release formulation, maximum concentration C_max and area under the curve AUC are not proportionally increased to the administered dose. The AUC after a single oral administration of 2000 mg of metformin hydrochloride prolonged release tablets is similar to that observed after administration of 1000 mg of metformin hydrochloride immediate release tablets b.i.d.

Intrasubject variability of C_max and AUC of metformin hydrochloride prolonged release tablets is comparable to that observed with metformin hydrochloride immediate release tablets.

When the 1000 mg prolonged release tablet is administered in fed conditions the AUC is increased by 77% (C_max is increased by 26% and T_max is slightly prolonged by about 1 hour).

Mean metformin absorption from the prolonged release formulation is almost not altered by meal composition. No accumulation is observed after repeated administration of up to 2000 mg of metformin hydrochloride as prolonged release tablets.

Distribution. Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower than the plasma peak and appears approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean volume of distribution (Vd) ranged between 63 – 276 L.

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

Elimination. Renal clearance of metformin is > 400 ml/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 h. When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin in plasma.

Special populations

Renal impairment

The available data in subjects with moderate renal insufficiency are scarce and no reliable estimation of the systemic exposure to metformin in this subgroup as compared to subjects with normal renal function could be made. Therefore, the dose adaptation should be made upon clinical efficacy/tolerability considerations (see section “Posology and method of administration”).

Clinical particulars

Indications

• Reduction in the risk or delay of the onset of type 2 diabetes mellitus in adult, overweight patients with IGT* and/or IFG*, and/or increased HbA1C who are:
• at high risk for developing overt type 2 diabetes mellitus (see section “Pharmacodynamics”);
• still progressing towards type 2 diabetes mellitus despite implementation of intensive lifestyle change for 3 to 6 months.

Treatment with Diaformin^® SR prolonged release tablet must be based on a risk score incorporating appropriate measures of glycaemic control and including evidence of high cardiovascular risk.

Lifestyle modifications should be continued when metformin is initiated, unless the patient is unable to do so because of medical reasons.

*IGT: Impaired Glucose Tolerance; IFG:  Impaired Fasting Glucose.

• Treatment of type 2 diabetes mellitus in adults, particularly in overweight patients, when dietary management and exercise alone does not result in adequate glycaemic control. Diaformin^® SR prolonged release tablets may be used as monotherapy or in combination with other oral antidiabetic agents, or with insulin.

Contraindications

– Hypersensitivity to metformin or any of the drug component;

– any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis);

– diabetic pre-coma;

– severe renal failure (glomerular filtration rate (GFR) < 30 mL/min);

– acute conditions with the potential to alter renal function such as: dehydration, severe infection, shock;

– disease which may cause tissue hypoxia (especially acute disease, or worsening of chronic disease) such as: decompensated heart failure, respiratory failure, recent myocardial infarction or shock;

– hepatic insufficiency, acute alcohol intoxication or alcoholism.

Interaction with other medicinal products and other forms of interaction

Concomitant use not recommended

Alcohol

Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in case of fasting or malnutrition, hepatic insufficiency.

Iodinated contrast media

Metformin should be discontinued prior to, or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable (see sections “Posology and method of administration” and “Special warnings and precautions for use”).

Combinations to be used with caution

Some medicinal products can adversely affect renal function which may increase the risk of lactic acidosis, e.g. nonsteroidal anti-inflammatory drugs (NSAID), including selective cyclooxygenase (COX) II inhibitors, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists and diuretics, especially loop diuretics. When starting or using such products in combination with metformin, close monitoring of renal function is necessary.

Medicinal products with intrinsic hyperglycaemic activity (e.g. glucocorticoids (systemic and local routes) and sympathomimetics). More frequent blood glucose monitoring may be required, especially at the beginning of treatment. If necessary, adjust Diaformin^® SR dosage during therapy with the respective medicinal product and upon its discontinuation.

Organic cation transporters (OCT). Metformin is a substrate of both transporters OCT1 and OCT2.

Co-administration of metformin with

– inhibitors of OCT1 (such as verapamil) may reduce efficacy of metformin;

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

– inhibitors of OCT2 (such as cimetidine, dolutegravir, ranolazine, trimethoprime, vandetanib, isavuconazole) may decrease the renal elimination of metformin and thus lead to an increase in metformin plasma concentration;

– inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may alter efficacy and renal elimination of metformin.

Caution is therefore advised, especially in patients with renal impairment, when these drugs are co-administered with metformin, as metformin plasma concentration may increase. If needed, dose adjustment of metformin may be considered as OCT inhibitors/inducers may alter the efficacy of metformin.

Special warnings and precautions for use

Lactic acidosis, a very rare but serious metabolic complication, most often occurs at acute worsening of renal function or cardiorespiratory illness or sepsis. Metformin accumulation occurs at acute worsening of renal function and increases the risk of lactic acidosis. In case of dehydration (severe diarrhoea or vomiting, fever or reduced fluid intake), metformin should be temporarily discontinued and contact with a health care professional is recommended.

Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and NSAIDs) should be initiated with caution in metformin-treated patients.

Other risk factors for lactic acidosis are excessive alcohol intake, hepatic insufficiency, inadequately controlled diabetes, ketosis, prolonged fasting and any condition associated with hypoxia, as well as concomitant use of medicinal products that may cause lactic acidosis (see also sections “Contraindications” and “Interaction with other medicinal products and other forms of interaction”).

Patients and/or their caregivers should be informed of the risk of lactic acidosis.

Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. In case of suspected symptoms, the patient should stop taking metformin and seek immediate medical attention.

Diagnostic laboratory findings are decreased blood pH (<7.35), increased plasma lactate levels (>5 mmol/L) and an increased anion gap and lactate/pyruvate ratio.

Renal impairment

GFR should be assessed before treatment initiation and regularly thereafter, see section “Posology and method of administration”). Metformin is contraindicated in patients with GFR < 30 mL/min and should be temporarily discontinued in the presence of conditions that alter renal function (see section “Contraindications”).

Cardiac function

Patients with heart failure are more at risk of hypoxia and renal insufficiency. In patients with stable chronic heart failure, metformin may be used with a regular monitoring of cardiac and renal function. For patients with acute and unstable heart failure, metformin is contraindicated (see section “Contraindications”).

Elderly

Benefit in the reduction of risk or delay of the onset of type 2 diabetes mellitus has not been established in patients 75 years and older and metformin initiation is therefore not recommended in these patients.

Iodinated contrast agents

Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy resulting in metformin accumulation and an increased risk of lactic acidosis. Metformin should be discontinued prior to, or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable (see sections “Posology and method of administration” and “Interaction with other medicinal products and other forms of interaction”).

Surgery

Diaformin^® SR must be discontinued at the time of surgery under general, spinal or epidural anaesthesia. Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and provided that renal function has been re-evaluated and found to be stable.

Other precautions

Patients should continue their diet with a regular distribution of carbohydrate intake during the day. Overweight patients should continue their energy-restricted diet. The usual laboratory tests for diabetes monitoring should be performed regularly.

Metformin alone does not cause hypoglycaemia, but caution is advised when Diaformin^® SR is used in combination with insulin or other oral antidiabetics (e.g. sulfonylureas or meglitinides).

Tablet coating fragments may be found in the feces. This is normal and has no clinical significance.

Use during pregnancy and lactation

Pregnancy

Uncontrolled diabetes during pregnancy (gestational or permanent) is associated with increased risk of congenital abnormalities and perinatal mortality. A limited amount of data from the use of metformin in pregnant women does not indicate an increased risk of congenital abnormalities. Animal studies do not indicate harmful effects with respect to pregnancy, embryonic or foetal development, parturition or postnatal development. When the patient plans to become pregnant and during pregnancy, it is recommended that diabetes is not treated with metformin but insulin be used to maintain blood glucose levels as close to normal as possible, to reduce the risk of malformations of the foetus.

Breast-feeding

Metformin is excreted into human breast milk. No adverse effects were observed in breastfed newborns/infants. However, as only limited data are available, breastfeeding is not recommended during treatment with metformin. A decision on whether to discontinue breast-feeding should be made, taking into account the benefit of breastfeeding and the potential risk to adverse effects on the child.

Fertility

Fertility of animals was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons.

Effects on speed of reactions when driving or using machinery

Metformin monotherapy does not cause hypoglycaemia and therefore Diaformin^® SR has no effect on the ability to drive or to use machines.

However, patients should be alerted to the risk of hypoglycaemia when metformin is used in combination with other antidiabetic agents (e.g. sulfonylureas, insulin, or meglitinides).

Posology and method of administration

The tablets should be swallowed whole without chewing.

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

Reduction in the risk or delay of type 2 diabetes mellitus

Metformin should only be considered where intensive lifestyle modifications for 3 to 6 months have not resulted in adequate glycaemic control.

The therapy should be initiated with one tablet Diaformin^® SR 500 mg prolonged release tablet once daily with the evening meal.

After 10 to 15 days dose adjustment on the basis of blood glucose measurements is recommended (OGTT (oral glucose tolerance test) and/or FPG (fasting plasma glucose) and/or HbA1C values to be within the normal range). A slow increase of dose may improve gastro-intestinal tolerability.  The maximum recommended dose is 2000 mg once daily with the evening meal.

It is recommended to regularly monitor (every 3-6 months) the glycaemic status (OGTT and/or FPG and/or HbA1c value) as well as the risk factors to evaluate whether treatment needs to be continued, modified or discontinued.

A decision to re-evaluate therapy is also required if the patient subsequently implements improvements to diet and/or exercise, or if changes to the medical condition will allow increased lifestyle interventions to be possible.

Monotherapy and combination with other oral antidiabetic agents

The recommended initial dose is 500 mg daily.

After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability. The highest recommended dose is 2000 mg once daily.

Diaformin^® SR should be taken once daily with meals in the evening, increasing by 500 mg every 10-15 days to 2000 mg. If the required glycemic level cannot be achieved with Diaformin^® SR at a maximum dose of 2000 mg taken by the patient once daily, this dose can be divided into two 1000 doses daily during meals. If the required glycemic level is not reached, Diaformin^® can be used at the maximum recommended dose of 3000 mg daily.

The dose of Diaformin^® SR prolonged release tablet should be equivalent to the daily dose of metformin immediate release tablets to the maximal dose of 2000 mg in the evening during meals.

Combination with insulin

Metformin and insulin may be used in combination therapy to achieve better blood glucose control. The usual starting dose of Diaformin^® SR is 500 mg daily during evening meal, while insulin dosage is adjusted on the basis of blood glucose measurements.

For patients already treated with metformin and insulin in combination therapy, the dose of Diaformin® SR should be equivalent to the already used daily dose of metformin tablets up to a maximum of 2000 mg respectively, given with the evening meal, while insulin dosage is adjusted on the basis of blood glucose measurements.

In elderly patients due to potential for decreased renal function in elderly subjects, the metformin dosage should be adjusted based on renal function. Regular assessment of renal function is necessary (see section “Special warnings and precautions for use”).

Benefit in the reduction of risk or delay of the onset of type 2 diabetes mellitus has not been established in patients 75 years and older (see section “Pharmacodynamics”) and metformin initiation is therefore not recommended in these patients (see section “Special warnings and precautions for use”).

Renal impairment

A GFR should be assessed before initiation of treatment with metformin containing products and at least annually thereafter. In patients at an increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months.

Paediatric population

Do not use in children as there are no clinical data on this age group of patients.

Overdose

Hypoglycaemia has not been seen with the doses of up to 85 g, although lactic acidosis has occurred in such circumstances. High overdose of metformin or concomitant risks may lead to lactic acidosis. Lactic acidosis is a medical emergency. In case of lactic acidosis, Diaformin® SR should be discontinued and the patient should be hospitalised immediately. The most effective method to remove lactate and metformin is haemodialysis.

Undesirable effects

In post marketing data and in controlled clinical studies, adverse event reporting in patients treated with Metformin hydrochloride prolonged release tablet was similar in nature and severity to that reported in patients treated with Metformin hydrochloride immediate release.

During treatment initiation, the most common adverse reactions are nausea, vomiting, diarrhoea, abdominal pain and loss of appetite which resolve spontaneously in most cases.

The following definitions apply to the frequency terminology used hereafter: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000).

Metabolism and nutrition disorders

Very rare: lactic acidosis (see “Special warnings and precautions for use”).

Decrease of vitamin B₁₂ absorption with decrease of serum levels during long term use of metformin hydrochloride. Consideration of such aetiology is recommended if a patient present with megaloblastic anaemia.

Nervous disorders

Common: taste disturbance.

Gastrointestinal disorders

Very common: nausea, vomiting, diarrhoea, abdominal pains, loss of appetite. These undesirable effects occur most frequently during initiation of therapy and resolve spontaneously in most cases. A slow increase of dose may improve gastrointestinal tolerability.

Hepatobiliary disorders

Very rare: isolated reports of liver function tests abnormalities or hepatitis resolving upon metformin discontinuation.

Skin and subcutaneous tissue disorders

Very rare: skin reactions such as erythema, pruritus, urticaria.

Shelf life

3 years.

Do not use after expiry date indicated on the carton.

Storage          

Store below 30 °С.

Keep out of the reach of children.

Nature and contents of container

10 tablets in a blister. 3, 6 or 10 blisters per carton (in bulk packaging of the manufacturer USV Private Limited, India).

Prescription status

Prescription only.

Manufacturer

JSC Farmak

Location and address of manufacturer

74, Kyrylivska str., Kyiv, 04080, Ukraine.

Date of revision of the text

20.10.2021.