Active ingredients: Metformin (metformin hydrochloride)
METFORAL 850 mg film-coated tablets
Metforal package inserts are available for pack sizes:- METFORAL 850 mg film-coated tablets
- METFORAL 500 mg film-coated tablets
Why is Metforal used? What is it for?
PHARMACOTHERAPEUTIC CATEGORY
Oral antidiabetic
THERAPEUTIC INDICATIONS
Treatment of type 2 diabetes mellitus, particularly in overweight patients, when diet and exercise alone are not sufficient for adequate glycemic control.
- In adults Metforal can be used alone or in combination with other oral antidiabetic medicines or together with insulin.
- In children over 10 years of age and adolescents, Metforal can be used alone or in combination with insulin.
A reduction in diabetes complications has been demonstrated in overweight adult type 2 diabetes patients treated with metformin as first-line therapy after diet failure.
Contraindications When Metforal should not be used
- Hypersensitivity to metformin hydrochloride or to any of the excipients.
- Diabetic ketoacidosis, diabetic pre-coma.
- Renal failure or renal dysfunction (creatinine clearance
- Acute conditions with the possibility of impaired renal function such as: - dehydration - severe infection - shock
- Intravenous or intra-arterial administration of iodinated contrast agents (see Special Warnings).
- Acute or chronic diseases that may cause tissue hypoxia such as: - heart or respiratory failure - recent myocardial infarction - shock - Hepatic failure, acute alcohol intoxication, alcoholism
- Pregnancy and breastfeeding (see Special warnings).
Precautions for use What you need to know before taking Metforal
Lactic acidosis
Lactic acidosis is a rare but serious (high mortality rate in the absence of immediate treatment) metabolic complication, which may arise following accumulation of metformin. The reported cases of lactic acidosis in patients treated with metformin have mainly occurred in Diabetic patients with severe renal insufficiency. The incidence of lactic acidosis can and should be reduced by evaluating other associated risk factors, such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, liver failure and any other associated conditions. to hypoxia. Patients should be instructed to recognize the warning symptoms of lactic acidosis such as muscle cramps with digestive disturbances such as abdominal pain and severe asthenia. If lactic acidosis is suspected, patients should discontinue metformin hydrochloride and notify their physician promptly. Lactic acidosis is characterized by dyspnoea with acidosis, abdominal pain and hypothermia followed by coma. Physicians should alert patients to the risk of lactic acidosis and explain the symptoms.
Kidney function
Since metformin is excreted by the kidneys, creatinine clearance should be determined before starting treatment and regularly thereafter (at least annually in patients with normal renal function, at least two to four times a year in patients with normal renal function). patients with serum creatinine clearance levels at the lower limit of normal and in elderly subjects). Decreased renal function in the elderly is frequent and asymptomatic. Particular attention should be paid to situations in which renal function may be compromised, for example when initiating antihypertensive therapy, therapy with diuretics or when initiating therapy with non-steroidal anti-inflammatory drugs (NSAIDs).
Administration of iodinated contrast agents
Intravascular administration of iodinated contrast media in radiological investigations can lead to renal failure. This can cause an accumulation of metformin which increases the risk of lactic acidosis. Metformin administration should be discontinued before or at the time of examination. and should not be resumed until 48 hours after the examination and only after having checked that renal function is normal.
Surgery
Metformin administration should be discontinued 48 hours prior to scheduled surgery under general, spinal or epidural anesthesia. Treatment can be resumed no earlier than 48 hours after surgery or resumption of oral feeding and only after demonstrating normal renal function.
Children and adolescents:
The diagnosis of type 2 diabetes mellitus must be confirmed before starting treatment with metformin.
During controlled clinical trials lasting one year, no effects of metformin on growth and puberty were found; however, no long-term data are available on these specific aspects. It is therefore recommended to carefully observe the possible effects of metformin with respect to these parameters in children treated with metformin, particularly in those children in the prepubertal period.
Children aged between 10 and 12:
Only 15 subjects between the ages of 10 and 12 were included in the controlled clinical trials in children and adolescents. Although the efficacy and safety of metformin in these children did not differ from the efficacy and safety in older children. and in adolescents, special care is recommended when prescribing metformin to children between the ages of 10 and 12 years.
Other precautions
All patients should continue their diet by distributing their carbohydrate intake regularly throughout the day. Overweight patients should continue on a low calorie diet. The laboratory tests normally required in cases of diabetes should be performed regularly. Metformin Hydrochloride alone never causes hypoglycaemia, although caution is advised when used in combination with insulin or other oral antidiabetic agents (eg sulfonylureas or meglitinides).
Interactions Which drugs or foods can modify the effect of Metforal
Tell your doctor or pharmacist if you have recently taken any other medicines, including those obtained without a prescription.
Combinations not recommended
Alcohol
Increased risk of lactic acidosis in acute alcohol poisoning, especially in cases of:
- fasting or malnutrition
- liver failure
Avoid consumption of alcohol and alcohol-containing medications.
Iodized contrast agents
Intravascular administration of iodinated contrast agents may cause renal failure, with consequent accumulation of metformin and risk of lactic acidosis. Metformin should therefore be discontinued before or at the time of analysis, resuming administration no earlier than 48 hours after the test. "examination and only after checking that the kidney function has returned to normal (see section" Precautions for use ").
Associations requiring precautions for use
- Medicinal products with intrinsic hyperglycemic activity (such as systemic and local glucocorticoids and sympathomimetics). Inform the patient and perform more frequent blood glucose checks, especially at the start of treatment. If necessary, adjust the metformin dosage during therapy with the other drug.
- Diuretics, particularly loop diuretics, may increase the risk of lactic acidosis due to their ability to reduce kidney function.
- In case of concomitant use of metformin (especially at high doses) with cationic drugs eliminated by renal tubular secretion (eg: ranolazine and cimetidine) close monitoring of glycemic control should be considered. recommended posology and changes in the treatment of diabetic disease.
Warnings It is important to know that:
Each treatment and in particular the transition from or to other hypoglycemic agents, must be prescribed by the doctor. It is necessary to strictly adhere to the medical prescriptions regarding the dosage and methods of intake, as well as with regard to the concomitant dietary regimen and physical activity.
Pregnancy and breastfeeding
Pregnancy
Uncontrolled diabetes during pregnancy (gestational or permanent) is associated with an increased risk of congenital anomalies and perinatal mortality. A limited amount of data on the intake of metformin by pregnant women does not indicate an increased risk of congenital abnormalities. Animal studies do not indicate harmful effects with respect to pregnancy, embryonic or fetal development, parturition or birth. postnatal development. When the patient plans to become pregnant and during pregnancy itself, it is recommended not to treat diabetes with metformin but to use insulin to keep blood glucose levels as close to normal as possible and thereby reduce risks of fetal malformations
Feeding time
Metformin is excreted in breast milk. No adverse reactions were observed in breastfed newborns / infants. However, as only limited data are available, breastfeeding is not recommended during treatment with metformin. A decision must therefore be made whether to discontinue breastfeeding considering the benefits of breastfeeding and the possible risk of adverse events for the baby.
Effects on ability to drive and use machines
Metformin alone does not cause hypoglycaemia, therefore it has no or negligible influence on the ability to drive or use machines. However, patients should be advised of the risk of hypoglycaemia when metformin is used in combination with other antidiabetic drugs (sulfonylureas, insulin, meglitinides).
Dosage and method of use How to use Metforal: Dosage
Adults
Monotherapy and combination with other oral antidiabetic drugs
- Usually the starting dose is one tablet 2 or 3 times a day taken with or after meals. After 10-15 days the dose should be adjusted on the basis of the blood glucose level. A gradual increase in dosage can improve gastrointestinal tolerability. The maximum recommended dose of metformin hydrochloride is 3 g per day, taken in 3 divided doses.
- In case of switching from another oral antidiabetic drug to metformin hydrochloride: discontinue the previous drug and start with metformin at the dose indicated above.
Combination with insulin
Metformin hydrochloride and insulin can be used in combination to improve blood glucose control. Metformin hydrochloride is administered at the usual starting dose of 2-3 times a day, while the insulin dose is adjusted based on the blood level. of glucose.
Senior citizens
Due to possible impaired renal function in elderly patients, metformin dosage should be adjusted based on renal function. A periodic evaluation of renal function is therefore necessary.
Children over the age of 10 and adolescents
Monotherapy and association with insulin
The starting dose generally consists of administering one coated tablet once a day with or after a meal.
After 10-15 days the dose should be adjusted based on the blood glucose level. A gradual increase in dosage may improve the gastrointestinal tolerability of the medicinal product.
The maximum recommended dose of metformin hydrochloride is 2 g per day, taken in 2 or 3 divided doses.
Overdose What to do if you have taken too much Metforal
No forms of hypoglycaemia have been observed with metformin hydrochloride dosages up to 85 g, although lactic acidosis has developed under such circumstances. Severe overdoses or concomitant risks of metformin can lead to lactic acidosis.
Lactic acidosis is an emergency medical case and should be treated in a hospital. The most effective method of eliminating lactate and metformin is hemodialysis.
Side Effects What are the side effects of Metforal
- Gastrointestinal symptoms such as nausea, vomiting, diarrhea, abdominal pain and loss of appetite are very common (frequency ≥10%): they generally occur at the start of therapy and in most cases resolve spontaneously. To prevent the onset of these gastrointestinal symptoms it is recommended to take metformin in 2 or 3 daily doses during or after meals. A gradual increase in dosage can improve gastrointestinal tolerability.
- Metallic taste in the mouth (3% frequency) is common.
- A slight erythema has been found in some hypersensitive individuals. However, the incidence of this effect is very rare (frequency <0.01%) - A decrease in vitamin B12 absorption with reduced serum levels has been observed very rarely in patients receiving long-term metformin treatment (frequency < 0.01%). This should be considered as a possible cause in patients with megaloblastic anemia.
- Lactic acidosis (0.03 cases / 1000 patient years) is very rare.
- There have been isolated reports of liver function test abnormalities or hepatitis which resolved upon discontinuation of metformin hydrochloride.
Children and adolescents
In published and post-marketing data and in controlled clinical trials in a limited pediatric population aged 10 to 16 years undergoing 1 year treatment, the reported undesirable effects were similar in type and severity to those reported. for adults.
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. Undesirable effects can also be reported directly through the national reporting system at "www.agenziafarmaco.gov.it/it/responsabili". By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Expiry: see the expiry date printed on the package.
The expiry date indicated refers to the product in intact packaging, correctly stored.
Warning: do not use the medicine after the expiry date shown on the package.
Store the medicine in a dry place. Keep this medicine out of the sight and reach of children
Composition and pharmaceutical form
COMPOSITION
Each film-coated tablet contains:
Active ingredient: 850 mg of metformin hydrochloride, equivalent to 662.9 mg of metformin
Excipients: anhydrous colloidal silica, povidone, macrogol 4000, magnesium stearate, Opadry II 85F29116 clear (polyvinyl alcohol, macrogol 3350, talc).
PHARMACEUTICAL FORM AND CONTENT
Round, biconvex, white film-coated tablet. 30 coated tablets
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
METFORAL
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
METFORAL 500 mg film-coated tablets
Each film-coated tablet contains:
500 mg of metformin hydrochloride, equivalent to 390 mg of metformin.
METFORAL 850 mg film-coated tablets
Each film-coated tablet contains:
850 mg of metformin hydrochloride, equivalent to 662.9 mg of metformin.
For the full list of excipients see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablets
METFORAL 500 mg film-coated tablets:
Round, biconvex, white film-coated tablet.
METFORAL 850 mg film-coated tablets:
White, oblong film-coated tablet with a pre-break line on both sides.
The score line on the tablet is to facilitate breaking for easier swallowing and not to divide into equal doses.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Treatment of type 2 diabetes mellitus, particularly in overweight patients, when diet and exercise alone are not sufficient for adequate glycemic control.
• In adults METFORAL 500 mg / METFORAL 850 mg can be used alone or in combination with other oral antidiabetic medicines or together with insulin.
• In children over 10 years of age and adolescents, METFORAL 500 mg / METFORAL 850 mg can be used alone or in combination with insulin.
A reduction in diabetes complications has been demonstrated in overweight type 2 diabetic adult patients treated with metformin as first-line therapy after diet failure (see section 5.I.).
04.2 Posology and method of administration
Adults
Monotherapy
The usual starting dose is 500 mg or 850 mg of metformin hydrochloride 2 or 3 times a day taken with or after meals.
After 10-15 days the dose should be adjusted on the basis of the blood glucose level. A gradual increase in dosage can improve gastrointestinal tolerability.
The maximum recommended dose of metformin hydrochloride is 3 g per day, taken in 3 divided doses.
In case of switching from another oral antidiabetic drug: discontinue the previous drug and start with metformin hydrochloride at the dose indicated above.
Combination therapy with insulin
Metformin hydrochloride and insulin can be used in combination to improve blood glucose control. Metformin hydrochloride is administered at the usual starting dose of 500 mg or 850 mg 2 or 3 times a day, while the insulin dose is adjusted. based on the blood glucose level.
Senior citizens
Due to possible impaired renal function in elderly patients, metformin hydrochloride dosage should be adjusted based on renal function. Therefore, periodic evaluation of renal function is required (see section 4.4).
Pediatric population
Monotherapy and association with insulin
• METFORAL 500 mg / METFORAL 850 mg can be used in children over 10 years of age and adolescents.
• The starting dose usually consists of the administration of 500 mg or 850 mg of metformin hydrochloride once daily with or after a meal.
After 10-15 days the dose should be adjusted based on the blood glucose level. A gradual increase in dosage may improve the gastrointestinal tolerability of the medicinal product. The maximum recommended dose of metformin hydrochloride is 2 g per day, taken in 2 or 3 divided doses.
04.3 Contraindications
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
- Diabetic ketoacidosis, diabetic pre-coma.
- Renal failure or renal dysfunction (creatinine clearance
- Acute conditions with the possibility of impaired renal function such as: dehydration, severe infection, shock
- Acute or chronic diseases that can cause tissue hypoxia such as: heart or respiratory failure, recent myocardial infarction, shock
- Liver failure, acute alcohol intoxication, alcoholism
04.4 Special warnings and appropriate precautions for use
Lactic acidosis
Lactic acidosis is a rare but serious (high mortality rate in the absence of immediate treatment) metabolic complication, which may arise following accumulation of metformin. The reported cases of lactic acidosis in patients treated with metformin have mainly occurred in Diabetic patients with severe renal insufficiency. The incidence of lactic acidosis can and should be reduced by evaluating other associated risk factors, such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, liver failure and any other associated conditions. to hypoxia.
Diagnosis:
The risk of lactic acidosis should be considered in case of non-specific symptoms such as muscle cramps with digestive disorders such as abdominal pain and severe asthenia.
Lactic acidosis is characterized by dyspnoea with acidosis, abdominal pain and hypothermia followed by coma. Diagnostic laboratory tests show a decrease in blood pH, plasma lactate levels above 5 mmol / l, and an increase in the anion gap. and lactate / pyruvate ratio If metabolic acidosis is suspected, discontinue metformin and admit the patient immediately (see section 4.9).
Physicians should warn patients of the risk of lactic acidosis and explain the symptoms.
Kidney function
As metformin is excreted by the kidneys, creatinine clearance (which can be assessed based on serum creatinine levels using the Cockcroft-Gault formula) should be determined before starting treatment and regularly thereafter. :
- at least annually in patients with normal renal function,
- at least two to four times a year in patients with creatinine clearance levels at the lower limit of normal and in elderly subjects.
Decreased renal function in the elderly is frequent and asymptomatic. Particular attention should be paid to situations in which renal function may be compromised, for example when initiating antihypertensive therapy, therapy with diuretics or when initiating therapy with non-steroidal anti-inflammatory drugs (NSAIDs).
Administration of iodinated contrast agents
Intravascular administration of iodinated contrast media in radiological investigations can lead to renal failure. This can cause an accumulation of metformin which increases the risk of lactic acidosis.
Metformin administration should be discontinued before or at the time of examination and should not be resumed until 48 hours later and only after double-checking that renal function is normal (see section 4.5).
Surgical interventions
Metformin administration should be discontinued 48 hours prior to scheduled surgery under general, spinal or epidural anesthesia. Treatment can be resumed no earlier than 48 hours after surgery or resumption of oral feeding and only after demonstrating normal renal function.
Other precautions
All patients should continue their diet with a regular distribution of carbohydrate intake throughout the day. Overweight patients should continue the low calorie diet.
The laboratory tests normally required in cases of diabetes will need to be performed regularly.
Metformin alone does not cause hypoglycaemia, although caution is advised when used in combination with insulin or other oral antidiabetic agents (eg sulfonylureas or meglitinides).
Pediatric population
The diagnosis of type 2 diabetes mellitus must be confirmed before starting treatment with metformin.
During controlled clinical trials lasting one year, no effects of metformin on growth and puberty were found; however, no long-term data are available on these specific aspects. It is therefore recommended to carefully observe the possible effects of metformin with respect to these parameters in children treated with metformin, particularly in those children in the prepubertal period.
Children aged between 10 and 12 years
Only 15 subjects between the ages of 10 and 12 were included in the controlled clinical trials in children and adolescents. Although the efficacy and safety of metformin in these children did not differ from the efficacy and safety in older children. and in adolescents, special care is recommended when prescribing metformin to children between the ages of 10 and 12 years.
04.5 Interactions with other medicinal products and other forms of interaction
CONCOMITANT USE NOT RECOMMENDED
Alcohol
• Acute alcohol intoxication is associated with an increased risk of lactic acidosis, especially in cases of:
• fasting or malnutrition,
• liver failure.
• Avoid consumption of alcohol or alcohol-containing drugs.
Iodized contrast agents
• Intravascular administration of iodinated contrast agents may cause renal failure, resulting in accumulation of metformin and risk of lactic acidosis.
Metformin should therefore be discontinued before or at the time of analysis, resuming administration no earlier than 48 hours after examination and only after checking for normal renal function (see section 4.4).
ASSOCIATIONS REQUIRING PRECAUTION FOR USE
• Medicinal products with intrinsic hyperglycemic activity (such as systemic and local glucocorticoids and sympathomimetics). More frequent blood glucose checks may be needed, especially at the start of treatment. If necessary, adjust the metformin dosage during therapy with the other drug.
• Diuretics, especially loop diuretics, may increase the risk of lactic acidosis due to their ability to reduce kidney function.
• Medicines transported by the Organic Cation Transporter-2 (OCT2), eg. ranolazine or cimetidine:
In subjects with type II diabetes mellitus, concomitant administration of metformin (1000 mg twice daily) and ranolazine 500 mg and 1000 mg twice daily increased the plasma exposure of metformin 1.4 and 1.8-fold, respectively. One study conducted in seven healthy volunteers showed that cimetidine, given at a dose of 400 mg twice daily, increased the systemic exposure of metformin (AUC) by 50% and the Cmax by 81%.
Therefore, close monitoring of glycemic control, dose adjustment within the recommended posology and changes in the treatment of diabetic disease should be considered during concomitant administration of metformin and cationic drugs that are cleared by renal tubular secretion.
04.6 Pregnancy and lactation
Pregnancy
Uncontrolled diabetes during pregnancy (gestational or permanent) is associated with an increased risk of congenital anomalies and perinatal mortality.
A limited amount of data on the intake of metformin by pregnant women does not indicate an increased risk of congenital abnormalities. Animal studies do not indicate harmful effects with respect to pregnancy, embryonic or fetal development, parturition or development postnatal.
When the patient plans to become pregnant and during pregnancy itself, it is recommended not to treat diabetes with metformin, but to use insulin to keep blood glucose levels as close to normal as possible, in order to reduce the risk of malformations. fetal.
Feeding time
Metformin is excreted in human breast milk. No effect of metformin has been shown in breastfed newborns / infants of treated women. However, as only limited data are available, breastfeeding is not recommended during treatment with metformin. A decision must therefore be made whether to discontinue breastfeeding, considering the benefits of breastfeeding and the possible risk of adverse events for the baby.
Fertility
The fertility of male or female rats was not affected by metformin when administered at doses up to 600 mg / kg / day, which is approximately three times the maximum recommended human daily dose for body surface area.
04.7 Effects on ability to drive and use machines
Metformin alone does not cause hypoglycaemia, therefore it has no or negligible influence on the ability to drive or use machines. However, patients should be advised of the risk of hypoglycaemia when metformin is used in combination with other antidiabetic agents (sulfonylureas, insulin, meglitinides).
04.8 Undesirable effects
The following adverse reactions can occur during treatment with metformin.
Frequencies are defined as follows: very common: ≥ 1/10; common:> 1/100, ≥ 1/10; uncommon:> 1/1000, ≥ 1/100; rare:> 1 / 10,000, ≥ 1 / 1,000; very rare: ≥ 1 / 10,000, not known (cannot be estimated from the available data)
Nervous system disorders:
Common: Changes in taste
Gastrointestinal disorders:
Very common: Gastrointestinal disorders such as nausea, vomiting, diarrhea, abdominal pain and loss of appetite. These side effects occur more frequently during the initiation of therapy and resolve spontaneously in most cases. To avoid these effects, it is recommended that metformin be taken 2 or 3 times a day with or after meals. A gradual increase in dosage can also improve gastrointestinal tolerability.
Skin and subcutaneous tissue disorders:
Very rare:
skin reactions such as erythema, itching and hives.
Metabolism and nutrition disorders:
Very rare:
- lactic acidosis (see section 4.4).
- Decreased absorption of vitamin B12 with decreased serum levels has been observed in patients treated long-term with metformin. This should be considered as a possible cause in patients with megaloblastic anemia.
Hepatobiliary disorders:
Very rare:
There have been isolated reports of liver function test abnormalities or hepatitis which resolved upon discontinuation of metformin treatment.
Pediatric population
In published and post-marketing data and in controlled clinical trials in a limited pediatric population aged 10 to 16 years undergoing 1 year treatment, the reported undesirable effects were similar in nature and severity to those reported. for adults.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions that occur after authorization of the medicine is important. It allows for continuous monitoring of the benefit / risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. address http://www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
No forms of hypoglycaemia have been observed with metformin hydrochloride dosages up to 85 g, although lactic acidosis has developed under such circumstances. Severe overdoses or concomitant risks of metformin can lead to lactic acidosis. Lactic acidosis is an emergency medical case and should be treated in a hospital. The most effective method of eliminating lactate and metformin is hemodialysis.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
ORAL HYPOGLYCEMISATION
Pharmacotherapeutic group: hypoglycemic agents, excluding insulins. Biguianids.
ATC code: A10BA02.
Mechanism of action
Metformin can act through 3 mechanisms:
Reduction of hepatic glucose production through inhibition of gluconeogenesis and glycogenolysis;
In the muscles, increasing insulin sensitivity, improving the uptake and utilization of glucose at the peripheral level;
Delaying intestinal absorption of glucose.
Metformin stimulates intracellular glycogenosynthesis by acting on glycogen synthetase.
Metformin increases the transport capacity of all currently known types of membrane glucose transporters (GLUT).
Pharmacodynamic effects
Metformin is a biguanide with antiperglycemic effects, which reduces basal and postprandial blood glucose. It does not stimulate insulin secretion and therefore does not cause hypoglycemia.
In humans, regardless of its action on glycaemia, metformin has favorable effects on lipid metabolism. This phenomenon has been demonstrated at therapeutic doses in medium and long-term controlled clinical trials: metformin reduces the levels of total cholesterol, LDL cholesterol and triglycerides.
Clinical efficacy and safety
The prospective randomized study (UKPDS) demonstrated the long-term benefit of intensive blood glucose control in adult patients with type 2 diabetes.
Analysis of the results of overweight patients treated with metformin hydrochloride after dietary failure alone demonstrated the following:
- a significant reduction in the absolute risk of diabetes-related complications in the metformin hydrochloride group (29.8 events / 1000 patient years) compared to the diet alone (43.3 events / 1000 patient years), p = 0.0023, and compared to the insulin and sulfonylurea monotherapy groups (40.1 events / 1000 patient years), p = 0.0034;
- a significant reduction in the absolute risk of diabetes-related mortality: metformin hydrochloride 7.5 events / 1000 patient years, diet alone 12.7 events / 1000 patient years, p = 0.017;
- a significant reduction in the absolute risk of overall mortality: metformin hydrochloride 13.5 events / 1000 patient years compared to diet alone 20.6 events / 1000 patient years (p = 0.011), and compared to the groups treated with insulin and sulfonylureas 18.9 events / 1000 patient years (p = 0.021);
- a significant reduction in the absolute risk of myocardial infarction: metformin hydrochloride 11 events / 1000 patient years, diet alone 18 events / 1000 patient years (p = 0.01).
For metformin hydrochloride used as second-line therapy in combination with a sulfonylurea, no clinical benefit was seen.
In cases of type 1 diabetes, the combination of metformin hydrochloride and insulin has been used on selected patients but the clinical benefit of this combination has not been formally determined.
Pediatric population
Controlled clinical trials conducted in a limited pediatric population aged 10 to 16 years treated for 1 year demonstrated a glycemic control response similar to that seen in adults.
05.2 Pharmacokinetic properties
Absorption
After an oral dose of metformin hydrochloride, T is reached in 2.5 hours. The absolute bioavailability of a 500 mg or 850 mg metformin hydrochloride tablet is approximately 50-60% in healthy subjects. After an oral dose the unabsorbed fraction found in faeces was 20-30%.
Following oral administration, the absorption of metformin is saturable and incomplete. The pharmacokinetics of metformin absorption are assumed to be non-linear.
At metformin hydrochloride dosages and commonly applied dosing schedules, equilibrium plasma concentrations are achieved within 24-48 hours and are generally less than 1 mcg / mL. In controlled clinical trials, maximum plasma metformin levels (Cmax) did not exceed 4 mcg / mL, even at maximum doses.
Feeding reduces and slightly delays the absorption of metformin. Following administration of an 850 mg dose of metformin hydrochloride, a 40% lower peak plasma concentration, a 25% decrease in AUC (area under the curve) and a 35 minute prolongation of time were observed. needed to reach peak plasma concentration The clinical relevance of these decreases is unknown.
Distribution
Plasma protein binding is negligible. Metformin hydrochloride distributes into erythrocytes. The peak in blood is less than the peak in plasma and appears around the same time. The erythrocytes most likely represent a secondary compartment of distribution. The mean volume of distribution (Vd) is between 63 and 276 l.
Biotransformation
Metformin is excreted unchanged in the 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 hours.
When renal function is impaired, renal clearance decreases in proportion to that of creatinine, resulting in a prolonged elimination half-life and increased plasma metformin levels.
Pediatric population
Single dose study: After administration of a single dose of 500 mg metformin hydrochloride, pediatric patients exhibited a pharmacokinetic profile identical to that observed in healthy adult subjects.
Multiple dose study: Data is limited to one study. After administration of repeated doses of metformin hydrochloride 500 mg twice daily for 7 days, the peak plasma concentration (Cmax) and systemic exposure (AUC0-t) decreased by approximately 33%, respectively, in pediatric patients. and 40%, compared to adult diabetic patients who received repeat doses of 500 mg twice daily for 14 days Since the dose is individually titrated based on glycemic control, this is of limited clinical relevance.
05.3 Preclinical safety data
On the basis of conventional studies concerning safety, pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity reproduction, preclinical data show no particular hazards for humans.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Colloidal anhydrous silica, povidone, macrogol 4000, magnesium stearate, Opadry II 85F29116 clear (polyvinyl alcohol, macrogol 3350, talc).
06.2 Incompatibility
Not relevant.
06.3 Period of validity
5 years.
06.4 Special precautions for storage
To be kept in a dry place.
06.5 Nature of the immediate packaging and contents of the package
Thermoformed blisters from rigid PVC / PVDC tape, sealed by heat sealing with aluminum tape lacquered with heat-sealing resin, packed in a lithographed cardboard box.
METFORAL 500 mg film-coated tablets - 50 coated tablets
METFORAL 850 mg film-coated tablets - 30 coated tablets
06.6 Instructions for use and handling
Unused medicine and waste derived from this medicine must be disposed of in accordance with current legislation.
07.0 MARKETING AUTHORIZATION HOLDER
Laboratori Guidotti S.p.A., Via Livornese 897, Pisa - La Vettola
08.0 MARKETING AUTHORIZATION NUMBER
METFORAL 500 mg film-coated tablets AIC: 019449014
METFORAL 850 mg film-coated tablets AIC: 019449038
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Renewal of Authorization: May 2010
10.0 DATE OF REVISION OF THE TEXT
April 2014
