Active ingredients: Metformin (Metformin hydrochloride)
GLUCOPHAGE 500 mg powder for oral solution in sachets
Glucophage package inserts are available for pack sizes:- GLUCOPHAGE 500 mg powder for oral solution in sachets
- GLUCOPHAGE 850 mg powder for oral solution in sachets
- GLUCOPHAGE 1000 mg powder for oral solution in sachets
Why is Glucophage used? What is it for?
Glucophage contains metformin, a medicine to treat diabetes. It belongs to a group of active substances called biguanides.
Insulin is a hormone produced by the pancreas that allows the body to assimilate glucose (sugar) from the blood. The body uses glucose for energy or stores it for future use.
If you have diabetes, your pancreas does not make enough insulin or your body is unable to use the insulin it produces properly. This causes high levels of glucose in the blood. Glucophage helps lower blood glucose to a higher level. level that is as normal as possible.
If you are an overweight adult, taking Glucophage for an extended period of time also helps to lower the risk of complications associated with diabetes. Glucophage was associated with both stabilization and modest body weight loss.
Glucophage is used to treat patients with type 2 diabetes (also called "non-insulin dependent diabetes") when diet and exercise alone have not been sufficient to control blood glucose levels. It is used in particular in patients. overweight.
Adults can take Glucophage alone or in combination with other medicines to treat diabetes (drugs given by mouth or insulin). Children 10 years of age and older and adolescents can take Glucophage alone or in combination with insulin.
Contraindications When Glucophage should not be used
Do not take Glucophage
- if you are allergic (hypersensitive) to metformin or any of the other ingredients of this medicine (see "What Glucophage contains")
- if you have liver or kidney problems (glomerular filtration rate less than 45ml / min)
- if you have uncontrolled diabetes, with such as severe hyperglycaemia (high blood glucose levels), nausea, vomiting, dehydration, rapid weight loss or ketoacidosis). Ketoacidosis is a disorder in which substances called "ketone bodies" accumulate in the blood and can lead to diabetic pre-coma. Symptoms include stomach pain, rapid and deep breathing, sleepiness and an unusual fruity smell of the breath.
- if your body has lost too much water (dehydration), eg. due to prolonged or severe diarrhea or if you have vomited several times in a row. Dehydration can cause kidney problems which can put you at risk of lactic acidosis (see section "Warnings and precautions").
- if you have a serious infection, such as an "infection affecting the lungs or bronchial system or kidneys. Serious infections can cause kidney problems, which may put you at risk of lactic acidosis (see section" Warnings and precautions ").
- if you are being treated for acute heart failure or have recently had a heart attack, if you have severe circulatory problems (such as shock) or breathing difficulties. This can cause deficiencies in the oxygen supply to the tissues which may expose you to the risk of lactic acidosis (see section "Warnings and precautions").
- if you drink a lot of alcohol
If you have any of the above conditions, consult your doctor before starting to take this medicine.
Be sure to ask your doctor for advice if:
- you must undergo tests such as x-rays or diagnostic scans that require iodine-containing contrast media to be injected into your bloodstream
- if you are due to have surgery
You must stop taking Glucophage for a certain period of time before and after the examination or surgery. Your doctor will decide if you need another treatment for that period. It is important that you follow all instructions precisely. of the doctor.
Precautions for use What you need to know before taking Glucophage
Please take note of the possible risk of lactic acidosis
Glucophage can cause a very rare but very serious complication called lactic acidosis, particularly if the kidneys are not functioning properly. The risk of developing lactic acidosis is also increased by having uncontrolled diabetes, prolonged fasting or alcohol intake, lack of body fluids (dehydration) due to severe diarrhea or vomiting, liver problems and from any other medical condition in which an area of the body is deprived of the supply of oxygen (such as severe acute heart disease).
It is important to follow the rules of taking the medicine, the instructions regarding the dietary regimen and the regular exercise program prescribed, as this can reduce the risk of lactic acidosis.
The onset of lactic acidosis can be insidious and symptoms may be nonspecific, such as vomiting, stomach pain (abdominal pain) with muscle cramps, a feeling of general malaise with extreme tiredness and difficulty in breathing. Additional symptoms include decreased body temperature and If you experience any of these symptoms you should seek medical attention immediately, as lactic acidosis can lead to coma. Stop taking Glucophage immediately and contact a doctor or the nearest hospital immediately.
Glucophage alone does not cause hypoglycemia (blood glucose levels that are too low). However, if you take Glucophage together with other medicines to treat diabetes that can cause hypoglycaemia (such as sulphonylureas, insulin, meglitinides), there is a risk of hypoglycaemia. If you experience symptoms of low blood sugar such as weakness, dizziness, increased sweating, fast heart rate, visual disturbances or difficulty concentrating, it is usually helpful to eat or drink something that contains sugar.
Interactions Which drugs or foods can modify the effect of Glucophage
If you are to receive an injection of iodine-containing contrast media into your bloodstream, for example for tests such as x-rays or diagnostic scans, you must stop taking Glucophage for a certain period of time before and after (at least 48 hours) the examination. (see paragraph above "Ask your doctor for advice if").
Tell your doctor if you take any of the following medicines and Glucophage at the same time. You may need to measure your blood sugar more frequently or your doctor may adjust your dose of Glucophage:
- diuretics (used to remove water from the body by making more urine).
- beta-2 agonists such as salbutamol or terbutaline (used to treat asthma)
- corticosteroids (used to treat various conditions, such as severe skin inflammation or asthma)
- other medicines used to treat diabetes
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.
Glucophage with food and drink
Do not drink alcohol while taking this medicine. Alcohol can increase the risk of lactic acidosis, particularly if you have liver problems or are undernourished. This also applies to medicines that contain alcohol.
Warnings It is important to know that:
Pregnancy and breastfeeding
During pregnancy you need insulin to treat diabetes. Tell your doctor if you are, think you are or plan to become pregnant, so that they can change your treatment.
This medicine is not recommended if you are breast-feeding or planning to breast-feed your baby.
Driving and using machines
Glucophage alone does not cause hypoglycemia (blood glucose levels that are too low). This means that it does not affect the ability to drive or use machines.
However, take special care if you take Glucophage together with other medicines to treat diabetes which can cause hypoglycaemia (such as sulphonylureas, insulin, meglitinides). Symptoms of hypoglycaemia include weakness, dizziness, increased sweating, rapid heartbeat, impaired vision or difficulty concentrating. Do not drive or operate machinery if you start experiencing these symptoms.
Dose, Method and Time of Administration How to use Glucophage: Posology
Always take Glucophage exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
Glucophage cannot replace the benefits of a healthy lifestyle. Continue to follow any dietary advice your doctor has given you and exercise regularly.
Recommended dose
Children 10 years of age and older and adolescents usually start with 500 mg or 850 mg of Glucophage once a day. The maximum daily dose is 2000 mg taken in 2 or 3 divided doses. Treatment of children aged 10 to 12 years is only recommended on specific medical advice, as experience in this age group is limited.
Adults usually start with 500 mg or 850 mg of Glucophage two or three times a day. The maximum daily dose is 3000 mg taken in 3 divided doses. In patients with impaired renal function with a GFR between 45 and 60 ml / min, the starting dose is 500 mg or 850 mg of metformin hydrochloride once daily. The maximum dose is 1000 mg per day, taken in 2 divided doses.
Renal function should be carefully monitored (every 3 - 6 months).
If you also take insulin, your doctor will tell you how to start Glucophage.
Monitoring
- Your doctor will have regular blood glucose tests and will adjust the dose of Glucophage to your blood sugar levels. Check with your doctor regularly. This is especially important for children and adolescents or if you are an elderly person.
- Your doctor will also check how your kidneys are working at least once a year. You may need more frequent checks if you are an elderly person or if your kidneys are not working normally.
How to take Glucophage
Take the tablets with or after a meal. This will prevent you from having unwanted effects that disturb your digestion.
Do not crush or chew the tablets. Swallow each tablet with a glass of water.
- If you take one dose a day, take it in the morning (breakfast)
- If you take two divided doses a day, take them in the morning (breakfast) and in the evening (dinner)
- If you take three divided doses a day, take them in the morning (breakfast), at noon (lunch) and in the evening (dinner).
If, after some time, you think that the effect of Glucophage is too strong or too weak, consult your doctor or pharmacist
Overdose What to do if you have taken too much Glucophage
If you take more Glucophage than you should
If you have taken more Glucophage than you should, you may get lactic acidosis. Symptoms of lactic acidosis are non-specific such as vomiting, stomach pain (abdominal pain) with muscle cramps, generally feeling unwell with extreme tiredness and difficulty in breathing. Additional symptoms include decreased body temperature and heart rate. If you experience any of these. symptoms should seek medical attention immediately, as lactic acidosis can lead to coma. Stop taking Glucophage and contact a doctor or the nearest hospital immediately.
If you forget to take Glucophage
Do not take a double dose to make up for a forgotten dose. Take the next dose at the scheduled time.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Glucophage
Like all medicines, Glucophage can cause side effects, although not everybody gets them. The following side effects may occur:
Very common side effects (affects more than 1 in 10 people)
- digestive problems such as nausea, vomiting, diarrhea, stomach pain (abdominal pain) and loss of appetite. These side effects appear more often at the start of treatment with Glucophage. It may be helpful to divide the doses throughout the day and take Glucophage with or immediately after a meal. If symptoms persist, stop taking Glucophage and contact your doctor. .
Common side effects (affects less than 1 in 10 people)
- change in taste.
Very rare side effects (affects less than 1 in 10,000 people)
- lactic acidosis. It is a very rare but serious complication, particularly if the kidneys are not functioning properly. Symptoms of lactic acidosis are non-specific such as vomiting, stomach pain (abdominal pain) with muscle cramps, generally feeling unwell with extreme tiredness and difficulty in breathing. Additional symptoms include decreased body temperature and heart rate. these symptoms should seek medical attention immediately, as lactic acidosis can lead to coma. Stop taking Glucophage and contact a doctor or the nearest hospital immediately.
- abnormal liver function tests or hepatitis (inflammation of the liver; can cause tiredness, loss of appetite, weight loss, with or without yellowing of the skin or whites of the eyes). If you get these symptoms, stop taking Glucophage and contact your doctor;
- skin reactions such as redness of the skin (erythema), itching or itchy rash (hives);
- low level of vitamin B12 in the blood.
Children and adolescents
Limited data in children and adolescents demonstrated that adverse events were similar in nature and severity to those reported in adults.
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. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects you can help provide more information on safety. of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children. If a child is treated with Glucophage, parents and carers of the child should supervise the use of this medicine.
This medicinal product does not require any special storage conditions.
Do not use Glucophage after the expiry date which is stated on the carton or bottle or blister after "EXP". The expiry date refers to the last day of that month.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What Glucophage contains
- The active ingredient is metformin hydrochloride. One Glucophage 1000 mg film-coated tablet contains 1000 mg of metformin hydrochloride corresponding to 780 mg of metformin base.
- The other ingredients are povidone K 30, magnesium stearate, hypromellose, macrogol 400 and macrogol 8000.
Description of what Glucophage looks like and contents of the pack
Glucophage 1000 mg film-coated tablets are white, oval and biconvex shaped, with a score line on both sides of the tablet and a "1000" engraved on one side. The tablet can be divided into equal halves.
The tablets are available in blister packs of 1 (x30), 20, 30, 50, 60, 90, 100, 120, 180 or 600 tablets or in plastic bottles with child resistant closure of 20, 30, 50, 60 , 90, 100, 120, 180 or 600 tablets.
Not all pack sizes may be marketed.
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
GLUCOPHAGE 500 MG
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
One film-coated tablet contains 500 mg of metformin hydrochloride corresponding to 390 mg of metformin base.
For the full list of excipients see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet.
White, circular, convex film-coated tablets.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Treatment of Type 2 diabetes mellitus, particularly in overweight patients, when diet and exercise alone are insufficient for adequate glycemic control.
• In adults, Glucophage can be used on its own or in combination with other oral antidiabetics or with insulin.
• In children over 10 years of age and adolescents, Glucophage can be used alone or in combination with insulin.
A reduction in diabetic complications has been demonstrated in overweight type 2 diabetic adult patients treated with metformin as first-line therapy after dietary control failure (see section 5.1).
04.2 Posology and method of administration
Adults:
Monotherapy And association with other oral antidiabetic drugs:
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 based on the blood glucose values. A gradual increase in dose may improve gastrointestinal tolerability. The maximum recommended dose of metformin hydrochloride is 3 g per day, to be taken in 3 separate administrations.
In case of switching from another oral antidiabetic drug: Discontinue the previous drug and start with metformin at the dose indicated above.
Association with insulin:
Metformin and insulin can be used in combination to improve blood glucose. Metformin hydrochloride is usually given at the starting dose of 500 mg or 850 mg 2 or 3 times a day, while the insulin dose is adjusted based on blood glucose values.
Senior citizens:
Due to the potential for decreased renal function in elderly subjects, the metformin dose should be adjusted based on renal function. Regular evaluation of renal function is therefore necessary (see section 4.4).
Children and adolescents:
Monotherapy and association with insulin:
• Glucophage can be used in children over 10 years of age and in adolescents.
• The usual starting dose is 500 mg or 850 mg of metformin hydrochloride once a day, taken with or after a meal.
After 10-15 days the dose should be adjusted based on the blood glucose values. A gradual increase in dose may improve gastrointestinal tolerability. The maximum recommended dose of metformin hydrochloride is 2 g per day, taken as 2 or 3 separate administrations.
04.3 Contraindications
• Hypersensitivity to metformin or to any of the excipients.
• Diabetic ketoacidosis, diabetic precoma.
• Renal failure or renal dysfunction (creatinine clearance
• Acute conditions potentially capable of altering 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 rapid treatment) metabolic complication, which may arise following accumulation of metformin. Reported cases of lactic acidosis in patients treated with metformin have occurred in particular in diabetic patients with significant renal insufficiency. The incidence of lactic acidosis can and should be reduced by also evaluating other associated risk factors, such as uncontrolled diabetes, ketosis, prolonged fasting, excessive alcohol intake, liver failure and any other conditions associated with hypoxia.
Diagnosis:
The risk of lactic acidosis should be considered if there are nonspecific signs such as muscle cramps combined with digestive system disorders such as abdominal pain and severe asthenia.
These symptoms can be followed by dyspnoea with acidosis, abdominal pain, hypothermia and 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, metformin should be discontinued and the patient admitted immediately (see section 4.9).
Kidney function:
Metformin is excreted by the kidneys, so creatinine clearance (which can be estimated from 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 at the lower limit of normal and in elderly subjects.
Decreased renal function in the elderly is frequent and asymptomatic. Special attention should be paid to situations in which renal function may be compromised, for example when initiating antihypertensive therapy or diuretic therapy and when initiating therapy with a non-steroidal anti-inflammatory drug (NSAID).
Administration of iodinated contrast media:
Intravascular administration of iodinated contrast media in radiological studies may lead to renal failure. This may result in accumulation of metformin and may expose the patient to lactic acidosis. Metformin administration should be discontinued before or at the time of examination; it should also not be restarted earlier than 48 hours after the examination, and only after checking whether renal function has returned to normal (see section 4.5).
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 after resuming oral feeding, and only after it has been established that renal function is normal.
Children and adolescents:
The diagnosis of type 2 diabetes mellitus must be confirmed before starting treatment with metformin.
No effects of metformin on growth and puberty were found in controlled clinical trials lasting one year, but no long-term data are available on these specific points. Careful follow-up of the effect of metformin on these parameters is therefore recommended in children treated with metformin, especially prepubertal.
Children aged between 10 and 12 years:
Only 15 subjects between the ages of 10 and 12 were included in the controlled clinical trials conducted in children and adolescents. Although the efficacy and safety of metformin in these children did not differ from those reported for older children and adolescents, special care is recommended when prescribing it to children aged 10 to 12 years.
Other precautions:
Patients should continue their diet by distributing carbohydrates regularly throughout the day. Overweight patients should continue the low-calorie diet.
The laboratory tests normally required in cases of diabetes must be performed regularly.
Metformin alone does not cause hypoglycaemia, but caution is advised when used in combination with insulin or other oral antidiabetic agents (eg sulfonylureas or meglitinides).
04.5 Interactions with other medicinal products and other forms of interaction
Combinations not recommended:
Alcohol:
Acute alcoholic intoxication is associated with an increased risk of lactic acidosis, especially in cases of: fasting or malnutrition, liver failure.
Avoid consumption of alcohol and alcohol-containing medications.
Iodized contrast media:
Intravascular administration of iodinated contrast media may cause renal failure, resulting in accumulation of metformin and an increased risk of lactic acidosis.
Metformin administration should be discontinued before or at the time of the examination and should not be resumed earlier than 48 hours after the examination, and only after checking whether renal function has returned to normal (see section 4.4).
Associations requiring precautions for use:
Drugs with intrinsic hyperglycemic activity (e.g. glucocorticoids (systemic and local) and sympathomimetics):
More frequent blood glucose checks may be required, especially at the start of treatment. If necessary, adjust the dose of metformin during therapy with the respective drug and upon discontinuation of the drug.
Diuretics, especially loop diuretics:
They may increase the risk of lactic acidosis due to their potential to reduce kidney function.
04.6 Pregnancy and lactation
Pregnancy
During pregnancy, uncontrolled (gestational or permanent) diabetes is associated with an increased risk of congenital malformations and perinatal mortality.
The amount of information on the use of metformin in pregnant women is limited and does not indicate an increased risk of congenital malformations. Animal studies do not indicate harmful effects on pregnancy, embryo or fetal development, parturition or postnatal development ( see paragraph 5.3).
When the patient plans to become pregnant and during pregnancy itself, it is recommended not to treat diabetes with metformin but with insulin to keep blood sugar as close to normal as possible, to reduce the risk of fetal malformation.
Feeding time
Metformin is excreted in 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. The decision to discontinue breastfeeding should be made considering the beneficial effects of breastfeeding and the risk. potential for adverse effects on the child.
Fertility
In rats, male or female fertility was not affected by metformin when administered at doses up to 600 mg / kg per day; this dose is approximately three times the maximum recommended daily dose in humans, calculated on the basis of body surface area
04.7 Effects on ability to drive and use machines
Metformin alone does not cause hypoglycaemia, therefore it has no effect 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 (e.g. sulfonylureas, insulin or meglitinides).
04.8 Undesirable effects
During the initiation of treatment, the most common adverse reactions are nausea, vomiting, diarrhea, abdominal pain and loss of appetite, which resolve spontaneously in most cases.
To prevent them, it is recommended to take metformin in 2 or 3 daily doses and to gradually increase the dose.
The following adverse reactions may occur during treatment with metformin. Their frequency is defined as follows: very common ≥1 / 10; common ≥1 / 100,
Within each frequency class, adverse reactions are reported in order of decreasing severity.
Metabolism and nutrition disorders:
Very rare: Lactic acidosis (see section 4.4).
Reduced absorption of vitamin B12 with decreased serum levels during long-term use of metformin. It is recommended that this etiology be considered in patients with megaloblastic anemia.
Nervous system disorders:
Common: Changes in taste
Gastrointestinal disorders:
Very common: Alterations of the gastrointestinal tract such as nausea, vomiting, diarrhea, abdominal pain and loss of appetite. These side effects occur more frequently during initiation of therapy and resolve spontaneously in most cases. To prevent them, it is recommended that metformin be taken in 2 or 3 daily doses during or after meals. Even a gradual increase in the dose may improve gastrointestinal tolerability.
Hepatobiliary disorders:
Very rare: Changes in liver function tests or hepatitis that have resolved following discontinuation of metformin treatment
Skin and subcutaneous tissue disorders:
Very rare: Skin reactions such as erythema, itching, urticaria
Pediatric population
In published and post-marketing data, and in controlled clinical trials in a limited pediatric population between 10 and 16 years treated for one year, adverse event reports were similar in severity and nature to those reported for adults.
04.9 Overdose
No forms of hypoglycaemia have been observed with metformin hydrochloride doses up to 85 g, although lactic acidosis has developed in such circumstances. High metformin overdoses or concomitant risks can lead to lactic acidosis. Lactic acidosis is an emergency medical case and must be treated in hospital. The most effective method of eliminating lactate and metformin is hemodialysis.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: hypoglycemic drugs. Biguanides.
ATC code: A10BA02.
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.
Metformin can act through 3 mechanisms:
reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis;
in the muscles, increasing insulin sensitivity, improving the absorption and use of peripheral glucose;
and delaying intestinal absorption of glucose.
Metformin stimulates intracellular glycogenosynthesis by acting on glycogen synthetase.
Metformin increases the transport capacity of all types of glucose membrane transporters (GLUTs) known to date.
In clinical trials, the use of metformin was associated with stabilization or modest loss of body weight.
In humans, regardless of its action on glycaemia, metformin has favorable effects on lipid metabolism. This phenomenon has been demonstrated in controlled medium- and long-term clinical trials at therapeutic doses: metformin reduces the levels of total cholesterol, LDL cholesterol and triglycerides.
Clinical efficacy:
The prospective randomized study (UKPDS) demonstrated the long-term benefit of intensive blood glucose control in adult patients with type 2 diabetes.
The analysis of the results on overweight patients treated with metformin after failure of the diet alone showed the following:
- a significant reduction in the absolute risk of diabetes-associated complications in the metformin 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 combined insulin monotherapy and sulfonylurea monotherapy groups (40.1 events / 1000 patient-years), p = 0.0034;
- a significant reduction in the absolute risk of diabetes-associated mortality: metformin 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 13.5 events / 1000 patient-years compared to diet alone 20.6 events / 1000 patient-years (p = 0.011), and compared to the combined groups treated as monotherapy with sulfonylureas and insulin monotherapy 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).
There was no clinical benefit found for metformin used as second-line therapy in combination with a sulfonylurea.
In cases of type 1 diabetes, the combination of metformin 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 on a limited pediatric population between 10 and 16 years treated for one year, have demonstrated a response in terms of glycemic control similar to that of adults.
05.2 Pharmacokinetic properties
Absorption:
After an oral dose of metformin hydrochloride tablet, the maximum plasma concentration (Cmax) is reached in approximately 2.5 hours (tmax). 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 the recommended metformin doses and dosing regimens, steady-state plasma concentrations are achieved within 24 to 48 hours and are generally less than 1 microgram / ml. In controlled clinical trials, maximum plasma metformin levels (Cmax) did not exceed 5 mcg / mL, even at maximum doses.
Feeding reduces and slightly delays the absorption of metformin. Following oral administration of an 850 mg tablet, a 40% lower maximum plasma concentration, a 25% decrease in AUC (area under the curve) were observed. and a 35 minute extension of the time to reach maximum plasma concentration The clinical relevance of these findings is unknown.
Distribution:
Plasma protein binding is negligible. Metformin distributes into erythrocytes. The blood peak is less than the plasma peak and appears at approximately the same time. The erythrocytes most likely represent a secondary compartment of distribution. The mean volume of distribution (Vd) ranges from 63 to 276 l.
Metabolism:
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. After 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 single doses of 500 mg metformin hydrochloride, pediatric patients demonstrated a similar pharmacokinetic profile to that seen in healthy adults.
Multiple dose study: Data are limited to one study. After repeated doses of 500 mg twice daily for 7 days in pediatric patients, the maximum plasma concentration (Cmax) and systemic exposure (AUC0-t) were reduced by approximately 33% and 40%, respectively, compared to diabetic adults treated with repeated doses of 500 mg twice daily for 14 days Since the dose is individually titrated based on glycemic control, this fact is of limited clinical relevance.
05.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety, pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and reproductive toxicity.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Core of the tablet
Povidone K30
Magnesium stearate
Coating
Hypromellose.
06.2 Incompatibility
Not relevant.
06.3 Period of validity
5 years
06.4 Special precautions for storage
This medicine does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
1 (x100), 9, 20, 21, 30, 40, 50, 56, 60, 84, 90, 100, 120, 200, 500, 600 or 1000 tablets in blister (PVC-aluminum)
21, 30, 40, 50, 60, 100, 120, 300, 400, 500, 600 or 1000 tablets in plastic (high density polyethylene) bottles with child resistant (polypropylene) closure.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Bruno Farmaceutici S.p.A.
Via delle Ande, 15
00144 Rome
Italy
08.0 MARKETING AUTHORIZATION NUMBER
30 film-coated tablets A.I.C. n.017758018 / M
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
7 October 1960/1 October 2002
10.0 DATE OF REVISION OF THE TEXT
March 2013
