Active ingredients: Metformin (Metformin hydrochloride)
Zuglimet 850 mg film-coated tablets
The package leaflets of Zuglimet are available for pack sizes:- Zuglimet 850 mg film-coated tablets
- Zuglimet 500 mg film-coated tablets
- Zuglimet 1000 mg film-coated tablets
Why is Zuglimet used? What is it for?
What is Zuglimet 850 mg
Zuglimet 850 mg contains metformin, a medicine used to treat diabetes. This belongs to a group of medicines called biguanides.
Insulin is a hormone produced by the pancreas that works by taking glucose (sugar) from the blood in the body.
The body uses glucose for energy or stores it for later use.
If you have diabetes, your pancreas does not make enough insulin or your body is unable to readily use the insulin it produces. This leads to a high blood glucose level. Zuglimet 850 mg helps to lower the level of blood. blood glucose up to a normal level if possible.
If you are an overweight adult take Zuglimet 850 mg for a long time as this helps to lower the risk of complications associated with diabetes. Zuglimet 850 mg helps to keep weight stable or can decrease it.
What Zuglimet 850 mg is used for
Zuglimet 850 mg 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. overweight patients.
Adult patients can take Zuglimet 850 mg alone or together with other medicines to treat diabetes (medicines taken by mouth or insulin).
Children 10 years of age and older and adolescents can take Zuglimet 850 mg alone or together with insulin.
Contraindications When Zuglimet should not be used
Do not take Zuglimet 850 mg
- If you are allergic (hypersensitive) to metformin hydrochloride or any of the other ingredients of this medicine (listed in section 6)
- If you have kidney or liver problems
- If you have uncontrolled diabetes with nausea, vomiting, severe dehydration, weight loss or ketoacidosis. Ketoacidosis is a condition in which substances called "ketone bodies" build up in the blood which can lead to diabetic pre-coma. Symptoms include stomach pain, fast and deep breathing, sleepiness or an unusual fruity smell of the breath.
- If you have lost a lot of water from your body (dehydration) for a long time or have had severe diarrhea, or if you have been vomiting several times and for a long time. Dehydration can lead to kidney problems which may put you at risk of lactic acidification (lactic acidosis, see "Take special care with Zuglimet 850 mg" below).
- If you have a severe infection such as a "lung or bronchial" or kidney infection. Severe infections can lead to kidney problems, which can put you at risk of acidification with lactic acid (lactic acidosis see "Take special care with Zuglimet 850 mg" below).
- If you are being treated for heart failure or if you have recently had a heart attack, or if you have severe blood circulation problems (such as shock) or have difficulty breathing. This can lead to a reduction in oxygen reaching the tissues that may put you at risk of acidification with lactic acid (lactic acidosis, see "Take special care with Zuglimet 850 mg" below).
- If you drink large amounts of alcohol.
If any of the conditions listed above apply to you, talk to your doctor before taking this medicine.
Precautions for use What you need to know before you take Zuglimet
Talk to your doctor or pharmacist before taking Zuglimet 850 mg
- He needs to have an X-ray examination or an ultrasound scan that involves the use, by injection into the bloodstream, of a contrast medium that contains iodine;
- If you need major surgery.
You must stop taking Zuglimet 850 mg for a certain period of time before and after testing or having an operation. Your doctor will decide if you need any other treatment during this time. It is important that you strictly follow your doctor's instructions.
Take special care with Zuglimet 850 mg
Carefully consider the following risk of lactic acidosis.
Zuglimet 850 mg can cause a very serious but very rare complication characterized by acidification of the blood with lactic acid called lactic acidosis, particularly if the kidneys are not functioning well. The risk of lactic acidosis is also increased in poorly controlled diabetes and after a long period of fasting or alcohol consumption. Symptoms of lactic acidosis are vomiting, abdominal pain (abdominal pain) with muscle cramps, a general feeling of being unwell with marked tiredness and difficulty in breathing. If these symptoms occur, you may need immediate hospital treatment as the "lactic acidosis can lead to coma. Stop taking Zuglimet 850 mg immediately and talk to your doctor or go to the nearest hospital.
Zuglimet 850 mg alone does not cause excessive lowering of blood glucose (hypoglycaemia). However, if you take Zuglimet 850 mg together with other medicines to treat diabetes, which can cause hypoglycaemia (such as sulphonylureas, insulin, meglitinides) there is a risk of hypoglycaemia. If you experience symptoms of hypoglycaemia such as weakness, dizziness, increased blood pressure sweating, fast heart rate, vision problems or difficulty concentrating usually help by eating or drinking something that contains sugar.
Interactions Which drugs or foods may change the effect of Zuglimet
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
If you need to inject a contrast medicine that contains iodine into your bloodstream, such as x-ray or ultrasound examination, you must stop taking Zuglimet 850 mg for a certain period of time before and after the examination. (see "Warnings and Precautions" above).
Talk to your doctor if you take any of the following medicines and Zuglimet 850 mg at the same time. Your blood glucose test may need to be tested more often or your doctor may change your dose of Zugliemt 850:
- Diuretics (used to remove water from the body by urinating more);
- Beta2-agonists such as salbutamol terbutaline (used to treat asthma);
- Corticosteroids (used to treat a variety of conditions such as severe skin inflammation or asthma);
- Other medicines used to treat diabetes.
Taking Zuglimet 850 mg with food and drink
Do not drink alcohol when taking this medicine. Alcohol can increase the risk of lactic acidosis especially 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
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
Insulin is needed during pregnancy to treat diabetes. Talk to your doctor if you are, may be pregnant or plan to become pregnant, in order to change your treatment.
The use of Zuglimet 850 mg while breastfeeding is not recommended.
Driving and using machines
Zuglimet 850 mg alone does not cause excessive lowering of blood glucose (hypoglycaemia). This means that it has no effect on the ability to drive or use machines.
However, take special care if you take Zuglimet 850 mg together with other medicines to treat diabetes which can cause hypoglycaemia (such as sulphonylureas, insulin, meglitinides). Symptoms of hypoglycemia include tiredness, dizziness, increased sweating, rapid heartbeat, problems with vision or difficulty concentrating.
Do not drive or use machines if you start to feel these symptoms.
Dose, Method and Time of Administration How to use Zuglimet: Posology
Always take Zuglimet 850 mg exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
Zuglimet 850 mg cannot replace a healthy lifestyle and the benefits that come with it. Therefore, continue to follow the dietary advice given to you by your doctor and exercise regularly.
Usual dose
Children of 10 years of age and older and adolescents usually start with 500 mg or 850 mg once daily. The maximum daily dose is 2000 mg divided into 2 or 3 doses. Treatment of children between 10 and 12 years of age is only recommended if specifically advised by the physician, as experience in this age group of patients is limited.
Adults usually start with 500 mg or 850 mg two or three times a day. The maximum recommended daily dose is 3000 mg divided into 3 doses.
The tablets can be broken to simplify administration, but the two halves must be taken together at the same time.
If you also take insulin, your doctor will tell you how to start taking Zuglimet 850 mg.
Monitoring
- Your doctor will periodically check your blood glucose level and adjust the dose of Zuglimet 850 mg to your blood glucose level. Make sure you speak to your doctor regularly. This is especially important if you are a child of adolescent or if you are an elderly person.
- Your doctor will check, at least once a year, if your kidneys are working well. You may need more frequent checks if you are an elderly person or if your kidneys are not normally working well.
How to take Zuglimet 850 mg
Take the tablets with or after a meal. This will avoid unwanted effects related to digestion. Do not break or chew the tablets. Swallow each tablet with a glass of water.
- If you take one dose a day, take it in the morning (with breakfast),
- If you take two doses a day, take them in the morning (for breakfast) and in the evening (for dinner);
- If you take three doses a day, take them in the morning (for breakfast) at noon (for lunch) and in the evening (for dinner). If after some time you think that the effect of Zuglimet 850 mg is too strong or too weak, talk to your doctor or pharmacist.
If you forget to take Zuglimet 850 mg
Do not take the double dose to make up for a forgotten dose. Take your next dose at the usual time. If you have any further questions on the use of Zuglimet 850 mg, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Zuglimet
If you take more Zuglimet than you should, lactic acidosis may occur. Symptoms of lactic acidosis are vomiting, abdominal pain (abdominal pain) with muscle cramps, a general feeling of malaise with marked tiredness, difficulty in breathing.
If you suffer from these complaints you may need immediate hospital treatment as lactic acidosis can lead to coma.
Contact your doctor or go to the nearest hospital.
Side Effects What are the side effects of Zuglimet
Like all medicines, Zuglimet 850 mg can cause side effects, although not everybody gets them. The following side effects may occur.
Very common (may affect more than 1 in 10 people):
- Digestive problems, such as feeling sick (nausea), feeling sick (vomiting), diarrhea, stomach pain (abdominal pain) and loss of appetite. These side effects very often occur at the start of treatment with Zuglimet 850 mg. It helps to divide the dose over the whole day and to take the tablets with or immediately after a meal. If symptoms continue, stop taking Zuglimet 850 mg and talk to your doctor.
Common (may affect up to 1 in 10 people)
- change of flavor
Very rare (may affect up to 1 in 10,000 people)
- Acidification of blood with lactic acid (lactic acidosis). This complication is very rare but serious especially if the kidneys are not working properly. Symptoms of lactic acidosis are vomiting, abdominal pain (abdominal pain) with muscle cramps, a general feeling of discomfort with marked tiredness, and difficulty in breathing. "lactic acidosis can lead to coma. Stop taking Zuglimet 850 mg immediately and contact your doctor immediately or go to the nearest hospital.
- Abnormal liver function tests or hepatitis (inflammation of the liver, which can cause tiredness, loss of appetite, weight loss, with or without yellowing of the skin or whitish eyes. If this happens, stop taking Zuglimet 850 mg and talk with your doctor immediately - skin reactions with red skin (erythema), itchy or itchy rash (hives).
- Low levels of vitamin B12 in the blood.
Children and adolescents
Limited data in children and adolescents show that undesirable effects 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 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
Keep this medicine out of the sight and reach of children. If a child is treated with Zuglimet 850 mg, parents and carers are advised that they should check how the medicine is used.
The medicinal product does not require any special storage conditions.
Do not use Zuglimet 850 mg after the expiry date which is stated on the blister and carton (EXP is the abbreviation used for the expiry date). The expiry date refers to the last day of the month.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Deadline "> Other information
What Zuglimet 850 mg contains
The active ingredient is metformin hydrochloride.
Each film-coated tablet contains 850 mg of metformin hydrochloride equivalent to 662.8 mg of metformin.
The other excipients are
- Tablet core: hypromellose, povidone K25, magnesium stearate.
- Coating: hypromellose, macrogol 6000, titanium dioxide (E171).
What Zuglimet 850 mg looks like and contents of the pack
Zuglimet 850 mg is a white, oblong, beveled, film-coated tablet narrower in the middle. There is a score line on both sides. The score line is only to help break the tablet if you have difficulty swallowing it whole.
Zuglimet 850 mg is available in packs of 15, 30, 40, 50, 90, 100, 120, film-coated 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 -
ZUGLIMET 850 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
Each film-coated tablet contains 850 mg of metformin hydrochloride equivalent to 662.9 mg of metformin base.
For the full list of excipients, see 6.1.
03.0 PHARMACEUTICAL FORM -
Film-coated tablet.
White, beveled, oblong, film-coated tablet with a narrowing in the center. There is a fracture line on both sides. The score line is only to facilitate breaking and therefore swallowing not to divide it into two equal doses.
04.0 CLINICAL INFORMATION -
04.1 Therapeutic indications -
Treatment of type 2 diabetes mellitus, particularly in overweight patients, in cases where diet and exercise alone are not sufficient to achieve adequate glycemic control.
• In adults, metformin can be used alone or in combination with other oral antidiabetic medicines, or with insulin.
• In children from 10 years of age and adolescents, metformin 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 following diet failure (see section 5.1).
04.2 Posology and method of administration -
Dosage
Adults:
Monotherapy and in combination with other oral antidiabetic agents
Normally, the starting dose is 500 mg or 850 mg of metformin hydrochloride 2 or 3 times a day with or after meals.
After 10 - 15 days the dose should be adjusted based on the blood glucose level. A gradual increase in dose may improve gastrointestinal tolerability. The maximum recommended dose of metformin hydrochloride is 3 g per day in 3 divided doses.
If you intend to switch from another oral antidiabetic drug to metformin, discontinue treatment with the other drug and start treatment with metformin at the doses indicated above.
Combination with insulin
Metformin and insulin can be used in combination to achieve better control of the blood glucose level. Metformin hydrochloride is usually given with a starting dose of 500 mg or 850 mg 2 or 3 times a day, while the dosage of "insulin is defined based on the blood glucose level.
Senior citizens:
Given the potential for decreased renal function in elderly subjects, the metformin dosage should be adjusted based on renal function. Regular evaluation of renal function is required (see section 4.4).
Kidney damage
Metformin can be used in patients with moderate, stage 3a renal impairment (creatinine clearance [CrCl] 45-59 ml / min or estimated glomerular filtration rate [eVFG] 45 -59 ml / min / 1.73 m²) only in absence of other conditions that may increase the risk of lactic acidosis and with the following dose adjustments:
The starting dose is 500 mg or 850 mg of metformin hydrochloride once daily. The maximum dose is 1000 mg per day, divided into 2 doses. Renal function should be closely monitored (every 3-6 months).
If CrCl or eVFG decreases a
Pediatric population:
Monotherapy and combination with insulin
• Metformin can be used in children from 10 years of age and adolescents.
• Normally, the starting dose is one 500 mg or 850 mg tablet of metformin hydrochloride once a day, with or after a meal.
After 10 - 15 days the dose should be adjusted based on the blood glucose measurements. A gradual increase in dose may improve gastrointestinal tolerability. The maximum recommended dose of metformin is 2 g per day in two or three divided doses.
Method of administration
The tablets can be broken in half to simplify administration, but the two halves must be taken together at the same time.
04.3 Contraindications -
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1;
• Diabetic ketoacidosis, diabetic pre-coma;
• Moderate (stage 3b) and severe renal insufficiency or renal dysfunction (CrCl
• Acute conditions with the potential to alter renal function, such as dehydration, severe infection, shock;
• Diseases that can cause tissue hypoxia (especially acute disease or worsening of chronic disease), such as: decompensated heart failure 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 very rare, but serious (high mortality rate in the absence of immediate treatment) metabolic complication, which can occur as a result of accumulation of metformin. Cases of lactic acidosis have been reported in patients treated with metformin which mainly occurred in diabetic patients with renal insufficiency or acute worsening of renal function. Special attention should be taken for situations where renal function may be impaired, for example in the event of dehydration (severe diarrhea or vomiting), or when initiating antihypertensive or diuretic therapy and when initiating therapy with a non-inflammatory anti-inflammatory. steroid (NSAID). Under the acute conditions listed, metformin should be temporarily withdrawn. Other associated risk factors should be considered to avoid lactic acidosis such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, liver failure and any conditions associated with hypoxia (such as decompensated heart failure, acute myocardial infarction) ( see also section 4.3).
The risk of lactic acidosis must be considered in cases of non-specific signs such as muscle cramps, digestive disorders such as abdominal pain and severe asthenia. Patients should be instructed to report these signs immediately to their physician if they occur, particularly if patients have had good tolerability to metformin in the past. Metformin should be discontinued at least temporarily until the situation is clarified. Reintroduction should be discussed taking into consideration the individual benefit / risk ratio as well as renal function.
Diagnosis:
Lactic acidosis is characterized by acidotic dyspnoea, abdominal pain, and hypothermia followed by coma. Diagnostic laboratory tests show decreased blood pH, plasma lactate levels above 5 mmol / l, and an increase in anion deficiency and lactate ratio. / pyruvate In case of lactic acidosis, the patient should be hospitalized immediately (see section 4.9).
The physician should warn the patient about the risks and symptoms of lactic acidosis.
Kidney function:
Since metformin is excreted by the kidney, creatinine clearance (which can be assessed from serum creatinine levels using the Cockcroft-Gault formula) or eVFG should be determined before starting treatment and checked 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 limits of normal and in elderly patients.
In case the CrCl is
Decreased renal function in elderly patients is common and asymptomatic. Particular caution should be exercised in situations where renal function is likely to be impaired, for example in the event of dehydration or when initiating antihypertensive or diuretic therapy or when initiating treatment with non-steroidal anti-inflammatory drugs (NSAIDs). In such cases, a check of renal function is also recommended before starting treatment with metformin.
Cardiac function
Patients with heart failure are at increased risk for hypoxia and renal failure. In patients with stable chronic heart failure, metformin can be used with regular monitoring of heart and kidney function.
For patients with unstable acute heart failure, metformin is contraindicated (see section 4.3).
Administration of iodinated contrast media:
Intravascular administration of iodinated contrast media during radiological examinations can lead to renal failure. This can lead to accumulation of metformin and can increase the risk of lactic acidosis. In patients with eVFG> 60 ml / min / 1.73 m², metformin should be discontinued before or at the time of administration of iodinated contrast media and should not be reintroduced until at least 48 hours after and only after renal function has been re-evaluated and there is no further deterioration (see section 4.5).
In patients with moderate renal impairment (eGFR between 45 and 60 mL / min / 1.73 m²), metformin should be discontinued 48 hours prior to administration of iodinated contrast media and should not be resumed for the next 48 hours, and only after that renal function has been re-evaluated and not further deteriorated (see section 4.5).
Surgery:
Metformin treatment should be discontinued 48 hours prior to elective surgery under general, spinal or epidural anesthesia. Therapy should be resumed no earlier than 48 hours after surgery or restoration of oral feeding and only if normal renal function has been established.
Pediatric population:
Before starting treatment with metformin, the diagnosis of type 2 diabetes mellitus must be confirmed.
In one-year controlled clinical trials, no effects of metformin on growth or puberty were observed; however, no long-term data is available regarding these specific situations. Therefore, careful follow-up with respect to these parameters is recommended in children treated with metformin, particularly in pre-pubertal children.
Children between the ages of 10 and 12:
In controlled clinical trials, conducted in children and adolescents, only 15 subjects between the ages of 10 and 12 were included. Although the efficacy and safety data of metformin for these children did not differ from those found for adolescents, particular caution is recommended when prescribing the medicine to children aged 10 to 12 years.
Other precautions:
- All patients should continue their diet with a regular distribution of carbohydrate intake throughout the day.Overweight patients must continue their energy restriction diet.
- Normal laboratory tests for monitoring diabetes should be performed regularly.
- Metformin alone does not cause hypoglycaemia, but caution should be exercised when used in combination with insulin or other oral antidiabetics (such as sulphonylureas or meglitinides).
- Regular monitoring of thyroid stimulating hormone (TSH) levels is recommended in patients with hypothyroidism (see section 4.8).
- Long-term treatment with metformin has been associated with a decrease in serum vitamin B12 levels which can cause peripheral neuropathy. Monitoring of serum vitamin B12 levels is recommended (see section 4.8).
04.5 Interactions with other medicinal products and other forms of interaction -
Combinations not recommended:
Alcohol
Acute alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in the following cases:
• fasting or malnutrition,
• liver failure.
Avoid consumption of alcohol and alcohol-containing medicinal products.
Iodine contrast media
Intravenous administration of iodinated contrast media may cause renal failure, resulting in accumulation of metformin and an increased risk of lactic acidosis.
In patients with eVFG> 60 mL / min / 1.73 m², metformin should be discontinued before or at the time of testing and should not be reintroduced until 48 hours after, and only after renal function has been re-evaluated and is not reintroduced. further deteriorated (see section 4.4).
In patients with moderate renal impairment (eGFR between 45 and 60 mL / min / 1.73 m²), metformin should be discontinued 48 hours prior to administration of iodinated contrast media and should not be restarted for 48 hours thereafter, and only after that renal function has been re-evaluated and not further deteriorated.
Associations requiring precautions for use:
Medicinal products with intrinsic hyperglycemic activity (e.g. glucocorticoids (systemic and local route), and sympathomimetics): More frequent monitoring of blood glucose may be required particularly at the start of treatment with these medicines; it may also be necessary to adjust the dose of metformin during therapy with these medicines and following their discontinuation.
Diuretics, especially loop diuretics:
They can increase the risk of lactic acidosis due to their ability to reduce kidney function.
Phenprocoumon
Metformin may decrease the anticoagulant effect of phenprocoumon. Close monitoring of INR is therefore recommended.
Levothyroxine
Levothyroxine may decrease the blood glucose lowering effect of metformin. Monitoring of glucose levels is recommended, especially when thyroid hormone therapy is initiated or discontinued, and metformin dosage should be adjusted if necessary.
04.6 Pregnancy and breastfeeding -
Pregnancy
Uncontrolled diabetes during pregnancy (gestational or permanent) is associated with an increased risk of congenital abnormalities and perinatal mortality.
A limited amount of data on the use of metformin in pregnant women has not indicated an increased risk of congenital abnormalities. Animal studies do not indicate harmful effects on pregnancy, embryonic or fetal development, parturition or postnatal development (see paragraph 5.3).
If a woman with diabetes plans to become pregnant or is already pregnant, diabetes should not be treated with metformin, but a switch to insulin is recommended in order to keep blood glucose levels as close to normal as possible and reduce the risk of fetal malformations.
Feeding time
Metformin is excreted in human milk. No adverse events were observed in breastfed infants or children. However, as available data are limited, breastfeeding is not recommended during treatment with metformin. A decision to discontinue breastfeeding must be made taking into account the benefit of breastfeeding and the potential risk of adverse effects on the breast. child.
Fertility
Metformin had no effect on the fertility of male and female rats when administered at high doses, 600 mg / kg / day, which is approximately three times the maximum recommended daily dose when comparing body surface area.
04.7 Effects on ability to drive and use machines -
Metformin given alone does not cause hypoglycaemia and therefore has no effect on the ability to drive or use machines.
However, patients should be advised of the risk of hypoglycaemia if metformin is used in combination with other antidiabetic drugs (e.g. sulphonylureas, insulin, or meglitinides).
04.8 Undesirable effects -
At the start 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 increase them slowly.
The following adverse reactions can occur in treatment with metformin.
Frequencies are defined below: very common:> 1/10; common:> 1/100, 1 / 1,000, 1 / 10,000,
Within each frequency group, adverse reactions are listed in order of decreasing severity.
Disorders of the blood and lymphatic system
Not known:
• Hemolytic anemia.
Metabolism and nutrition disorders
Very rare:
• Lactic acidosis (see section 4.4);
• Reduced absorption of vitamin B12 with reduction of its serum levels during long-term use of metformin. It is recommended that etiology be considered if a patient presents with megaloblastic anemia.
Not known:
• Cases of peripheral neuropathy in patients with vitamin B12 deficiency have been reported in post marketing experience (see section 4.4).
Nervous system disorders
common:
• Taste disturbances.
Not known:
• Encephalopathy.
Gastrointestinal disorders
Very common:
• Gastrointestinal disorders such as nausea, vomiting, diarrhea, abdominal pain and loss of appetite. These side effects occur more frequently at the start of therapy and in most cases resolve spontaneously. To prevent them, it is recommended that metformin be taken in two or three daily doses with or after meals. also promote gastrointestinal tolerability.
Hepatobiliary disorders
Very rare:
• Isolated cases of liver function tests abnormal or hepatitis resolved after discontinuation of metformin.
Skin and subcutaneous tissue disorders
Very rare:
• Skin reactions such as erythema, itching and hives.
Not known:
• Photosensitivity.
Diagnostic tests
Not known:
• Reduction of thyrotropin levels in patients with hypothyroidism;
• Hypomagnesemia in the context of diarrhea.
Pediatric population
Published and post-marketing data and those from controlled clinical trials conducted in a limited pediatric population aged 10 to 16 years treated for one year indicate adverse events of a similar nature and severity to those reported for adults.
Reporting of suspected adverse reactions.
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose -
Hypoglycaemia has not been observed with metformin hydrochloride doses up to 85 g, although lactic acidosis has occurred in such circumstances. A high overdose of metformin or concomitant risks can lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in a hospital. The most effective method of removing lactate and metformin is hemodialysis.
Pancreatitis may occur in the context of a metformin overdose.
05.0 PHARMACOLOGICAL PROPERTIES -
05.1 "Pharmacodynamic properties -
Pharmacotherapeutic group: hypoglycemic drugs, excluding insulins; Biguanides.
ATC code: A10BA02.
Mechanism of action
Metformin is a biguanide with antiperglycemic effects that reduces both basal plasma glucose and postprandial glucose. It does not stimulate insulin secretion and therefore does not cause hypoglycemia.
Metformin can act by 3 mechanisms:
reducing the production of hepatic glucose through the inhibition of gluconeogenesis and glycogenolysis;
in the muscles, increasing insulin sensitivity, improving the absorption and utilization of peripheral glucose;
and delaying intestinal glucose absorption.
Metformin stimulates the synthesis of intracellular glycogen by acting on the glycogen synthetase.
Metformin increases the transport capacity of all types of membrane glucose transporters (GLUT) known to date.
Pharmacodynamic effects
In clinical trials, the use of metformin was associated with stabilization of body weight or modest weight loss.
In humans regardless of the mechanism of action, metformin promotes the effect on lipid metabolism. This has been seen in controlled medium- and long-term clinical trials at therapeutic doses: metformin reduces total cholesterol, LDL cholesterol and triglyceride levels.
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 for overweight patients treated with metformin, following the failure of the diet alone, showed:
• a significant reduction in the absolute risk of any diabetes-related complications in the metformin hydrochloride group (29.8 events / 1,000 patient / year) versus diet alone (43.3 events / 1,000 patient / year), p = 0.0023, and compared to the sulfonylurea combination and insulin monotherapy groups (40.1 events / 1,000 patient / year), p = 0.0034;
• a significant reduction in the absolute risk of diabetes-related mortality: metformin hydrochloride: 7.5 events / 1,000 patients / year; diet alone: 12.7 events / 1,000 patient / year, p = 0.017;
• a significant reduction in the absolute risk of overall mortality: metformin hydrochloride: 13.5 events / 1,000 patient / year compared to diet alone: 20.6 events / 1,000 patient / year (p = 0.011), and compared to the combined therapy groups with sulfonylureas and insulin monotherapy: 18.9 events / 1,000 patient / years (p = 0.021);
• a significant reduction in the absolute risk of myocardial infarction: metformin: 11 events / 1,000 patient / year; diet alone: 18 events / 1,000 patient / year (p = 0.01).
There was no clinical outcome benefit of metformin hydrochloride used as second-line therapy in combination with a sulphonylurea.
In type 1 diabetes, the combination of metformin and insulin has been administered to selected patients, however the clinical benefit of this combination has not been formally established.
Pediatric population
Controlled clinical trials, conducted in a limited pediatric population aged 10 to 16 years treated for one year, demonstrated a glycemic control response similar to that seen in adults.
05.2 "Pharmacokinetic properties -
Absorption :
After an oral dose of metformin hydrochloride tablets, the maximum plasma concentration (Cmax) is reached in approximately 2.5 hours (Tmax). The absolute bioavailability of a 500 mg or 850 mg tablet of metformin hydrochloride is approximately 50-60% in healthy subjects. After an oral dose, the unabsorbed fraction detected in faeces was 20-30%.
After oral administration, the absorption of metformin is saturable and incomplete. It is assumed that the absorption pharmacokinetics of metformin are non-linear.
At recommended metformin doses and defined dosing schedules, steady-state plasma concentrations are achieved within 24 to 48 hours and are generally less than 1 mcg / mL. In controlled clinical trials, maximum metformin plasma levels (Cmax) do not exceed 5 mcg / mL, even at maximum doses.
Food reduces the extent of metformin absorption and delays it slightly. Following oral administration of an 850 mg tablet dose, a 40% decrease in peak plasma concentration, a 25% decrease in AUC (area under the curve) and a 35 minute lengthening of the plasma were observed. time to peak plasma concentrations The clinical relevance of these decreases is unknown.
Distribution :
Plasma protein binding is negligible. Metformin distributes into erythrocytes. The blood peak is lower than the plasma peak and occurs almost simultaneously. Red blood cells probably represent a secondary distribution compartment. 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. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours.
In cases of impaired renal function, renal clearance decreases proportionally to creatinine clearance, which prolongs the elimination half-life, resulting in increased plasma metformin levels.
Characteristics in specific groups of patients
Kidney damage
Available data in subjects with moderate renal impairment are scarce and not feasible
an estimate of the systemic exposure to metformin in this subgroup relative to subjects
with normal renal function.
Therefore, dose adjustment should be made considering clinical efficacy / tolerability (see section 4.2).
Pediatric population :
Single dose studies: Following single dose administration of 500 mg metformin hydrochloride, pediatric patients demonstrated similar pharmacokinetic profiles to those seen in healthy adults.
Multiple dose studies: Data are limited to one study only. Following doses of 500 mg repeated twice daily (BID) for 7 days in pediatric patients, peak plasma concentration (Cmax) and systemic exposure (AUC0-t) were reduced by approximately 33% and 40%, respectively. , compared to diabetic adults who took repeated doses of 500 mg BID for 14 days Since the dose is individually titrated based on glycemic control, this is of little clinical relevance.
05.3 Preclinical safety data -
On the basis of conventional studies concerning pharmacological safety, repeated dose toxicity, genotoxicity, carcinogenic potential, reproductive toxicity, preclinical data show no particular hazards for humans.
06.0 PHARMACEUTICAL INFORMATION -
06.1 Excipients -
Core of the tablet:
Hypromellose
Povidone K25
Magnesium stearate
Coating:
Hypromellose
Macrogol 6000
Titanium dioxide (E171)
06.2 Incompatibility "-
Not relevant.
06.3 Period of validity "-
3 years.
06.4 Special precautions for storage -
This medicinal product does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package -
PVC / aluminum blisters of 15, 30,40, 50, 90, 100, 120 film-coated tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling -
No special instructions.
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
Zentiva Italia S.r.l.
Viale L. Bodio n. 37 / B - 20158 Milan
08.0 MARKETING AUTHORIZATION NUMBER -
• 15 film-coated tablets in PVC / AL AIC blister n. 038257061
• 30 film-coated tablets in PVC / AL AIC blister n. 038257073
• 40 film-coated tablets in PVC / AL AIC blister n. 038257085
• 50 film-coated tablets in PVC / AL AIC blister n. 038257097
• 90 film-coated tablets in PVC / AL AIC blister n. 038257109
• 100 film-coated tablets in PVC / AL AIC blister n. 038257111
• 120 film-coated tablets in PVC / AL AIC blister n. 038257123
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
Determination no. 897 of 30.07.2008 - Official Gazette no. 184 of 07.08.2008.
10.0 DATE OF REVISION OF THE TEXT -
July 2016
