- Introduction: what is it?
- Dosage: how is it used and how does it work?
- Warnings and Precautions
- Interactions and side effects
- Pregnancy and breastfeeding
- Notes (validity, methods of storage, disposal)
Questions and answers
Introduction: what is it?
Metformin is a hypoglycemic drug used to treat diabetes . It belongs to a family of active substances called biguanides. Metformin is indicated for the treatment of type 2 diabetes mellitus (also called “non-insulin-dependent diabetes”), particularly in overweight patients, when a controlled diet and exercise alone cannot produce glycemic control. adequate.
In adults , metformin can be used alone or in combination with other oral antidiabetic agents or with insulin . In childrenfrom 10 years of age and in adolescents, metformin can be used alone or in combination with insulin.
Metformin is able to reduce diabetes-related complications in overweight adult patients with type 2 diabetes as first-line therapy following dietary failure. In diabetic patients, the pancreas can no longer produce sufficient insulin or is unable to use the insulin it produces properly. Insulin is a hormone that allows the body to assimilate glucose(sugar) from the blood. The body uses glucose for energy or stores it for future use. The worst risks for patients with type 2 diabetes mellitus are due to the onset of complications. A proper management of the disease , compliance with the diet , the ‘ physical activity and constant monitoring of the values of blood sugar are important in the prevention of this disease.
If insulin is lacking, blood glucose (blood sugar) levels rise excessively, causing damage to various organs(eyes, cardiovascular system, kidneys and nervous system). In particular, people with diabetes can develop several types of eye disease , including retinopathy (caused by a tear in the blood vessels of the retina), cataracts (clouding of the lens) and glaucoma (increased pressure in the eye). , all diseases that can lead to blindness. Damage to the blood vessels can develop in the kidneys, making it difficult for the blood to cleanse, causing kidney failure. High blood sugar levels can damage blood vessels causing an increased risk of developing strokes and other cardiovascular diseases (such as hypertensionand increased blood cholesterol levels) which account for about 75% of all deaths in diabetic subjects. Finally, hyperglycemia can damage the nervous system (neuropathy) particularly in the hands and feet (causing diabetic foot ), digestive tract, bladder and sexual organs leading to cases of erectile dysfunction.
Metformin helps lower blood glucose levels to a level that is as normal as possible.
In overweight adults, taking metformin for a long time also helps to lower the risk of complications associated with diabetes. Also, it can cause both stabilization and onemodest loss of body weight .
Metformin is available in different pharmaceutical forms at different strengths :
- 1000 mg tablets;
- 500 mg, 850 mg and 1000 mg film-coated tablets divided into two equal doses;
- prolonged-release tablets of 500 mg, 750 mg and 1000 mg;
- 500 mg, 850 mg and 1000 mg powder for solution for oral use.
Metformin is dispensed only after presentation of a repeatable prescription (RR – medicines subject to medical prescription).
Dosage: how is it used and how does it work?
Metformin is used to treat patients with type 2 diabetes when diet and exercise alone have not been sufficient to control blood glucose levels. It is used in particular in overweight patients.
Metformin cannot replace the benefits of a healthy lifestyle. You should continue to follow all dietary advice you received from your doctor and exercise regularly. It is important to always take metformin exactly following your doctor’s instructions. If in doubt, consult your doctor or pharmacist.
The initial dosage may vary based on ageof the patient and his renal function. Thereafter, the dosage is adjusted based on the patient’s individual response (change in blood glucose).
Adults with normal renal function (glomerular filtration rate (GFR) ≥ 90 mL / min).
- As monotherapy and in combination with other oral antidiabetic agents: the usual starting dose is 500 mg or 850 mg of metformin 2 or 3 times daily given with or after meals. After 10 – 15 days the dose should be adjusted based on the results of the blood glucose measurements. A slow increase in the dose may lead to an improvement in the gastrointestinal tolerability of the drug. The maximum recommended dose of metformin in adults is 3 g per day, to be taken in 3 separate doses. If a patient who was already being treated with another oral antidiabetic agent is expected to switch to metformin, therapy with the other agent should be discontinued and metformin treatment initiated at the dose indicated above.
- Combination with insulin: Metformin and insulin can be used in combination therapy to achieve better blood glucose control. Metformin is usually given at a starting dose of 500 mg or 850 mg 2 or 3 times a day , while the insulin dose is adjusted on the basis of daily blood glucose measurements.
Due to the possibility of impaired renal function in elderly subjects, the metformin dose should be adjusted according to renal function (measurement of GFR) which should be monitored regularly.
Patients with renal impairment
GFR should be evaluated before starting treatment with metformin and, thereafter, at least annually.
In patients at increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently (every 3-6 months).
Monotherapy and combination with insulin: Metformin can be used in children 10 years of age and older and adolescents. Typically, the starting dose is 500 mg or 850 mg of metformin once a day , taken with or after a meal. After 10-15 days the dose should be adjusted based on blood glucose values. To improve the gastrointestinal tolerability of the drug it is advisable to slowly increase the dosage.
The maximum recommended dose of metformin in the pediatric population is 2 g per day , taken as 2 or 3 separate administrations.
Metformin should be taken during or after a meal with a glass of water. This avoids having the undesirable effects that disturb digestion. If you take one dose per 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). Do not crush or chew the tablets, but take them whole .
If you take more metformin than you need, lactic acidosis can occur . Accumulation of metformin results in acute worsening of renal function and an increased risk of lactic acidosis. L ‘ lactic acidosisit is a very rare, but serious, metabolic complication that occurs more frequently following acute worsening of kidney function or cardiorespiratory disease or sepsis. Lactic acidosis is manifested by nonspecific symptoms such as vomiting , stomach ache (abdominal pain) with muscle cramps , feeling of malaise with severe fatigue and difficulty breathing. Additional symptoms include decreased body temperature and heart rate . If any of these symptoms occur, medical attention should be sought immediately, as lactic acidosis can lead to coma. Stop taking metformin and contact a doctor or the nearest hospital immediately.
In case of dehydration (severe diarrhea or vomiting, fever or reduced fluid intake), the administration of metformin should be temporarily interrupted and medical attention should be consulted . Caution should be exercised in initiating treatment with medicinal products that may acutely impair renal function such as antihypertensives, diuretics and non-steroidal anti-inflammatory drugs (NSAIDs) in patients treated with metformin. Other risk factors for lactic acidosis are excessive alcohol consumption , hepatic impairment, poorly controlled diabetes, ketosis , prolonged fasting and any other conditions associated with hypoxia, as well as the concomitant use of drugs that can cause lactic acidosis.
If you forget to take metformin, do not take a double dose to make up for a forgotten dose. Take the next dose at the scheduled time.
Metformin is a biguanide with hypoglycemic effects, that is, it is able to reduce both basal and postprandial plasma glucose levels. It does not stimulate insulin secretion and therefore does not produce hypoglycemia.
Metformin can act through 3 mechanisms :
- reducing hepatic glucose productionby inhibiting gluconeogenesis and glycogenolysis in muscle,
- increasing insulin sensitivity, leading to better uptake and utilization of circulating glucose in the blood
- delaying the absorption of glucosein the intestine.
Metformin stimulates the production of glycogen intracellularly by acting on the enzyme that synthesizes glycogen ( glycogen synthetase ). Furthermore, metformin increases the transport capacity of all types of membrane glucose transporters (GLUT) known to date. The use of metformin has been associated with stabilization or modest loss of body weight. In humans, metformin has favorable effects on lipid metabolism, regardless of its action on blood sugar. This effect has been demonstrated at therapeutic doses in medium and long-term controlled clinical trials: metformin reduces the levels of total cholesterol, LDL cholesterol (the bad, highly atherogenic cholesterol) and triglycerides.
Warnings and Precautions
Metformin is contraindicated in certain categories of patients who show that they have:
- hypersensitivity to metforminor to any of the excipients
- any type of acute metabolic acidosis(such as lactic acidosis, diabetic ketoacidosis)
- severe renal failure (GFR <30 mL / min)
- acute conditionspotentially capable of altering renal function such as dehydration, severe infection, shock
- pathologies that may cause tissue hypoxia(especially acute pathologies or worsening of chronic pathologies) such as decompensated heart failure, respiratory failure, recent myocardial infarction, shock
- liver failure, acute alcohol intoxication, alcoholism.
Patients with a GFR between 60 and 89 mL / min may require a reduction in metformin dosage .
Patients with a GFR between 59 and 30 mL / min may have an increased risk of lactic acidosis and therefore the risks and benefits of any treatment with metformin must be carefully weighed. In any case, the initial dose should not exceed half the maximum dose .
Renal function : GFR should be assessed before starting treatment and at regular intervals thereafter. Metformin is contraindicated in patients with GFR <30 mL / min and should be temporarily stopped.in the presence of pathological conditions that alter renal function.
Cardiac function : Patients with heart failure are more at risk of hypoxia and renal failure . In patients with stable chronic heart failure, metformin can be used with regular monitoring of heart and kidney function. In patients with acute and unstable heart failure , metformin is contraindicated .
Pediatric population : the diagnosis of type 2 diabetes mellitusmust be confirmed before starting treatment with metformin. No effects of metformin on growth and puberty have been observed in controlled clinical trials lasting one year, but no long-term data are available on these specific points. Therefore, careful follow-up of the effects of metformin on these parameters is recommended in children treated with this drug, particularly prepubertal children.
Children aged 10-12 years:Although the evaluation of the efficacy and safety of metformin administered to these children does not differ from the efficacy and safety parameters found in older children and adolescents, particular caution is recommended when prescribing this drug to children aged 10 and 12 years.
All patients should continue to follow a diet that includes a regular distribution of carbohydrate intake throughout the day. Overweight patients must continue to follow a diet with a limited energy intake . The usual laboratory tests for diabetes control should be done regularly.
Metformin monotherapy does not cause hypoglycaemia and therefore has no effect on the ability to drive or use machines. Nevertheless, patients should be warned about the risk of developing hypoglycaemia if metformin is used in combination with other antidiabetic agents (sulphonylureas, insulin or meglitinides).
Hypoglycaemia has not been observed with metformin doses up to 85 g , although lactic acidosis has occurred in some cases. L ‘ lactic acidosisit is a medical emergency and must be treated in a hospital. If necessary, the most effective method of removing lactate and metformin is hemodialysis .
The powder for oral solution contains aspartame , which is a source of phenylalanine . In patients suffering from phenylketonuria (a rare inherited disease that prevents the body from using phenylalanine), metformin powder for oral solution could be harmful. Ask your doctor for advice before starting to take this medicine.
Interactions and side effects
If you need to take metformin, it is important to tell your doctor if you are taking, have recently taken, or might take any other medicines . Blood glucose tests and kidney function tests may need to be done more often. In some cases, your doctor may decide to change your metformin dosage. Particular precautions
should be taken in the case of co-administration with medicinal products that may adversely affect renal function, thus increasing the risk of lactic acidosis. It is especially important to warn your doctor about the use of:
- drugs that increase urine production(diuretics, especially loop diuretics)
- pain relieving and anti-inflammatorydrugs (NSAIDs), including selective cyclooxygenase (COX) 2 inhibitors, such as ibuprofen and celecoxib.
- some drugs used to treat hypertension, such as ACE inhibitors and angiotensin II receptor antagonists.
- some drugs used to treat asthma, such as beta-2 agonists, such as salbutamol or terbutaline.
- some drugs may affect the blood levels of metformin, particularly in patients with impaired renal function (such as verapamil, rifampicin, cimetidine, dolutegravir, ranolazine, trimethoprim, vendertanib, isavuconazole, crizotinib, olaparib).
When these medicinal products are used in combination with metformin, renal function should be carefully monitored.
In the case of co-administration with drugs with intrinsic hyperglycemic activity (e.g. systemically or locally administered glucocorticoids and sympathomimetics), more frequent blood glucose monitoring may be required, especially at the start of treatment.
Particular care should also be taken if metformin is co-administered with other antidiabetic drugs that can cause hypoglycaemia (sulphonylureas, insulin, meglitinides). L ‘ hypoglycemia has specific symptoms, such as weakness , dizziness, increased sweating , rapid heart rate , visual disturbances or difficulty concentrating. If necessary, adjust the dose of metformin during therapy with the interacting drug and upon discontinuation of the drug.
Concomitant use with alcohol is not recommended. Acute ethyl poisoning is associated with an increased risk of lactic acidosis, especially in cases of fasting, malnutrition or hepatic impairment . Avoid consumption of alcohol and alcohol-containing medications.
Use of iodinated contrast agents: Intravascular administration of iodinated contrast agents during radiological examination may cause contrast-induced nephropathy . This can lead to accumulation of metformin and can increase the risk of lactic acidosis. Metformin administration should be discontinued prior to, or at the time of the diagnostic test , and should not be resumed until at least 48 hours have elapsed since the test , provided renal function has been re-evaluated and found to be stable.
At the start of treatment with metformin the most common side effects are nausea, vomiting, diarrhea, loss of taste, abdominal pain and loss of appetite.which, in most cases, resolve spontaneously. To prevent these symptoms from occurring, it is recommended to take metformin in 2 or 3 daily doses and to increase the dose slowly.
Pregnancy and breastfeeding
The uncontrolled diabetes ( gestational or permanent) during pregnancy seems to be associated with an increased risk of congenital abnormalities and perinatal mortality .
A limited amount of data on the use of metformin in pregnant women did not indicate an increased risk of congenital anomalies . Animal studies do not indicate harmful effects with respect to pregnancy, embryonal / fetal development, parturition or postnatal development. When the patient plans pregnancy and during pregnancy itself, it is recommended not to treat diabetes with metformin but to use insulinto keep blood glucose levels as close to normal as possible in order to reduce the risk of fetal malformations.
Metformin is excreted in human breast milk . No adverse effects were noted in breastfed infants / children. However, as only limited data are available, it is recommended not to breast-feed during treatment with metformin. Therefore, consideration should be given to discontinuing breastfeeding, taking into account the benefit of breastfeeding and the potential risk of adverse effects on the baby.
Metformin did not affect fertility in experimental animals at doses approximately three times the maximum recommended human daily dose.
Notes (validity, methods of storage, disposal)
- The tabletsare valid for 5 years (500 mg and 850 mg) or 3 years (1000 mg) and do not require any special storage conditions.
- The powder for oral solutionis valid for 3 years and does not require any special storage conditions.
Leftover medicines should not be disposed of via wastewater or household waste . Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
Questions and answers
IS METFORMIN A DRUG USED FOR …?
Metformin is a drug used to treat diabetes when diet and exercise alone have not been enough to control blood glucose (blood sugar) levels. It is used in particular in overweight patients. It belongs to a group of active substances called biguanides .
WHAT EXACTLY DOES METFORMIN DO IN THE BODY?
Metformin helps lower the blood sugar level to a level that is as normal as possible.
HOW COMMON ARE THE SIDE EFFECTS?
Typical side effects that may be seen after taking metformin in about one in 10 patients are digestive problems such as nausea, vomiting, diarrhea, stomach pain (abdominal pain) and loss of appetite . In some patients there may also be an alteration in taste. These side effects appear more often at the start of treatment. It may be helpful to split the drug doses over the day and take metformin with or immediately after a meal. If symptoms persist, stop taking the drug and consult a doctor.
WHAT IS THE BENEFIT OF TAKING METFORMIN?
Taking metformin for a long period of time, in addition to reducing blood glucose levels , also contributes to lowering the risk of complications associated with diabetes and is associated with both stabilization and modest loss of body weight .
WHAT IS THE BEST TIME OF DAY TO TAKE IT?
It is advisable to take metformin during or immediately after a meal, 2 or 3 times a day to minimize gastrointestinal problems.