Metforal

Package leaflet: Information for the user

METFORAL 500 mg film-coated tablets, 850 mg film-coated tablets

metformin hydrochloride
Please read this leaflet carefully before taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not give it to others, even if they have the same symptoms as you, because it could be harmful.
• If you experience any side effects, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4.

Contents of this leaflet:

1. What METFORAL is and what it is used for
2. What you need to know before taking METFORAL
3. How to take METFORAL
4. Possible side effects
5. How to store METFORAL
6. Contents of the pack and other information

1. What METFORAL is and what it is used for

METFORAL contains metformin hydrochloride (belonging to the class of biguanides) and is an oral antidiabetic medicinal product
(used in the treatment of diabetes, a chronic metabolic disorder characterized by
high blood glucose levels due to insufficient insulin production by the body and/or
insulin action abnormalities).
METFORAL is used for the treatment of type 2 diabetes mellitus that cannot be controlled by diet and physical exercise alone, particularly in overweight patients.
In adults, METFORAL can be used either alone (monotherapy) or in combination with other oral antidiabetic drugs or with insulin.
In children over 10 years of age and adolescents, METFORAL can be used alone or in combination with insulin.
A reduction in diabetes-related complications has been demonstrated in overweight adult patients with type 2 diabetes treated with metformin as first-line therapy (initial treatment) following failure of dietary management.

2. What you need to know before taking METFORAL

Do not take METFORAL

• If you are allergic to the active substance (metformin hydrochloride) or to any of the other ingredients of this medicine (listed in section 6).

• If you have diabetic ketoacidosis (a complication of diabetes in which ketone bodies in the blood cause a significant drop in pH to highly acidic levels).

• If you are in a state of diabetic pre-coma.

• If you have severely reduced kidney function.

• If you have uncontrolled diabetes associated, for example, with severe hyperglycemia (high blood glucose levels), nausea, vomiting, diarrhea, rapid weight loss, lactic acidosis (see below “Risk of
  lactic acidosis”) or ketoacidosis. Ketoacidosis is a condition in which substances called “ketone bodies”
  accumulate in the blood and may lead to diabetic pre-coma. Symptoms include
  abdominal pain, rapid and deep breathing, drowsiness, and breath with an unusually
  fruity odor.

• In case of acute conditions that could worsen your kidney function, such as:

  • Dehydration
  • Severe infection
  • Shock

• When receiving intravenous or intra-arterial administration of iodinated contrast agents (see “Warnings and precautions” and “Other medicines and METFORAL”).

• In case of acute or chronic diseases that may cause tissue hypoxia (lack of oxygen), such as:

  • Cardiac or respiratory failure (reduced organ function)
  • Recent myocardial infarction (death of heart tissue due to blockage or marked reduction in blood flow to the heart)
  • Shock

• In case of hepatic impairment (reduced liver function).

• In case of acute alcohol intoxication or alcoholism.

• During breastfeeding (see section “Pregnancy, breastfeeding and fertility”).

Warnings and precautions
Talk to your doctor or pharmacist before taking METFORAL.
During treatment with METFORAL, follow a dietary regimen in which carbohydrates are evenly distributed throughout the day.
If you are overweight, continue a low-calorie diet.
Regularly perform the laboratory tests normally recommended for diabetes.
Although metformin alone does not cause hypoglycemia (decrease in blood sugar concentration), exercise particular caution if metformin hydrochloride is used in combination with insulin or other oral antidiabetic agents such as sulfonylureas or meglitinides.

Risk of lactic acidosis
METFORAL may cause a very rare but very serious adverse effect called lactic acidosis, particularly if the kidneys are not functioning properly. The risk of developing lactic acidosis is higher in the presence of uncontrolled diabetes, severe infections, prolonged fasting or alcohol consumption, dehydration (see below for further information), liver problems, or any other medical condition characterized by reduced oxygen supply to part of the body (such as severe heart disease).
If you have any of the above medical conditions, consult your doctor for further instructions.
Temporarily stop taking METFORAL if you develop a medical condition
that may be associated with dehydration (significant loss of body fluids), such as severe vomiting, diarrhea, fever, heat exposure, or if you are drinking less fluid than normal. Consult your doctor for further instructions.
If you experience any of the symptoms of lactic acidosis, stop taking METFORAL and contact
your doctor or the nearest hospital immediately, as lactic acidosis can lead to coma.
Symptoms of lactic acidosis include:

• Vomiting
• Stomach ache (abdominal pain)
• Muscle cramps
• A general feeling of malaise associated with severe fatigue
• Difficulty breathing
• Low body temperature and slower heart rate

Lactic acidosis is a medical emergency and must be treated in hospital.
Reported cases of lactic acidosis in patients treated with metformin have occurred particularly in diabetic patients with significant renal impairment. The incidence of lactic acidosis can and should be reduced by also evaluating other associated risk factors, such as poorly controlled diabetes, ketosis (increased blood concentration of ketone bodies, substances derived from fat metabolism), prolonged fasting, excessive alcohol intake, hepatic impairment, and any other conditions associated with hypoxia.
You should be instructed to recognize the warning signs of lactic acidosis such as muscle cramps associated with digestive disturbances like abdominal pain and severe asthenia (lack of strength) (see section 4 “Possible side effects”).
If you are undergoing major surgery, you must stop taking METFORAL during the procedure and for a certain period afterward. Your doctor will decide when to stop and when to restart treatment with METFORAL.

Kidney function
Before starting treatment, creatinine clearance (the rate at which creatinine is removed from the blood, a parameter used to assess kidney function) must be determined, as metformin is eliminated by the kidneys.
During treatment with METFORAL, your doctor will monitor your kidney function at least once a year, or more frequently (at least two to four times a year) if you are elderly and/or if kidney function worsens.
Reduced kidney function in elderly patients is common and asymptomatic (without symptoms).
Pay particular attention in situations where kidney function may be compromised, for example when starting treatment with antihypertensive drugs (which lower blood pressure) or diuretics (drugs that increase urine production), and when starting treatment with non-steroidal anti-inflammatory drugs (NSAIDs).

Administration of iodinated contrast agents
Stop taking metformin before or at the time of the examination, as intravascular (into blood vessels) administration of iodinated contrast agents during radiological investigations may lead to kidney failure. This can cause accumulation of metformin, increasing the risk of lactic acidosis (see section “Other medicines and METFORAL”).
Resume taking metformin 48 hours after the examination and only after your doctor has confirmed that your kidney function is normal.

Surgical procedures
Stop taking metformin 48 hours before undergoing surgery under general or local (spinal or epidural) anesthesia, and do not restart until at least 48 hours after surgery or resumption of oral feeding, and only after normal kidney function has been confirmed.

Children and adolescents
Before starting treatment with metformin, type 2 diabetes mellitus must be confirmed.
Despite the absence of long-term studies in this age group, and although no effects of metformin on growth or puberty have been observed in short-term studies, careful monitoring of possible effects of metformin on these parameters is recommended in children treated with metformin, particularly in prepubertal children.

Children aged 10 to 12 years
Although the efficacy and safety of metformin in children under 12 years of age are similar to those observed in older children, particular caution is recommended when administering metformin to children aged between 10 and 12 years.

Other medicines and METFORAL
If you are scheduled to receive an injection of an iodinated contrast agent into the bloodstream, for example for an X-ray, you must stop taking METFORAL before or at the time of the injection. Your doctor will decide when to stop and when to restart treatment with METFORAL.
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. You may need to monitor your blood glucose and kidney function more frequently, or your doctor may adjust your dose of METFORAL. It is particularly important to mention the following:

Avoid taking metformin in combination with:

• Alcohol (and medicines containing alcohol), because in cases of acute alcohol intoxication, especially during prolonged fasting or malnutrition and in the presence of hepatic impairment, the risk of lactic acidosis increases (see “METFORAL with alcohol”).
• Iodinated contrast agents. This combination may cause kidney failure, leading to metformin accumulation and risk of lactic acidosis. Metformin hydrochloride must therefore be discontinued before or at the time of the examination, and treatment should not be resumed earlier than 48 hours after the examination and only after your doctor has confirmed normal kidney function (see “Do not take METFORAL” and “Warnings and precautions”).

Exercise particular caution when taking metformin with:

• Sympathomimetic agents (drugs that mimic the effects of sympathetic nervous system activation on various tissues, such as ephedrine, amphetamines, cocaine, etc., which may have vasoconstrictive or hypertensive effects) and glucocorticoids (drugs used as anti-inflammatories and in some cases of allergic reactions), administered systemically (via a route that may affect the whole body) or locally. These drugs have hyperglycemic effects (they increase blood sugar concentration); therefore, blood glucose levels should be monitored frequently, especially at the beginning of treatment, and the dose of metformin may need to be adjusted during therapy with the other drug.
• Medicines that increase urine production (diuretics), particularly loop diuretics (because these drugs may increase the risk of lactic acidosis due to their ability to reduce kidney function).
• Medicines used to treat pain and inflammation (NSAIDs and COX-2 inhibitors, such as ibuprofen and celecoxib).
• Certain medicines used to treat high blood pressure (ACE inhibitors and angiotensin II receptor antagonists).
• Insulin and other oral antidiabetic agents such as sulfonylureas or meglitinides: due to the possible occurrence of hypoglycemia.
• Medicines that may alter the blood levels of METFORAL, especially if you have reduced kidney function (such as verapamil, rifampicin, cimetidine, dolutegravir, ranolazine, trimethoprim, vandetanib, isavuconazole, crizotinib, olaparib).

Any treatment, and in particular switching to or from other antihyperglycemic agents, must be prescribed by your doctor.

METFORAL with alcohol
Avoid excessive alcohol consumption during treatment with METFORAL, as this may increase the risk of lactic acidosis (see section “Warnings and precautions”).

Pregnancy, breastfeeding and fertility
If you are pregnant, think you may be pregnant, are planning to become pregnant, or are breastfeeding, consult your doctor before taking this medicine.
Uncontrolled diabetes during pregnancy (gestational or permanent) is associated with an increased risk of congenital anomalies (i.e., present at birth) and perinatal mortality (i.e., death during the period immediately before and after birth).

Pregnancy and fertility
If you have diabetes and are planning a pregnancy or are pregnant, you should undergo a specialist evaluation to determine whether treatment with metformin should be initiated or continued. You may need to take insulin to keep blood glucose levels as close to normal as possible, thereby reducing the risk of fetal malformations related to high blood glucose levels.

Breastfeeding
Metformin is excreted in breast milk. No effects of metformin have been shown in newborns/infants breastfed by treated women. However, taking metformin is contraindicated during breastfeeding. In this case, your doctor will decide whether to discontinue breastfeeding, taking into account the benefits of breastfeeding and the potential risk of adverse effects for the infant.

Driving and using machines
Metformin hydrochloride alone does not cause hypoglycemia, so it does not impair or impairs only insignificantly the ability to drive or use machines.
However, you should be aware of the risk of hypoglycemia when metformin is used in combination with other antidiabetic medicines (sulfonylureas, insulin, meglitinides), as in such cases the ability to drive or use machines may be impaired.

3. How to take METFORAL

Take this medicine exactly as directed by your doctor or pharmacist. If you are unsure, consult your doctor or pharmacist.

Adults
Monotherapy and combination with other oral antidiabetic agents
The recommended starting dose is one tablet taken 2 or 3 times daily, during or immediately after meals.
If you have impaired renal function, your doctor may prescribe a lower dose.
After 10–15 days, the dose should be adjusted according to blood glucose levels. A gradual increase in dosage may improve gastrointestinal tolerance (of the stomach and intestine) (see section 4, “Possible side effects”).
The maximum recommended dose is 3,000 mg per day, taken in 3 separate doses.
When switching from another oral antidiabetic medicine to metformin hydrochloride, discontinue the previous medicine and start metformin at the dose indicated above.

Combination with insulin
Metformin hydrochloride and insulin may be used together to improve blood glucose control. Metformin hydrochloride is administered at the usual initial dose of one tablet 2–3 times daily, while the insulin dose is adjusted based on blood glucose levels.

Elderly
Due to the possible reduced renal function in elderly patients, the dosage of metformin hydrochloride must be adjusted according to renal function. Therefore, periodic assessment of renal function is necessary (see section “Warnings and precautions”, “Renal function”).

Use in children over 10 years of age and adolescents
Monotherapy and combination with insulin
The recommended starting dose is one tablet once daily, taken during or immediately after meals.
After 10–15 days, the dose should be adjusted according to blood glucose levels. A gradual increase in dosage may improve gastrointestinal tolerance of the medicine.
The maximum recommended dose of metformin hydrochloride is 2,000 mg per day, taken in 2 or 3 divided doses.

If you take more METFORAL than you should
Hypoglycaemia has not been observed with doses of metformin hydrochloride up to 85,000 mg, although lactic acidosis has occurred under such circumstances. Large overdoses of metformin or concomitant risk factors may lead to lactic acidosis.
Lactic acidosis is a medical emergency and requires hospital treatment. The most effective method to remove lactate and metformin from the body is haemodialysis (a procedure used to filter the blood and replace the function of a failing kidney).

If you forget to take METFORAL
Do not take a double dose to make up for the missed dose.
If you have any doubts about how to use this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody will get them.
METFORAL may cause a very rare (may affect up to 1 in 10,000 people) but very serious side effect called lactic acidosis (see section “Warnings and precautions”).
If this occurs, you must stop taking METFORAL and must contact your doctor or go to the nearest hospital immediately, because lactic acidosis can lead to coma.

Other side effects that may occur with METFORAL

Very common side effects (may affect more than 1 in 10 people)
Gastrointestinal disturbances (nausea, loss of appetite, abdominal pain, vomiting or diarrhoea).
These disturbances usually occur at the beginning of treatment and in most cases resolve spontaneously. To prevent these symptoms, it is recommended to take metformin in 2 or 3 daily doses during or after meals. A gradual increase in dose may improve gastrointestinal tolerability (see “How to take METFORAL”).

Common side effects (may affect up to 1 in 10 people)

• Altered taste
• Reduced or low levels of vitamin B12 in the blood (symptoms may include extreme tiredness (fatigue), red and painful tongue (glossitis), tingling sensations (paraesthesias), or pale or yellowish skin). Your doctor may prescribe certain tests to determine the cause of your symptoms, as some of these may also be caused by diabetes or other health problems unrelated to diabetes.

Very rare side effects (may affect up to 1 in 10,000 people)

• Skin reactions such as erythema, itching and urticaria.
• Abnormal liver function tests and hepatitis (liver inflammation), which resolve upon discontinuation of metformin treatment.

Following the instructions contained in this leaflet reduces the risk of side effects.
It is important to inform your doctor or pharmacist if you experience any side effect, even if it is not described in this leaflet.

Additional side effects in children and adolescents
Side effects are similar in type and severity to those reported in adults.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system at the following website: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store METFORAL

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging. The expiry date refers to the last day of that month and to the product in its original, undamaged packaging, properly stored.
Store the medicine in a dry place.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What METFORAL contains
METFORAL 500 mg film-coated tablets
Each film-coated tablet contains:
Active substance: metformin hydrochloride 500 mg (equivalent to 390 mg of metformin).
Other components: anhydrous colloidal silica, povidone, macrogol 4000, magnesium stearate, Opadry II 85F29116
clear (polyvinyl alcohol, macrogol 3350, talc).
METFORAL 850 mg film-coated tablets
Each film-coated tablet contains:
Active substance: metformin hydrochloride 850 mg (equivalent to 662.9 mg of metformin).
Other components: anhydrous colloidal silica, povidone, macrogol 4000, magnesium stearate, Opadry II 85F29116
clear (polyvinyl alcohol, macrogol 3350, talc).

Description of the appearance of METFORAL and contents of the pack
METFORAL 500 mg film-coated tablets
Film-coated, round, biconvex tablet, white in colour.
Blister pack containing 50 film-coated tablets, packaged in a cardboard carton.

METFORAL 850 mg film-coated tablets
Film-coated, oval-shaped tablet, white in colour, with a break line on both sides.
The score line on the tablet is intended to facilitate breaking the tablet for easier swallowing and is not intended to divide the tablet into equal doses.
Blister pack containing 30 film-coated tablets, packaged in a cardboard carton.

Marketing Authorization Holder and Manufacturer
Marketing Authorization Holder
Laboratori Guidotti S.p.A. - Via Livornese, 897 – PISA – La Vettola.
Manufacturers
Berlin Chemie AG - Glienicker Weg 125 - 12489 Berlin – Germany.
A. Menarini Manufacturing Logistics and Services srl - Campo di Pile, L’Aquila – Italy.
Menarini – Von Heyden GmbH - Leipziger Strasse, 7 – 13 - Dresden – Germany.