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Generic Name: metformin (met FOR min)Brand Names: Fortamet, Glucophage, Glucophage XR, Glumetza. Riomet

Medically reviewed by Sanjai Sinha, MD Last updated on Dec 6, 2018.

Metformin is an oral diabetes medicine that helps control blood sugar levels.

Metformin is used together with diet and exercise to improve blood sugar control in adults with type 2 diabetes mellitus.

Metformin is sometimes used together with insulin or other medications, but it is not for treating type 1 diabetes.

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You should not use metformin if you have severe kidney disease, metabolic acidosis, or diabetic ketoacidosis (call your doctor for treatment).

If you need to have any type of x-ray or CT scan using a dye that is injected into your veins, you will need to temporarily stop taking metformin.

Though extremely rare, you may develop lactic acidosis, a dangerous build-up of lactic acid in your blood. Call your doctor or get emergency medical help if you have unusual muscle pain, trouble breathing, stomach pain, dizziness, feeling cold, or feeling very weak or tired.

You should not use metformin if you are allergic to it, or if you have:

severe kidney disease; or

metabolic acidosis or diabetic ketoacidosis (call your doctor for treatment).

If you need to have surgery or any type of x-ray or CT scan using a dye that is injected into your veins, you will need to temporarily stop taking metformin. Be sure your caregivers know ahead of time that you are using this medication.

Tell your doctor if you have ever had:

kidney disease (your kidney function may need to be checked before you take this medicine);

high ketone levels in your blood or urine;

heart disease, congestive heart failure;

liver disease; or

if you also use insulin, or other oral diabetes medications.

You may develop lactic acidosis, a dangerous build-up of lactic acid in your blood. This may be more likely if you have other medical conditions, a severe infection, chronic alcoholism, or if you are 65 or older. Ask your doctor about your risk.

Follow your doctor’s instructions about using this medicine if you are pregnant. Blood sugar control is very important during pregnancy, and your dose needs may be different during each trimester of pregnancy. Tell your doctor if you become pregnant while taking metformin.

Metformin may stimulate ovulation in a premenopausal woman and may increase the risk of unintended pregnancy. Talk to your doctor about your risk.

You should not breast-feed while using this medicine.

Metformin should not be given to a child younger than 10 years old. Some forms of metformin are not approved for use by anyone younger than 18 years old.

Take metformin exactly as prescribed by your doctor. Follow all directions on your prescription label and read all medication guides or instruction sheets. Your doctor may occasionally change your dose. Use the medicine exactly as directed.

Take metformin with a meal, unless your doctor tells you otherwise. Some forms of metformin are taken only once daily with the evening meal. Follow your doctor’s instructions.

Do not crush, chew, or break an extended-release tablet. Swallow it whole.

Measure liquid medicine carefully. Use the dosing syringe provided, or use a medicine dose-measuring device (not a kitchen spoon).

Some tablets are made with a shell that is not absorbed or melted in the body. Part of this shell may appear in your stool. This is normal and will not make the medicine less effective.

Low blood sugar (hypoglycemia) can happen to everyone who has diabetes. Symptoms include headache, hunger, sweating, irritability, dizziness, nausea, fast heart rate, and feeling anxious or shaky. To quickly treat low blood sugar, always keep a fast-acting source of sugar with you such as fruit juice, hard candy, crackers, raisins, or non-diet soda.

Your doctor can prescribe a glucagon emergency injection kit to use in case you have severe hypoglycemia and cannot eat or drink. Be sure your family and close friends know how to give you this injection in an emergency.

Blood sugar levels can be affected by stress, illness, surgery, exercise, alcohol use, or skipping meals. Ask your doctor before changing your dose or medication schedule.

Metformin is only part of a complete treatment program that may also include diet, exercise, weight control, regular blood sugar testing, and special medical care. Follow your doctor’s instructions very closely.

Your doctor may have you take extra vitamin B12 while you are taking this medicine. Take only the amount of vitamin B12 that your doctor has prescribed.

Store at room temperature away from moisture, heat, and light.

Metformin dosage information (in more detail)

Take the medicine as soon as you can, but skip the missed dose if it is almost time for your next dose. Do not take two doses at one time.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. An overdose can cause severe hypoglycemia or lactic acidosis.

Avoid drinking alcohol. It lowers blood sugar and may increase your risk of lactic acidosis.

Get emergency medical help if you have signs of an allergic reaction to metformin: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Some people using this medicine develop lactic acidosis, which can be fatal. Get emergency medical help if you have even mild symptoms such as:

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unusual muscle pain;

feeling cold;

trouble breathing;

feeling dizzy, light-headed, tired, or very weak;

stomach pain, vomiting; or

slow or irregular heart rate.

Common metformin side effects may include:

low blood sugar;

nausea, upset stomach; or

diarrhea.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Metformin side effects (in more detail)

Many drugs can interact with metformin, making it less effective or increasing your risk of lactic acidosis. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed here. Tell your doctor about all your current medicines and any medicine you start or stop using.

Metformin drug interactions (in more detail)

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use metformin only for the indication prescribed.

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Copyright 1996-2019 Cerner Multum, Inc. Version: 16.01.

Medical Disclaimer

Other brands: Glucophage, Glumetza, Fortamet, Glucophage XR, Riomet

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Brand name

Metformin Sandoz 500 mg and 850 mg

Active ingredient

Metformin hydrochloride

Schedule

S4

Please read this leaflet carefully before you start using Metformin Sandoz 500mg, 850mg.

This leaflet answers some common questions about Metformin Sandoz.

It does not contain all the available information. It does not take the place of talking to your doctor, pharmacist or diabetes educator.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking this medicine against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor, pharmacist or diabetes educator.

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Keep this leaflet with the medicine.
You may need to read it again.

This medicine is used to control blood sugar (glucose) in patients with diabetes mellitus.

Metformin Sandoz is used to treat Type 2 diabetes when it cannot be properly controlled by diet and exercise. It can also be used in patients with Type 1 diabetes mellitus where insulin alone is not enough to control your blood glucose levels. Metformin Sandoz can be used alone, or in combination with other medicines for treating diabetes.

It contains the active ingredient metformin hydrochloride.

Metformin belongs to a group of medicines called oral hypoglycaemics.

It works to reduce high levels of blood glucose by helping your body to make better use of the insulin produced by your pancreas.

Diabetes mellitus is a condition in which the blood glucose levels are not adequately controlled.

People with type 2 diabetes are not able to make enough insulin or do not respond normally to the insulin their bodies make. When this happens, sugar (glucose) builds up in the blood. This can lead to serious medical problems including heart disease, kidney damage, poor blood circulation, gangrene, amputation and blindness.

If your blood glucose is not properly controlled, you may experience hypoglycaemia (low blood glucose) or hyperglycaemia (high blood glucose).

Hypoglycaemia (low blood glucose) can occur suddenly. Initial signs include:

If not treated promptly, these may progress to:

Hyperglycaemia (high blood glucose) usually occurs more slowly than hypoglycaemia. Signs of hyperglycaemia may include:

Long term hyperglycaemia can lead to serious problems with your heart, eyes, kidneys or blood circulation.

Diabetes is also closely linked to heart disease. The main goal of treating diabetes is to lower your blood sugar to a normal level. High blood sugar levels can be lowered by diet and exercise, by a number of oral medicines, and by insulin injections.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.
Your doctor may have prescribed it for another reason.

This medicine is not addictive.

This medicine is available only with a doctor’s prescription.

Metformin Sandoz is not recommended for use in children, except for those with insulin-resistant diabetes who are being treated in hospital.

Do not take this medicine if you have an allergy to:

Some of the symptoms of an allergic reaction may include:

Do not take this medicine if you have or have had any of the following medical conditions:

Do not breastfeed if you are taking this medicine.
Metformin Sandoz is not recommended while you are breastfeeding. Your doctor will discuss other treatment options with you.

Do not take this medicine if you need to have major surgery or an examination such as an X-ray or a scan requiring an injection of iodinated contrast (dye).
You must stop taking Metformin Sandoz for a certain period of time before and after the examination or the surgery. Your doctor will decide whether you need any other treatment for this time. It is important that you follow your doctor’s instructions precisely.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.
If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Before starting this medicine your doctor will ask you to have a blood test to check your kidney function.

Tell your doctor if you have or have had any of the following medical conditions:

Your doctor may want to take special care if you have any of these conditions.

Tell your doctor if you are pregnant or plan to become pregnant.
Insulin is more suitable for controlling blood glucose during pregnancy. Your doctor will replace Metformin Sandoz with insulin while you are pregnant.

Tell your doctor if you drink alcohol.
Alcohol can affect the control of your diabetes. Drinking excessive amounts of alcohol while you are being treated with Metformin Sandoz may also lead to serious side effects. Your doctor may suggest you stop drinking or reduce the amount of alcohol you drink.

If you have not told your doctor about any of the above, tell him/ her before you start taking Metformin Sandoz.

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Metformin Sandoz may interfere with each other. These include:

These medicines may be affected by Metformin Sandoz or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

Follow all directions given to you by your doctor or pharmacist carefully.
They may differ from the information contained in this leaflet.

If you do not understand the instructions, ask your doctor or pharmacist for help.

The standard dose for this medicine varies from patient to patient. The usual starting dose is one 500mg tablet once or twice a day with breakfast and the evening meal.

Your doctor may have prescribed a different dose depending on your blood glucose levels. The maximum recommended dose is 1000mg three times a day.

Elderly patients and people with kidney problems may need smaller doses.

If your child has diabetes which is resistant to insulin and is being treated in hospital, your child’s doctor will decide the dose.

Ask your doctor or pharmacist if you are unsure of the correct dose for you.
They will tell you exactly how much to take.

Follow the instructions they give you.

If you take the wrong dose, Metformin Sandoz may not work as well and your problem may not improve.

The 500 mg tablet may be divided in half along the breakline, if advised by your doctor.

Swallow the tablets whole with a full glass of water.

Do not chew them.

Take your medicine at about the same time each day.
Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

Take your medicine during or immediately after a meal, at about the same time each day.
If you take it on an empty stomach, it may cause stomach upset.

Continue taking your medicine for as long as your doctor tells you.

This medicine helps to control your condition, but does not cure it. Most people will need to take Metformin Sandoz on a long-term basis. It is important to keep taking your medicine even if you feel well.

Take your dose as soon as you remember (with food), and continue to take it as you would normally.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose that you missed.
This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Metformin Sandoz. Do this even if there are no signs of discomfort or poisoning.
You may need urgent medical attention.

Symptoms of an overdose may include:

These may be early signs of a serious condition called lactic acidosis (build up of lactic acid in the blood).

You may also experience symptoms of hypoglycaemia (low blood glucose). This usually only happens if you take too much Metformin Sandoz together with other medicines for diabetes or with alcohol.

If you do experience any signs of hypoglycaemia, raise your blood glucose quickly by eating jelly beans, sugar or honey, drinking a non-diet soft drink or taking glucose tablets.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Metformin Sandoz.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you become pregnant while taking this medicine, tell your doctor immediately.

Keep all of your doctor’s appointments so that your progress can be checked.
Your doctor may do some tests to check your kidneys, liver, heart, blood and vitamin B12 levels from time to time to make sure the medicine is working and to prevent unwanted side effects.

Prolonged treatment with Metformin Sandoz can deplete reserves of vitamin B12 and this may cause anaemia. Regular blood tests for kidney function and vitamin B12 should therefore be carried out.

Check your blood glucose levels regularly.

This is the best way to tell if your diabetes is being controlled properly. Your doctor or diabetes educator will show you how and when to do this.

When you start treatment with Metformin Sandoz, it can take up to two weeks for your blood glucose levels to be properly controlled.

Make sure that you, your friends, family and work colleagues can recognise the symptoms of hypoglycaemia and hyperglycaemia and know how to treat them.

If you do experience any signs of hypoglycaemia (low blood glucose), raise your blood glucose quickly by taking one of the following:

Unless you are within 10-15 minutes of your next meal or snack, follow up with extra carbohydrates such as plain biscuits, fruit or milk.
Taking this extra carbohydrate will prevent a second drop in your blood glucose level.

Hyperglycaemia usually occurs more slowly than hypoglycaemia. If you experience any of the signs of hyperglycaemia (passing large amounts of urine, excessive thirst and having a dry mouth and skin), contact your doctor immediately.

Your doctor may need to consider additional or other treatments for your diabetes.

The risk of hyperglycaemia is increased in the following situations:

Tell your doctor it you:

Your blood glucose may become difficult to control at these times. You may also be more at risk of developing a serious condition called lactic acidosis. At these times, your doctor may replace Metformin Sandoz with insulin.

Carefully follow the advice of your doctor and dietician on diet, drinking alcohol and exercise.

Do not take Metformin Sandoz to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking Metformin Sandoz without your doctor’s permission.

Do not skip meals while taking Metformin Sandoz.

Be careful driving or operating machinery until you know how Metformin Sandoz affects you.
Low blood glucose levels may slow your reaction time and affect your ability to drive or operate machinery. If your blood glucose levels fall too low, do not drive, operate machinery or do anything else that could be dangerous.

If you become sick with a cold, fever or flu, it is very important to continue eating your normal meals.

Your diabetes educator can give you a list of foods to eat on sick days.

When you are travelling, it is a good idea to:

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Metformin Sandoz.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

If you are over 65 years of age you may have an increased chance of getting side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

These are mild side effects of the medicine. Stomach upset and diarrhoea are short-lived, they generally get better after the first few weeks. Taking Metformin Sandoz with meals can help reduce stomach pain, nausea and diarrhoea. Rarely skin reactions may occur.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

Lactic acidosis is a very rare but serious side effect requiring urgent medical treatment in hospital. The risk of lactic acidosis is higher in some people, including the elderly, those taking doses greater than 2000 mg a day, those whose diabetes is poorly controlled, those with prolonged fasting, those drinking excessive amounts of alcohol, those with certain heart conditions and people with kidney or liver problems.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell.
Other side effects not listed above may also occur in some people.

Some side effects (e.g. reduced vitamin B12 level) can only be found when your doctor does tests from time to time to check your progress.

Keep your medicine in the original container.
If you take it out of its original container it may not keep well.

Keep your medicine in a cool dry place where the temperature stays below 25°C.

Do not store Metformin Sandoz or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car.
Heat and dampness can destroy some medicines.

Keep it where children cannot reach it.
A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Metformin Sandoz comes in two types of tablets:

Metformin Sandoz 500 mg – white, film coated, biconvex capsule shaped tablet with central breakline on one side and ‘500’ embossed on the other side.

Available in blisters and bottles of 100 tablets.

Metformin Sandoz 850 mg – white, film coated, round, biconvex tablet plain on one side and ‘850’ embossed on the other side.

Available in blisters and bottles of 60 tablets.

Active ingredients:

Inactive ingredients:

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park NSW 2113
Australia
Tel: 1800 634 500

This leaflet was revised in April 2019.

Australian Register Numbers

500 mg tablet: AUST R 125661 (blisters)

500 mg tablet: AUST R 148268 (bottles)

850 mg tablet: AUST R 125662 (blisters)

850 mg tablet: AUST R 148270 (bottles)

Published by MIMS June 2019

Reasonable care is taken to provide accurate information at the time of creation. This information is not intended as a substitute for medical advice and should not be exclusively relied on to manage or diagnose a medical condition. NPS MedicineWise disclaims all liability (including for negligence) for any loss, damage or injury resulting from reliance on or use of this information. Read our full disclaimer. This website uses cookies. Read our privacy policy.

PO Box 1147 Strawberry Hills NSW 2012

Level 7, 418A Elizabeth St, Surry Hills NSW 2010

ABN: 61 082 034 393

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WARNING: LACTIC ACIDOSIS Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions (5.1)]. Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g. carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided [see Dosage and Administration (2.3), (2.7), Contraindications (4), Warnings and Precautions (5.1)]. If metformin-associated lactic acidosis is suspected, immediately discontinue metformin hydrochloride extended-release tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1)].

Metformin hydrochloride extended-release tablets are biguanide indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. (1)

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Adult Dosage for Metformin hydrochloride extended-release tablets: • Swallow Metformin hydrochloride extended-release tablets whole and never crush, cut or chew (2.1) • Starting dose:500 mg orally once daily with the evening meal (2.1) • Increase the dose in increments of 500 mg weekly, up to a maximum of 2000 mg once daily with the evening meal (2.1) • Patients receiving Metformin hydrochloride tablets may be switched to Metformin hydrochloride extended-release tablets once daily at the same total daily dose, up to 2000 mg once daily (2.1) Renal Impairment •Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) (2.3) o Do not use in patients with eGFR below 30 mL/minute/1.73 m2 (2.3) o Initiation is not recommended in patients with eGFR between 30-45 mL/minute/1.73 m2 (2.3) o Assess risk/benefit of continuing if eGFR falls below 45 mL/minute/1.73 m2 (2.3) o Discontinue if eGFR falls below 30 mL/minute/1.73 m2(2.3) Discontinuation for Iodinated Contrast Imaging Procedures: • Metformin hydrochloride extended-release tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures (2.4)

• Severe renal impairment (eGFR below 30 mL/min/1.73 m2) (4, 5.1) • Hypersensitivity to metformin (4) • Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.

For Metformin hydrochloride extended-release tablets, the most common adverse reactions (>5.0%) are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.(6.1) To report SUSPECTED ADVERSE REACTIONS, contact Granules USA, Inc. at 1-877-770-3183 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

• Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring (7) • Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the accumulation of metformin. Consider the benefits and risks of concomitant use (7) • Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake

• Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. (8.3) • Geriatric Use: Assess renal function more frequently. (8.5) • Hepatic Impairment: Avoid use in patients with hepatic impairment. (8.7)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 5/2019

Metformin hydrochloride extended-release tablets are indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.

2.1 Adult Dosage Metformin Hydrochloride Extended-Release Tablets • Swallow Metformin hydrochloride extended- release tablets whole and never crush, cut or chew. • The recommended starting dose of Metformin hydrochloride extended- release tablets is 500 mg orally once daily with the evening meal. • Increase the dose in increments of 500 mg weekly on the basis of glycemic control and tolerability, up to a maximum of 2000 mg once daily with the evening meal. • If glycemic control is not achieved with Metformin hydrochloride extended- release tablets 2000 mg once daily, consider a trial of Metformin hydrochloride extended-release tablets 1000 mg twice daily. If higher doses are required, switch to metformin hydrochloride tablets at total daily doses up to 2550 mg administered in divided daily doses, as described above. • Patients receiving Metformin hydrochloride tablets may be switched to Metformin hydrochloride extended-release tablets once daily at the same total daily dose, up to 2000 mg once daily. 2.3 Recommendations for Use in Renal Impairment • Assess renal function prior to initiation of Metformin hydrochloride extended-release tablets and periodically thereafter. • Metformin hydrochloride extended-release tablets is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m2. • Initiation of Metformin hydrochloride extended-release tablets in patients with an eGFR between 30-45 mL/minute/1.73 m2 is not recommended. • In patients taking Metformin hydrochloride extended-release tablets whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit risk of continuing therapy. • Discontinue Metformin hydrochloride extended- release tablets if the patient’s eGFR later falls below 30 mL/minute/1.73 m2 [see Warnings and Precautions (5.1) ]. 2.4 Discontinuation for Iodinated Contrast Imaging Procedures Discontinue Metformin hydrochloride extended-release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart Metformin hydrochloride extended-release tablets if renal function is stable.

Metformin hydrochloride extended-release tablets is available as: • Extended-release tablets:500 mg White to off white uncoated, modified capsule shaped tablets de bossed with “G7” on one side and plain on other side.

• Extended-release tablets:750 mg White to off white uncoated modified capsule shaped tablets debossed with “G8” on one side and plain on other side.

Metformin hydrochloride extended-release tablets, USP are contraindicated in patients with:

5.1 Lactic Acidosis There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels were generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of metformin hydrochloride extended-release tablets. In metformin hydrochloride extended- release tablets treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery. Educate patients and their families about the symptoms of lactic acidosis and, if these symptoms occur, instruct them to discontinue metformin hydrochloride extended-release tablets and report these symptoms to their healthcare provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: • Renal impairment — The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patients renal function include [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)]: o Before initiating metformin hydrochloride extended-release tablets, obtain an estimated glomerular filtration rate (eGFR). o Metformin hydrochloride extended-release tablets are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see Contraindications (4)]. o Initiation of metformin hydrochloride extended-release tablets are not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m2. o Obtain an eGFR at least annually in all patients taking metformin hydrochloride extended-release tablets. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. o In patients taking metformin hydrochloride extended-release tablets whose eGFR falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy. • Drug interactions — The concomitant use of metformin hydrochloride extended-release tablets with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere wit acid-base balance, or increase metformin accumulation. Consider more frequent monitoring of patients. • Age 65 or greater — The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients. • Radiologic studies with contrast — Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop metformin hydrochloride extended-release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart metformin hydrochloride extended- release tablets if renal function is stable.

•Surgery and other procedures — Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment. Metformin hydrochloride extended- release tablets should be temporarily discontinued while patients have restricted food and fluid intake. •Hypoxic states — Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may cause prerenal azotemia. When such an event occurs, discontinue metformin hydrochloride extended- release tablets. •Excessive alcohol intake — Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving metformin hydrochloride extended-release tablets. •Hepatic impairment — Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of metformin hydrochloride extended-release tablets in patients with clinical or laboratory evidence of hepatic disease.

5.2 Vitamin B12 Deficiency In metformin hydrochloride tablets clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin hydrochloride tablets or vitamin B12 supplementation. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis and vitamin B12 at 2 to 3 year intervals in patients on metformin hydrochloride extended-release tablets and manage any abnormalities [see Adverse Reactions (6.1) ]. 5.3 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. Metformin hydrochloride extended-release tablets may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with metformin hydrochloride extended-release tablets [see Drug Interactions (7) ]. 5.4 Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin hydrochloride extended-release tablets.

The following adverse reactions are also discussed elsewhere in the labeling:

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Metformin Hydrochloride Extended-Release Tablets In placebo-controlled trials, 781 patients were administered metformin hydrochloride extended-release tablets. Adverse reactions reported in greater than 5% of the metformin hydrochloride extended release tablets patients, and that were more common in metformin hydrochloride extended-release tablets-than placebo-treated patients, are listed in Table 2. Table 2: Adverse Reactions from Clinical Trials of Metformin Hydrochloride Extended-Release Tablets Occurring >5% and More Common than Placebo in Patients with Type 2 Diabetes Mellitus

Diarrhea led to discontinuation of metformin hydrochloride extended-release tablets in 0.6% of patients. Additionally, the following adverse reactions were reported in ≥1.0% to ≤5.0% of metformin hydrochloride extended-release tabletspatients and were more commonly reported with metformin hydrochloride extended-release tablets than placebo: abdominal pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance.

6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of metformin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin.

Table 3 presents clinically significant drug interactions with metformin hydrochloride extended-release tablets. Table 3: Clinically Significant Drug Interactions with Metformin Hydrochloride Extended-Release Tablets

Risk Summary Limited data with metformin hydrochloride extended-release tablets in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [see Data]. There are risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy [see Clinical Considerations].

No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2-and 5-times, respectively, a 2550 mg clinical dose, based on body surface area [see Data].

The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes mellitus with an HbA1C >7 and has been reported to be as high as 20 to 25% in women with a HbA1C >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations Disease-associated maternal and/or embryo/fetal risk

قرص metformin 500

Poorly-controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.

Data Human Data Published data from post-marketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups.

Animal Data Metformin hydrochloride did not adversely affect development outcomes when administered to pregnant rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 5 times a 2550 mg clinical dose based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.

Risk Summary Limited published studies report that metformin is present in human milk [see Data]. However, there is insufficient information to determine the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for metformin hydrochloride extended-release tablets and any potential adverse effects on the breastfed child from metformin hydrochloride extended-release tablets or from the underlying maternal condition.

Data Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants.

Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin hydrochloride extended-release tablets may result in ovulation in some anovulatory women.

Metformin Hydrochloride Extended-Release Tablets

Safety and effectiveness of metformin hydrochloride extended-release tabletsin pediatric patients have not been established.

Controlled clinical studies of metformin hydrochloride extended-release tablets did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients [see Warnings and Precautions (5.1) ].

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Metformin hydrochloride extended-release tablets are contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2 [see Dosage and Administration (2.3),Contraindications (4),Warnings and Precautions (5.1),and Clinical Pharmacology (12.3) ].

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Metformin hydrochloride extended-release tablets are not recommended in patients with hepatic impairment. [see Warnings and Precautions (5.1) ].

Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.1) ]. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

Metformin hydrochloride extended-release tablets, USP contain the antihyperglycemic agent metformin, which is a biguanide, in the form of monohydrochloride. The chemical name of metformin hydrochloride is N,N-dimethylimidodicarbonimidic diamide hydrochloride. The structural formula is as shown below:

Metformin hydrochloride, USP is a white to off-white crystalline compound with a molecular formula of C4H11N5.HCl and a molecular weight of 165.62. Metformin hydrochloride is freely soluble in water, slightly soluble in ethanol, practically insoluble in acetone and in methylene chloride. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.35. Metformin hydrochloride extended-release tablets USP, contains 500 mg or 750 mg of metformin hydrochloride, which is equivalent to 389.93 mg, 584.90 mg metformin base, respectively. Metformin hydrochloride extended-release tablets USP, 500 mg tablets contain the inactive ingredients hypromellose, magnesium stearate, and polyvinyl pyrrolidone Metformin hydrochloride extended-release tablets USP, 750 mg tablets contain the inactive ingredients hypromellose, magnesium stearate, and polyvinyl pyrrolidone Dissolution method: Test 10

Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.

Absorption Following a single oral dose of metformin hydrochloride extended-release tablets, Cmax is achieved with a median value of 7 hours and a range of 4 to 8 hours. Peak plasma levels are approximately 20% lower compared to the same dose of metformin hydrochloride tablets, however, the extent of absorption (as measured by AUC) is comparable to metformin hydrochloride tablets.

At steady state, the AUC and Cmax are less than dose proportional for metformin hydrochloride extended-release tablets within the range of 500 to 2000 mg administered once daily. Peak plasma levels are approximately 0.6, 1.1, 1.4 and 1.8 mcg/mL for 500, 1000, 1500, and 2000 mg once-daily doses, respectively. The extent of metformin absorption (as measured by AUC) from metformin hydrochloride extended-release tablets at a 2000 mg once-daily dose is similar to the same total daily dose administered as metformin hydrochloride tablets 1000 mg twice daily. After repeated administration of metformin hydrochloride extended-release tablets, metformin did not accumulate in plasma. Effect of food: Food decreases the extent of absorption and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850 mg tablet of metformin hydrochloride tablets with food, compared to the same tablet strength administered fasting.

Although the extent of metformin absorption (as measured by AUC) from the metformin hydrochloride extended-release tablet increased by approximately 50% when given with food, there was no effect of food on Cmax and Tmax of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of metformin hydrochloride extended-release tablets. Distribution The apparent volume of distribution (V/F) of metformin following single oral doses of metformin hydrochloride tablets 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time.

Metabolism Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion.

Elimination Renal clearance (see Table 4) is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Specific Populations Renal Impairment In patients with decreased renal function the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased (see Table 3) [see Dosage and Administration (2.3),Contraindications (4), Warnings and Precautions (5.1) andUse in Specific Populations (8.6) ].

Hepatic Impairment No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment [see Warnings and Precautions (5.1) and Use in Specific Populations (8.7)].

Geriatrics Limited data from controlled pharmacokinetic studies of metformin hydrochloride tablets in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects. It appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 4). [see Warnings and Precautions (5.1) and Use in Specific Populations (8.5)].

Table 4: Select Mean (±S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin Hydrochloride Tablets

Gender

Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes mellitus when analyzed according to gender (males=19, females=16).

Race

No studies of metformin pharmacokinetic parameters according to race have been performed.

Drug Interactions

In Vivo Assessment of Drug Interactions

Table 5: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure

Table 6: Effect of Metformin on Coadministered Drug Systemic Exposure

*All metformin and coadministered drugs were given as single doses

+AUC = AUC (INF) unless otherwise noted

‡ Ratio of arithmetic means, p-value of difference <0.05

§AUC (0-24 hr) reported

¶ Ratio of arithmetic means

Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately 3 times the maximum recommended human daily dose of 2550 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.

There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.

Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately 2 times the maximum recommended human daily dose of 2550 mg based on body surface area comparisons.

14.2 Metformin Hydrochloride Extended-Release Tablets

A 24-week, double-blind, placebo-controlled study of metformin hydrochloride extended-release tablets, taken once daily with the evening meal, was conducted in patients with type 2 diabetes mellitus who had failed to achieve glycemic control with diet and exercise. Patients entering the study had a mean baseline HbA1c of 8.0% and a mean baseline FPG of 176 mg/dL. The treatment dose was increased to 1500 mg once daily if at Week 12 HbA1c was ≥7.0% but <8.0% (patients with HbA1c ≥8.0% were discontinued from the study). At the final visit (24-week), mean HbA1c had increased 0.2% from baseline in placebo patients and decreased 0.6% with metformin hydrochloride extended-release tablets.

A 16-week, double-blind, placebo-controlled, dose-response study of metformin hydrochloride extended-release tablets, taken once daily with the evening meal or twice daily with meals, was conducted in patients with type 2 diabetes mellitus who had failed to achieve glycemic control with diet and exercise. The results are shown in Table 10. Table 10: Mean Changes from Baseline* in HbA1c and Fasting Plasma Glucose at Week 16 Comparing Metformin Extended-Release Tablets vs Placebo in Patients with Type 2 Diabetes Mellitus

Mean baseline body weight was 193 lbs, 192 lbs, 188 lbs, 196 lbs, 193 lbs and 194 lbs in the metformin hydrochloride extended-release tablets 500 mg , 1000 mg, 1500 mg, and 2000 mg once daily, 1000 mg twice daily and placebo arms, respectively. Mean change in body weight from baseline to week 16 was -1.3 lbs, 1.3 lbs, -0.7 lbs, -1.5 lbs, -2.2 lbs and -1.8 lbs, respectively.

A 24-week, double-blind, randomized study of metformin hydrochloride extended-release tablets, taken once daily with the evening meal, and metformin hydrochloride tablets, taken twice daily (with breakfast and evening meal), was conducted in patients with type 2 diabetes mellitus who had been treated with metformin hydrochloride tablets 500 mg twice daily for at least 8 weeks prior to study entry. The results are shown in Table 11.

Table 11: Mean Changes from Baseline* in HbA1c and Fasting Plasma Glucose at Week 24 Comparing Metformin Hydrochloride Extended-Release Tablets vs Metformin Hydrochloride Tablets in Patients with Type 2 Diabetes Mellitus

†a n=68

Mean baseline body weight was 210lbs, 203 lbs and 193 lbs in the metformin hydrochloride tablets 500 mg twice daily, and metformin hydrochloride extended-release tablets1000 mg and 1500 mg once daily arms, respectively. Mean change in body weight from baseline to week 24 was 0.9 lbs, 1.1 lbs and 0.9 lbs, respectively.

16.1 How Supplied Table 13: Metformin Hydrochloride Extended-Release Tablets, USP Available Strengths, Units, and Appearance

16.2 Storage

Store at 20° to 25°C (68° to 77°F); excursions permitted within 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.] Dispense in light-resistant container.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Lactic Acidosis: Explain the risks of lactic acidosis, its symptoms, and conditions that predispose to its development. Advise patients to discontinue metformin hydrochloride extended-release tablets immediately and to promptly notify their healthcare provider if unexplained hyperventilation, myalgias, malaise, unusual somnolence or other nonspecific symptoms occur. Counsel patients against excessive alcohol intake and inform patients about importance of regular testing of renal function while receiving metformin hydrochloride extended-release tablets. Instruct patients to inform their doctor that they are taking metformin hydrochloride extended-release tablets prior to any surgical or radiological procedure, as temporary discontinuation may be required [see Warnings and Precautions (5.1)].

Hypoglycemia Inform patients that hypoglycemia may occur when metformin hydrochloride extended-release tablets are coadministered with oral sulfonylureas and insulin. Explain to patients receiving concomitant therapy the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development [see Warnings and Precautions (5.3)].

Vitamin B12 Deficiency: Inform patients about importance of regular hematological parameters while receiving metformin hydrochloride extended-release tablets [see Warnings and Precautions (5.2)].

Females of Reproductive Age: Inform females that treatment with metformin hydrochloride extended-release tablets may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy [see Use in Specific Populations (8.3)].

Metformin Hydrochloride Extended-Release Tablets Administration Information: Inform patients that metformin hydrochloride extended-release tablets must be swallowed whole and not crushed, cut, or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.

Manufactured by:

Granules India Limited

Hyderabad-500 081, India

MADE IN INDIA

Manufactured For:

Granules USA, Inc.

Parsippany, NJ 07054

Toll-free:1-877-770-383

Revision date:

05/2019

PATIENT INFORMATION Metformin Hydrochloride Extended-Release Tablets (met-FOR-min HYE-droe-KLOR-ide)

Read the Patient Information that comes with metformin hydrochloride extended-release tablets before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or treatment.

What is the most important information I should know about metformin hydrochloride extended-release tablets? Serious side effects can happen in people taking metformin hydrochloride extended-release tablets, including: Lactic Acidosis. Metformin hydrochloride, the medicine in metformin hydrochloride extended-release tablets, can cause a rare, but serious, side effect called lactic acidosis (a build-up of lactic acid in the blood) that can cause death. Lactic acidosis is a medical emergency and must be treated in a hospital.

Stop taking metformin hydrochloride extended-release tablets and call your healthcare provider right away if you get any of the following symptoms of lactic acidosis: • feel very weak and tired • have unusual (not normal) muscle pain • have trouble breathing • have unusual sleepiness or sleep longer than usual • have unexplained stomach or intestinal problems with nausea and vomiting, or diarrhea • feel cold, especially in your arms and legs • feel dizzy or lightheaded • have a slow or irregular heartbeat

You have a higher chance of getting lactic acidosis if you: • have kidney problems. People whose kidneys are not working properly should not take metformin hydrochloride extended-release tablets. • have liver problems. • have congestive heart failure that requires treatment with medicines. • drink a lot of alcohol (very often or short-term “binge” drinking). • get dehydrated (lose a large amount of body fluids). This can happen if you are sick with a fever, vomiting, or diarrhea. Dehydration can also happen when you sweat a lot with activity or exercise and do not drink enough fluids. • have certain x-ray tests with injectable dyes or contrast agents. • have surgery. • have a heart attack, severe infection, or stroke. • are 80 years of age or older and have not had your kidney function tested.

What are metformin hydrochloride extended-release tablets? •Metformin hydrochloride extended-release tablets are prescription medicines that contain metformin hydrochloride. Metformin hydrochloride extended-release tablets are used with diet and exercise to help control high blood sugar (hyperglycemia) in adults with type 2 diabetes. •Metformin hydrochloride extended-release tablets are not for people with type 1 diabetes. •Metformin hydrochloride extended-release tablets are not for people with diabetic ketoacidosis (increased ketones in your blood or urine).

Metformin hydrochloride tablets and metformin hydrochloride extended-release tablets have the same active ingredient. However, metformin hydrochloride extended-release tablets works longer in your body. Both of these medicines help control your blood sugar in a number of ways. These include helping your body respond better to the insulin it makes naturally, decreasing the amount of sugar your liver makes, and decreasing the amount of sugar your intestines absorb. Metformin hydrochloride tablets and metformin hydrochloride extended-release tablets do not cause your body to make more insulin.

Who should not take metformin hydrochloride extended-release tablets? Some conditions increase your chance of getting lactic acidosis, or cause other problems if you take either of these medicines. Most of the conditions listed below can increase your chance of getting lactic acidosis.

Do not take metformin hydrochloride extended-release tablets if you: • have kidney problems • are allergic to the metformin hydrochloride in metformin hydrochloride extended-release tablets or any of the ingredients in metformin hydrochloride extended-release tablets. See the end of this leaflet for a complete list of ingredients in metformin hydrochloride extended-release tablets. • are going to get an injection of dye or contrast agents for an x-ray procedure or if you are going to have surgery and not able to eat or drink much. In these situations, metformin hydrochloride extended-release tablets will need to be stopped for a short time. Talk to your healthcare provider about when you should stop metformin hydrochloride extended-release tablets and when you should start metformin hydrochloride extended-release tablets again. See “What is the most important information I should know about metformin hydrochloride extended-release tablets?”

What should I tell my healthcare provider before taking metformin hydrochloride extended-release tablet? Before taking metformin hydrochloride extended- release tablets, tell your healthcare provider if you: • have type 1 diabetes. Metformin hydrochloride extended-release tablets should not be used to treat people with type 1 diabetes. • have a history or risk for diabetic ketoacidosis (high levels of certain acids, known as ketones, in the blood or urine). Metformin hydrochloride extended-release tablets should not be used for the treatment of diabetic ketoacidosis. • have kidney problems. • have liver problems. • have heart problems, including congestive heart failure. • are older than 80 years. If you are over 80 years old you should not take metformin hydrochloride extended-release tablets unless your kidneys have been checked and they are normal. • drink alcohol very often, or drink a lot of alcohol in short-term “binge” drinking. • are taking insulin. • have any other medical conditions. •are pregnant or plan to become pregnant. It is not known if metformin hydrochloride extended- release tablets will harm your unborn baby. If you are pregnant, talk with your healthcare provider about the best way to control your blood sugar while you are pregnant. • are breast-feeding or plan to breast-feed. It is not known if metformin hydrochloride extended- release tablets passes into your breast milk. Talk with your healthcare provider about the best way to feed your baby while you take metformin hydrochloride extended- release tablets.

Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. •Metformin hydrochloride extended-release tablets may affect the way other medicines work, and other medicines may affect how metformin hydrochloride extended-release tablets works. Can metformin hydrochloride extended-release tablets be used in children? Metformin hydrochloride extended-release tablets has not been studied in children. How should I take metformin hydrochloride extended-release tablets? • Take metformin hydrochloride extended-release tablets exactly as your healthcare provider tells you. • Metformin hydrochloride extended-release tablets should be taken with meals to help lessen an upset stomach side effect. • Swallow metformin hydrochloride extended-release tablets whole. Do not crush, cut, or chew metformin hydrochloride extended-release tablets. •You may sometimes pass a soft mass in your stools (bowel movement) that looks like metformin hydrochloride extended-release tablets. This is not harmful and will not affect the way metformin hydrochloride extended-release tablets works to control your diabetes. • When your body is under some types of stress, such as fever, trauma (such as a car accident), infection, or surgery, the amount of diabetes medicine that you need may change. Tell your healthcare provider right away if you have any of these problems. • Your healthcare provider should do blood tests to check how well your kidneys are working before and during your treatment with metformin hydrochloride extended-release tablets. • Your healthcare provider will check your diabetes with regular blood tests, including your blood sugar levels and your hemoglobin A1C. • Follow your healthcare provider’s instructions for treating blood sugar that is too low (hypoglycemia). Talk to your healthcare provider if low blood sugar is a problem for you. See “What are the possible side effects of metformin hydrochloride extended-release tablets?” • Check your blood sugar as your healthcare provider tells you to. • Stay on your prescribed diet and exercise program while taking metformin hydrochloride extended-release tablets. • If you miss a dose of metformin hydrochloride extended-release tablets, take your next dose as prescribed unless your healthcare provider tells you differently. Do not take an extra dose the next day. • If you take too much metformin hydrochloride extended-release tablets, call your healthcare provider, local Poison Control Center, or go to the nearest hospital emergency room right away. What should I avoid while taking metformin hydrochloride extended-release tablets? Do not drink a lot of alcoholic drinks while taking metformin hydrochloride extended-release tablets. This means you should not binge drink for short periods, and you should not drink a lot of alcohol on a regular basis. Alcohol can increase the chance of getting lactic acidosis.

What are the side effects of metformin hydrochloride extended-release tablets? Lactic acidosis. Metformin, the active ingredient in metformin hydrochloride extended-release tablets, can cause a rare but serious condition called lactic acidosis (a buildup of an acid in the blood) that can cause death. Lactic acidosis is a medical emergency and must be treated in the hospital. Call your doctor right away if you have any of the following symptoms, which could be signs of lactic acidosis: • you feel cold in your hands or feet • you feel dizzy or lightheaded • you have a slow or irregular heartbeat • you feel very weak or tired • you have trouble breathing • you feel sleepy or drowsy • you have stomach pains, nausea or vomiting

Most people who have had lactic acidosis with metformin have other things that, combined with the metformin, led to the lactic acidosis. Tell your doctor if you have any of the following, because you have a higher chance for getting lactic acidosis with metformin hydrochloride extended- release tablets, if you: • have severe kidney problems, or your kidneys are affected by certain x-ray tests that use dye • have liver problems • drink alcohol very often, or drink a lot of alcohol in short-term “binge” drinking • get dehydrated (lose a large amount of body fluids). This can happen if you are sick with a fever, vomiting, or diarrhea. Dehydration can also happen when you sweat a lot with activity or exercise and do not drink enough fluids • have surgery • have a heart attack, severe infection, or stroke

Common side effects of metformin hydrochloride extended-release tablets, include diarrhea, nausea, and upset stomach. These side effects generally go away after you take the medicine for a while. Taking your medicine with meals can help reduce these side effects. Tell your doctor if the side effects bother you a lot, last for more than a few weeks, come back after they’ve gone away, or start later in therapy. You may need a lower dose or need to stop taking the medicine for a short period or for good.

About 3 out of every 100 people who take metformin hydrochloride extended-release tablets have an unpleasant metallic taste when they start taking the medicine. It lasts for a short time.

Metformin hydrochloride extended-release tablets rarely cause hypoglycemia (low blood sugar) by themselves. However, hypoglycemia can happen if you do not eat enough, if you drink alcohol, or if you take other medicines to lower blood sugar.

How should I store metformin hydrochloride extended-release tablets? Store metformin hydrochloride extended-release tablet at 68°F to 77°F (20°C to 25°C).

Keep metformin hydrochloride extended-release tablets and all medicines out of the reach of children.

General information about the use of metformin hydrochloride extended-release tablet If you have questions or problems, talk with your doctor or other healthcare provider. You can ask your doctor or pharmacist for the information about metformin hydrochloride extended-release tablets that is written for healthcare professionals. Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use metformin hydrochloride extended-release tablets for a condition for which it was not prescribed. Do not share your medicine with other people.

What are the ingredients of metformin hydrochloride extended-release tablets? Active ingredients of metformin hydrochloride extended-release tablets: metformin hydrochloride.

Inactive ingredients in each tablet of metformin hydrochloride extended-release tablet 500 mg: hypromellose, magnesium stearate, and polyvinyl pyrrolidone.

Inactive ingredients in each tablet of metformin hydrochloride extended- release tablet 750 mg: hypromellose, magnesium stearate, and polyvinyl pyrrolidone.

What is type 2 diabetes?

Type 2 diabetes is a condition in which your body does not make enough insulin, and the insulin that your body produces does not work as well as it should. Your body can also make too much sugar. When this happens, sugar (glucose) builds up in the blood. This can lead to serious medical problems. The main goal of treating diabetes is to lower your blood sugar to a normal level. High blood sugar can be lowered by diet and exercise, and by certain medicines when necessary.

Talk to your healthcare provider about how to prevent, recognize, and take care of low blood sugar (hypoglycemia), high blood sugar (hyperglycemia), and problems you have because of your diabetes.

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Manufactured for: Granules USA, Inc. Parsippany, NJ 07054 Toll-free:1-877-770-383

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Revision Date: 05/2019

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Kim BH(1), Shin KH, Kim J, Lim KS, Kim KP, Kim JR, Cho JY, Shin SG, Jang IJ, Yu
KS.

Author information:
(1)Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital, Seoul, Korea.

BACKGROUND: Coadministration of glimepiride and metformin has been used to
achieve glucose control. Because compliance with a multiple medication regimen
can be difficult for some patients, combination tablets of glimepiride +
metformin might be a suitable alternative for these patients.
OBJECTIVE: This study was conducted to compare the pharmacokinetics of test and
reference formulations of glimepiride + metformin fixed-dose combination tablets
under fasting conditions to meet the regulatory requirements for marketing
approval of a new drug in Korea.
METHODS: This was a single-dose, randomized, open-label, 2-period, 2-way
crossover study conducted between March 2007 and May 2007. Healthy fasting Korean
men were randomized to 1 of 2 dosing sequences: a single oral administration of a
fixed-dose glimepiride 1-mg + metformin 500-mg combination tablet (test) followed
by single oral administration of a fixed-dose glimepiride 2 mg + metformin 500 mg
combination tablet (reference), separated by a 1-week washout period between
doses; or a single oral administration of a fixed-dose glimepiride 2-mg +
metformin 500-mg combination tablet followed by single oral administration of a
fixed-dose glimepiride 1 mg + metformin 500-mg combination tablet, separated by a
1-week washout period between doses. Serial samples of blood were collected up to
24 hours after oral administration, and drug concentrations in plasma were
determined by HPLC-MS/MS. Tolerability was assessed based on adverse events and
changes in clinical parameters. Serious adverse events included those that
resulted in death, a life-threatening condition, congenital anomaly or birth
defect, or required hospitalization or prolongation of existing hospitalization.
RESULTS: A total of 30 healthy male subjects (mean age, 25.6 years [range, 20-36
years]; weight, 69.5 kg [range, 58.2-90.7 kg]) participated in the study. After
administration of the test and reference formulations, glimepiride was rapidly
absorbed, reaching C(max) with a median T(max) of 1.75 and 2.0 hours,
respectively, and then declined exponentially with an average t(1/2) of 8.2 and
8.5 hours. The individual C(max) and AUC(last) of glimepiride were observed to be
proportionally increased according to the administered glimepiride dose. The mean
(SD) dose-normalized Cmax values of glimepiride 1 and 2 mg were 168.2 (54.9) and
149.9 (47.4) ng/mL/mg, respectively; the mean dose-normalized AUC(last) values of
glimepiride 1 and 2 mg were 681.5 (190.3) and 635.8 (194.1) ng x h/mL/mg.
Individual plots of dose-normalized C(max) and AUC(last) values identified a
similarity between the 2 groups but no significant between-group differences. A
total of 25 adverse events (12 after the test dose and 13 after the reference
dose) were reported by 13 of the 30 subjects. All adverse events were considered
mild. Twenty-one adverse events were considered related to the study drug (8
after the test dose and 13 after the reference dose). Adverse events believed to
be related to the test formulation were diarrhea (4 cases), dizziness (1),
headache (1), tingling sensation (1), and weakness (1). Adverse events believed
to be related to the reference formulation were diarrhea (6 cases), headache (3),
cold sweats (1), dyspepsia (1), epigastric discomfort (1), and lethargy (1).
There were no clinically significant findings in the laboratory test results or
vital sign monitoring during the study. There were no serious adverse events
reported.
CONCLUSIONS: The C(max) and AUC(last) of glimepiride increased proportionally
according to the administered glimepiride dose in this study of healthy, fasting
Korean men. The safety profiles of the 2 combination tablets were comparable.

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© 2019 Kaiser Foundation Health Plan, Inc.

© 2019 Kaiser Foundation Health Plan, Inc.

Medically reviewed by Sanjai Sinha, MD Last updated on Dec 6, 2018.

Metformin is an oral diabetes medicine that helps control blood sugar levels.

قرص metformin 500

You should not use metformin if you are allergic to it, or if you have:

severe kidney disease; or

metabolic acidosis or diabetic ketoacidosis (call your doctor for treatment).

Tell your doctor if you have ever had:

high ketone levels in your blood or urine;

heart disease, congestive heart failure;

liver disease; or

if you also use insulin, or other oral diabetes medications.

You should not breast-feed while using this medicine.

Do not crush, chew, or break an extended-release tablet. Swallow it whole.

Store at room temperature away from moisture, heat, and light.

Metformin dosage information (in more detail)

قرص metformin 500

unusual muscle pain;

feeling cold;

trouble breathing;

feeling dizzy, light-headed, tired, or very weak;

stomach pain, vomiting; or

slow or irregular heart rate.

Common metformin side effects may include:

low blood sugar;

nausea, upset stomach; or

diarrhea.

Metformin side effects (in more detail)

Metformin drug interactions (in more detail)

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Brand name

Metformin Sandoz 500 mg and 850 mg

Active ingredient

Metformin hydrochloride

Schedule

S4

This leaflet answers some common questions about Metformin Sandoz.

قرص metformin 500

Keep this leaflet with the medicine. You may need to read it again.

It contains the active ingredient metformin hydrochloride.

Metformin belongs to a group of medicines called oral hypoglycaemics.

Hypoglycaemia (low blood glucose) can occur suddenly. Initial signs include:

If not treated promptly, these may progress to:

Keep this leaflet with the medicine.
You may need to read it again.