World level of manufacturing company :: metformin glibenclamide :: Glucophage

Metformin

Molecular Structure

Metformin Hcl

Molecular Weight 165.62

CAS number 1115-70-4

ATC code A10BA02

A10BD02 (with sulfonylureas)
A10BD03 (with rosiglitazone)
A10BD05 (with pioglitazone)
A10BD07 (with sitagliptin)
A10BD08 (with vildagliptin)
PubChem 4091
DrugBank APRD01099

Chemical data

Formula C4H11N5
Mol. mass 129.164 g/mol
165.63 g/mol (hydrochloride)
Synonyms 1,1-dimethylbiguanide
Pharmacokinetic data
Bioavailability 50 to 60% under fasting conditions
Metabolism None
Half life 6.2 hours
Excretion Active renal tubular excretion by OCT2

Information Associated with Product:
DRUG DESCRIPTION DOSAGE SIDE EFFECTS PRECAUTIONS INTERACTION CONSUMER INFORMATION
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Identifiers

CAS number 1115-70-4

ATC code A10BA02

A10BD02 (with sulfonylureas)

A10BD03 (with rosiglitazone)

A10BD05 (with pioglitazone)

A10BD07 (with sitagliptin)

A10BD08 (with vildagliptin)

PubChem 4091

DrugBank APRD01099

Chemical data

Formula C4H11N5

Mol. mass 129.164 g/mol

165.63 g/mol (hydrochloride)

Synonyms 1,1-dimethylbiguanide

Pharmacokinetic data

Bioavailability 50 to 60% under fasting conditions

Metabolism None

Half life 6.2 hours

Excretion Active renal tubular excretion by OCT2

Therapeutic considerations

Licence data

US FDA:link

Pregnancy cat.

C(AU) B(US)

Legal status

POM(UK) ℞-only(US)

Routes Oral

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Metformin (INN trade names Glucophage, Glucophage XR, Riomet, Fortamet, Glumetza, Obimet, Dianben, Diabex, Diaformin, and others) is an oral anti-diabetic drug from the biguanide class. It is the first-line drug for the treatment of type 2 diabetes particularly in overweight and obese people and those with normal kidney function and evidence suggests it may be the best choice for people with heart failure. It is also used in the treatment of polycystic ovary syndrome.

Metformin is the most popular anti-diabetic drug in the United States and one of the most prescribed drugs in the country overall, with more than 40 million prescriptions filled in 2008 for generic metformin alone. When prescribed appropriately, metformin causes few adverse effects—the most common is gastrointestinal upset—and, unlike many other anti-diabetic drugs, does not cause hypoglycemia if used alone. It also helps reduce LDL cholesterol and triglyceride levels, and may aid weight loss. As of 2009 metformin is one of only two oral anti-diabetics in the World Health Organization Model List of Essential Medicines (the other being glibenclamide).

Contents

* 1 History

* 2 Clinical use

* 3 Off-label use

3.1 Gestational diabetes

3.2 Investigational findings

* 4 Contraindications

* 5 Adverse effects

5.1 Lactic acidosis

5.2 Gastrointestinal

* 6 Overdosage

* 7 Pharmacokinetics

* 8 Mechanism of action

* 9 Interactions

* 10 Formulations

o 10.1 Combinations with other drugs

* 11 References

* 12 External links

The biguanide class of anti-diabetic drugs, which also includes the withdrawn agents phenformin and buformin, originates from the French lilac (Galega officinalis), a plant known for several centuries to reduce the symptoms of diabetes mellitus.

Metformin was first described in the scientific literature in 1957. It was first marketed in France in 1979, but did not receive approval by the U.S. Food and Drug Administration (FDA) for type 2 diabetes until 1994.Bristol-Myers Squibb's Glucophage was the first branded formulation of metformin to be marketed in the United States, beginning on March 3, 1995. Generic formulations are now available.

Clinical use:

The main use for metformin is in the treatment of diabetes mellitus type 2, especially when this accompanies obesity and insulin resistance. Metformin is the only anti-diabetic drug that has been proven to protect against the cardiovascular complications of diabetes. This was first shown in the United Kingdom Prospective Diabetes Study, a large study of overweight patients with diabetes.

Unlike the other most-commonly prescribed class of oral diabetes drugs, the sulfonylureas, metformin (taken alone) does not induce hypoglycemia.Hypoglycemia during intense exercise has been documented, but is extremely rare. It also does not cause weight gain, and may indeed produce minor weight loss. Metformin also modestly reduces LDL and triglyceride levels.

Off-label use

Metformin is being used increasingly in polycystic ovary syndrome (PCOS), non-alcoholic fatty liver disease (NAFLD) and premature puberty, three other diseases that feature insulin resistance; these indications are still[update] considered experimental. Although metformin is not licensed for use in PCOS, the United Kingdom's National Institute for Health and Clinical Excellence recommends that women with PCOS and a body mass index above 25 be given metformin when other therapy has failed to produce results. The benefit of metformin in NAFLD has not been extensively studied and may be only temporary. although some randomized controlled trials have found significant improvement with its use, the evidence is still insufficient.

Gestational diabetes

Several observational studies and randomized controlled trials have found that metformin is as effective and safe as insulin for the management of gestational diabetes. and a small case-control study has suggested that the children of women given metformin instead of insulin may be healthier in the neonatal period. Nonetheless, several concerns have been raised regarding studies published thus far, and evidence on the long-term safety of metformin for both mother and child is still lacking.

Investigational findings

A large case-control study conducted at M.D. Anderson Cancer Center has suggested that metformin may protect against pancreatic cancer. The risk of pancreatic cancer in study participants who took metformin was found to be 62% lower than in participants who had never taken it, whereas participants who had used insulin or secretagogues (such as the sulfonylureas) were found to have a 5-fold and 2.5-fold higher risk of pancreatic cancer, respectively, compared to participants that had been treated with neither. The study had several limitations, however, and the reason for this risk reduction is still unclear. Observational studies conducted by the University of Dundee have shown a decrease of 25–37% in cancer cases in diabetics taking metformin.

A single randomized controlled trial suggested that metformin may reduce weight gain in patients taking atypical antipsychotics, particularly when combined with lifestyle interventions (education, dieting, and exercise).

Contraindications

Metformin is contraindicated in people with any condition that could increase the risk of lactic acidosis, including kidney disorders (creatinine levels over 150 although this is an arbitrary limit), lung disease and liver disease. Heart failure has long been considered a contraindication for metformin use, although a 2007 systematic review showed metformin to be the only anti-diabetic drug not associated with harm in people with heart failure.

It is recommended that metformin be temporarily discontinued before any radiographic study involving iodinated contrast (such as a contrast-enhanced CT scan or angiogram), as contrast dye may temporarily impair kidney function, indirectly leading to lactic acidosis by causing retention of metformin in the body. It is recommended that metformin be resumed after two days, assuming kidney function is normal.

Adverse effects

Lactic acidosis

The most serious potential side effect of metformin is lactic acidosis; this complication is very rare, and seems limited to those with impaired liver or kidney function. Phenformin, another biguanide, was withdrawn because of an increased risk of lactic acidosis (up to 60 cases per million patient-years). However, metformin is safer than phenformin, and the risk of developing lactic acidosis is not increased by the medication so long as it is not prescribed to known high-risk groups.

The reason for the lactic acidosis is believed to be an increase in intestinal anaerobic respiration; normally, the liver would convert this lactate buildup into glucose via gluconeogenesis, but it is this very pathway that metformin inhibits. Any condition which may precipitate lactic acidosis contraindicates the use of metformin.

Gastrointestinal

The most common adverse effect of metformin is gastrointestinal upset, including diarrhea, cramps, nausea, vomiting and increased flatulence; metformin is more commonly associated with gastrointestinal side effects than most other anti-diabetic drugs. In a clinical trial of 286 subjects, 53.2% of the 141 who were given immediate-release metformin (as opposed to placebo) reported diarrhea, versus 11.7% for placebo, and 25.5% reported nausea/vomiting, versus 8.3% for those on placebo.

Gastrointestinal upset can cause severe discomfort for patients; it is most common when metformin is first administered, or when the dose is increased. The discomfort can often be avoided by beginning at a low dose (1 to 1.7 grams per day) and increasing the dose gradually. Gastrointestinal upset after prolonged, steady use is less common.

Long-term use of metformin has been associated with increased homocysteine levels and malabsorption of vitamin B12. Higher doses and prolonged use are associated with increased incidence of B12 deficiency, and some researchers recommend screening or prevention strategies.

Overdosage

A review of intentional and accidental metformin overdoses reported to poison control centers over a five-year period found that serious adverse events were rare, though elderly patients appeared to be at greater risk. Intentional overdoses with up to 63 g of metformin have been reported in the medical literature. The major potentially life-threatening complication of metformin overdose is lactic acidosis. Treatment of metformin overdose is generally supportive, but may include sodium bicarbonate to address acidosis and standard hemodialysis or continuous veno-venous hemofiltration to rapidly remove metformin and correct acidosis.

Pharmacokinetics

Metformin has an oral bioavailability of 50–60% under fasting conditions, and is absorbed slowly. Peak plasma concentrations (Cmax) are reached within one to three hours of taking immediate-release metformin and four to eight hours with extended-release formulations. The plasma protein binding of metformin is negligible, as reflected by its very high apparent volume of distribution (300–1000 L after a single dose). Steady state is usually reached in one or two days.

Metformin is not metabolized. It is cleared from the body by tubular secretion and excreted unchanged in the urine; metformin is undetectable in blood plasma within 24 hours of a single oral dose. The average elimination half-life in plasma is 6.2 hours. Metformin is distributed to (and appears to accumulate in) red blood cells, with a much longer elimination half-life: 17.6 hours. (reported as ranging from 18.5 to 31.5 hours in a single-dose study of non-diabetic people).

Mechanism of action

Metformin improves hyperglycemia primarily through its suppression of hepatic glucose production (hepatic gluconeogenesis).The "average" person with type 2 diabetes has three times the normal rate of gluconeogenesis; metformin treatment reduces this by over one third. Metformin activates AMP-activated protein kinase (AMPK), a liver enzyme that plays an important role in insulin signaling, whole body energy balance, and the metabolism of glucose and fats; activation of AMPK is required for metformin's inhibitory effect on the production of glucose by liver cells. Research published in 2008 further elucidated metformin's mechanism of action, showing that activation of AMPK is required for an increase in the expression of SHP, which in turn inhibits the expression of the hepatic gluconeogenic genes PEPCK and Glc-6-Pase. Metformin is frequently used in research along with AICAR as an AMPK agonist. The mechanism by which biguanides increase the activity of AMPK remains uncertain; however, research suggests that metformin increases the amount of cytosolic AMP (as opposed to a change in total AMP or total AMP/ATP).

In addition to suppressing hepatic glucose production, metformin increases insulin sensitivity, enhances peripheral glucose uptake, increases fatty acid oxidation, and decreases absorption of glucose from the gastrointestinal tract. Increased peripheral utilization of glucose may be due to improved insulin binding to insulin receptors. AMPK probably also plays a role, as metformin administration increases AMPK activity in skeletal muscle. AMPK is known to cause GLUT4 translocation, resulting in insulin-independent glucose uptake. Some metabolic actions of metformin do appear to occur by AMPK-independent mechanisms; a 2008 study found that "the metabolic actions of metformin in the heart muscle can occur independent of changes in AMPK activity and may be mediated by p38 MAPK- and PKC-dependent mechanisms.

Interactions

The H2-receptor antagonist cimetidine causes an increase in the plasma concentration of metformin, by reducing clearance of metformin by the kidneys; both metformin and cimetidine are cleared from the body by tubular secretion, and both, particularly the cationic (positively charged) form of cimetidine, may compete for the same transport mechanism. A small double-blind, randomized study found the antibiotic cefalexin to also increase metformin concentrations by a similar mechanism; theoretically, other cationic medications may produce the same effect.

Formulations

Metformin 500 mg tablets

Metformin IR (immediate release) is available in 500 mg, 850 mg, and 1000 mg tablets, all now generic in the US.

Metformin SR (slow release) or XR (extended release) was introduced in 2004, in 500 mg and 750 mg strengths, mainly to counteract the most common gastrointestinal side effects, as well as to increase patient compliance by reducing pill burden. No difference in effectiveness exists between the two preparations.

Combinations with other drugs

Metformin is often prescribed to type 2 diabetes patients in combination with rosiglitazone. This drug actively reduces insulin resistance, complementing the action of the metformin. In 2002, the two drugs were combined into a single product, Avandamet, marketed by GlaxoSmithKline.In 2005, all current stock of Avandamet was seized by the FDA and removed from the market, after inspections showed the factory where it was produced was violating Good Manufacturing Practices. The drug pair continued to be prescribed separately in the absence of Avandamet, which was available again by the end of that year.

In the United States, metformin is also available in combination with pioglitazone (trade name Actoplus Met), the sulfonylureas glipizide (trade name Metaglip) and glibenclamide (known as glyburide in the United States, trade name Glucovance), the dipeptidyl peptidase-4 inhibitor sitagliptin (trade name Janumet), and the meglitinide repaglinide (PrandiMet). Generic formulations of metformin/glipizide and metformin/glibenclamide are available. A generic formulation of metformin/rosiglitazone from Teva has received tentative approval from the FDA, and is expected to reach the market in early 2012.

Metformin (Glucophage) treatment of Clomid resistant polycystic ovarian syndrome (PCOS) and ovulation problems causing infertility

Background on PCOS and Ovulation Problems

Polycystic ovarian syndrome is a common cause of anovulation and infertility in women. Women with this syndrome do not ovulate (release eggs) regularly and therefore have irregular menstrual cycles. Their ovaries contain multiple small cystic structures, or antral follicles, usually about 2-9 mm in diameter. This gives the ovaries a characteristic "polycystic" (many cysts) appearance on ultrasound.

There are several possible ways to attempt ovulation induction in women with polycystic ovaries. The least complicated method is the use of Clomid tablets, also called Serophene, or clomiphene citrate. Another oral medication, letrozole, which is an aromatase inhibitor can also be tried - and is sometimes effective after Clomid has failed.

Many will be able to get pregnant using clomiphene to induce ovulation. For women that do not ovulate with clomiphene, the "traditional" next step has been to use injectable gonadotropins. About 90% of women that do not ovulate with clomiphene will ovulate with injectable medication and the majority will get pregnant if they do enough treatment cycles.

However, the injectable medications are expensive and there are risks of ovarian hyperstimulation syndrome and high order multiple pregnancy. The daily injections and trips to the office for monitoring are also inconvenient.

Use of Metformin for PCOS

A relatively new method of treating ovulation problems in women with polycystic ovarian syndrome is to use an oral medication called metformin (brand name is Glucophage) with or without clomiphene citrate.

Metformin has been used in the past as an oral agent to help control diabetes. Recently, it has been found to facilitate ovulation in some women with PCOS. Some women who do not ovulate after taking metformin will be able to ovulate when taking metformin in combination with clomiphene. Therefore using metformin would be a benefit to some women with polycystic ovarian syndrome by allowing them to potentially avoid the injectable FSH medications.

We currently give metformin treatment to women that are appropriate candidates. Unfortunately, not all women will respond to metformin and clomiphene and therefore some will still need to take the injectable FSH medications, or have in vitro fertilization in order to have a baby.

We will initially use metformin alone without clomiphene and do weekly blood tests to look for spontaneous ovulation. If the metformin does not result in ovulation we will add clomiphene to the regimen and again try to document ovulation by doing some blood tests. If the combination of metformin and clomiphene does not result in ovulation then we will terminate the treatment and the patient will need to take injectable FSH in order to ovulate and achieve pregnancy.

In up to 25% of women metformin causes side effects which may include abdominal discomfort, cramping, diarrhea and nausea. The side effects may be severe enough to make the woman want to stop the metformin treatment. We are not aware of any serious complications resulting from metformin treatment.

Another oral medication used for diabetes called Troglitazone has been associated with liver failure and death in rare cases. This has been publicized on television shows, in newspapers, etc. These problems have not been associated with the use of metformin.

How we are currently using metformin

We use metformin in many women experiencing fertility problems. Mainly it is used in women that do not ovulate with polycystic ovarian syndrome, PCOS. However, we also use it in women going through in vitro fertilization that have high antral follicle counts - in other words if their ovaries are polycystic by ultrasound evaluation.

Lab tests that are sometimes done before starting metformin:

# LH, FSH, E2 (estradiol), DHEAS, T, 17-OHP, Prolactin, TSH, BUN, CR, AST, ALT, LDH, fasting blood sugar

Sample Metformin Protocol

Baseline ultrasound prior to starting metformin – follicles and lining. If lining > 5 mm – induce withdrawal bleed.

Patients need to be counseled regarding possibility of ovulation occurring and need for regular intercourse (about every 2-3 days) in order to maximize chances for pregnancy.

The most effective dose of Metformin is generally 500mg 3 times daily. We usually start metformin at one 500mg tablet per day for 1 week, then 1 tablet twice a day for a week, then start the full dose of 1 tablet 3 times a day. By gradually increasing the dose, there is a greatly reduced chance for the unpleasant side effects.

After 4 weeks of metformin, check P4 (progesterone) weekly X 4. Check a fasting blood sugar at least once.

If P4 indicates ovulation, check HCG and P4 if no menses by 12 days after elevated P4. If not pregnant, check weekly P4 levels again beginning about day 20-25 of next cycle.

If no ovulation (P4 > 7) after 4 weeks, offer the patient a choice between continued weekly P4 checks and metformin/clomiphene combined therapy. If no ovulation (P4 > 7) after 8 weeks of metformin, begin Clomid treatment or stop metformin.

Patients are to keep menstrual calendars with all bleeding days and days of intercourse recorded.

metformin is approved for treatment with sulfonylureas, or with insulin, or as monotherapy (by itself).

Glucophage XR Extended Release tablets, a once daily version of metformin, is available. Also, metformin is available as part of combination products with two different sulfonylureas (glyburide and glipizide), called Glucovance and Metaglip, respectively. And, on September 15, 2003, a liquid version was announced (Ranbaxy Gains FDA Approval for Commercialization of Riomet (Metformin HCl) Oral Solution 100 mg/mL).

As part of the approval process, Bristol-Myers Squibb Company, the pharmaceutical company that sells Glucophage in the U.S., developed a patient information insert. We include the text of the April 2003 version of the insert (below), and the original version (below).

In February, 1998, Bristol-Myers Squibb announced revised labeling for the use of Glucophage in patients requiring radiologic studies involving intravascular administration of iodinated contrast materials. (That is, in situations where a person on Glucophage will need X-rays using an injection of "dye" to help get better-appearing X-ray results, such as studies of blood vessels and the interior of the heart.)

Revised labeling for use when radiologic studies are planned "is based on the experience of leading radiologists, the short half-life of Glucophage (6 hours), and its relatively rapid clearance by the kidneys. The labeling now recommends that:

• Glucophage should be stopped at the time of or prior to the procedure.
• Glucophage should then be withheld for 48 hours after the procedure. Once renal function is found to be normal, Glucophage therapy can be started again."

What are GLUCOPHAGE and GLUCOPHAGE XR?

GLUCOPHAGE and GLUCOPHAGE XR are used to treat type 2 diabetes .This is also known as non-insulin-dependent diabetes mellitus. People with type 2 diabetes are not able to make enough insulin or 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 kidney damage, amputations, and blindness. 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 can be lowered by diet and exercise, by a number of medicines taken by mouth, and by insulin shots. Before you take GLUCOPHAGE or GLUCOPHAGE XR, try to control your diabetes by exercise and weight loss. While you take your diabetes medicine, continue to exercise and follow the diet advised for your diabetes. No matter what your recommended diabetes management plan is, studies have shown that maintaining good blood sugar control can prevent or delay complications of diabetes, such as blindness.

GLUCOPHAGE and GLUCOPHAGE XR have the same active ingredient. However,

GLUCOPHAGE XR 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. GLUCOPHAGE and GLUCOPHAGE XR do not cause your body to make more insulin. Because of this, when taken alone, they rarely cause hypoglycemia (low blood sugar), and usually do not cause weight gain. However, when they are taken with a sulfonylurea or with insulin, hypoglycemia is more likely to occur, as is weight gain.

What is metformin?

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

Metformin is for people with type 2 (non-insulin-dependent) diabetes. Metformin is sometimes used in combination with insulin or other medications, but it is not for treating type 1 diabetes.

Metformin may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about metformin?

Do not use metformin if you have kidney disease, or if you are in a state of diabetic ketoacidosis (call your doctor for treatment with insulin).

Before taking metformin, tell your doctor if you have liver disease or a history of heart disease.

Some people have developed a life-threatening condition called lactic acidosis while taking metformin. Get emergency medical help if you have any of these symptoms of lactic acidosis: weakness, increasing sleepiness, slow heart rate, cold feeling, muscle pain, shortness of breath, stomach pain, feeling light-headed, and fainting.

If you need to have any type of x-ray or CT scan using a dye that is injected into a vein, you may need to temporarily stop taking metformin. Be sure the doctor knows ahead of time that you are using metformin.

Know the signs of low blood sugar (hypoglycemia) and how to recognize them, including hunger, headache, confusion, irritability, drowsiness, weakness, dizziness, tremors, sweating, fast heartbeat, seizure (convulsions), fainting, or coma (severe hypoglycemia can be fatal). Always keep a source of sugar available in case you have symptoms of low blood sugar.

Metformin may rarely cause a serious, life-threatening condition called lactic acidosis. Tell your doctor if you have or have ever had a heart attack; stroke; high blood pressure; diabetic ketoacidosis ( blood sugar that is high enough to cause severe symptoms and requires emergency medical treatment) or coma; surgery to remove part of your small intestine; anemia (not enough red blood cells), or heart, kidney, lung, or liver disease.

Tell your doctor if you have recently had any of the following conditions, or if you develop them during treatment: serious infection; severe diarrhea, vomiting, or fever; or if you drink much less fluid than usual for any reason. You may have to stop taking metformin until you recover.

If you are having surgery, including dental surgery, any x-ray procedure in which dye is injected, or any major medical procedure, tell the doctor that you are taking metformin. You may need to stop taking metformin before the procedure and wait 48 hours to restart treatment. Your doctor will tell you exactly when you should stop taking metformin and when you should start taking it again.

Tell your doctor and pharmacist if you are taking or have taken the following medications: acyclovir (Zovirax); acetaminophen (Tylenol); aminoglycoside antibiotics such as amikacin (Amikin), gentamicin (Garamycin), Kanamycin (Kantrex), Neomycin (Neo-Fradin, Neo-Rx), netilmycin (netromycin), paramomycin (Humatin), streptomycin and tobramycin (Nebcin, Tobi); amphotericin B (Abelcet, Amphocin, others); angiotensin converting enzyme (ACE) inhibitors such as benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinvil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), and trandolapril (Mavik); aspirin and other non-steroidal anti-inflammatory agents (NSAIDs) such as ibuprofen (Advil, Motrin) and naproxen (Aleve, Naprosyn); cancer chemotherapy medications; cyclosporine (Sandimmune, Neoral); dapsone (Avlosulfon); diuretics (water pills); foscarnet (Foscavir); gold compounds such as auranofin (Ridaura), aurothioglucose (Aurolate, Solganol), and gold sodium thiomalate (Myochrysine); hydralazine (Hydra-Zide); lithium (Eskalith, Lithobid); medications to treat human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS); methicillin (Staphcillin); nitrates; penicillin and sulfa antibiotics; penicillamine (Cuprimine, Depen); primaquine; propranolol (Inderal); rifampin (Rifadin, Rimactane); tacrolimus (Prograf); vancomycin (Vancocin); or if you have ever taken the Chinese weight-loss herb aristolochia.

If you experience any of the following symptoms, call your doctor immediately: extreme tiredness, weakness, or discomfort; upset stomach; vomiting; stomach pain; decreased appetite; deep and rapid breathing or shortness of breath; dizziness; light-headedness; fast or slow heartbeat; flushing of the skin; muscle pain; or feeling cold.

Tell your doctor if you regularly drink alcohol or sometimes drink large amounts of alcohol in a short time (binge drinking). Drinking alcohol increases your risk of developing lactic acidosis or may cause a decrease in blood sugar. Ask your doctor how much alcohol is safe to drink while you are taking metformin.

Keep all appointments with your doctor and the laboratory. Your doctor will order certain tests to check your body's response to metformin. Talk to your doctor about the risk(s) of taking metformin.

GLUCOPHAGE® (metformin hydrochloride) Tablets and GLUCOPHAGE® XR (metformin hydrochloride) Extended-Release Tablets are oral antihyperglycemic drugs used in the management of type 2 diabetes Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents.

Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C4H11N5• HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.

GLUCOPHAGE tablets contain 500 mg, 850 mg, or 1000 mg of metformin hydrochloride. Each tablet contains the inactive ingredients povidone and magnesium stearate. In addition, the coating for the 500 mg and 850 mg tablets contains hypromellose and the coating for the 1000 mg tablet contains hypromellose and polyethylene glycol.

GLUCOPHAGE XR contains 500 mg or 750 mg of metformin hydrochloride as the active ingredient.

GLUCOPHAGE XR 500 mg tablets contain the inactive ingredients sodium carboxymethyl cellulose, hypromellose, microcrystalline cellulose, and magnesium stearate.

GLUCOPHAGE XR 750 mg tablets contain the inactive ingredients sodium carboxymethyl cellulose, hypromellose, and magnesium stearate.

www.tajpharma.com

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