Description Section

Metformin hydrochloride 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. The structural formula is as shown:



Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C 4H 11N 5 • 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 pK a of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.

Metformin hydrochloride tablets, for oral administration, contains 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, 850 mg, and 1000 mg contains hypromellose and polyethylene glycol.

Clinical Pharmacology Section

Indications & Usage Section

Metformin hydrochloride tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults and children with type 2 diabetes mellitus.

Contraindications Section

Metformin hydrochloride tablets are contraindicated in patients with:

• Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥ 1.5 mg/dL [males], ≥ 1.4 mg/dL [females] or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia (see WARNINGS and PRECAUTIONS.)
• Known hypersensitivity to metformin hydrochloride.
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

  Metformin should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function. (See also PRECAUTIONS.)

Warnings Section

Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with metformin; when it occurs, it is fatal in approximately 50% of cases.  Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 mcg/mL are generally found.

The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications.  Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin and by use of the minimum effective dose of metformin.  In particular, treatment of the elderly should be accompanied by careful monitoring of renal function.  Metformin treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis.  Because impaired hepatic function may significantly limit the ability to clear lactate, metformin should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking metformin

hydrochloride tablets, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, metformin should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see also PRECAUTIONS).

The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The  patient and  the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur (see also PRECAUTIONS). Metformin hydrochloride tablets should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of metformin, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling. (See also PRECAUTIONS.)

Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).

Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin.  Such management often results in prompt reversal of symptoms and recovery. (See also CONTRAINDICATIONS and PRECAUTIONS.)

 

Precautions Section

Adverse Reactions Section

Overdosage Section

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 hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases (see

WARNINGS

). 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.

Dosage & Administration Section

There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with metformin or any other pharmacologic agent. Dosage of metformin must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily doses. The maximum recommended daily dose of metformin hydrochloride tablets is 2550 mg in adults and 2000 mg in pediatric patients (10 to 16 years of age).

Metformin hydrochloride tablets should be given in divided doses with meals and should be started at a low dose, with gradual dose escalation, to reduce gastrointestinal side effects and to permit identification of the minimum dose required for adequate glycemic control of the patient.

During treatment initiation and dose titration (see

Recommended Dosing Schedule

), fasting plasma glucose should be used to determine the therapeutic response to metformin and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately three months.

The therapeutic goal should be to decrease both fasting plasma glucose and glycosylated hemoglobin levels to normal or near normal by using the lowest effective dose of metformin, either when used as monotherapy or in combination with sulfonylurea or insulin.

Monitoring of blood glucose and glycosylated hemoglobin will also permit detection of primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication, and secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period of effectiveness.

Short-term administration of metformin may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone.

Adults -

In general, clinically significant responses are not seen at doses below 1500 mg per day. However, a lower recommended starting dose and gradually increased dosage is advised to minimize gastrointestinal symptoms.

The usual starting dose of metformin hydrochloride tablets is 500 mg twice a day or 850 mg once a day, given with meals. Dosage increases should be made in increments of 500 mg weekly or 850 mg every 2 weeks, up to a total of 2000 mg per day, given in divided doses. Patients can also be titrated from 500 mg twice a day to 850 mg twice a day after 2 weeks. For those patients requiring additional glycemic control, metformin hydrochloride tablets may be given to a maximum daily dose of 2550 mg per day. Doses above 2000 mg may be better tolerated given three times a day with meals.

Pediatrics –

The usual starting dose of metformin hydrochloride tablets is 500 mg twice a day, given with meals. Dosage increases should be made in increments of 500 mg weekly up to a maximum of 2000 mg per day, given in divided doses.

When transferring patients from standard oral hypoglycemic agents other than chlorpropamide to metformin, no transition period generally is necessary. When transferring patients from chlorpropamide, care should be exercised during the first two weeks because of the prolonged retention of chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia.

If patients have not responded to four weeks of the maximum dose of metformin monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing metformin at the maximum dose, even if prior primary or secondary failure to a sulfonylurea has occurred. Clinical and pharmacokinetic drug-drug interaction data are currently available only for metformin plus glyburide (glibenclamide).

With concomitant metformin and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. In a clinical trial of patients with type 2 diabetes and prior failure on glyburide, patients started on metformin hydrochloride tablets 500 mg and glyburide 20 mg were titrated to 1000/20 mg, 1500/20 mg, 2000/20 mg or 2500/20 mg of metformin hydrochloride tablets and glyburide, respectively, to reach the goal of glycemic control as measured by FPG, HbA 1c and plasma glucose response (see

CLINICAL PHARMACOLOGY: Clinical Studies

). However, attempts should be made to identify the minimum effective dose of each drug to achieve this goal. With concomitant metformin and sulfonylurea therapy, the risk of hypoglycemia associated with sulfonylurea therapy continues and may be increased. Appropriate precautions should be taken. (See Package Insert of the respective sulfonylurea.)

If patients have not satisfactorily responded to one to three months of concomitant therapy with the maximum dose of metformin and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without metformin.

The current insulin dose should be continued upon initiation of metformin therapy. Metformin therapy should be initiated at 500 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of metformin should be increased by 500 mg after approximately 1 week and by 500 mg every week thereafter until adequate glycemic control is achieved. The maximum recommended daily dose is 2500 mg for metformin hydrochloride tablets. It is recommended that the insulin dose be decreased by 10% to 25% when fasting plasma glucose concentrations decrease to less than 120 mg/dL in patients receiving concomitant insulin and metformin. Further adjustment should be individualized based on glucose-lowering response.

Metformin is not recommended for use in pregnancy. Metformin hydrochloride tablets are not recommended in patients below the age of 10 years.

The initial and maintenance dosing of metformin should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment should be based on a careful assessment of renal function. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of metformin.

Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly. (See

WARNINGS

.)

How Supplied Section

SPL Patient Package Insert Section

Rx only

Read this information carefully before you start taking this medicine and each time you refill your prescription. There may be new information. This information does not take the place of your doctor’s advice. Ask your doctor or pharmacist if you do not understand some of this information or if you want to know more about this medicine.

Metformin is 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 metformin, 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.

Metformin 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 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.

WARNING: A small number of people who have taken metformin hydrochloride tablets have developed a serious condition called lactic acidosis. Lactic acidosis is caused by a buildup of lactic acid in the blood. This happens more often in people with kidney problems. Most people with kidney problems should not take metformin. (See “What are the side effects of metformin?”)

Some conditions increase your chance of getting lactic acidosis, or cause other problems if you take metformin hydrochloride tablets. Most of the conditions listed below can increase your chance of getting lactic acidosis.

Do not take metformin if you:

• have kidney problems
• have liver problems
• have heart failure that is treated with medicines, such as Lanoxin ® (digoxin) or Lasix ® (furosemide)
• drink a lot of alcohol. This means you binge drink for short periods or drink all the time
• are seriously dehydrated (have lost a lot of water from your body)
• are going to have an x-ray procedure with injection of dyes (contrast agents)
• are going to have surgery
• develop a serious condition, such as heart attack, severe infection, or a stroke
• are 80 years or older and you have NOT had your kidney function tested

Tell your doctor if you are pregnant or plan to become pregnant. Metformin may not be right for you. Talk with your doctor about your choices. You should also discuss your choices with your doctor if you are nursing a child.

Metformin hydrochloride tablets have been shown to effectively lower glucose levels in children (ages 10 to 16 years) with type 2 diabetes. Metformin hydrochloride tablets have not been studied in children younger than 10 years old. Metformin hydrochloride tablets have not been studied in combination with other oral glucose-control medicines or insulin in children. If you have any questions about the use of metformin hydrochloride tablets in children, talk with your doctor or other healthcare provider.

Your doctor will tell you how much medicine to take and when to take it. You will probably start out with a low dose of the medicine. Your doctor may slowly increase your dose until your blood sugar is better controlled. You should take metformin with meals.

Your doctor may have you take other medicines along with metformin to control your blood sugar. These medicines may include insulin shots. Taking metformin hydrochloride tablets with insulin may help you better control your blood sugar while reducing the insulin dose.

Continue your exercise and diet program and test your blood sugar regularly while taking metformin. Your doctor will monitor your diabetes and may perform blood tests on you from time to time to make sure your kidneys and your liver are functioning normally. There is no evidence that metformin causes harm to the liver or kidneys.

Tell your doctor if you

• have an illness that causes severe vomiting, diarrhea or fever, or if you drink a much lower amount of liquid than normal. These conditions can lead to severe dehydration (loss of water in your body). You may need to stop taking metformin for a short time.
• plan to have surgery or an x-ray procedure with injection of dye (contrast agent). You may need to stop taking metformin hydrochloride tablets for a short time.
• start to take other medicines or change how you take a medicine. Metformin can affect how well other drugs work, and some drugs can affect how well metformin work. Some medicines may cause high blood sugar.

Do not drink a lot of alcoholic drinks while taking metformin. 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.

Lactic Acidosis. In rare cases, metformin can cause a serious side effect called lactic acidosis. This is caused by a buildup of lactic acid in your blood. This buildup can cause serious damage.

Lactic acidosis caused by metformin is rare and has occurred mostly in people whose kidneys were not working normally. Lactic acidosis has been reported in about one in 33,000 patients taking metformin hydrochloride tablets over the course of a year. Although rare, if lactic acidosis does occur, it can be fatal in up to half the people who develop it.

It is also important for your liver to be working normally when you take metformin. Your liver helps remove lactic acid from your blood.

Make sure you tell your doctor before you use metformin if you have kidney or liver problems. You should also

stop using metformin and call your doctor right away if you have signs of lactic acidosis. Lactic acidosis is a medical emergency that must be treated in a hospital.

Signs of lactic acidosis are:

• feeling very weak, tired, or uncomfortable
• unusual muscle pain
• trouble breathing
• unusual or unexpected stomach discomfort
• feeling cold
• feeling dizzy or lightheaded
• suddenly developing a slow or irregular heartbeat

If your medical condition suddenly changes, stop taking metformin and call your doctor right away. This may be a sign of lactic acidosis or another serious side effect.

Other Side Effects.

Common side effects of metformin 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 have an unpleasant metallic taste when they start taking the medicine. It lasts for a short time.

Metformin 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.

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 that is written for health care professionals. Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use metformin for a condition for which it was not prescribed. Do not share your medicine with other people.<
Manufactured for:

Aurobindo Pharma USA, Inc.

2400 Route 130 North

Dayton, NJ 08810

Manufactured by:

Aurobindo Pharma Limited

Hyderabad–500 072, India

Revised: 07/2010

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION

DRUG: Metformin Hydrochloride

GENERIC: Metformin Hydrochloride

DOSAGE: TABLET, FILM COATED

ADMINSTRATION: ORAL

NDC: 49349-675-15

STRENGTH:500 mg

COLOR: white

SHAPE: ROUND

SCORE: No score

SIZE: 11 mm

IMPRINT: 15

QTY: 15