GLUMETZA (metformin hydrochloride) extended release tablet is an oral antihyperglycemic drug 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 of metformin hydrochloride (metformin HCl) is as shown:

Metformin HCl is a white to off-white crystalline compound with a molecular formula of C₄H₁₁N₅•HCl and a molecular weight of 165.63. Metformin HCl 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. GLUMETZA tablets are modified release dosage forms that contain 500 mg or 1000 mg of metformin HCl. Each 500 mg tablet contains coloring, hypromellose, magnesium stearate, microcrystalline cellulose and polyethylene oxide. Each 1000 mg tablet contains colloidal silicon dioxide, polyvinyl alcohol, crospovidone, glyceryl behenate, polyacrylate dispersion, hypromellose, talc, polyethylene glycol, eudragit, titanium dioxide, simethicone emulsion, polysorbate and coloring. GLUMETZA 500 and 1000 mg tablets both utilize polymer-based, oral drug delivery systems, which allow delivery of metformin HCl to the upper gastrointestinal (GI) tract.

GLUMETZA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

GLUMETZA should be taken once daily. However, there is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with GLUMETZA or any other pharmacologic agent. Dosage of GLUMETZA must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily dose. The maximum recommended daily dose of GLUMETZA is 2000 mg. GLUMETZA therapy should generally be initiated with 1000 mg daily which should be taken with food preferably in the evening. Gradual dose escalation from this low dose is recommended both to reduce gastrointestinal side effects and to permit identification of the minimum dose required for adequate glycemic control. During treatment initiation and dose titration (see Recommended Dosing Schedule), fasting plasma glucose should be used to determine the therapeutic response to GLUMETZA and identify the minimum effective dose. 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 GLUMETZA, 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 GLUMETZA may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone. GLUMETZA tablets must be swallowed whole and never split, crushed or chewed. Occasionally, the inactive ingredients of GLUMETZA 500 mg may be eliminated in the feces as a soft, hydrated mass, while the 1000 mg may leave an insoluble shell. (See PATIENT INFORMATION.)

Recommended Dosing Schedule

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 starting dose of GLUMETZA is 1000 mg once daily which in order to maximize therapeutic efficacy must be taken with food preferably in the evening. Dosage increases should be made in increments of 500 mg weekly, up to a maximum of 2000 mg once daily with the evening meal. If glycemic control is not achieved on GLUMETZA 2000 mg once daily, a trial of GLUMETZA 1000 mg twice daily should be considered. (See CLINICAL PHARMACOLOGY, Clinical Studies).

In one trial, patients treated with immediate release metformin were switched to GLUMETZA. Results of this trial suggest that patients receiving immediate release metformin treatment can be switched to GLUMETZA once daily at the same total daily dose, up to 2000 mg once daily. Following a switch from immediate release metformin to GLUMETZA, glycemic control should be closely monitored and dosage adjustments made accordingly. (See CLINICAL PHARMACOLOGY, Clinical Studies).

Pediatrics - GLUMETZA has been studied in adult patients only.

Transfer From Other Antidiabetic Therapy

When transferring patients from standard oral hypoglycemic agents other than chlorpropamide to GLUMETZA, no transition period is generally 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.

Concomitant GLUMETZA and Oral Sulfonylurea Therapy in Adult Patients

If patients have not responded to four weeks of the maximum dose of GLUMETZA monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing GLUMETZA 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 GLUMETZA and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug.

However, attempts should be made to identify the minimum effective dose. With concomitant GLUMETZA 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 GLUMETZA and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without GLUMETZA.

Concomitant GLUMETZA and Insulin Therapy in Adult Patients

The current insulin dose should be continued upon initiation of GLUMETZA. GLUMETZA therapy should be initiated at 500 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of GLUMETZA 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 of GLUMETZA is 2000 mg.

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 GLUMETZA. Further adjustment should be individualized based on glucose-lowering response.

Specific Patient Populations

GLUMETZA is not recommended for use in pregnancy. GLUMETZA is not recommended in pediatric patients (below the age of 18 years). The initial and maintenance dosing of GLUMETZA 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 GLUMETZA. Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly. (See WARNINGS.)

GLUMETZA tablets-500 mg are available as blue, film coated, oval-shaped tablets debossed with "GMZ" on one side and "500" on the other side.

GLUMETZA tablets 1000 mg are available as white, film coated, oval-shaped tablets with "M1000" on one side.

They are supplied as follows:

Storage

Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F); see [USP Controlled Room Temperature.]

Depomed, Inc. Menlo Park, CA (866) 458-6389. www.GlumetzaXR.com. Issued December, 2007. FDA rev date: 12/04/2007

In clinical trials conducted in the U.S., over 1000 patients with type 2 diabetes mellitus have been treated with GLUMETZA 1500-2000 mg/day in active-controlled and placebo-controlled studies with the 500 mg dosage form.

In the 24-week active-controlled monotherapy trial, serious adverse events were reported in 3.6% (19/528) of the GLUMETZA-treated patients compared to 2.9% (5/174) of the patients treated with immediate-release metformin. During the 6-month open-label, uncontrolled, extension trial, an additional 10 (4.0%) GLUMETZA-treated patients reported a serious adverse event In the add-on to sulfonylurea study, a serious adverse event was reported in 2.1% (9/431) of the GLUMETZA+glyburide treated patients compared to 1.4% (2/144) of the placebo+glyburide treated patients. When the data from all clinical trials were combined, the most frequently (incidence ≥ 0.5 %) reported serious adverse events classified by system organ class were gastrointestinal disorders (1.0% of GLUMETZA-treated patients compared to 0% of patients not treated with GLUMETZA) and cardiac disorders (0.4% of GLUMETZA-treated patients compared to 0.5% of patients not treated with GLUMETZA). Only 2 serious adverse events (unstable angina [n=2] and pancreatitis [n=2]) were reported in more than one GLUMETZA-treated patient.

In the placebo-controlled study, patients receiving background glyburide (SU; sulfonylurea) therapy were randomized to receive add-on treatment of either one of three different regimens of GLUMETZA or placebo. In total, 431 patients received GLUMETZA + SU and 144 patients placebo + SU. Adverse events reported in greater than 5% of patients treated with GLUMETZA that were more common in the combined GLUMETZA + SU group than in the placebo + SU group are shown in Table 5.

In 0.7% of patients treated with GLUMETZA + SU, diarrhea was responsible for discontinuation of study medication compared to zero in the placebo + SU group.

Table 5: Treatment-Emergent Adverse Events Reported By > 5%* of Patients for the Combined Glumetza Group Versus Placebo Group

In the same study, the following adverse events were reported by 1-5% of patients for the combined Glumetza + SU group and these events occurred more commonly in the Glumetza-treated than in the placebo-treated patients:

Ear and labyrinth disorders: ear pain

Gastrointestinal disorders: vomiting NOS, dyspepsia, flatulence, abdominal pain upper, abdominal distension, abdominal pain NOS, toothache, loose stools

General disorders and administration site conditions: asthenia, chest pain

Immune system disorders: seasonal allergy

Infections and infestations: gastroenteritis viral NOS, tooth abscess, tonsillitis, fungal infection NOS

Injury, poisoning and procedural complications: muscle strain

Musculoskeletal and connective tissue disorders: pain in limb, myalgia, muscle cramp

Nervous system disorders: dizziness, tremor, sinus headache, hypoaesthesia

Respiratory, thoracic and mediastinal disorders: nasal congestion

Skin and subcutaneous tissue disorders: contusion

Vascular disorders: hypertension NOS

(Clinical Evaluation of Drug Interactions Conducted with metformin)

Glyburide - The influence of glyburide on GLUMETZA pharmacokinetics was assessed in a single-dose interaction study in healthy subjects. Co-administration of a single dose of 500 mg GLUMETZA and 5 mg glyburide did not result in any changes in metformin pharmacokinetics as AUC; Cmax as well as Tmax were unchanged. Changes in pharmacodynamics were not evaluated in this study (see DOSAGE AND ADMINISTRATION: Concomitant GLUMETZA and Oral Sulfonylurea Therapy).

Furosemide - A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. Furosemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when co-administered chronically.

Nifedipine - A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. Tmax and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.

Cationic drugs - Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics.

Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of GLUMETZA and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

Other - Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving GLUMETZA, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving GLUMETZA, the patient should be observed closely for hypoglycemia. In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when co-administered in single-dose interaction studies. Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.

General

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Glumetza or any other oral anti-diabetic drug.

Monitoring of renal function - Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive GLUMETZA. In patients with advanced age, GLUMETZA should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, particularly those ≥ 80 years of age, renal function should be monitored regularly and GLUMETZA should generally not be titrated to the maximum dose (see WARNINGS and DOSAGE AND ADMINISTRATION). Before initiation of GLUMETZA therapy and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and GLUMETZA discontinued if evidence of renal impairment is present.

Use of concomitant medications that may affect renal function or metformin disposition - Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion (see PRECAUTIONS: DRUG INTERACTIONS), should be used with caution. Radiologic studies involving the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast materials) - Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin (see CONTRAINDICATIONS).

Therefore, in patients in whom any such study is planned, GLUMETZA should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.

Hypoxic states - Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on GLUMETZA therapy, the drug should be promptly discontinued.

Surgical procedures - GLUMETZA therapy should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.

Alcohol intake - Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving GLUMETZA.

Impaired hepatic function - Since impaired hepatic function has been associated with some cases of lactic acidosis GLUMETZA should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.

Vitamin B12 levels - In controlled, 29-week clinical trials of immediate release metformin, a decrease to subnormal levels of previously normal serum Vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of GLUMETZA or Vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on GLUMETZA and any apparent abnormalities should be appropriately investigated and managed (see PRECAUTIONS: Laboratory Tests). Certain individuals (those with inadequate Vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal Vitamin B12 levels. In these patients, routine serum Vitamin B12 measurements at two- to three-year intervals may be useful.

Change in clinical status of patients with previously controlled type 2 diabetes - A patient with type 2 diabetes previously well controlled on GLUMETZA who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, GLUMETZA must be stopped immediately and other appropriate corrective measures initiated (see also WARNINGS).

Hypoglycemia- Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs.

Loss of control of blood glucose - When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold GLUMETZA and temporarily administer insulin. GLUMETZA may be reinstituted after the acute episode is resolved. The effectiveness of oral antidiabetic drugs in lowering blood glucose to a targeted level decreases in many patients over a period of time. This phenomenon, which may be due to progression of the underlying disease or to diminished responsiveness to the drug, is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective during initial therapy. Should secondary failure occur with either GLUMETZA or sulfonylurea monotherapy, combined therapy with GLUMETZA and sulfonylurea may result in a response. Should secondary failure occur with combined GLUMETZA/sulfonylurea therapy, it may be necessary to consider therapeutic alternatives including initiation of insulin therapy.

Information for Patients

Patients should be informed of the potential risks and benefits of GLUMETZA and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose, glycosylated hemoglobin, renal function, and hematologic parameters.

The risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in the GLUMETZA sections, should be explained to patients. Patients should be advised to discontinue GLUMETZA immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of GLUMETZA, gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease. Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving GLUMETZA. GLUMETZA (metformin hydrochloride extended-release tablets) alone does not usually cause hypoglycemia, although it may occur when GLUMETZA is used in conjunction with oral sulfonylureas and insulin. When initiating combination therapy, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. Patients should be informed that GLUMETZA must be swallowed whole and not crushed or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet. (See PATIENT INFORMATION .)

Laboratory Tests

Response to all diabetic therapies should be monitored by periodic measurements of fasting blood glucose and glycosylated hemoglobin levels, with a goal of decreasing these levels toward the normal range. During initial dose titration, fasting glucose can be used to determine the therapeutic response. Thereafter, both glucose and glycosylated hemoglobin should be monitored. Measurements of glycosylated hemoglobin may be especially useful for evaluating long-term control (see also DOSAGE AND ADMINISTRATION). Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with metformin therapy, if this is suspected, Vitamin B12 deficiency should be excluded.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies have been performed in Sprague Dawley rats at doses of 150, 300, and 450 mg/kg/day in males and 150, 450, 900, and 1200 mg/kg/day in females. These doses are approximately 2, 4, and 8 times in males, and 3, 7, 12, and 16 times in females of the maximum recommended human daily dose of 2000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female rats. A carcinogenicity study was also performed in Tg.AC transgenic mice at doses up to 2000 mg applied dermally. No evidence of carcinogenicity was observed in male or female mice.

Genotoxicity assessments in the Ames test, gene mutation test (mouse lymphoma cells), chromosomal aberrations test (human lyhpocytes) and in vivo mouse micronucleus tests were negative. Fertility of male or female rats was not affected by metformin when administered at dose up to 600 mg/kg/day, which is approximately 3 times the maximum recommended human daily dose based on body surface area comparisons.

Pregnancy

Teratogenic Effects: Pregnancy Category B.

Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day, which represent 3 and 6 times the maximum recommended human daily dose of 2000 mg based on body surface area comparison for rats and rabbits, respectively. However, because animal reproduction studies are not always predictive of human response, Metformin HCL should not be used during pregnancy unless clearly needed.

Nursing Mothers

Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Thus, the potential for hypoglycemia in nursing infants after Metformin HCL Oral Solution may exist.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of GLUMETZA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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.

This drug may be known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. (See WARNINGS: Lactic Acidosis.)

No cases of overdose were reported during GLUMETZA clinical trials. It would be expected that adverse reactions of a more intense character including epigastric discomfort, nausea, and vomiting followed by diarrhea, drowsiness, weakness, dizziness, malaise and headache might be seen. Should those symptoms persist, lactic acidosis should be excluded. The drug should be discontinued and proper supportive therapy instituted. In other metformin clinical trials, hypoglycemia has not been seen even with ingestion of up to 85 grams of metformin, although lactic acidosis has occurred in such circumstances (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.

GLUMETZA is contraindicated in patients with:

1. 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).
2. Known hypersensitivity to metformin hydrochloride.
3. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

GLUMETZA 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.)

Mechanism of Action

Metformin is an antihyperglycemic agent, which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see PRECAUTIONS) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and daylong plasma insulin response may actually decrease.

Pharmacokinetics

Absorption and Bioavailability

The following pharmacokinetic studies were performed with the 500 mg dosage form. Following a single oral dose of 1000 mg (2x500 mg tablets) GLUMETZA after a meal, the time to reach maximum plasma metformin concentration (Tmax) is achieved at approximately 7-8 hours. In both single and multiple-dose studies in healthy subjects, once daily 1000 mg (2x500 mg tablets) dosing provides equivalent systemic exposure, as measured by area-under-the-curve (AUC), and up to 35% higher Cmax, of metformin relative to the immediate release given as 500 mg twice daily. GLUMETZA tablets must be administered immediately after a meal to maximize therapeutic benefit.

Table 1: Summary Mean (±SD) of Pharmacokinetic Parameters after One Day Dosing

Single oral doses of GLUMETZA from 500 mg to 2500 mg resulted in less than proportional increase in both AUC and Cmax. The mean Cmax values were 473 ± 145, 868 ± 223, 1171 ± 297, and 1630 ± 399 ng/mL for single doses of 500, 1000, 1500, and 2500 mg, respectively. For AUC, the mean values were 3501 ± 796, 6705 ± 1918, 9299 ± 2833, and 14161 ± 4432 ng·hr/mL for single doses of 500, 1000, 1500, and 2500 mg, respectively.

Low-fat and high-fat meals increased the systemic exposure (as measured by AUC) from GLUMETZA tablets by about 38% and 73%, respectively, relative to fasting. Both meals prolonged metformin Tmax by approximately 3 hours but Cmax was not affected.

In a two-way, single-dose crossover study in healthy volunteers, the 1000 mg tablet was found to be bioequivalent to two 500 mg tablets under fed conditions based on equivalent Cmax and AUCs for the two formulations (Table 2).

Table 2: Mean (SD) Pharmacokinetic Parameters for Glumetza 1000 mg Tablet and Glumetza 2x500 mg Tablets

Distribution

The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg immediate release metformin hydrochloride averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin, steady state plasma concentrations of metformin are reached within 24-48 hours and are generally < 1 µg/mL. During controlled clinical trials, which served as the basis of approval for metformin, maximum metformin plasma levels did not exceed 5 µg/mL, even at maximum doses.

Metabolism and Excretion

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. Renal clearance 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.

Special Populations

Renal Impairment: In patients with mild and moderate renal failure (based on measured creatinine clearance) the oral and renal clearance of metformin were decreased by 33% and 50% and 16% and 53%, respectively (see WARNINGS). Metformin peak and systemic exposure were significantly greater in patients with renal failure relative to healthy volunteers with normal renal function. There was a rank-order correlation of metformin AUC and Cmax with degree of renal failure. Since metformin can accumulate to toxic levels in patients with renal impairment, administration of GLUMETZA is contraindicated in these patients.

Hepatic Impairment: No pharmacokinetic studies of GLUMETZA have been conducted in subjects with hepatic insufficiency.

Geriatrics: Limited data from controlled pharmacokinetic studies of metformin hydrochloride 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. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see, CLINICAL PHARMACOLOGY, Pharmacokinetics). Metformin treatment should not be initiated in patients 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced (see WARNINGS and DOSAGE AND ADMINISTRATION).

Gender: In the pharmacokinetic studies in healthy volunteers, there were no important differences between male and female subjects with respect to metformin AUC (males = 268, females = 293) and t_1/2 (males = 229, females = 260). However, Cmax for metformin were somewhat higher in female subjects (Female/Male Cmax Ratio = 1.4). The gender differences for Cmax are unlikely to be clinically important. Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin hydrochloride tablets was comparable in males and females.

Race: There were no definitive conclusions on the differences between the races with respect to the pharmacokinetics of metformin because of the imbalance in the respective sizes of the racial groups. However, the data suggest a trend towards higher metformin Cmax and AUC values for metformin are obtained in Asian subjects when compared to Caucasian, Hispanic and Black subjects. The differences between the Asian and Caucasian groups are unlikely to be clinically important. In controlled clinical studies of metformin hydrochloride in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n = 249), blacks (n = 51) and Hispanics (n = 24).

Pediatrics: No pharmacokinetic data from studies of GLUMETZA in pediatric subjects are available.

Clinical Studies

GLUMETZA has been studied as monotherapy and in combination with a sulfonylurea and insulin.

In a multicenter, randomized, double-blind, active-controlled, dose-ranging, parallel group study GLUMETZA 1500 mg once a day, GLUMETZA 1500 per day in divided doses (500 mg in the morning and 1000 mg in the evening), and GLUMETZA 2000 mg once a day were compared to immediate release metformin 1500 mg per day in divided doses (500 mg in the morning and 1000 mg in the evening). (See Table 3.) Newly diagnosed patients, diet-and-exercise-treated (diet/exercise) patients, patients who received combination therapy consisting of metformin up to 1500 mg/day plus a sulfonylurea at a dose equal to or less than one-half the maximum dose allowed (following a 6-week washout), or patients on monotherapy with an antihyperglycemic agent (following a 6-week washout) were randomized to treatment and began titration from 1000 mg/day up to their assigned treatment dose over 3 weeks. Metformin IR treatment was initiated as 500 mg BID for 1 week followed by 500 mg with breakfast and 1000 mg with dinner for the second week. The 3-week treatment period was followed by an additional 21-week period at the randomized dose. Each of the GLUMETZA regimens were at least as effective as immediate release metformin in all measures of glycemic control. Additionally, once daily dosing was as effective as the commonly prescribed twice daily dosing of the immediate release metformin formulation.

Table 3: Mean±SE Changes from Baseline to Final Visit in HbA1c, Fasting Plasma Glucose and Body Weight for the GLUMETZA and Metformin IR Treatment Groups (First 24-Week Study)

In a double-blind, randomized, placebo-controlled (glyburide add-on) multicenter study, patients with type 2 diabetes mellitus who were newly diagnosed or treated with diet and exercise, or who were receiving monotherapy with metformin, sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, or meglinitides, or treated with combination therapy consisting of metformin/glyburide at doses up to 1000 mg metformin + 10 mg glyburide per day (or equivalent doses of glipizide or glimepiride up to half the maximum therapeutic dose) were enrolled. They were stabilized on glyburide for a 6-week period, and then randomized to 1 of 4 treatments: placebo + glyburide (glyburide alone); GLUMETZA 1500 mg once a day + glyburide, GLUMETZA 2000 mg once a day + glyburide, or GLUMETZA 1000 mg twice a day + glyburide. A 3-week GLUMETZA titration phase was followed by a 21-week maintenance treatment phase. The difference in the change from Baseline in HbA1c levels between the combined M-ER+ SU (sulfonylurea) groups and the SU only group was statistically significant (p < 0.001). The changes in glycemic control across the three GLUMETZA+glyburide groups were comparable. (See Table 4.)

Table 4: Mean±SE Changes from Baseline to Final Visit in HbA_1c, Fasting Plasma Glucose and Body Weight for the GLUMETZA/Glyburide Groups and Placebo/Glyburide Treatment Group (Second 24-Week Study)

A 24-week, double-blind, placebo-controlled study of immediate release metformin plus insulin versus insulin plus placebo was conducted in patients with type 2 diabetes who failed to achieve adequate glycemic control on insulin alone. Patients randomized to receive metformin plus insulin achieved a reduction in HbA_1c of 2.10%, compared to a 1.56% reduction in HbA1c achieved by insulin plus placebo. The improvement in glycemic control was achieved at the final study visit with 16% less insulin, 93.0 U/day vs. 110.6 U/day, metformin plus insulin versus insulin plus placebo, respectively, p=0.04. A second double-blind, placebo-controlled study (n=51), with 16 weeks of randomized treatment, demonstrated that in patients with type 2 diabetes controlled on insulin for 8 weeks with an average HbA_1c of 7.46 ± 0.97%, the addition of metformin maintained similar glycemic control (HbA1c 7.15 ± 0.61 versus 6.97 ± 0.62 for metformin plus insulin and placebo plus insulin, respectively) with 19% less insulin versus baseline (reduction of 23.68 ± 30.22 versus an increase of 0.43 ± 25.20 units for metformin plus insulin and placebo plus insulin, p < 0.01). In addition, this study demonstrated that the combination of metformin plus insulin resulted in reduction in body weight of 3.11 ± 4.30 lbs, compared to an increase of 1.30 ± 6.08 lbs for placebo plus insulin, p=0.01.

GLUMETZA
(Gloo-met-za)
(metformin hydrochloride extended-release tablets)

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.

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

Warning: GLUMETZA 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. Stop taking GLUMETZA and call your doctor right away if you get the following symptoms of lactic acidosis.

• You feel very weak or tired.
• You have unusual (not normal) muscle pain.
• You have trouble breathing.
• You have stomach pain with nausea and vomiting, and diarrhea.
• You feel cold, especially in your arms and legs.
• You feel dizzy or lightheaded.
• You have a slow or irregular heartbeat.
• Your medical condition suddenly changes.

You have a higher chance for getting lactic acidosis with GLUMETZA if you:

• have kidney or liver problems.
• have congestive heart failure that requires treatments 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 don't drink enough fluids.
• have certain x-ray test with injectable dye used.
• have surgery.
• have a heart attack, severe infection, or a stroke.
• are 80 years of age or older and have not had your kidney function tested.

What is GLUMETZA?

GLUMETZA is used along with diet and exercise to improve blood sugar control in adults with type 2 diabetes. GLUMETZA may also be used with another anti-diabetes medicine called a sulfonylurea or with insulin to improve blood sugar levels in adults. GLUMETZA helps 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. GLUMETZA has not been studied in children under 18 years of age.

Who should not take GLUMETZA?

Do not take GLUMETZA if you:

• have kidney problems.
• have heart failure that is treated with medicines.
• have a condition called metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin.
• are allergic to GLUMETZA or to any of its ingredients. See the end of this leaflet for a list of ingredients in GLUMETZA.

What should I tell my doctor before taking GLUMETZA?

Tell your doctor about all of your medical conditions including if you:

• have kidney problems.
• have liver problems.
• have heart problems.
• drink a lot of alcohol.
• are pregnant or planning to become pregnant. It is not known if
  GLUMETZA can harm your unborn baby. Talk to your doctor about the best way to control your blood sugar levels while pregnant.
• are breastfeeding. It is not known if GLUMETZA passes into your milk and if it can harm your baby. Talk to your doctor about the best way to feed your baby while taking GLUMETZA.

Tell your doctor about all the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. GLUMETZA and some of your other medicines can interact. You may need to have the dose of GLUMETZA or certain other medicines adjusted. Certain other medicines can affect your blood sugar control.

Know the medicines you take. Keep a list of them to show your doctor and pharmacist. Talk to your doctor before you start any new medicine.

How should I take GLUMETZA?

• Take GLUMETZA exactly as prescribed. Your doctor will usually start you on a low dose and increase your dose slowly to control your blood sugar levels. Do not change your dose unless told to do so by your doctor.
• Take GLUMETZA once a day in the evening with food.
• Swallow GLUMETZA tablets whole. Never crush, split or chew GLUMETZA tablets. Tell your doctor if you cannot swallow tablets whole. Your doctor will prescribe a different medicine for you.
• You may see the GLUMETZA tablet shell in your stool. You may also see a soft mass of the GLUMETZA inactive ingredients in your stool. Both of these are normal to see in your stool.
• Stay on your exercise and diet program and test your blood sugar regularly while taking GLUMETZA.
• Your doctor should monitor your diabetes and do blood tests on you from time to time to check your kidneys and your liver.
• If you miss a dose of GLUMETZA resume dosing according to schedule.
• If you take too much GLUMETZA or overdose, call your doctor or poison control center right away.
• You may need to stop GLUMETZA for a short period of time if you:
  • are sick with severe vomiting, diarrhea or fever, or if you drink a much lower amount of liquid than normal.
  • plan to have surgery.
  • are having an x-ray procedure with an injection of dye.

Call your doctor right away for instructions.

What should I avoid while taking GLUMETZA?

Do not drink a lot of alcoholic drinks while taking GLUMETZA. 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 GLUMETZA?

GLUMETZA can cause a rare, but serious side effect called lactic acidosis (a buildup of an acid in your blood) that can cause death. See "What is the most important information I should know about GLUMETZA?"

The most common side effects of GLUMETZA include diarrhea, nausea, and upset stomach. These side effects usually go away after you take the medicine for a while. Taking your medicine with the evening meal can help reduce these side effects.

GLUMETZA rarely causes low blood sugar (hypoglycemia) by itself. However, low blood sugar can happen if you do not eat enough, if you drink alcohol, or if you take other medicines to lower blood sugar.

Tell your doctor if you have side effects that bother you, last for more than a few weeks, come back after they have gone away, or start later in therapy. You may need a lower dose or need to stop taking GLUMETZA.

These are not all the side effects with GLUMETZA. For more information, ask your doctor or pharmacist.

How should I store GLUMETZA?

• Store GLUMETZA at room temperature, 59° to 86° F (15° to 30° C).
• Keep GLUMETZA and all medicines out of the reach of children.

General information about GLUMETZA.

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use GLUMETZA for a condition for which it was not prescribed. Do not give GLUMETZA to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about GLUMETZA. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about GLUMETZA that is written for health professionals or contact 1-866-458-6389.

What are the ingredients in GLUMETZA?

Active Ingredient: 500 mg or 1000 mg of metformin HCL

Inactive Ingredient: Each 500 mg tablet contains coloring, hypromellose, magnesium stearate, microcrystalline cellulose and polyethylene oxide. Each 1000 mg tablet contains colloidal silicon dioxide, polyvinyl alcohol, crospovidone, glyceryl behenate, polyacrylate dispersion, hypromellose, talc, polyethylene glycol, titanium dioxide, simethicone emulsion, polysorbate and coloring. GLUMETZA 500 mg and 1000 mg tablets both utilize advanced, polymer-based, oral drug delivery systems, which allow delivery of metformin HCL to the upper GI tract.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

METFORMIN SUSTAINED-ACTION TABLET - ORAL

(met-FOR-min)

COMMON BRAND NAME(S): Fortamet, Glucophage XR, Glumetza

WARNING: Metformin can rarely cause a serious (sometimes fatal) condition called lactic acidosis. Stop taking metformin and seek immediate medical attention if you develop any of the following symptoms of lactic acidosis: unusual tiredness, severe drowsiness, chills, blue/cold skin, muscle pain, fast/difficult breathing, unusually slow/irregular heartbeat.

Lactic acidosis is more likely to occur in patients who have certain medical conditions, including kidney or liver disease, conditions that may cause a low oxygen blood level or poor circulation (e.g., severe congestive heart failure, recent heart attack, recent stroke), heavy alcohol use, a severe loss of body fluids (dehydration), X-ray or scanning procedures that require an injectable iodinated contrast drug, recent surgery, or a serious infection. Tell your doctor immediately if any of these conditions occur or if you notice a big change in your overall health. You may need to stop taking metformin temporarily. The elderly are also at higher risk, especially those older than 80 years who have not had kidney tests. (See also Side Effects and Precautions sections.)

USES: Metformin is used with a proper diet and exercise program to control high blood sugar in people with type 2 diabetes (non-insulin-dependent diabetes). Controlling high blood sugar helps prevent heart disease, strokes, kidney disease, blindness, circulation problems, and decreased sexual ability. Metformin belongs to the class of drugs known as biguanides. It works by helping to restore your body's proper response to the insulin you naturally produce, and by decreasing the amount of sugar that your liver makes and that your stomach/intestines absorb.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

Metformin may be used with lifestyle changes such as diet and exercise to prevent diabetes in people who are at high risk for becoming diabetic. It is also used in women with a certain disease of the ovaries (polycystic ovarian syndrome). By helping your body to respond better to insulin, metformin may decrease the risk of diabetes, make menstrual cycles more regular, and increase fertility.

HOW TO USE: Read the Patient Information Leaflet if available from your pharmacist before you start using metformin and each time you get a refill. If you have any questions, consult your doctor or pharmacist.

Take this medication by mouth, usually once daily with the evening meal or as directed by your doctor. Drink plenty of fluids while taking this medication unless otherwise directed by your doctor.

Swallow this medication whole. Do not crush, chew, or break the tablets. Doing so can destroy the long action of the drug and may increase side effects.

The dosage is based on your medical condition and response to therapy. Your doctor may direct you to take a low dose at first, gradually increasing the dose to lower the chance of side effects such as upset stomach. Your doctor will adjust your dose based on your blood sugar levels to find the best dose for you. Follow your doctor's directions carefully.

If you are already taking another anti-diabetic drug (e.g., chlorpropamide), follow your doctor's directions carefully for stopping/continuing the old drug and starting metformin.

Use this medication regularly in order to get the most benefit from it. Remember to use it at the same time each day.

Inform your doctor if your condition persists or worsens (e.g., blood sugar levels are high). It may take up to 2 weeks before the full benefit of this drug takes effect.

SIDE EFFECTS: See also Warning section.

Nausea, stomach upset, diarrhea, or a metallic taste in the mouth may occur at first as your body adjusts to the medication. If any of these effects persist or worsen, tell your doctor or pharmacist promptly. If stomach symptoms return later (after you are on the same dose for several days or weeks), tell your doctor immediately. Stomach symptoms that occur after the first days of your treatment may be a sign of lactic acidosis.

An empty tablet shell may appear in your stool. This is harmless.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

This medication does not usually cause low blood sugar (hypoglycemia). However, low blood sugar may occur, especially if you take other medications for diabetes, drink large amounts of alcohol, do unusually heavy exercise, or do not consume enough calories from food. Symptoms include cold sweat, blurred vision, dizziness, drowsiness, shaking, fast heartbeat, headache, fainting, tingling of the hands/feet, and hunger. It is a good habit to carry glucose tablets or gel to treat low blood sugar. If you don't have these reliable forms of glucose, rapidly raise your blood sugar by eating a quick source of sugar such as table sugar, honey, or candy, or drink fruit juice or non-diet soda. Tell your doctor about the reaction immediately. To help prevent low blood sugar, eat meals on a regular schedule, and do not skip meals. Check with your doctor or pharmacist to find out what you should do if you miss a meal.

Symptoms of high blood sugar (hyperglycemia) include thirst, increased urination, confusion, drowsiness, flushing, rapid breathing, and fruity breath odor. If these symptoms occur, tell your doctor immediately. Your dosage may need to be increased.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking metformin, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: kidney disease, liver disease, conditions that may cause a low level of oxygen in the blood or poor circulation (e.g., severe congestive heart failure, recent heart attack, recent stroke), metabolic acidosis (e.g., diabetic ketoacidosis), serious infection, severe loss of body fluids (dehydration).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: adrenal/pituitary gland problems, severe breathing problems (e.g., obstructive lung disease, severe asthma), blood problems (e.g., anemia, vitamin B12 deficiency), fertility problems (e.g., ovulation problems), alcohol use.

Before having surgery or any X-ray/scanning procedure using injectable iodinated contrast material, tell your doctor that you are taking this medication. You will need to temporarily stop this medication before the time of your surgery/procedure. Consult your doctor for further instructions.

You may experience blurred vision, dizziness, or drowsiness due to extremely low or high blood sugar levels. Use caution while driving, using machinery, or taking part in any other activity that requires clear vision and alertness.

Limit alcohol while using this medication to lower your risk of lactic acidosis.

It may be harder to control your blood sugar when your body is stressed (e.g., due to fever, infection, injury, or surgery). Consult your doctor because this may require a change in your treatment plan, medications, or blood sugar testing.

Kidney function declines as you grow older. This medication is removed by the kidneys. Therefore, elderly people may be at greater risk for side effects such as lactic acidosis or low blood sugar while using this drug.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor. Your doctor may substitute insulin for this drug during your pregnancy. Follow your doctor's instructions carefully.

This medication can cause changes in the menstrual cycle (promote ovulation) and increase the risk of becoming pregnant. Consult your doctor or pharmacist about the use of reliable birth control while using this medication.

It is not known whether this drug passes into breast milk. This drug could have undesirable effects on a nursing infant. Therefore, breast-feeding is not recommended while using this drug. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with them first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: drugs that may affect the kidney's ability to remove metformin from the body (e.g., cimetidine, cephalexin), "water pills"/diuretics (e.g., furosemide, thiazide diuretics such as hydrochlorothiazide).

Many drugs can affect your blood sugar levels, making it more difficult to control your blood sugar. Before you start, stop, or change any medication, talk with your doctor or pharmacist about how the medication may affect your blood sugar. Check your blood sugar levels regularly as directed by your doctor. Tell your doctor about the results and of any symptoms of high or low blood sugar. (See also Side Effects section.) Your doctor may need to adjust your anti-diabetic medication, exercise program, or diet.

Some medications (e.g., beta blockers such as propranolol) may mask the fast/pounding heartbeat you would usually feel when your blood sugar level falls too low (hypoglycemia). Other symptoms of low blood sugar such as dizziness, hunger, or sweating are unaffected by these drugs.

Check the labels on nonprescription/herbal products carefully. Some products may contain sugar/alcohol and may affect blood sugars. Ask your doctor or pharmacist about using these products safely.

Cimetidine is a nonprescription drug that is commonly used to treat extra stomach acid. Because it may interact with metformin, ask your pharmacist about other products to treat stomach acid.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Overdose can cause lactic acidosis and low blood sugar. Symptoms of overdose may include: rapid breathing, severe drowsiness, slow/irregular heartbeat.

NOTES: Do not share this medication with others.

You should attend a diabetes education program to learn more about diabetes and all the important aspects of its treatment, including meals/diet, exercise, personal hygiene, medications, and getting regular eye/foot/medical exams.

Keep all medical appointments. Laboratory and/or medical tests (e.g., liver and kidney function tests, fasting blood glucose, hemoglobin A1c, complete blood counts) should be performed periodically to check for side effects and monitor your response to therapy. Check your blood sugar levels regularly as directed.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store the US product between 68-77 degrees F (20-25 degrees C) away from light and moisture. Brief storage from 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.