Glumetza

Santarus, Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use GLUMETZA safely and effectively. See full prescribing information for GLUMETZAGLUMETZA (metformin hydrochloride extended-release tablets), 500 mg and 1000 mg Initial U.S. Approval: 1995 RECENT MAJOR CHANGESDosing and Administration: Inclusion of the 1000 mg tablet (3) 12/2007 BOXED WARNING WARNING: LACTIC ACIDOSIS See full prescribing information for complete boxed warning Lactic acidosis can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic insufficiency, renal impairment, and acute congestive heart failure. (5.1) Symptoms include malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap and elevated blood lactate. (5.1) If acidosis is suspected, discontinue GLUMETZA and hospitalize the patient immediately. (5.1) INDICATIONS AND USAGE GLUMETZA is a biguanide indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. (1) Important limitations of use: Not for treatment of type 1 diabetes or diabetic ketoacidosis. (1.1) DOSAGE AND ADMINISTRATION Administer once daily with the evening meal. (2) Individualize the dose based on effectiveness and tolerability, while not exceeding the maximum recommended daily dose of 2000 mg. (2) If naïve to metformin treatment, initiate with 500 mg daily. (2) Swallow whole. Never split, crush or chew. (2) DOSAGE FORMS AND STRENGTHSExtended Release Tablets, 500 mg and 1000 mg (3) CONTRAINDICATIONS Renal impairment (4) Metabolic acidosis, including diabetic ketoacidosis (4) Hypersensitivity to metformin hydrochloride (4) WARNINGS AND PRECAUTIONS Lactic acidosis: Warn against excessive alcohol intake. GLUMETZA is not recommended in hepatic impairment and is contraindicated in renal impairment. Ensure normal renal function before initiating and at least annually thereafter. (5.1) Temporarily discontinue in patients undergoing radiologic studies with intravascular administration of iodinated contrast materials or any surgical procedures necessitating restricted intake of food and fluids. (5.2) Vitamin B12 deficiency: Metformin may lower vitamin B12 levels. Monitor hematologic parameters annually. (5.6) Macrovascular outcomes: No conclusive evidence of macrovascular risk reduction with GLUMETZA or any other antidiabetic drug. (5.8) Side EffectsThe incidence and type of adverse reactions reported by >5% of patients for the combined GLUMETZA group versus placebo group are hypoglycemia, diarrhea, and nausea. (6) To report SUSPECTED ADVERSE REACTIONS, contact Santarus, Inc. at 1-888-778-0887 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Cationic drugs: May reduce metformin elimination. Use with caution in patients who are taking cationic medications eliminated by renal tubular secretion. (7.1) USE IN SPECIFIC POPULATIONS Pediatric Use: Safety and effectiveness in children younger than 18 years of age have not been established. (8.4) Geriatric Use: Caution should be used when prescribing GLUMETZA to elderly patients because reduced renal functions are associated with increasing age. (8.5)

FULL PRESCRIBING INFORMATION: CONTENTS*

• WARNING: Lactic Acidosis
• 1 GLUMETZA INDICATIONS AND USAGE
• 2 GLUMETZA DOSAGE AND ADMINISTRATION
  • 2.1 Recommended Dosing
• 3 DOSAGE FORMS AND STRENGTHS
• 4 GLUMETZA CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Lactic Acidosis
  • 5.2 Monitoring of Renal Function
  • 5.3 Hypoxic States
  • 5.4 Alcohol Intake
  • 5.5 Impaired Hepatic Function
  • 5.6 Vitamin B Levels
  • 5.7 Hypoglycemia
  • 5.8 Macrovascular Outcomes
• 6 GLUMETZA ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Laboratory Tests
• 7 DRUG INTERACTIONS
  • 7.1 Carbonic Anhydrase Inhibitors —
  • 7.2 Cationic Drugs —
  • 7.3 Drugs Affecting Glycemic Control —
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.2 Labor and Delivery
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
• 10 OVERDOSAGE
• 11 GLUMETZA DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.3 Pharmacokinetics
  • 12.4 Specific Populations
  • 12.5 Drug Interactions
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

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

Important Limitations of Use

GLUMETZA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

GLUMETZA should be taken once daily with the evening meal. The dosage of GLUMETZA must be individualized on the basis of both effectiveness and tolerability, while not exceeding the maximum recommended daily dose of 2000 mg. The starting dose of GLUMETZA in patients who are not currently taking metformin is 500 mg once daily, with the evening meal. The dose can be uptitrated in 500 mg increments no sooner than every 1-2 weeks if a higher dose of GLUMETZA is needed and there are no gastrointestinal adverse reactions.

If GLUMETZA is considered appropriate for a patient already receiving immediate-release metformin, the patient can be switched to GLUMETZA once daily at the same total daily dose, up to 2000 mg once daily.

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 that may resemble the original tablet. If a dose of GLUMETZA is missed, patients should be cautioned against taking two doses of 2000 mg the same day. Resume dosing as according to prescribing recommendations. (See PATIENT COUNSELING INFORMATION (17))

Patients treated with an insulin secretagogue or insulin

Co-administration of GLUMETZA with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.

3 DOSAGE FORMS AND STRENGTHS

GLUMETZA (metformin hydrochloride extended-release 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 (metformin hydrochloride extended-release tablets) 1000 mg are available as white, film coated, oval-shaped tablets with “M1000” on one side.

4 CONTRAINDICATIONS

GLUMETZA is contraindicated in patients with:

• Renal impairment (e.g., serum creatinine levels ≥ 1.5 mg/dL for men, ≥ 1.4 mg/dL for women or abnormal creatinine clearance), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia. (See WARNINGS AND PRECAUTIONS (5))
• Known hypersensitivity to metformin hydrochloride.
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin.

5 WARNINGS AND PRECAUTIONS

5.1 Lactic Acidosis

Lactic acidosis is a serious, metabolic complication that can occur due to metformin accumulation during treatment with GLUMETZA and 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 concentrations (>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 μg/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is 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 impairment, 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, particularly when accompanied by hypoperfusion and hypoxemia due to unstable or acute failure, 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 GLUMETZA. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. GLUMETZA treatment should not be initiated in any patient unless measurement of creatinine clearance demonstrates that renal function is not reduced. In addition, GLUMETZA 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, GLUMETZA should generally be avoided in patients with clinical or laboratory evidence of hepatic impairment. Patients should be cautioned against excessive alcohol intake when taking GLUMETZA, because alcohol potentiates the effects of metformin on lactate metabolism. In addition, GLUMETZA should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure necessitating restricted intake of food or fluids. Use of topiramate, a carbonic anhydrase inhibitor, in epilepsy and migraine prophylaxis may frequently cause dose-dependent metabolic acidosis (In controlled trials, 32% and 67% for adjunctive treatment in adults and pediatric patients, respectively, and 15 to 25% for monotherapy of epilepsy, with decrease in serum bicarbonate to less than 20 mEq/L; 3% and 11% for adjunctive treatment in adults and pediatric patients, respectively, and 1 to 7% for monotherapy of epilepsy, with decrease in serum bicarbonate to less than 17 mEq/L) and may exacerbate the risk of metformin-induced lactic acidosis. (See 7.1 Drug Interactions and 12.5 Clinical Pharmacology) 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.

Patients should be educated to promptly report these symptoms should they occur. If present, GLUMETZA should be withdrawn until lactic acidosis is ruled out. Serum electrolytes, ketones, blood glucose, blood pH, lactate levels, and blood metformin levels may be useful. Once a patient is stabilized on any dose level of GLUMETZA, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to recur. 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 GLUMETZA 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. 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 GLUMETZA, 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 CONTRAINDICATIONS (4))

5.2 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 renal impairment. Therefore GLUMETZA is contraindicated in patients with renal impairment.

Before initiation of GLUMETZA and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated (e.g., elderly), renal function should be assessed more frequently and GLUMETZA discontinued if evidence of renal impairment is present. 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.

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 DRUG INTERACTIONS (7)), should be used with caution.

Radiological studies and surgical procedures:

Radiologic studies involving the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography) can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin. 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.

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.

5.3 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.

5.4 Alcohol Intake

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

5.5 Impaired Hepatic Function

Because 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.

5.6 Vitamin B 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. 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.

5.7 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.

5.8 Macrovascular Outcomes

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

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

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 monotherapy trial comparing GLUMETZA to immediate-release metformin, serious adverse reactions 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. In the add-on to sulfonylurea study, patients receiving background glyburide 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 and glyburide and 144 patients received placebo and glyburide. A serious adverse reaction was reported in 2.1% (9/431) of the GLUMETZA and glyburide-treated patients compared to 1.4% (2/144) of the placebo and glyburide-treated patients. When the data from the monotherapy and add-on to sulfonylurea clinical trials were combined, the most frequently (incidence ≥ 0.5 %) reported serious adverse reactions 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 reactions (unstable angina [n=2] and pancreatitis [n=2]) were reported in more than one GLUMETZA-treated patient.

Adverse reactions reported in greater than 5% of patients treated with GLUMETZA that were more common in the combined GLUMETZA and glyburide group than in the placebo and glyburide group are shown in Table 1.

In 0.7% of patients treated with GLUMETZA and glyburide, diarrhea was responsible for discontinuation of study medication compared to no patients in the placebo and glyburide group.

6.2 Laboratory Tests

Vitamin B ₁₂ concentrations

Metformin may lower serum vitamin B₁₂ concentrations. 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 WARNINGS AND PRECAUTIONS (5.6))

7 DRUG INTERACTIONS

7.1 Carbonic Anhydrase Inhibitors —

Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently decrease serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs may induce metabolic acidosis. Use these drugs with caution in patients treated with metformin, as the risk of lactic acidosis may increase.

7.2 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. 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.

7.3 Drugs Affecting Glycemic Control —

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 blockers, 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.

8 USE IN SPECIFIC POPULATIONS

8.1 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.

8.2 Labor and Delivery

The safety and effectiveness of GLUMETZA used during labor and delivery has not been evaluated in human studies.

8.3 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.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established. GLUMETZA is not recommended in pediatric patients below the age of 18 years.

8.5 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 and the higher risk of lactic acidosis. (See WARNINGS AND PRECAUTIONS (5))

10 OVERDOSAGE

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.

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 AND PRECAUTIONS (5.1)) Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

11 DESCRIPTION

GLUMETZA (metformin hydrochloride) extended release tablet is an oral antihyperglycemic medication 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 mg and 1000 mg tablets are formulated to gradually release metformin to the upper gastrointestinal (GI) tract.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Metformin is a biguanide that improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not produce hypoglycemia in patients with type 2 diabetes or in healthy subjects except in special circumstances, (see WARNINGS AND PRECAUTIONS (5)) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and daylong plasma insulin response may actually decrease.

12.3 Pharmacokinetics

Absorption

Following a single oral dose of 1000 mg (2x500 mg tablets) GLUMETZA after a meal, the time to reach maximum plasma metformin concentration (T_max) 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 C_max, 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.

Single oral doses of GLUMETZA from 500 mg to 2500 mg resulted in less than proportional increase in both AUC and C_max. 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 T_max by approximately 3 hours but C_max 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 C_max and AUCs for the two formulations.

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 5μg/mL, even at maximum doses.

Metabolism

Intravenous single-dose studies in healthy 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. Metabolism studies with extended-release metformin tablets have not been conducted.

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.

12.4 Specific Populations

Renal Impairment: Following a single dose administration of GLUMETZA 500 mg 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 AND PRECAUTIONS (5)). Metformin peak and systemic exposure was 27% and 61% greater, respectively in mild renal impaired and 74% and 2.36-fold greater in moderate renal impaired patients as compared to healthy subjects. Use of metformin in patients with renal impairment increases the risk for lactic acidosis. GLUMETZA is contraindicated in patients with renal impairment. (See CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS (5.2))

Hepatic Impairment: No pharmacokinetic studies of GLUMETZA have been conducted in subjects with hepatic impairment. Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. GLUMETZA is not recommended in patients with hepatic impairment. (See WARNINGS AND PRECAUTIONS (5.5))

Geriatrics: Limited data from controlled pharmacokinetic studies of metformin hydrochloride in healthy elderly subjects suggest that total plasma clearance of metformin is decreased by 35%, the half-life is prolonged by 64% and C_max is increased by 76%, 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. Metformin treatment should not be initiated in patients of any age unless measurement of creatinine clearance demonstrates that renal function is normal. (See WARNINGS AND PRECAUTIONS (5) and DOSAGE AND ADMINISTRATION (2))

Gender: In the pharmacokinetic studies in healthy volunteers, there were no important differences between male and female subjects with respect to metformin AUC and t1/2. However, C_max for metformin was 40% higher in female subjects as compared to males. The gender differences for C_max 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 C_max 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.

12.5 Drug Interactions

Specific pharmacokinetic drug interaction studies with GLUMETZA have not been performed except for one with glyburide. However, such studies have been performed on metformin.

13 NONCLINICAL TOXICOLOGY

13.1 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 lymphocytes) 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.

14 CLINICAL STUDIES

GLUMETZA has been studied as monotherapy and in combination with a sulfonylurea and insulin. Other formulations of metformin have been studied with other classes of antihyperglycemic agents, either as immediate or as extended release tablets.

Double-Blind, Randomized, Parallel Group Clinical Trial to Compare the Efficacy, Safety, and Tolerability of Metformin ER (M-ER) Tablets and Metformin Immediate Release (M-IR) Tablets in the Treatment of Type 2 Diabetes Mellitus

In a multicenter, randomized, double-blind, active-controlled, dose-ranging, parallel group trial GLUMETZA 1500 mg once daily, GLUMETZA 1500 per day in divided doses (500 mg in the morning and 1000 mg in the evening), and GLUMETZA 2000 mg once daily were compared to immediate-release metformin 1500 mg per day in divided doses (500 mg in the morning and 1000 mg in the evening). This trial enrolled patients (n = 338) who were newly diagnosed with diabetes, patients treated only with diet and exercise, patients treated with a single anti-diabetic medication (sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, or meglinitides ), and patients (n = 368) receiving metformin up to 1500 mg/day plus a sulfonylurea at a dose equal to or less than one-half the maximum dose. Patients who were enrolled on monotherapy or combination anti-diabetic therapy underwent a 6-week washout. Patients randomized to GLUMETZA began titration from 1000 mg/day up to their assigned treatment dose over 3 weeks. Patients randomized to immediate-release metformin initiated 500 mg twice daily 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. For HbA_1c and fasting plasma glucose, each of the GLUMETZA regimens was at least as effective as immediate-release metformin. Additionally, once daily dosing of GLUMETZA was as effective as twice daily dosing of the immediate release metformin formulation.

A Double-Blind, Randomized, Parallel-Group Study to Compare the Safety, Efficacy, and Tolerability of Metformin Extended Release (M-ER) Tablets in Combination with a Sulfonylurea (SU) and SU Alone in the Management of Patients with Type 2 Diabetes Mellitus

In a double-blind, randomized, placebo-controlled (glyburide add-on) multicenter trial, patients with type 2 diabetes mellitus who were newly diagnosed or treated with diet and exercise (n = 144), 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) (n = 431) were enrolled. All patients were stabilized on glyburide for a 6-week run-in 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. Use of insulin and oral hypoglycemic agents other than the study drugs were prohibited. The difference in the change from Baseline in HbA_1c levels between the combined GLUMETZA + glyburide groups and the glyburide only group was statistically significant at week 24 (p<0.001). The changes in glycemic control across the three GLUMETZA+glyburide groups were comparable.

A 24-week, double-blind, placebo-controlled trial 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 mean reduction in HbA_1c of 2.10%, compared to a 1.56% reduction in HbA_1c 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.

16 HOW SUPPLIED/STORAGE AND HANDLING

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:

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

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling.

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, and hemoglobin A_1c. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be advised to seek medical advice promptly.

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 recur. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

Patients should be advised to notify their health practitioner or call the Poison Control Center immediately in case of GLUMETZA overdose.

Patients should be informed about the importance of regular testing of renal function and hematological parameters when receiving treatment with GLUMETZA.

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 insulin secretagogues, such as sulfonylureas and insulin.

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.

Manufactured for Santarus, Inc., San Diego, CA 92130 • 1-888-778-0887.

500 mg product:  U.S. Patent Nos. 6,340,475, 6,488,962, 6,635,280, and 6,723,340.

1000 mg product: U.S. Patent Nos. 6,488,962, 7,780,987, and 8,323,692.

SANTARUS_,INC. ^®

© 2013 Santarus, Inc.

S-0055B

FDA-APPROVED PATIENT LABELING

GLUMETZA (Gloo-met-za)

(metformin hydrochloride extended-release tablets)

Read the patient information that comes with GLUMETZA 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 talking with your doctor about your medical condition or treatment. 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?

Serious side effects can happen in people taking GLUMETZA, including:

Lactic Acidosis. Metformin hydrochloride, the medicine in 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 any of the following symptoms of lactic acidosis:

• feel very weak or tired
• have unusual (not normal) muscle pain
• have trouble breathing
• have unusual sleepiness or sleep longer than usual
• have unexplained stomach or intestinal problems with nausea and vomiting, or diarrhea
• feel cold, especially in your arms and legs
• feel dizzy or lightheaded
• have a slow or irregular heartbeat

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

• have kidney problems. People whose kidneys are not working properly should not take GLUMETZA.
• have 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 do not drink enough fluids.
• have certain x-ray tests with injectable dyes or contrast agent
• have surgery
• have a heart attack, severe infection, or stroke

What is GLUMETZA?

• GLUMETZA is a prescription medicine that contains metformin hydrochloride used with diet and exercise to help control high blood sugar in adults with type 2 diabetes.
• GLUMETZA is not for people with type 1 diabetes.
• GLUMETZA is not for people with diabetic ketoacidosis (increased ketones in your blood or urine).

It is not known if GLUMETZA is safe and effective in children younger than 18 years old.

Who should not take GLUMETZA?

Do not take GLUMETZA if you:

• have kidney problems
• are allergic to the metformin hydrochloride in GLUMETZA or any of the ingredients in GLUMETZA. See the end of this leaflet for a list of ingredients in GLUMETZA.
• you are going to get an injection of dye or contrast agents for an x-ray procedure, GLUMETZA will need to be stopped for a short time. Talk to your doctor about when you should stop GLUMETZA and when you should start GLUMETZA again. See “What is the most important information I should know about GLUMETZA?”
• have a condition called metabolic acidosis or diabetic ketoacidosis (increased ketones in your blood or urine).

What should I tell my doctor before taking GLUMETZA?

Before you take GLUMETZA, tell your doctor if you:

• have type 1 diabetes. GLUMETZA should not be used to treat people with type 1 diabetes.
• have a history or risk for diabetic ketoacidosis (high levels of certain acids, known as ketones, in the blood or urine). GLUMETZA should not be used for the treatment of diabetic ketoacidosis.
• have kidney problems
• have liver problems
• have heart problems, including congestive heart failure.
• drink alcohol very often, or drink a lot of alcohol in short-term (binge) drinking
• are taking insulin
• have any other medical conditions
• are pregnant or planning to become pregnant. It is not known if GLUMETZA can harm your unborn baby. If you are pregnant, talk with your doctor about the best way to control your blood sugar while you are pregnant.
• are breastfeeding or plan to breastfeed. It is not known if GLUMETZA passes into your breast milk. Talk with your doctor about the best way to feed your baby while you take GLUMETZA.

Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins and herbal supplements. Know the medicines you take. Keep a list of them to show your doctor and pharmacist. Talk to your doctor before you start any new medicine.

GLUMETZA may affect the way other medicines work, and other medicines may affect how GLUMETZA works.

How should I take GLUMETZA?

• Take GLUMETZA exactly as your doctor tells you.
• GLUMETZA should be taken 1 time per day with your evening meal.
• Swallow GLUMETZA tablets whole. Do not crush, cut, dissolve, or chew GLUMETZA.
• Tell your doctor if you cannot swallow tablets whole. Your doctor may prescribe a different medicine for you.
• You may sometimes pass a soft mass in your stools (bowel movement) that looks like GLUMETZA tablets. It is normal to see this in your stool.
• When your body is under some type of stress, such as fever, trauma (such as a car accident), infection, or surgery, the amount of diabetes medicine that you need may change. Tell your doctor right away if you have any of these problems.
• Your doctor should do blood tests to check how well your kidneys and liver are working before and during your treatment with GLUMETZA.
• Your healthcare provider will check your diabetes with regular blood tests, including your blood sugar levels and your hemoglobin A_1C.
• Follow your doctor's instructions for treating blood sugar that is too low (hypoglycemia). Talk to your doctor if low blood sugar is a problem for you. See “What are the possible side effects of GLUMETZA?”
• Check your blood sugar regularly and as your doctor tells you to.
• Stay on your prescribed diet and exercise program and test your blood sugar regularly while taking GLUMETZA.
• If you miss a dose of GLUMETZA, resume dosing according to schedule.
• If you take too much GLUMETZA, call your doctor, or go to the nearest hospital emergency room right away.

What are the side effects of GLUMETZA?

GLUMETZA can cause serious side effects, including:

• See “ What is the most important information I should know about GLUMETZA?”
• Low blood sugar (hypoglycemia). If you take GLUMETZA with another medicine that can cause low blood sugar, such as sulfonylureas or insulin, you have a higher risk of having low blood sugar. Tell your doctor if you take other diabetes medicines. If you have symptoms of low blood sugar, you should check your blood sugar and treat if low, then call your doctor. Symptoms of low blood sugar include:
  • shaking
  • sweating
  • rapid heartbeat
  • change in vision
  • hunger
  • headache
  • change in mood

Common side effects of GLUMETZA include:

• hypoglycemia
• diarrhea
• nausea
• upset stomach or stomach pain

Taking GLUMETZA with your evening meal can help lessen the common stomach side effects of metformin that usually happens at the beginning of treatment. If you have unexplained stomach problems, tell your doctor. Stomach problems that start later, during treatment may be a sign of something more serious.

Tell your doctor if these symptoms return, as they may be symptoms of lactic acidosis.

Tell your doctor if you have side effects that bother you or that do not go away.

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

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store GLUMETZA?

• Store GLUMETZA at 59°F to 86°F (15°C to 30°C).

Keep GLUMETZA and all medicines out of the reach of children.

General information about the safe and effective use of GLUMETZA.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. 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 Patient Information summarizes the most important information about GLUMETZA. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about GLUMETZA that is written for health professionals.

For more information, go to www.GlumetzaXR.com or call 1-888-778-0887.

What are the ingredients in GLUMETZA?

Active Ingredient: metformin hydrochloride

Inactive Ingredient: 500 mg tablet: coloring, hypromellose, magnesium stearate, microcrystalline cellulose and polyethylene oxide.

1000 mg tablet: colloidal silicon dioxide, polyvinyl alcohol, crospovidone, glyceryl behenate, polyacrylate dispersion, hypromellose, talc, polyethylene glycol, eudragit, titanium dioxide, simethicone emulsion, polysorbate and coloring.

What is type 2 diabetes?

Type 2 diabetes is a condition in which your body does not make enough insulin, and the insulin that your body produces does not work as well as it should. Your body can also make too much sugar. When this happens, sugar (glucose) builds up in the blood. This can lead to serious medical problems.

The main goal of treating diabetes is to lower your blood sugar to a normal level.

High blood sugar can be lowered by diet and exercise, and by certain medicines when necessary.

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

Santarus, Inc.
San Diego, CA 92130
1-888-778-0887
www.GlumetzaXR.com
For prescription only

Revised January 2013

©2013 Santarus, Inc.

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL 500MG

100 Tablets

NDC 68012-002-13

Glumetza ®

(metformin hydrochloride

extended-release tablets)

500mg

ONCE DAILY

Rx Only

Santarus, Inc. ®