About The Drug Metformin Hcl aka Fortamet

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Metformin Hcl

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About Metformin Hcl aka Fortamet

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Clinical Pharmacology

CLINICAL PHARMACOLOGY 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) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease [see WARNINGS AND PRECAUTIONS]. Pharmacokinetics Absorption and Bioavailability Two pharmacokinetic studies have been performed in healthy volunteers to evaluate the bioavailability of Riomet in comparison with the commercially available metformin tablets under fasting and fed conditions (study 1 and study 2). A third pharmacokinetic study (study 3) assessed effects of food on absorption of Riomet. The rate and extent of absorption of Riomet was found to be comparable to that of Metformin tablets under fasting or fed conditions (see Table 2). Table 2: Select Mean (± S.D.) Pharmacokinetic Parameters Following Single Oral Doses of 1000 mg Riomet and Metformin tablets in healthy, nondiabetic adults (n = 36) under fed and fasting conditions Formulation Cmax (ng/mL) AUC0-∞ (ng•h/mL) tmax (h) Study 1- Fasting state Riomet 1540.1 + 451.1 9069.6 + 2593.6 2.2 + 0.5 Metformin Tablets 1885.1 + 498.5 11100.1 + 2733.1 2.5 + 0.6 T/R Ratio X 100 (90% confidence interval) 81.2 (76.3 - 86.4) 81.2 (76.9 - 85.6) - Study 2- Fed State Riomet 1235.3 + 177.7 8950.1 + 1381.2 4.1 + 0.8 Metformin Tablets 1361 + 298.8 9307.7 + 1839.8 3.7 + 0.8 T/R Ratio X 100 (90% confidence interval) 91.8 (87.4 - 96.5) 97.0 (92.9 - 101.2) - T-test product (Riomet) R-reference product (metformin tablets) The food-effect study (study 3) assessed the effects of a high fat/high calorie meal and a low fat/low calorie meal on the bioavailability of Riomet in comparison with administration in the fasted state, in healthy volunteers. The extent of absorption was increased by 21% and 17% with the low fat/low calorie meal and the high fat/high calorie meal, respectively, compared with the administration in the fasted state. The rate and extent of absorption with high fat/high calorie and low fat/ low calorie meal were similar. The mean tmax was 2.5 hours under fasting conditions as compared to 3.9 hours with both low fat/ low calorie meal and high fat/high calorie meals (see Table 3). Table 3: Select Mean (± S.D.) Metformin Pharmacokinetic Parameters Following Single Oral Doses of 1000 mg Riomet in healthy, nondiabetic adults (n = 33) under fed (high fat/high calorie meal and low fat/low calorie meal) and fasting conditions (study 3) Meal type C vmax (ng/mL) AUC0-∞ (ng•h/mL) tmax (h) Fasting (F) 1641.5 + 551.8 9982.9 + 2544.5 2.5 + 0.9 Low fat/ low calorie meal (L) 1525.8 + 396.7 11542.0 + 2947.5 3.9 + 0.6 High fat/high calorie meal (H) 1432.5 + 346.8 11184.5 + 2446.1 3.9 + 0.8 L/F Ratio X 100 (90% confidence interval) 94.6 (84.0 - 106.5) 115.6 (103.6 - 128.9) - H/F Ratio X 100 (90% confidence interval) 89.4 (79.4 - 100.6) 112.6 (100.9 - 125.6) - L/H Ratio X 100 (90% confidence interval) 105.8 (94.0 -119.2) 102.7 (92.0 -114.6) - Studies using single oral doses of metformin tablet formulations 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Distribution The apparent volume of distribution (V/F) of metformin following single oral doses of metformin 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. 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 to 48 hours and are generally < 1 μg/mL. During controlled clinical trials of metformin, maximum metformin plasma levels did not exceed 5 μg/mL, even at maximum doses. Metabolism and Elimination 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 (see Table 4) is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. Special Populations Patients with Type 2 Diabetes In the presence of normal renal function, there are no differences between single- or multiple-dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects (see Table 4), nor is there any accumulation of metformin in either group at usual clinical doses. Renal Insufficiency In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (see Table 4) [see WARNINGS AND PRECAUTIONS]. Hepatic Insufficiency No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency. Geriatrics Limited data from controlled pharmacokinetic studies of metformin 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 Table 4). Riomet (metformin hydrochloride oral solution) 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 PRECAUTIONS and DOSAGE AND ADMINISTRATION]. Table 4: Select Mean (± S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin Subject Groups: Metformin dosea (number of subjects) Cmaxb (μg/mL) Tmax c (hrs) Renal Clearance (mL/min) Healthy, nondiabetic adults: 500 mg single dose (24) 1.03 (± 0.33) 2.75 (± 0.81) 600 (± 132) 850 mg single dose (74)d 1.60 (± 0.38) 2.64 (± 0.82) 552 (± 139) 850 mg three times daily for 19 dosese (9) 2.01 (± 0.42) 1.79 (± 0.94) 642 (± 173) Adults with type 2 diabetes: 850 mg single dose (23) 1.48 (± 0.5) 3.32 (± 1.08) 491 (± 138) 850 mg three times daily for 19 dosese (9) 1.90 (± 0.62) 2.01 (± 1.22) 550 (± 160) Elderlyf, healthy nondiabetic adults: 850 mg single dose (12) 2.45 (± 0.70) 2.71 (± 1.05) 412 (± 98) Renally-impaired adults: 850 mg single dose Mild (CLcrg 61 - 90mL/min) (5) 1.86 (± 0.52) 3.20 (± 0.45) 384 (± 122) Moderate (CLcr 31 - 60mL/min) (4) 4.12 (± 1.83) 3.75 (± 0.50) 108 (± 57) Severe (CLcr 10 - 30mL/min) (6) 3.93 (± 0.92) 4.01 (± 1.10) 130 (± 90) a-All doses given fasting except the first 18 doses of the multiple dose studies b-Peak plasma concentration c-Time to peak plasma concentration d-Combined results (average means) of five studies: mean age 32 years (range 23 -59 years) e-Kinetic study done following dose 19, given fasting f-Elderly subjects, mean age 71 years (range 65 -81 years) g-CLcr = creatinine clearance normalized to body surface area of 1.73 m² Pediatrics After administration of a single oral metformin 500 mg dose with food, geometric mean metformin Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 45 years of age), all with normal renal function. Gender Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males = 19, females = 16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females. Race No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n = 249), blacks (n = 51), and Hispanics (n = 24). Clinical Studies In a double-blind, placebo-controlled, multicenter U.S. clinical trial involving obese patients with type 2 diabetes whose hyperglycemia was not adequately controlled with dietary management alone (baseline fasting plasma glucose [FPG] of approximately 240 mg/dL), treatment with metformin (up to 2550 mg/day) for 29 weeks resulted in significant mean net reductions in fasting and postprandial plasma glucose (PPG) and hemoglobin A1c (HbA1c) of 59 mg/dL, 83 mg/dL, and 1.8%, respectively, compared to the placebo group (see Table 5). Table 5: Metformin vs Placebo Summary of Mean Changes from Baseline* in Fasting Plasma Glucose, HbA1c, Weight, at Final Visit (29-week study) Metformin (n = 141) Placebo (n = 145) p-Value FPG (mg/ dL) Baseline 241.5 237.7 NS** Change at FINAL VISIT -53.0 6.3 0.001 Hemoglobin A1c (%) Baseline 8.4 8.2 NS** Change at FINAL VISIT -1.4 0.4 0.001 Body Weight (lbs) Baseline 201.0 206.0 NS** Change at FINAL VISIT -1.4 -2.4 NS** *-All patients on diet therapy at Baseline **-Not statistically significant A 29-week, double-blind, placebo-controlled study of metformin and glyburide, alone and in combination, was conducted in obese patients with type 2 diabetes who had failed to achieve adequate glycemic control while on maximum doses of glyburide (baseline FPG of approximately 250 mg/dL) (see Table 6). Patients randomized to the combination arm started therapy with metformin 500 mg and glyburide 20 mg. At the end of each week of the first four weeks of the trial, these patients had their dosages of metformin increased by 500 mg if they had failed to reach target fasting plasma glucose. After week four, such dosage adjustments were made monthly, although no patient was allowed to exceed metformin 2500 mg. Patients in the metformin only arm (metformin plus placebo) followed the same titration schedule. At the end of the trial, approximately 70% of the patients in the combination group were taking metformin 2000 mg/glyburide 20 mg or metformin 2500 mg/glyburide 20 mg. Patients randomized to continue on glyburide experienced worsening of glycemic control, with mean increases in FPG, PPG, and HbA1c of 14 mg/dL, 3 mg/dL, and 0.2%, respectively. In contrast, those randomized to metformin (up to 2500 mg/day) experienced a slight improvement, with mean reductions in FPG, PPG, and HbA1c of 1 mg/dL, 6 mg/dL, and 0.4%, respectively. The combination of metformin and glyburide was effective in reducing FPG, PPG, and HbA1c levels by 63 mg/dL, 65 mg/dL, and 1.7%, respectively. Compared to results of glyburide treatment alone, the net differences with combination treatment were -77 mg/dL, -68 mg/dL, and -1.9%, respectively (see Table 6). Table 6: Combined Metformin/Glyburide (Comb) vs Glyburide (Glyb) or Metformin (Met) Monotherapy: Summary of Mean Changes from Baseline* in Fasting Plasma Glucose, HbA1c, and Body Weight, at Final Visit (29-week study) Comb (n = 213) Glyb (n = 209) Met (n = 210) p-values Glyb vs Comb Met vs Comb Met vs Glyb Fasting Plasma Glucose (mg/dL) Baseline 250.5 247.5 253.9 NS** NS** NS** Change at FINAL VISIT -63.5 13.7 -0.9 0.001 0.001 0.025 Hemoglobin A1c (%) Baseline 8.8 8.5 8.9 NS** NS** 0.007 Change at FINAL VISIT -1.7 0.2 -0.4 0.001 0.001 0.001 Body Weight (lbs) Baseline 202.2 203.0 204.0 NS** NS** NS** Change at FINAL VISIT 0.9 -0.7 -8.4 0.011 0.001 0.001 *-All patients on glyburide, 20 mg/day, at Baseline; **-Not statistically significant The magnitude of the decline in fasting blood glucose concentration following the institution of metformin therapy was proportional to the level of fasting hyperglycemia. Patients with type 2 diabetes with higher fasting glucose concentrations experienced greater declines in plasma glucose and glycosylated hemoglobin. In clinical studies, metformin, alone or in combination with a sulfonylurea, lowered mean fasting serum triglycerides, total cholesterol, and LDL cholesterol levels and had no adverse effects on other lipid levels (see Table 7). Table 7: Summary of Mean Percent Change from Baseline of Major Serum Lipid Variables at Final Visit (29-week studies) Metformin vs Placebo Combined Metformin/ Glyburide vs Monotherapy Metformin (n = 141) Placebo (n = 145) Metformin (n = 210) Metformin/ Glyburide (n = 213) Glyburide (n = 209) Total Cholesterol (mg/dL) Baseline 211.0 212.3 213.1 215.6 219.6 Mean % Change at FINAL VISIT -5% 1% -2% -4% 1% Total Triglycerides (mg/dL) Baseline 236.1 203.5 242.5 215.0 266.1 Mean % Change at FINAL VISIT -16% 1% -3% -8% 4% LDL-Cholesterol (mg/dL) Baseline 135.4 138.5 134.3 136.0 137.5 Mean % Change at FINAL VISIT -8% 1% -4% -6% 3% HDL-Cholesterol (mg/dL) Baseline 39.0 40.5 37.2 39.0 37.0 Mean % Change at FINAL VISIT 2% -1% 5% 3% 1% In contrast to sulfonylureas, body weight of individuals on metformin tended to remain stable or even decrease somewhat (see Tables 5 and 6). A 24-week, double-blind, placebo-controlled study of 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 (see Table 8). Patients randomized to receive metformin plus insulin achieved a reduction in HbA1c 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. Table 8: Combined Metformin/Insulin vs Placebo/Insulin Summary of Mean Changes from Baseline in HbA1c and Daily Insulin Dose Metformin/ Insulin (n = 26) Placebo/ Insulin (n = 28) Treatment Difference Mean ± SE Hemoglobin A1c (%) Baseline 8.95 9.32 Change at FINAL VISIT -2.10 -1.56 -0.54 ± 0.43a Insulin Dose (U/day) Baseline 93.12 94.64 Change at FINAL VISIT -0.15 15.93 -16.08 ± 7.77b a Statistically significant using analysis of covariance with baseline as covariate (p = 0.04). Not significant using analysis of variance (values shown in table) b- Statistically significant for insulin (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 HbA1c 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. Pediatric Clinical Studies In a double-blind, placebo-controlled study in pediatric patients aged 10 to 16 years with type 2 diabetes (mean FPG 182.2 mg/dL), treatment with metformin (up to 2000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks) resulted in a significant mean net reduction in FPG of 64.3 mg/dL, compared with placebo (see Table 9). Table 9: Metformin vs Placebo (Pediatricsa) Summary of Mean Changes from Baseline* in Plasma Glucose and Body Weight at Final Visit FPG (mg/dL) Metformin (n = 37) Placebo (n = 36) p-value Baseline 162.4 192.3 Change at FINAL VISIT -42.9 21.4 < 0.001 Body Weight (lbs) (n = 39) (n = 38) Baseline 205.3 189.0 Change at FINAL VISIT -3.3 -2.0 NS** a-Pediatric patients mean age 13.8 years (range 10 - 16 years) *- All patients on diet therapy at Baseline **-Not statistically significant

Clinical Pharmacology

CLINICAL PHARMACOLOGY 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) 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 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. Single oral doses of GLUMETZA from 500 mg to 2500 mg resulted in less than proportional increase in both AUC and Cmax. 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. 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. 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). 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 and WARNINGS AND PRECAUTIONS) 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) 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 Cmax 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 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 and t½. However, Cmax for metformin was 40% higher in female subjects as compared to males. 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. 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. Co- administered Drug Dose of Coadministered Drug1 Dose of .Metformin1 Geometric Mean Ratio (ratio with without coadministered drug) No effect = 1.00 AUC2 Cmax No dosing adjustments required for the following: Glybunde 5 mg 500 mg4 0.983 0.993 Furosemide 40 mg 850 mg 1.093 1.223 Nifedipine 10 mg 850 mg 1.16 1.21 Propranolol 40 mg 850 mg 0.90 0.94 Ibuprofen 400 mg 850 mg 1.053 1.073 Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination: use with caution. (See WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS) Cunetidme 400 mg 850 mg 1.40 1.61 C arbonic anhydrase inhibitors may cause metabolic acidosis: use with caution (See WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS) Topiramate 100 mg5 500 mg5 1.255 1.17 1 All metformin and coadministered drugs were given as single doses 2.AUC-AUC0-∞ 3. Ratio of anthmetic means 4. GLUMETZA (metformin hydrochloride extended-release tablets) 500 me 5. At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours: AUC “ AUC0-12h Table 3: Effect of Metformin on Coadministered Drug Systemic Exposure Coadminister ed Drug Dose of Coadministered Drug1 Dose of Metformin1 Geometric Mean Ratio (ratio trith without coadministered drug) No effect - 1.00 AUC2 Cmax No dosing adjustments required for the following Glybunde 5 mg 500 mg4 0.783 0.633 Furosemide 40 mg 850 mg 0.873 0.693 Nifedipine 10 mg 850 mg 1.104 1.08 Propranolol 40 mg 850 mg 1.014 0.94 Ibuprofen 400 mg 850 mg 0.975 1.015 Cimendine 400 mg 850 mg 0.954 1.01 1 All metformin and coadministered drug were given as single doses 2 AUC – AUC0-∞ 3 Ratio of anthmetic means, p-value of difference < 0 05 4 AUC0-24hr reported 5 Ratio of anthmetic means 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, activecontrolled, dose-ranging, parallel group trial GLUMETZA 1500 mg once daily, GLUMETZA 1500mg 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 antidiabetic 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 1week 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 HbA1c 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. Table 4: Mean±SE Changer from Barline to Final Visit in  HbA1c, Fasting Plasma Glucose and Body Weight for the GLUMETZA and Metformin Immediate-Release Treatment Groups (First 24-Week Study) Parameter GLUMETZA Metformin immediate- release 1500 mg in dhided doses (n=174) 1500 mg once daily (n= 178) 1500 mg in dhided doses (n =182) 2000 mg once daily (n = 172) HbA1c(%) N 169 175 159 170 Baseline 8.2 ± 03 8.5 ± 0.2 8.3 ± 0 2 8.7 ± 0.3 Mean Change ± SE at Final Visit -0.7 ±0.1 -0.7 ± 0.1 -1.1 ± 0.1 -0.7 ± 0.1 Mean Difference ± SE from Metformin IR 98 4% CI for Difference 0 ± 0.1 (-0.3,0.3) 0 ± 0.1 (-0 .3, 0.3) -0.4 ± 0.1 (-0.7, -0.1) N/A Fasting Plasma Glucose (mg dL) N 175 179 170 172 Baseline 190 ± 10 192.3 ± 10 184 ± 10 197 ± 11 Mean Change ± SE at Final Visit -39 ± 4 -32 ± 4 -42 ± 5 -32 ± 5 Mean Difference ± SE from Metformin IR 95% CI for Difference -6±4 (-15, 2) 0±4 (-8,9) -10 ± 4 (-19, -1) N/A Body Weight (kg) N 176 180 171 173 Baseline 88.2 ± 3.7 90.5 ± 3.7 87.7 ± 3 7 88.7 ± 3.9 Mean Change ± SE at Final Visit -0.9 ± 0.4 -0.7 ± 0.4 -1.1 ± 0.4 -0 9 ± 0 4 Mean Difference ± SE from Metformin IR 95% CI for Difference -0.1 ± 04 (-0.9,0.7) 0.2 ± 0.4 (-0.6, 0.9) -0.3 ± 0.4 (-1.0, 0.5) N/A 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, alphaglucosidase 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 HbA1c 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. Table 5: Mean±SE Changes from Baselie to Final Visit in HbA1c Fasting Plasma Glucose and Body Weight for the GLUMETZA/ Glyburide Groups and Placebo /Glyburide Treatment Group (Second 24-Week Study) Parameter GLUMETZA - Glyburide Placebo/ Ghbaridt* (n = 141) 1500 mg QD (n = 144) 1000 mg BID (n= 141) 2000 mg QD (n = 146) HbA(%) N 134 136 144 141 Baseline 7.9 ± 0.1 7.8 ± 0.1 7.7 ± 01 81 ± 0.1 Mean Change ± SE at Final Visit -0.7 ± 0.1 -0 8 ± 01 -0.7 ± 01 -0.1 ± 0.1 Mean Difference ± SE from Glyburide Alone -0.8 ± 0.1 -0.9 ± 0.1 -0.8 ± 0.1 N/A 95% CI for Difference (-1.0,-0.6) (-1.1, -0.7) (-1.0,- 0.6) p-value for pairwise comparison - 0 001 < 0.001 < 0.001 Fasting Pasma Glucose (mg/dL) N 143 141 145 144 Baseline 163 ± 5 163 ± 5 159 ± 5 164 ± 5 Mean Change± SE at Final Visit -14 ± 4 -16 ± 4 -9 ± 4 16 ± 4 Mean Difference± SE from Glyburide Alone -29.2 ± 4. 9 -31.2 ± 40.9 -24.9 ± 4.9 N/A 95% CI for Difference (-39,- 20) (41,-22) (-35,- 15) p-value for pairwise comparision < 0.001 < 0.001 < 0.001 Body Weight (kg) N 143 141 146 144 Baseline 89.4± 11.2 103.7± 11.2 102.9± 11.2 95.6± 8.0 Mean Change± SE at Final Visit 0.3 ± 1.1 0.1 ± 1.1 0 ± 1.1 0.7 ± 1.0 Mean Difference± SE from Glyburide Alone -0.4 ± 0.5 -0.6 ± 0.5 -0.7 ± 0.5 N/A 95% CI for Difference (-1.5, 0.6) (-1.7,0.4) (-1.8,0.3) p-value for pairwise comparision 0.410 0.230 0.154 * -Glyburide was administered as 10 mg at breakfast and 5mg at dinner. 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 HbA1c 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 HbA1c 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.

Clinical Pharmacology

CLINICAL PHARMACOLOGY 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 day-long plasma insulin response may actually decrease. Pharmacokinetics Absorption And Bioavailability The absolute bioavailability of a GLUCOPHAGE 500 mg tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of GLUCOPHAGE 500 to 1500 mg, and 850 to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown. Following a single oral dose of GLUCOPHAGE XR, Cmax is achieved with a median value of 7 hours and a range of 4 to 8 hours. Peak plasma levels are approximately 20% lower compared to the same dose of GLUCOPHAGE, however, the extent of absorption (as measured by AUC) is similar to GLUCOPHAGE. At steady state, the AUC and Cmax are less than dose proportional for GLUCOPHAGE XR within the range of 500 to 2000 mg administered once daily. Peak plasma levels are approximately 0.6, 1.1, 1.4, and 1.8 μg/mL for 500, 1000, 1500, and 2000 mg once-daily doses, respectively. The extent of metformin absorption (as measured by AUC) from GLUCOPHAGE XR at a 2000 mg once-daily dose is similar to the same total daily dose administered as GLUCOPHAGE tablets 1000 mg twice daily. After repeated administration of GLUCOPHAGE XR, metformin did not accumulate in plasma. Within-subject variability in Cmax and AUC of metformin from GLUCOPHAGE XR is comparable to that with GLUCOPHAGE. Although the extent of metformin absorption (as measured by AUC) from the GLUCOPHAGE XR tablet increased by approximately 50% when given with food, there was no effect of food on Cmax and Tmax of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of GLUCOPHAGE XR. Distribution The apparent volume of distribution (V/F) of metformin following single oral doses of GLUCOPHAGE 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of GLUCOPHAGE, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally < 1 μg/mL. During controlled clinical trials of GLUCOPHAGE, maximum metformin plasma levels did not exceed 5 μg/mL, even at maximum doses. Metabolism And Elimination 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 (see Table 1) 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 Patients with Type 2 Diabetes In the presence of normal renal function, there are no differences between single- or multiple-dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects (see Table 1), nor is there any accumulation of metformin in either group at usual clinical doses. The pharmacokinetics of GLUCOPHAGE XR in patients with type 2 diabetes are comparable to those in healthy normal adults. Renal Insufficiency In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (see Table 1; also see WARNINGS). Hepatic Insufficiency No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency. Geriatrics Limited data from controlled pharmacokinetic studies of GLUCOPHAGE 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 Table 1). GLUCOPHAGE Tablets and GLUCOPHAGE XR Extended-Release Tablets 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). Table 1: Select Mean (±S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of GLUCOPHAGE Subject Groups: GLUCOPHAGE dosea (number of subjects) Cmaxb (μg/mL) Tmaxc (hrs ) Renal Clearance (mL/min) Healthy, nondiabetic adults: 500 mg single dose (24) 1.03 (±0.33) 2.75 (±0.81) 600 (±132) 850 mg single dose (74)d 1.60 (±0.38) 2.64 (±0.82) 552(±139) 850 mg three times daily for 19 dosese (9) 2.01 (±0.42) 1.79 (±0.94) 642 (±173) Adults with type 2 diabetes: 850 mg single dose (23) 1.48 (±0.5) 3.32 (±1.08) 491 (±138) 850 mg three times daily for 19 dosese (9) 1.90 (±0.62) 2.01 (±1.22) 550 (±160) Elderlyf, healthy nondiabetic adults: 850 mg single dose (12) 2.45 (±0.70) 2.71 (±1.05) 412 (±98) Renal-impaired adults: 850 mg single dose Mild (CLcrg 61-90 mL/min) (5) 1.86 (±0.52) 3.20 (±0.45) 384 (±122) Moderate (CLcr 31-60 mL/min) (4) 4.12 (±1.83) 3.75 (±0.50) 108 (±57) Severe (CLcr 10-30 mL/min) (6) 3.93 (±0.92) 4.01 (±1.10) 130 (±90) aAll doses given fasting except the first 18 doses of the multiple dose studies bPeak plasma concentration cTime to peak plasma concentration dCombined results (average means) of five studies: mean age 32 years (range 23-59 years) eKinetic study done following dose 19, given fasting fElderly subjects, mean age 71 years (range 65-81 years) gCL = creatinine clearance normalized to body surface area of 1.73 m² Pediatrics After administration of a single oral GLUCOPHAGE 500 mg tablet with food, geometric mean metformin Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12-16 years of age) and gender- and weight-matched healthy adults (20-45 years of age), all with normal renal function. Gender Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males = 19, females = 16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of GLUCOPHAGE was comparable in males and females. Race No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of GLUCOPHAGE in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24). Clinical Studies Glucophage In a double-blind, placebo-controlled, multicenter US clinical trial involving obese patients with type 2 diabetes whose hyperglycemia was not adequately controlled with dietary management alone (baseline fasting plasma glucose [FPG] of approximately 240 mg/dL), treatment with GLUCOPHAGE (up to 2550 mg/day) for 29 weeks resulted in significant mean net reductions in fasting and postprandial plasma glucose (PPG) and hemoglobin A1c (HbA1c) of 59 mg/dL, 83 mg/dL, and 1.8%, respectively, compared to the placebo group (see Table 2). Table 2: GLUCOPHAGE vs Placebo Summary of Mean Changes from Baseline* in Fasting Plasma Glucose, HbA, and Body Weight, at Final Vis it (29-week study) GLUCOPHAGE (n=141) Placebo (n=145) p-Value FPG (mg/dL) Baseline 241.5 237.7 NS** Change at FINAL VISIT -53.0 6.3 0.001 Hemoglobin A1c (%) Baseline 8.4 8.2 NS** Change at FINAL VISIT -1.4 0.4 0.001 Body Weight (lbs) Baseline 201.0 206.0 NS** Change at FINAL VISIT -1.4 -2.4 NS** * All patients on diet therapy at Baseline ** Not statistically significant A 29-week, double-blind, placebo-controlled study of GLUCOPHAGE and glyburide, alone and in combination, was conducted in obese patients with type 2 diabetes who had failed to achieve adequate glycemic control while on maximum doses of glyburide (baseline FPG of approximately 250 mg/dL) (see Table 3). Patients randomized to the combination arm started therapy with GLUCOPHAGE 500 mg and glyburide 20 mg. At the end of each week of the first 4 weeks of the trial, these patients had their dosages of GLUCOPHAGE increased by 500 mg if they had failed to reach target fasting plasma glucose. After week 4, such dosage adjustments were made monthly, although no patient was allowed to exceed GLUCOPHAGE 2500 mg. Patients in the GLUCOPHAGE only arm (metformin plus placebo) followed the same titration schedule. At the end of the trial, approximately 70% of the patients in the combination group were taking GLUCOPHAGE 2000 mg/glyburide 20 mg or GLUCOPHAGE 2500 mg/glyburide 20 mg. Patients randomized to continue on glyburide experienced worsening of glycemic control, with mean increases in FPG, PPG, and HbA1c of 14 mg/dL, 3 mg/dL, and 0.2%, respectively. In contrast, those randomized to GLUCOPHAGE (up to 2500 mg/day) experienced a slight improvement, with mean reductions in FPG, PPG, and HbA1c of 1 mg/dL, 6 mg/dL, and 0.4%, respectively. The combination of GLUCOPHAGE and glyburide was effective in reducing FPG, PPG, and HbA1c levels by 63 mg/dL, 65 mg/dL, and 1.7%, respectively. Compared to results of glyburide treatment alone, the net differences with combination treatment were -77 mg/dL, -68 mg/dL, and -1.9%, respectively (see Table 3). Table 3: Combined GLUCOPHAGE/Glyburide (Comb) vs Glyburide (Glyb) or GLUCOPHAGE (GLU) Monotherapy: Summary of Mean Changes from Baseline* in Fasting Plasma Glucose, HbA1c, and Body Weight, at Final Visit (29-week study) Comb (n=213) Glyb (n=209) GLU (n=210) p-values Glyb vs Comb GLU vs Comb GLU vs Glyb Fasting Plasma Glucose (mg/dL) Baseline 250.5 247.5 253.9 NS** NS** NS** Change at FINAL VISIT -63.5 13.7 -0.9 0.001 0.001 0.025 Hemoglobin A1c (%) Baseline 8.8 8.5 8.9 NS** NS** 0.007 Change at FINAL VISIT -1.7 0.2 -0.4 0.001 0.001 0.001 Body Weight (lbs) Baseline 202.2 203.0 204.0 NS** NS** NS** Change at FINAL VISIT 0.9 -0.7 -8.4 0.011 0.001 0.001 * All patients on glyburide, 20 mg/day, at Baseline ** Not statistically significant The magnitude of the decline in fasting blood glucose concentration following the institution of GLUCOPHAGE Tablets therapy was proportional to the level of fasting hyperglycemia. Patients with type 2 diabetes with higher fasting glucose concentrations experienced greater declines in plasma glucose and glycosylated hemoglobin. In clinical studies, GLUCOPHAGE, alone or in combination with a sulfonylurea, lowered mean fasting serum triglycerides, total cholesterol, and LDL cholesterol levels, and had no adverse effects on other lipid levels (see Table 4). Table 4: Summary of Mean Percent Change From Baseline of Major Serum Lipid Variables at Final Visit (29-week studies ) GLUCOPHAGE vs Placebo Combined GLUCOPHAGE/Glyburide vs Monotherapy GLUCOPHAGE (n=141) Placebo (n=145) GLUCOPHAGE (n=210) GLUCOPHAGE/ Glyburide (n=213) Glyburide (n=209) Total Cholesterol (mg/dL) Baseline 211.0 212.3 213.1 215.6 219.6 Mean % Change at FINAL VISIT -5% 1% -2% -4% 1% Total Triglycerides (mg/dL) Baseline 236.1 203.5 242.5 215.0 266.1 Mean % Change at FINAL VISIT -16% 1% -3% -8% 4% LDL-Cholesterol (mg/dL) Baseline 135.4 138.5 134.3 136.0 137.5 Mean % Change at FINAL VISIT -8% 1% -4% -6% 3% HDL-Cholesterol (mg/dL) Baseline 39.0 40.5 37.2 39.0 37.0 Mean % Change at FINAL VISIT 2% -1% 5% 3% 1% In contrast to sulfonylureas, body weight of individuals on GLUCOPHAGE tended to remain stable or even decrease somewhat (see Tables 2 and 3). A 24-week, double-blind, placebo-controlled study of GLUCOPHAGE plus insulin versus insulin plus placebo was conducted in patients with type 2 diabetes who failed to achieve adequate glycemic control on insulin alone (see Table 5). Patients randomized to receive GLUCOPHAGE plus insulin achieved a reduction in HbA1c 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, GLUCOPHAGE plus insulin versus insulin plus placebo, respectively, p=0.04. Table 5: Combined GLUCOPHAGE/Insulin vs Placebo/Insulin Summary of Mean Changes from Baseline in HbA1c and Daily Insulin Dose GLUCOPHAGE /Insulin (n=26) Placebo /Insulin (n=28) Treatment Difference Mean ± SE Hemoglobin A1c (%) Baseline 8.95 9.32 Change at FINAL VISIT -2.10 -1.56 -0.54 ± 0.43a Insulin Dose (U/day) Baseline 93.12 94.64 Change at FINAL VISIT -0.15 15.93 -16.08 ± 7.77b a Statistically significant using analysis of covariance with baseline as covariate (p=0.04) Not significant using analysis of variance (values shown in table) bStatistically significant for insulin (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 HbA1c of 7.46 ± 0.97%, the addition of GLUCOPHAGE maintained similar glycemic control (HbA1c 7.15 ± 0.61 vs 6.97 ± 0.62 for GLUCOPHAGE plus insulin and placebo plus insulin, respectively) with 19% less insulin versus baseline (reduction of 23.68 ± 30.22 vs an increase of 0.43 ± 25.20 units for GLUCOPHAGE plus insulin and placebo plus insulin, p < 0.01). In addition, this study demonstrated that the combination of GLUCOPHAGE 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. Glucophage XR A 24-week, double-blind, placebo-controlled study of GLUCOPHAGE XR, taken once daily with the evening meal, was conducted in patients with type 2 diabetes who had failed to achieve glycemic control with diet and exercise (HbA1c 7.0%-10.0%, FPG 126-270 mg/dL). Patients entering the study had a mean baseline HbA1c of 8.0% and a mean baseline FPG of 176 mg/dL. After 12 weeks treatment, mean HbA1c had increased from baseline by 0.1% and mean FPG decreased from baseline by 2 mg/dL in the placebo group, compared with a decrease in mean HbA1c of 0.6% and a decrease in mean FPG of 23 mg/dL in patients treated with GLUCOPHAGE XR 1000 mg once daily. Subsequently, the treatment dose was increased to 1500 mg once daily if HbA1c was ≥ 7.0% but < 8.0% (patients with HbA1c ≥ 8.0% were discontinued from the study). At the final visit (24-week), mean HbA1c had increased 0.2% from baseline in placebo patients and decreased 0.6% with GLUCOPHAGE XR. A 16-week, double-blind, placebo-controlled, dose-response study of GLUCOPHAGE XR, taken once daily with the evening meal or twice daily with meals, was conducted in patients with type 2 diabetes who had failed to achieve glycemic control with diet and exercise (HbA1c 7.0%-11.0%, FPG 126-280 mg/dL). Changes in glycemic control and body weight are shown in Table 6. Table 6: Summary of Mean Changes from Baseline* in HbA1c, Fasting Plasma Glucose, and Body Weight at Final Visit (16-week study) GLUCOPHAGE XR Placebo 500 mg Once Daily 1000 mg Once Daily 1500 mg Once Daily 2000 mg Once Daily 1000 mg Twice Daily Hemoglobin A1c (%) (n=115) (n=115) (n=111) (n=125) (n=112) (n=111) Baseline 8.2 8.4 8.3 8.4 8.4 8.4 Change at FINAL VISIT -0.4 -0.6 -0.9 -0.8 -1.1 0.1 p-valuea < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 - FPG (mg/dL) (n=126) (n=118) (n=120) (n=132) (n=122) (n=113) Baseline 182.7 183.7 178.9 181.0 181.6 179.6 Change at FINAL VISIT -15.2 -19.3 -28.5 -29.9 -33.6 7.6 p-valuea < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 - Body Weight (lbs) (n=125) (n=119) (n=117) (n=131) (n=119) (n=113) Baseline 192.9 191.8 188.3 195.4 192.5 194.3 Change at FINAL VISIT -1.3 -1.3 -0.7 -1.5 -2.2 -1.8 p-valuea NS** NS** NS** NS** NS** - * All patients on diet therapy at Baseline aAll comparisons versus Placebo ** Not statistically significant Compared with placebo, improvement in glycemic control was seen at all dose levels of GLUCOPHAGE XR Extended-Release Tablets and treatment was not associated with any significant change in weight (see DOSAGE AND ADMINISTRATION for dosing recommendations for GLUCOPHAGE and GLUCOPHAGE XR). A 24-week, double-blind, randomized study of GLUCOPHAGE XR, taken once daily with the evening meal, and GLUCOPHAGE Tablets, taken twice daily (with breakfast and evening meal), was conducted in patients with type 2 diabetes who had been treated with GLUCOPHAGE 500 mg twice daily for at least 8 weeks prior to study entry. The GLUCOPHAGE dose had not necessarily been titrated to achieve a specific level of glycemic control prior to study entry. Patients qualified for the study if HbA1c was ≤ 8.5% and FPG was ≤ 200 mg/dL. Changes in glycemic control and body weight are shown in Table 7. Table 7: Summary of Mean Changes from Baseline* in HbA1c, Fasting Plasma Glucose, and Body Weight at Week 12 and at Final Visit (24-week study) GLUCOPHAGE 500 mg Twice Daily GLUCOPHAGE XR 1000 mg Once Daily 1500 mg Once Daily Hemoglobin A1c (%) (n=67) (n=72) (n=66) Baseline 7.06 6.99 7.02 Change at 12 Weeks 0.14 0.23 0.04 (95% CI) (-0.03, 0.31) (0.10, 0.36) (-0.08, 0.15) Change at FINAL VISIT 0.14a 0.27 0.13 (95% CI) (-0.04, 0.31) (0.11, 0.43) (-0.02, 0.28) FPG (mg/dL) (n=69) (n=72) (n=70) Baseline 127.2 131.0 131.4 Change at 12 Weeks 12.9 9.5 3.7 (95% CI) (6.5, 19.4) (4.4, 14.6) (-0.4, 7.8) Change at FINAL VISIT 14.0 11.5 7.6 (95% CI) (7.0, 21.0) (4.4, 18.6) (1.0, 14.2) Body Weight (lbs) (n=71) (n=74) (n=71) Baseline 210.3 202.8 192.7 Change at 12 Weeks 0.4 0.9 0.7 (95% CI) (-0.4, 1.5) (0.0, 2.0) (-0.4, 1.8) Change at FINAL VISIT 0.9 1.1 0.9 (95% CI) (-0.4, 2.2) (-0.2, 2.4) (-0.4, 2.0) * All patients on GLUCOPHAGE 500 mg twice daily at Baseline an=68 After 12 weeks of treatment, there was an increase in mean HbA in all groups; in the GLUCOPHAGE XR 1000 mg group, the increase from baseline of 0.23% was statistically significant (see DOSAGE AND ADMINISTRATION). Changes in lipid parameters in the previously described placebo-controlled dose-response study of GLUCOPHAGE XR are shown in Table 8. Table 8: Summary of Mean Percent Changes from Baseline* in Major Lipid Variables at Final Visit (16-week study) GLU COPHAGE XR Placebo 500 mg Once Daily 1000 mg Once Daily 1500 mg Once Daily 2000 mg Once Daily 1000 mg Twice Daily Total Cholesterol (mg/dL) (n=120) (n=113) (n=110) (n=126) (n=117) (n=110) Baseline 210.3 218.1 214.6 204.4 208.2 208.6 Mean % Change at FINAL VISIT 1.0% 1.7% 0.7% -1.6% -2.6% 2.6% Total Triglycerides (mg/dL) (n=120) (n=113) (n=110) (n=126) (n=117) (n=110) Baseline .2 0. 2 2 211.9 198.0 194.2 179.0 211.7 Mean % Change at FINAL VISIT % % .5 4. 1 9.4% 15.1% 14.9% 9.4% 10.9% LDL-Cholesterol (mg/dL) (n=119) (n=113) (n=109) (n=126) (n=117) (n=107) Baseline 131.0 134.9 135.8 125.8 131.4 131.9 Mean % Change at FINAL VISIT -1.4% -1.6% -3.5% -3.3% -5.5% 3.2% HDL-Cholesterol (mg/dL) (n=120) (n=108) (n=108) (n=125) (n=117) (n=108) Baseline 40.8 41.6 40.6 40.2 42.4 39.4 Mean % Change at FINAL VISIT 6.2% 8.6% 5.5% 6.1% 7.1% 5.8% * All patients on diet therapy at Baseline Changes in lipid parameters in the previously described study of GLUCOPHAGE and GLUCOPHAGE XR are shown in Table 9. Table 9: Summary of Mean Percent Changes from Baseline* in Major Lipid Variables at Final Visit (24-week study) GLUCOPHAGE GLUCOPHAGE XR 500 mg Twice Daily 1000 mg Once Daily 1500 mg Once Daily Total Cholesterol (mg/dL) (n=68) (n=70) (n=66) Baseline 199.0 201.9 201.6 Mean % Change at FINAL VISIT 0.1% 1.3% 0.1% Total Triglycerides (mg/dL) (n=68) (n=70) (n=66) Baseline 178.0 169.2 206.8 Mean % Change at FINAL VISIT 6.3% 25.3% 33.4% LDL-Cholesterol (mg/dL) (n=68) (n=70) (n=66) Baseline 122.1 126.2 115.7 Mean % Change at FINAL VISIT -1.3% -3.3% -3.7% HDL-Cholesterol (mg/dL) (n=68) (n=70) (n=65) Baseline 41.9 41.7 44.6 Mean % Change at FINAL VISIT 4.8% 1.0% -2.1% * All patients on GLUCOPHAGE 500 mg twice daily at Baseline Pediatric Clinical Studies In a double-blind, placebo-controlled study in pediatric patients aged 10 to 16 years with type 2 diabetes (mean FPG 182.2 mg/dL), treatment with GLUCOPHAGE (up to 2000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks) resulted in a significant mean net reduction in FPG of 64.3 mg/dL, compared with placebo (see Table 10). Table 10: GLUCOPHAGE vs Placebo (Pediatricsa) Summary of Mean Changes from Baseline* in Plasma Glucose and Body Weight at Final Visit GLUCOPHAGE Placebo p-Value FPG (mg/dL) (n=37) (n=36) Baseline 162.4 192.3 Change at FINAL VISIT -42.9 21.4 < 0.001 Body Weight (lbs) (n=39) (n=38) Baseline 205.3 189.0 Change at FINAL VISIT -3.3 -2.0 NS** a Pediatric patients mean age 13.8 years (range 10-16 years) * All patients on diet therapy at Baseline ** Not statistically significant

Clinical Pharmacology

CLINICAL PHARMACOLOGY 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 plasma insulin levels and day-long plasma insulin response may actually decrease. Pharmacokinetics And Drug Metabolism Absorption And Bioavailability The appearance of metformin in plasma from a FORTAMET® Extended-Release Tablet is slower and more prolonged compared to immediate-release metformin. In a multiple-dose crossover study, 23 patients with type 2 diabetes mellitus were administered either FORTAMET® 2000 mg once a day (after dinner) or immediate-release (IR) metformin hydrochloride 1000 mg twice a day (after breakfast and after dinner). After 4 weeks of treatment, steady-state pharmacokinetic parameters, area under the concentration-time curve (AUC), time to peak plasma concentration (Tmax), and maximum concentration (Cmax) were evaluated. Results are presented in Table 1. Table 1 : FORTAMET® vs . Immediate-Release Metformin Steady-State Pharmacokinetic Parameters at 4 Weeks Pharmacokinetic Parameters (mean ±SD) FORTAMET® 2000 mg (administered q.d.after dinner) Immediate - Release Metformin 2000 mg (1000 mg b.i.d.) AUC 0-24hr (ng•hr/mL) 26,811 ± 7055 27,371 ± 5,781 Tmax (hr) 6 (3-10) 3 (1-8) Cmax (ng/mL) 2849 ± 797 1820 ± 370 In four single-dose studies and one multiple-dose study, the bioavailability of FORTAMET® 2000 mg given once daily, in the evening, under fed conditions [as measured by the area under the plasma concentration versus time curve (AUC)] was similar to the same total daily dose administered as immediate-release metformin 1000 mg given twice daily. The geometric mean ratios (FORTAMET® / immediate-release metformin) of AUC0-24hr, AUC0-72h, and AUC0-inf. for these five studies ranged from 0.96 to 1.08. In a single-dose, four-period replicate crossover design study, comparing two 500 mg FORTAMET® tablets to one 1000 mg FORTAMET® tablet administered in the evening with food to 29 healthy male subjects, two 500 mg FORTAMET® tablets were found to be equivalent to one 1000 mg FORTAMET® tablet. In a study carried out with FORTAMET®, there was a dose-associated increase in metformin exposure over 24 hours following oral administration of 1000, 1500, 2000, and 2500 mg. In three studies with FORTAMET® using different treatment regimens (2000 mg after dinner; 1000 mg after breakfast and after dinner; and 2500 mg after dinner), the pharmacokinetics of metformin as measured by AUC appeared linear following multiple-dose administration. The extent of metformin absorption (as measured by AUC) from FORTAMET® increased by approximately 60% when given with food. When FORTAMET® was administered with food, Cmax was increased by approximately 30% and Tmax was more prolonged compared with the fasting state (6.1 versus 4.0 hours). Distribution Distribution studies with FORTAMET® have not been conducted. However, the apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of immediate-release metformin, steady state plasma concentrations of metformin are reached within 24-48 hours and are generally < 1 μg/mL. During controlled clinical trials of immediate-release metformin, maximum metformin plasma levels did not exceed 5 μg/mL, even at maximum doses. Metabolism And Excretion Metabolism studies with FORTAMET® have not been conducted. 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. In healthy nondiabetic adults (N=18) receiving 2500 mg q.d. FORTAMET®, the percent of the metformin dose excreted in urine over 24 hours was 40.9% and the renal clearance was 542 ± 310 mL/min. After repeated administration of FORTAMET®, there is little or no accumulation of metformin in plasma, with most of the drug being eliminated via renal excretion over a 24-hour dosing interval. The t½ was 5.4 hours for FORTAMET®. Renal clearance of metformin (Table 2) 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 halflife is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. Special Populations Geriatrics Limited data from controlled pharmacokinetic studies of immediate-release metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and C 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 (Table 2). FORTAMET® 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, PRECAUTIONS and DOSAGE AND ADMINISTRATION). Pediatrics No pharmacokinetic data from studies of pediatric patients are currently available (see PRECAUTIONS). Gender Five studies indicated that with FORTAMET® treatment, the pharmacokinetic results for males and females were comparable. Table 2 : Select Mean (±SD) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Immediate-Release Metformin Subject Groups: Immediate-Release Metformin dosea(number of subjects) Cmaxb (pg/mL) Tmaxc (hrs) Renal Clearance (mL/min) Healthy, nondiabetic adults: 500 mg single dose (24) 1.03 (± 0.33) 2.75 (± 0.81) 600 (± 132) 850 mg single dose (74)d 1.60 (± 0.38) 2.64 (± 0.82) 552(± 139) 850 mg three times daily for 19 dosese (9) 2.01 (± 0.42) 1.79 (± 0.94) 642 (± 173) Adults with type 2 diabetes: 850 mg single dose (23) 1.48 (± 0.5) 3.32 (± 1.08) 491 (± 138) 850 mg three times daily for 19 dosese (9) 1.90 (± 0.62) 2.01 (± 1.22) 550 (± 160) Elderlyf, healthy nondiabetic adults: 850 mg single dose (12) 2.45 (± 0.70) 2.71 (± 1.05) 412 (± 98) Renal-impaired adults:850 mg single dose Mild (CLcrg 61-90 mL/min) (5) 1.86 (± 0.52) 3.20 (± 0.45) 384 (± 122) Moderate (CLcr 31-60 mL/min) (4) 4.12 (± 1.83) 3.75 (± 0.50) 108 (± 57) Severe (CLcr 10-30 mL/min) (6) 3.93 (± 0.92) 4.01 (± 1.10) 130(± 90) aAll doses given fasting except the first 18 doses of the multiple dose studies bPeak plasma concentration cTime to peak plasma concentration dCombined results (average means) of five studies: mean age 32 years (range 23-59 years) eKinetic study done following dose 19, given fasting fElderly subjects, mean age 71 years (range 65-81 years) gCLcr = creatinine clearance normalized to body surface area of 1.73 m² Renal Insufficiency In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (Table 2; also see WARNINGS). Hepatic Insufficiency No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency. Race No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of immediate-release metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24). Clinical Studies In a double-blind, randomized, active-controlled, multicenter U.S. clinical study, which compared FORTAMET® q.d. to immediate-release metformin b.i.d., 680 patients with type 2 diabetes who had been taking metformin-containing medication at study entry were randomly assigned in equal numbers to double-blind treatment with either FORTAMET® or immediate-release metformin. Doses were adjusted during the first six weeks of treatment with study medication based on patients' FPG levels and were then held constant over a period of 20 weeks. The primary efficacy endpoint was the change in HbA from baseline to endpoint. The primary objective was to demonstrate the clinical non-inferiority of FORTAMET® compared to immediate-release metformin on the primary endpoint. FORTAMET® and metformin patients had mean HbA1c changes from baseline to endpoint equal to +0.40 and +0.14, respectively (Table 3). The least-square (LS) mean treatment difference was 0.25 (95% CI = 0.14, 0.37) demonstrating that FORTAMET® was clinically similar to metformin according to the pre-defined criterion to establish efficacy. Table 3 : FORTAMET® vs . Immediate-Release Metformin Switch Study: Summary of Mean Changes in HbA1c, Fasting Plasma Glucose, Body Weight, Body Mass Index, and Plasma Insulin FORTAMET® Imme diate-Release Metformin Treatment difference for change from baseline (FORTAMET® minus Immediate-Release Metformin) LS mean (2 sided 95% CIa) HbA1c(%) N 327 332 0.25 Baseline (mean ± SD) 7.04 ± 0.88 7.07 ± 0.76 (0.14,0.37)b Change from baseline (mean ±SD) 0.40 ± 0.75 0.14 ± 0.75 Fasting Plasma Glucose (mg/dL) N 329 333 6.43 Baseline (mean ± SD) 146.8 ± 32.1 145.6 ± 29.5 (0.57, 12.29) Change from baseline (mean ±SD) 10.0 ± 40.8 4.2 ± 35.9 Plasma Insulin (pu/mL) N 304 316 0.02 Baseline (mean ± SD) 17.9 ± 15.1 17.3 ± 10.5 (-1.47, 1.50) Change from baseline (mean ± SD) -3.6 ± 13.8 -3.2 ± 8.6 Body Weight (kg) N 313 320 0.30 Baseline (mean ± SD) 94.1 ± 17.8 93.3 ± 17.4 (-0.22, 0.81) Change from baseline(mean ± SD) 0.3 ± 2.9 0.0 ± 3.7 Body Mass Index (kg/m²) N 313 320 0.08 Baseline (mean ± SD) 31.1 ±4.7 31.4 ± 4.5 (-0.11, 0.26) Change from baseline(mean ± 0.1 ± 1.1 0.0 ± 1.3 aCI= Confidence Interval b FORTAMET® was clinically similar to immediate-release metformin based on the pre-defined criterion to establish efficacy. While demonstrating clinical similarity, the response to FORTAMET® compared to immediate-release metformin was also shown to be statistically smaller as seen by the 95% CI for the treatment difference which did not include zero. Footnote: Patients were taking metformin-containing medications at baseline that were prescribed by their personal physician. The mean changes for FPG (Table 3) and plasma insulin (Table 3) were small for both FORTAMET® and immediate-release metformin, and were not clinically meaningful. Seventy-six (22%) and 49 (14%) of the FORTAMET® and immediate-release patients, respectively, discontinued prematurely from the trial. Eighteen (5%) patients on FORTAMET® withdrew because of a stated lack of efficacy, as compared with 8 patients (2%) on immediate-release metformin (p=0.047). Results from this study also indicated that neither FORTAMET® nor immediate-release metformin were associated with weight gain or increases in body mass index. 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 (Table 4). Patients randomized to receive immediate-release metformin plus insulin achieved a reduction in HbA of 2.10%, compared to a 1.56% reduction in HbA 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 versus 110.6 U/day, immediate-release metformin plus insulin versus insulin plus placebo, respectively, p=0.04. Table 4 : Combined Immediate-Release Metformin/lnsulin vs . Placebo/Insulin: Summary of Mean Changes from Baseline in HbA1c and Daily Insulin Dose Immediate-Release Metformin /Insulin (n = 26) Placebo/ Insulin (n = 28) Treatment difference Mean ± SE HbA1c(%) Baseline 8.95 9.32 Change at FINAL VISIT -2.10 -1.56 -0.54 ± 0.43a Insulin Dose (U/day) Baseline 93.12 94.64 Change at FINAL VISIT -0.15 15.93 -16.08 ± 7.77b aStatistically significant using analysis of covariance with baseline as covariate (p=0.04). Not significant using analysis of variance (values shown in table) bStatistically significant for insulin (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 HbA1c of 7.46 ± 0.97%, the addition of immediate-release metformin maintained similar glycemic control (HbA1c 7.15 ± 0.61 versus 6.97 ± 0.62 for immediate-release 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 immediate-release metformin plus insulin and placebo plus insulin, p < 0.01). In addition, this study demonstrated that the combination of immediate-release 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. Pediatric Clinical Studies No pediatric clinical studies have been conducted with FORTAMET®. In a double-blind, placebocontrolled study in pediatric patients aged 10 to 16 years with type 2 diabetes (mean FPG 182.2 mg/dL), treatment with immediate-release metformin (up to 2000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks) resulted in a significant mean net reduction in FPG of 64.3 mg/dL compared with placebo (Table 5). Table 5 : Immediate-Release Metformin vs . Placebo (Pediatricsa): Summary of Mean Changes from Baseline* in Plasma Glucose and Body Weight at Final Visit Immediate-Release Metformin Placebo p-Value FPG (mg/dL) (n = 37) (n = 36) Baseline 162.4 192.3 Change at FINAL VISIT -42.9 21.4 < 0.001 Body Weight (lbs) (n = 39) (n = 38) Baseline 205.3 189.0 Change at FINAL VISIT -3.3 -2.0 NS** aPediatric patients mean age 13.8 years (range 10-16 years) * All patients on diet therapy at Baseline ** Not statistically significant

Drug Description

Find Lowest Prices on RIOMET® (metformin hydrochloride) Oral Solution WARNING LACTIC ACIDOSIS Lactic acidosis is a rare but serious complication that can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment, and acute congestive heart failure [see WARNINGS AND PRECAUTIONS]. The onset is often subtle accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate [see WARNINGS AND PRECAUTIONS]. If acidosis is suspected Riomet should be discontinued and the patient hospitalized immediately [see WARNINGS AND PRECAUTIONS]. DESCRIPTION Riomet (metformin hydrochloride oral solution) is an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin hydrochloride, USP (N,N­dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. The structural formula is as shown: Metformin hydrochloride, USP is a white crystalline powder with a molecular formula of C4H11N5•HCl and a molecular weight of 165.62. Metformin hydrochloride, USP 2.0 g is soluble in 20 mL of water. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. It is freely soluble in water; slightly soluble in alcohol; practically insoluble in acetone and in methylene chloride. Riomet (Cherry Flavor) contains 500 mg of metformin hydrochloride, USP per 5 mL and the following inactive ingredients: Artificial cherry flavor, hydrochloric acid, potassium bicarbonate, purified water, saccharin calcium, and xylitol. Riomet (Strawberry Flavor) contains 500 mg of metformin hydrochloride, USP per 5 mL and the following inactive ingredients: Hydrochloric acid, N&A strawberry flavor (propylene glycol and glycerin), potassium bicarbonate, purified water, sucralose, and xylitol.

Drug Description

Find Lowest Prices on GLUMETZA® (metformin hydrochloride) Extended-release Tablets WARNING Lactic Acidosis Lactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment, and acute congestive heart failure. The onset of lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate. If acidosis is suspected, GLUMETZA (metformin hydrochloride extended-release tablets), should be discontinued and the patient hospitalized immediately. (See WARNINGS AND PRECAUTIONS) 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.

Drug Description

Find Lowest Prices on GLUCOPHAGE® (metformin hydrochloride) Tablets GLUCOPHAGE® XR (metformin hydrochloride) Extended-Release Tablets DESCRIPTION GLUCOPHAGE® (metformin hydrochloride) Tablets and GLUCOPHAGE® XR (metformin hydrochloride) Extended-Release Tablets are oral antihyperglycemic drugs used in the management of type 2 diabetes. Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. The structural formula is as shown: Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C4H11N5 HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pK of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. GLUCOPHAGE tablets contain 500 mg, 850 mg, or 1000 mg of metformin hydrochloride. Each tablet contains the inactive ingredients povidone and magnesium stearate. In addition, the coating for the 500 mg and 850 mg tablets contains hypromellose and the coating for the 1000 mg tablet contains hypromellose and polyethylene glycol. GLUCOPHAGE XR contains 500 mg or 750 mg of metformin hydrochloride as the active ingredient. GLUCOPHAGE XR 500 mg tablets contain the inactive ingredients sodium carboxymethyl cellulose, hypromellose, microcrystalline cellulose, and magnesium stearate. GLUCOPHAGE XR 750 mg tablets contain the inactive ingredients sodium carboxymethyl cellulose, hypromellose, and magnesium stearate. System Components And Performance GLUCOPHAGE XR comprises a dual hydrophilic polymer matrix system. Metformin hydrochloride is combined with a drug release controlling polymer to form an “inner” phase, which is then incorporated as discrete particles into an “external” phase of a second polymer. After administration, fluid from the gastrointestinal (GI) tract enters the tablet, causing the polymers to hydrate and swell. Drug is released slowly from the dosage form by a process of diffusion through the gel matrix that is essentially independent of pH. The hydrated polymer system is not rigid and is expected to be broken up by normal peristalsis in the GI tract. The biologically inert components of the tablet may occasionally remain intact during GI transit and will be eliminated in the feces as a soft, hydrated mass.

Drug Description

Find Lowest Prices on FORTAMET® (metformin hydrochloride) Extended-Release Tablets DESCRIPTION FORTAMET® (metformin hydrochloride) Extended-Release Tablets contain an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin hydrochloride (N, Ndimethylimidodicarbonimidic diamide hydrochloride) is a member of the biguanide class of oral antihyperglycemics and is not chemically or pharmacologically related to any other class of oral antihyperglycemic agents. The empirical formula of metformin hydrochloride is C4H11N5•HCl and its molecular weight is 165.63. Its structural formula is: Metformin hydrochloride is a white to off-white crystalline powder that 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. FORTAMET® Extended-Release Tablets are designed for once-a-day oral administration and deliver 500 mg or 1000 mg of metformin hydrochloride. In addition to the active ingredient metformin hydrochloride, each tablet contains the following inactive ingredients: candellila wax, cellulose acetate, hypromellose, magnesium stearate, polyethylene glycols (PEG 400, PEG 8000), polysorbate 80, povidone, sodium lauryl sulfate, synthetic black iron oxides, titanium dioxide, and triacetin. FORTAMET® meets USP Dissolution Test 5. System Components And Performance FORTAMET® was developed as an extended-release formulation of metformin hydrochloride and designed for once-a-day oral administration using the patented single-composition osmotic technology (SCOT™). The tablet is similar in appearance to other film-coated oral administered tablets but it consists of an osmotically active core formulation that is surrounded by a semipermeable membrane. Two laser drilled exit ports exist in the membrane, one on either side of the tablet. The core formulation is composed primarily of drug with small concentrations of excipients. The semipermeable membrane is permeable to water but not to higher molecular weight components of biological fluids. Upon ingestion, water is taken up through the membrane, which in turn dissolves the drug and excipients in the core formulation. The dissolved drug and excipients exit through the laser drilled ports in the membrane. The rate of drug delivery is constant and dependent upon the maintenance of a constant osmotic gradient across the membrane. This situation exists so long as there is undissolved drug present in the core tablet. Following the dissolution of the core materials, the rate of drug delivery slowly decreases until the osmotic gradient across the membrane falls to zero at which time delivery ceases. The membrane coating remains intact during the transit of the dosage form through the gastrointestinal tract and is excreted in the feces.

Indications & Dosage

INDICATIONS Riomet (metformin hydrochloride oral solution) is indicated as an adjunct to diet and exercise to improve glycemic control in adults and children with type 2 diabetes mellitus [see Clinical Studies]. DOSAGE AND ADMINISTRATION There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with Riomet or any other pharmacologic agent. Dosage of Riomet must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily doses. The maximum recommended daily dose of Riomet is 2550 mg (25.5 mL) in adults and 2000 mg (20 mL) in pediatric patients (10 to 16 years of age). Riomet should be given in divided doses with meals. Riomet should be started at a low dose, with gradual dose escalation, both to reduce gastrointestinal side effects and to permit identification of the minimum dose required for adequate glycemic control of the patient. During treatment initiation and dose titration [see Recommended Dosing Schedule], fasting plasma glucose should be used to determine the therapeutic response to Riomet and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately three months. The therapeutic goal should be to decrease both fasting plasma glucose and glycosylated hemoglobin levels to normal or near normal by using the lowest effective dose of Riomet, 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 Riomet may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone. Recommended Dosing Schedule Adults In general, clinically significant responses are not seen at doses below 1500 mg (15 mL) per day. However, a lower recommended starting dose and gradually increased dosage is advised to minimize gastrointestinal symptoms. The usual starting dose of Riomet (metformin hydrochloride oral solution) is 500 mg (5 mL) twice a day or 850 mg (8.5 mL) once a day, given with meals. Dosage increases should be made in increments of 500 mg (5 mL) weekly or 850 mg (8.5 mL) every 2 weeks, up to a total of 2000 mg (20 mL) per day, given in divided doses. Patients can also be titrated from 500 mg (5 mL) twice a day to 850 mg (8.5 mL) twice a day after 2 weeks. For those patients requiring additional glycemic control, Riomet may be given to a maximum daily dose of 2550 mg (25.5 mL) per day. Doses above 2000 mg (20 mL) may be better tolerated given three times a day with meals. Pediatrics The usual starting dose of Riomet is 500 mg (5 mL) twice a day, given with meals. Dosage increases should be made in increments of 500 mg (5 mL) weekly up to a maximum of 2000 mg (20 mL) per day, given in divided doses. Transfer From Other Antidiabetic Therapy When transferring patients from standard oral hypoglycemic agents other than chlorpropamide to Riomet, no transition period generally is necessary. When transferring patients from chlorpropamide, care should be exercised during the first two weeks because of the prolonged retention of chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia. Concomitant Metformin And Oral Sulfonylurea Therapy In Adult Patients If patients have not responded to four weeks of the maximum dose of Riomet monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing Riomet at the maximum dose, even if prior primary or secondary failure to a sulfonylurea has occurred. Clinical and pharmacokinetic drug-drug interaction data are currently available only for metformin plus glyburide (glibenclamide). With concomitant Metformin and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. In a clinical trial of patients with type 2 diabetes and prior failure on glyburide, patients started on metformin 500 mg and glyburide 20 mg were titrated to 1000 mg/20 mg, 1500 mg/20 mg, 2000 mg/20 mg or 2500 mg/20 mg of metformin and glyburide, respectively, to reach the goal of glycemic control as measured by FPG, HbA1c and plasma glucose response [see Clinical Studies]. However, attempts should be made to identify the minimum effective dose of each drug to achieve this goal. With concomitant Riomet 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 Riomet and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without Riomet. Concomitant Metformin And Insulin Therapy In Adult Patients The current Insulin dose should be continued upon initiation of Riomet therapy. Riomet therapy should be initiated at 500 mg (5 mL) once daily in patients on insulin therapy. For patients not responding adequately, the dose of Riomet should be increased by 500 mg (5 mL) after approximately 1 week and by 500 mg (5 mL) every week thereafter until adequate glycemic control is achieved. The maximum recommended daily dose for Riomet is 2500 mg (25 mL). 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 Riomet. Further adjustment should be individualized based on glucose-lowering response. Specific Patient Populations Riomet is not recommended for use in pregnancy. Riomet is not recommended in patients below the age of 10 years. The initial and maintenance dosing of Riomet 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 Riomet. Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly [see WARNINGS AND PRECAUTIONS]. HOW SUPPLIED Dosage Forms And Strengths Riomet (metformin hydrochloride oral solution) 500 mg/5 mL is a clear colorless to light yellow liquid with characteristic cherry or strawberry flavor filled in 4 oz./16 oz. HDPE bottles with induction sealed child-resistant cap. Storage And Handling Riomet (metformin hydrochloride oral solution) 500 mg/5 mL is a clear colorless to light yellow liquid with characteristic cherry or strawberry flavor filled in 4 oz./16 oz. HDPE bottles with induction sealed child-resistant cap. Cherry Flavor NDC 10631-206-01 Bottles of 4 fl. oz. (118 mL) NDC 10631-206-02 Bottles of 16 fl. oz. (473 mL) Strawberry Flavor NDC 10631-238-01 Bottles of 4 fl. oz. (118 mL) NDC 10631-238-02 Bottles of 16 fl. oz. (473 mL) Storage Store at controlled room temperature 15° - 30° C (59° - 86° F) [see USP]. Manufactured for: Ranbaxy Laboratories Inc. Jacksonville, FL 32257 USA

Indications & Dosage

INDICATIONS 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. DOSAGE AND ADMINISTRATION 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 INFORMATION) 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 HOW SUPPLIED Dosage Forms And Strengths GLUMETZA (metformin hydrochloride extended-release tablets) 500 mg are available as blue, film coated, ovalshaped 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, ovalshaped tablets with “M1000” on one side. 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: Package Strength NDC Bottles of 100 500 mg 68012-002-13 Bottles of 90 1000 mg 68012-003-16 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]. Manufactured for Santarus, Inc., a wholly owned subsidiary of Salix Pharmaceuticals, Raleigh, NC 27615. Revised: Sep 2014

Indications & Dosage

INDICATIONS GLUCOPHAGE (metformin hydrochloride) Tablets is indicated as an adjunct to diet and exercise to improve glycemic control in adults and children with type 2 diabetes mellitus. GLUCOPHAGE XR (metformin hydrochloride) Extended-Release Tablets is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. DOSAGE AND ADMINISTRATION There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with GLUCOPHAGE or GLUCOPHAGE XR or any other pharmacologic agent. Dosage of GLUCOPHAGE or GLUCOPHAGE XR must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily doses. The maximum recommended daily dose of GLUCOPHAGE is 2550 mg in adults and 2000 mg in pediatric patients (10-16 years of age); the maximum recommended daily dose of GLUCOPHAGE XR in adults is 2000 mg. GLUCOPHAGE should be given in divided doses with meals while GLUCOPHAGE XR should generally be given once daily with the evening meal. GLUCOPHAGE or GLUCOPHAGE XR should be started at a low dose, with gradual dose escalation, both to reduce gastrointestinal side effects and to permit identification of the minimum dose required for adequate glycemic control of the patient. During treatment initiation and dose titration (see Recommended Dosing Schedule), fasting plasma glucose should be used to determine the therapeutic response to GLUCOPHAGE or GLUCOPHAGE XR and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately 3 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 GLUCOPHAGE or GLUCOPHAGE XR, 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 GLUCOPHAGE or GLUCOPHAGE XR may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone. GLUCOPHAGE XR tablets must be swallowed whole and never crushed or chewed. Occasionally, the inactive ingredients of GLUCOPHAGE XR will be eliminated in the feces as a soft, hydrated mass. (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 usual starting dose of GLUCOPHAGE Tablets is 500 mg twice a day or 850 mg once a day, given with meals. Dosage increases should be made in increments of 500 mg weekly or 850 mg every 2 weeks, up to a total of 2000 mg per day, given in divided doses. Patients can also be titrated from 500 mg twice a day to 850 mg twice a day after 2 weeks. For those patients requiring additional glycemic control, GLUCOPHAGE may be given to a maximum daily dose of 2550 mg per day. Doses above 2000 mg may be better tolerated given 3 times a day with meals. The usual starting dose of GLUCOPHAGE XR (metformin hydrochloride) Extended-Release Tablets is 500 mg once daily with the evening meal. 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 GLUCOPHAGE XR 2000 mg once daily, a trial of GLUCOPHAGE XR 1000 mg twice daily should be considered. If higher doses of metformin are required, GLUCOPHAGE should be used at total daily doses up to 2550 mg administered in divided daily doses, as described above. (See Clinical Studies.) In a randomized trial, patients currently treated with GLUCOPHAGE were switched to GLUCOPHAGE XR. Results of this trial suggest that patients receiving GLUCOPHAGE treatment may be safely switched to GLUCOPHAGE XR once daily at the same total daily dose, up to 2000 mg once daily. Following a switch from GLUCOPHAGE to GLUCOPHAGE XR, glycemic control should be closely monitored and dosage adjustments made accordingly (see Clinical Studies). Pediatrics The usual starting dose of GLUCOPHAGE is 500 mg twice a day, given with meals. Dosage increases should be made in increments of 500 mg weekly up to a maximum of 2000 mg per day, given in divided doses. Safety and effectiveness of GLUCOPHAGE XR in pediatric patients have not been established. Transfer From Other Antidiabetic Therapy When transferring patients from standard oral hypoglycemic agents other than chlorpropamide to GLUCOPHAGE or GLUCOPHAGE XR, no transition period generally is necessary. When transferring patients from chlorpropamide, care should be exercised during the first 2 weeks because of the prolonged retention of chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia. Concomitant GLUCOPHAGE Or GLUCOPHAGE XR And Oral Sulfonylurea Therapy In Adult Patients If patients have not responded to 4 weeks of the maximum dose of GLUCOPHAGE or GLUCOPHAGE XR monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing GLUCOPHAGE or GLUCOPHAGE XR 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 GLUCOPHAGE or GLUCOPHAGE XR and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. In a clinical trial of patients with type 2 diabetes and prior failure on glyburide, patients started on GLUCOPHAGE 500 mg and glyburide 20 mg were titrated to 1000/20 mg, 1500/20 mg, 2000/20 mg, or 2500/20 mg of GLUCOPHAGE and glyburide, respectively, to reach the goal of glycemic control as measured by FPG, HbA1c, and plasma glucose response (see Clinical Studies). However, attempts should be made to identify the minimum effective dose of each drug to achieve this goal. With concomitant GLUCOPHAGE or GLUCOPHAGE XR 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 1 to 3 months of concomitant therapy with the maximum dose of GLUCOPHAGE or GLUCOPHAGE XR and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without GLUCOPHAGE or GLUCOPHAGE XR. Concomitant GLUCOPHAGE Or GLUCOPHAGE XR And Insulin Therapy In Adult Patients The current insulin dose should be continued upon initiation of GLUCOPHAGE or GLUCOPHAGE XR therapy. GLUCOPHAGE or GLUCOPHAGE XR therapy should be initiated at 500 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of GLUCOPHAGE or GLUCOPHAGE XR should be increased by 500 mg after approximately 1 week and by 500 mg every week thereafter until adequate glycemic control is achieved. The maximum recommended daily dose is 2500 mg for GLUCOPHAGE and 2000 mg for GLUCOPHAGE XR. 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 GLUCOPHAGE or GLUCOPHAGE XR. Further adjustment should be individualized based on glucose-lowering response. Specific Patient Populations GLUCOPHAGE or GLUCOPHAGE XR are not recommended for use in pregnancy. GLUCOPHAGE is not recommended in patients below the age of 10 years. GLUCOPHAGE XR is not recommended in pediatric patients (below the age of 17 years). The initial and maintenance dosing of GLUCOPHAGE or GLUCOPHAGE XR 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 GLUCOPHAGE or GLUCOPHAGE XR. Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly. (See WARNINGS.) HOW SUPPLIED GLUCOPHAGE® (metformin hydrochloride) Tablets 500 mg Bottles of 100 NDC 0087-6060-05 500 mg Bottles of 500 NDC 0087-6060-10 850 mg Bottles of 100 NDC 0087-6070-05 1000 mg Bottles of 100 NDC 0087-6071-11 GLUCOPHAGE 500 mg tablets are round, white to off-white, film-coated tablets debossed with “BMS 6060” around the periphery of the tablet on one side and “500” debossed across the face of the other side. GLUCOPHAGE 850 mg tablets are round, white to off-white, film-coated tablets debossed with “BMS 6070” around the periphery of the tablet on one side and “850” debossed across the face of the other side. GLUCOPHAGE 1000 mg tablets are white, oval, biconvex, film-coated tablets with “BMS 6071” debossed on one side and “1000” debossed on the opposite side and with a bisect line on both sides. GLUCOPHAGE® XR (metformin hydrochloride) Extended-Release Tablets 500 mg Bottles of 100 NDC 0087-6063-13 750 mg Bottles of 100 NDC 0087-6064-13 GLUCOPHAGE XR 500 mg tablets are white to off-white, capsule shaped, biconvex tablets, with “BMS 6063” debossed on one side and “500” debossed across the face of the other side. GLUCOPHAGE XR 750 mg tablets are capsule shaped, biconvex tablets, with “BMS 6064” debossed on one side and “750” debossed on the other side. The tablets are pale red and may have a mottled appearance. Storage Store at 20°-25° C (68°-77° F); excursions permitted to 15°-30° C (59°-86° F). [See USP Controlled Room Temperature.] Dispense in light-resistant containers. Distributed by: Bristol-Myers Squibb Company, Princeton, NJ 08543 USA. Revised: June 2015

Indications & Dosage

INDICATIONS FORTAMET® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. DOSAGE AND ADMINISTRATION There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with FORTAMET® or any other pharmacologic agent. Dosage of FORTAMET® 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 FORTAMET® Extended-Release Tablets in adults is 2500 mg. FORTAMET® should be taken with a full glass of water once daily with the evening meal. FORTAMET® should be started at a low dose, with gradual dose escalation, both to reduce gastrointestinal side effects and to permit identification of the minimum dose required for adequate glycemic control of the patient. During treatment initiation and dose titration (see Recommended Dosing Schedule), fasting plasma glucose should be used to determine the therapeutic response to FORTAMET® and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately three months. The therapeutic goal should be to decrease both fasting plasma glucose and glycosylated hemoglobin levels to normal or near normal by using the lowest effective dose of FORTAMET®, 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 FORTAMET® may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone. Recommended Dosing Schedule The usual starting dose of FORTAMET® (metformin hydrochloride) Extended-Release Tablets is 1000 mg taken with a full glass of water once daily with the evening meal, although 500 mg may be utilized when clinically appropriate. Dosage increases should be made in increments of 500 mg weekly, up to a maximum of 2500 mg once daily with the evening meal (see CLINICAL PHARMACOLOGY, Clinical Studies ). In randomized trials, patients currently treated with immediate-release metformin were switched to FORTAMET®. Results of this trial suggest that patients receiving immediate-release metformin treatment may be safely switched to FORTAMET® once daily at the same total daily dose, up to 2500 mg once daily. Following a switch from immediate-release metformin to FORTAMET®, glycemic control should be closely monitored and dosage adjustments made accordingly (see CLINICAL PHARMACOLOGY, Clinical Studies ). Pediatrics There is no pediatric information available for FORTAMET®. Transfer From Other Antidiabetic Therapy When transferring patients from standard oral hypoglycemic agents other than chlorpropamide to FORTAMET®, no transition period generally is necessary. When transferring patients from chlorpropamide, care should be exercised during the first two weeks because of the prolonged retention of chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia. Concomitant FORTAMET® And Oral Sulfonylurea Therapy In Adult Patients If patients have not responded to four weeks of the maximum dose of FORTAMET® monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing FORTAMET® 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 (also known as glibenclamide). With concomitant FORTAMET® 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 of each drug to achieve this goal. With concomitant FORTAMET® 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 FORTAMET® and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without FORTAMET®. Concomitant FORTAMET® And Insulin Therapy In Adult Patients The current insulin dose should be continued upon initiation of FORTAMET® therapy. FORTAMET® therapy should be initiated at 500 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of FORTAMET® 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 for FORTAMET® Extended-Release Tablets is 2500 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 FORTAMET®. Further adjustment should be individualized based on glucose-lowering response. Specific Patient Populations FORTAMET® is not recommended for use in pregnancy, and is not recommended in patients below the age of 17 years. The initial and maintenance dosing of FORTAMET® 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 FORTAMET®. Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly (see WARNINGS). HOW SUPPLIED FORTAMET® (metformin hydrochloride) Extended-Release Tablets are supplied as biconvex-shaped, film-coated extended-release tablets containing 500 mg or 1000 mg of metformin hydrochloride. NDC 59630-574-60: 500 mg extended-release, white-colored tablets imprinted with Andrx logo and 574 on one side: bottles of 60. NDC 59630-575-60: 1000 mg extended-release, white-colored tablets imprinted with Andrx logo and 575 on one side: bottles of 60. Storage Store at 20°-25°C (68°-77°F) Excursions permitted to 15° - 30°C (59° - 86°F) [See USP Controlled Room Temperature]. Keep tightly closed (protect from moisture). Protect from light. Avoid excessive heat and humidity. Distributed by: Shionogi Inc., Florham Park, NJ 07932. Manufactured by: Watson Laboratories - Florida, Ft. Lauderdale, FL 33314. Revised: Feb 2013

Medication Guide

PATIENT INFORMATION Patients should be informed of the potential risks and benefits of Riomet 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 WARNINGS AND PRECAUTIONS section, should be explained to patients. Patients should be advised to discontinue Riomet 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 Riomet, 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 Riomet. Metformin alone does not usually cause hypoglycemia, although it may occur when metformin 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.

Medication Guide

PATIENT INFORMATION 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 A1C. 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 1-800-508-0024. 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.

Medication Guide

PATIENT INFORMATION GLUCOPHAGE® (metformin hydrochloride) Tablets GLUCOPHAGE® XR (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 are GLUCOPHAGE and GLUCOPHAGE XR? GLUCOPHAGE and GLUCOPHAGE XR are used to treat type 2 diabetes. This is also known as noninsulin- dependent diabetes mellitus. People with type 2 diabetes are not able to make enough insulin or respond normally to the insulin their bodies make. When this happens, sugar (glucose) builds up in the blood. This can lead to serious medical problems including kidney damage, amputations, and blindness. Diabetes is also closely linked to heart disease. The main goal of treating diabetes is to lower your blood sugar to a normal level. High blood sugar can be lowered by diet and exercise, by a number of medicines taken by mouth, and by insulin shots. Before you take GLUCOPHAGE or GLUCOPHAGE XR, try to control your diabetes byexercise and weight loss. While you take your diabetes medicine, continue to exercise and follow the diet advised for your diabetes. No matter what your recommended diabetes management plan is, studies have shown that maintaining good blood sugar control can prevent or delay complications of diabetes, such as blindness. GLUCOPHAGE and GLUCOPHAGE XR have the same active ingredient. However, GLUCOPHAGE XR works longer in your body. Both of these medicines help control your blood sugar in a number of ways. These include helping your body respond better to the insulin it makes naturally, decreasing the amount of sugar your liver makes, and decreasing the amount of sugar your intestines absorb. GLUCOPHAGE and GLUCOPHAGE XR do not cause your body to make more insulin. Because of this, when taken alone, they rarely cause hypoglycemia (low blood sugar), and usually do not cause weight gain. However, when they are taken with a sulfonylurea or with insulin, hypoglycemia is more likely to occur, as is weight gain. WARNING: A small number of people who have taken GLUCOPHAGE have developed a serious condition called lactic acidosis. Lactic acidosis is caused by a buildup of lactic acid in the blood. This happens more often in people with kidney problems. Most people with kidney problems should not take GLUCOPHAGE or GLUCOPHAGE XR. (See “What are the side effects of GLUCOPHAGE and GLUCOPHAGE XR?”) Who should not take GLUCOPHAGE or GLUCOPHAGE XR? Some conditions increase your chance of getting lactic acidosis, or cause other problems if you take either of these medicines. Most of the conditions listed below can increase your chance of getting lactic acidosis. Do not take GLUCOPHAGE or GLUCOPHAGE XR if you: have kidney problems have liver problems have heart failure that is treated with medicines, such as Lanoxin® (digoxin) or Lasix® (furosemide) drink a lot of alcohol. This means you binge drink for short periods or drink all the time are seriously dehydrated (have lost a lot of water from your body) are going to have an x-ray procedure with injection of dyes (contrast agents) are going to have surgery develop a serious condition, such as heart attack, severe infection, or a stroke are 80 years or older and you have NOT had your kidney function tested Tell your doctor if you are pregnant or plan to become pregnant. GLUCOPHAGE and GLUCOPHAGE XR may not be right for you. Talk with your doctor about your choices. You should also discuss your choices with your doctor if you are nursing a child. Can GLUCOPHAGE or GLUCOPHAGE XR be used in children? GLUCOPHAGE has been shown to effectively lower glucose levels in children (ages 10-16 years) with type 2 diabetes. GLUCOPHAGE has not been studied in children younger than 10 years old. GLUCOPHAGE has not been studied in combination with other oral glucose-control medicines or insulin in children. If you have any questions about the use of GLUCOPHAGE in children, talk with your doctor or other healthcare provider. GLUCOPHAGE XR has not been studied in children. How should I take GLUCOPHAGE or GLUCOPHAGE XR? Your doctor will tell you how much medicine to take and when to take it. You will probably start out with a low dose of the medicine. Your doctor may slowly increase your dose until your blood sugar is better controlled. You should take GLUCOPHAGE or GLUCOPHAGE XR with meals. Your doctor may have you take other medicines along with GLUCOPHAGE or GLUCOPHAGE XR to control your blood sugar. These medicines may include insulin shots. Taking GLUCOPHAGE or GLUCOPHAGE XR with insulin may help you better control your blood sugar while reducing the insulin dose. Continue your exercise and diet program and test your blood sugar regularly while taking GLUCOPHAGE or GLUCOPHAGE XR. Your doctor will monitor your diabetes and may perform blood tests on you from time to time to make sure your kidneys and your liver are functioning normally. There is no evidence that GLUCOPHAGE or GLUCOPHAGE XR causes harm to the liver or kidneys. Tell your doctor if you: have an illness that causes severe vomiting, diarrhea or fever, or if you drink a much lower amount of liquid than normal. These conditions can lead to severe dehydration (loss of water in your body). You may need to stop taking GLUCOPHAGE or GLUCOPHAGE XR for a short time. plan to have surgery or an x-ray procedure with injection of dye (contrast agent). You may need to stop taking GLUCOPHAGE or GLUCOPHAGE XR for a short time. start to take other medicines or change how you take a medicine. GLUCOPHAGE and GLUCOPHAGE XR can affect how well other drugs work, and some drugs can affect how well GLUCOPHAGE and GLUCOPHAGE XR work. Some medicines may cause high blood sugar. GLUCOPHAGE XR must be swallowed whole and never crushed or chewed. Occasionally, the inactive ingredients of GLUCOPHAGE XR may be eliminated as a soft mass in your stool that may look like the original tablet; this is not harmful and will not affect the way GLUCOPHAGE XR works to control your diabetes. What should I avoid while taking GLUCOPHAGE or GLUCOPHAGE XR? Do not drink a lot of alcoholic drinks while taking GLUCOPHAGE or GLUCOPHAGE XR. 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 GLUCOPHAGE and GLUCOPHAGE XR? Lactic Acidosis. In rare cases, GLUCOPHAGE and GLUCOPHAGE XR can cause a serious side effect called lactic acidosis. This is caused by a buildup of lactic acid in your blood. This buildup can cause serious damage. Lactic acidosis caused by GLUCOPHAGE and GLUCOPHAGE XR is rare and has occurred mostly in people whose kidneys were not working normally. Lactic acidosis has been reported in about one in 33,000 patients taking GLUCOPHAGE over the course of a year. Although rare, if lactic acidosis does occur, it can be fatal in up to half the people who develop it. It is also important for your liver to be working normally when you take GLUCOPHAGE or GLUCOPHAGE XR. Your liver helps remove lactic acid from your blood. Make sure you tell your doctor before you use GLUCOPHAGE or GLUCOPHAGE XR if you have kidney or liver problems. You should also stop using GLUCOPHAGE or GLUCOPHAGE XR and call your doctor right away if you have signs of lactic acidosis. Lactic acidosis is a medical emergency that must be treated in a hospital. Signs of lactic acidosis are: feeling very weak, tired, or uncomfortable unusual muscle pain trouble breathing unusual or unexpected stomach discomfort feeling cold feeling dizzy or lightheaded suddenly developing a slow or irregular heartbeat If your medical condition suddenly changes, stop taking GLUCOPHAGE or GLUCOPHAGE XR and call your doctor right away. This may be a sign of lactic acidosis or another serious side effect. Other Side Effects. Common side effects of GLUCOPHAGE and GLUCOPHAGE XR include diarrhea, nausea, and upset stomach. These side effects generally go away after you take the medicine for a while. Taking your medicine with meals can help reduce these side effects. Tell your doctor if the side effects bother you a lot, last for more than a few weeks, come back after they've gone away, or start later in therapy. You may need a lower dose or need to stop taking the medicine for a short period or for good. About 3 out of every 100 people who take GLUCOPHAGE or GLUCOPHAGE XR have an unpleasant metallic taste when they start taking the medicine. It lasts for a short time. GLUCOPHAGE and GLUCOPHAGE XR rarely cause hypoglycemia (low blood sugar) by themselves. However, hypoglycemia can happen if you do not eat enough, if you drink alcohol, or if you take other medicines to lower blood sugar. General advice about prescription medicines If you have questions or problems, talk with your doctor or other healthcare provider. You can ask your doctor or pharmacist for the information about GLUCOPHAGE and GLUCOPHAGE XR that is written for healthcare professionals. Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use GLUCOPHAGE or GLUCOPHAGE XR for a condition for which it was not prescribed. Do not share your medicine with other people.

Medication Guide

PATIENT INFORMATION Fortamet® (metformin hydrochloride) Extended-Release Tablets Q1. Why do I need to take FORTAMET® ? Your doctor has prescribed FORTAMET® to treat your type 2 diabetes, a condition in which blood sugar (blood glucose) is elevated. There are two types of diabetes. FORTAMET® is indicated for the most common type, known as type 2 diabetes. Q2. Why is it important to control type 2 diabetes ? Type 2 diabetes has multiple possible complications, including blindness, kidney failure, and circulatory and heart problems. Lowering your blood sugar to a normal level may prevent or delay these complications. Q3. How is type 2 diabetes usually controlled? High blood sugar can be lowered by diet and exercise, by a number of oral medications and by insulin injections. Your doctor may recommend that you try lifestyle modifications such as improved diet and exercise before initiating drug treatment for type 2 diabetes. Each patient will be treated individually by his or her physician, and should follow all treatment recommendations. Q4. Does FORTAMET® work differently from other glucosecontrol medications ? Yes. FORTAMET®, as well as other formulations of metformin, lowers the amount of sugar in your blood by controlling how much sugar is released by the liver. FORTAMET® (metformin hydrochloride) does not cause your body to produce more insulin. FORTAMET® rarely causes hypoglycemia (low blood sugar) and it does not usually cause weight gain when taken alone. However, if you do not eat enough, if you take other medications to lower blood sugar, or if you drink alcohol, you can develop hypoglycemia. Specifically, when FORTAMET® is taken together with a sulfonylurea or with insulin, hypoglycemia and weight gain are more likely to occur. Q5. What happens if my blood sugar is still too high? If your blood sugar is high, consult your physician. When blood sugar cannot be lowered enough by either FORTAMET® (metformin hydrochloride) Extended-Release Tablets or a sulfonylurea, the two medications can be effective when taken together. Other alternatives involve switching to other oral antidiabetic drugs (e.g., alpha glucoside inhibitors or glitazones). FORTAMET® may be stopped and replaced with other drugs and/or insulin. If you are unable to maintain your blood sugar with diet, exercise and glucose-control medications taken orally, then your doctor may prescribe injectable insulin to control your diabetes. Q6. Why should I take FORTAMET® in addition to insulin if I am already on insulin alone? Adding FORTAMET® to insulin can help you better control your blood sugar while reducing the insulin dose and possibly reducing your weight. Q7. Can FORTAMET® cause side effects ? FORTAMET®, like all blood sugar-lowering medications, can cause side effects in some patients. Most of these side effects are minor and will go away after you've taken FORTAMET® for a while. However, there are also serious but rare side effects related to FORTAMET® (see below). Q8. What kind of side effects can FORTAMET® cause? If side effects occur, they usually occur during the first few weeks of therapy. They are normally minor ones such as diarrhea, nausea, abdominal pain and upset stomach. FORTAMET® is generally taken with meals, which reduce these side effects. Although these side effects are likely to go away, call your doctor if you have severe discomfort or if these effects last for more than a few weeks. Some patients may need to have their doses lowered or stop taking FORTAMET®, either temporarily or permanently. You should tell your doctor if the problems come back or start later on during the therapy. WARNING: A rare number of people who have taken metformin have developed a serious condition called lactic acidosis. Properly functioning kidneys are needed to help prevent lactic acidosis. You should not take FORTAMET® if you have impaired kidney function, as measured by a blood test (see Q9-13). Q9. Are there any serious side effects that FORTAMET® can cause? FORTAMET® rarely causes serious side effects. The most serious side effect that FORTAMET® can cause is called lactic acidosis. Q10. What is lactic acidosis and can it happen to me? Lactic acidosis is caused by a build-up of lactic acid in the blood. Lactic acidosis associated with metformin is rare and has occurred mostly in people whose kidneys were not working normally. Lactic acidosis has been reported in about one in 33,000 patients taking metformin over the course of a year. Although rare, if lactic acidosis does occur, it can be fatal in up to half the cases. It is also important for your liver to be working normally when you take FORTAMET®. Your liver helps to remove lactic acid from your bloodstream. Your doctor will monitor your diabetes and may perform blood tests on you from time to time to make sure your kidneys and your liver are functioning normally. There is no evidence that FORTAMET® causes harm to the kidneys or liver. Q11. Are there other risk factors for lactic acidosis ? Your risk of developing lactic acidosis from taking FORTAMET® is very low as long as your kidneys and liver are healthy. However, some factors can increase your risk because they can affect kidney and liver function. You should discuss your risk with your physician. You should not take FORTAMET® if: You have some forms of kidney or liver problems You have congestive heart failure which is treated with medications, e.g., digoxin (Lanoxin®) or furosemide (Lasix®) You drink alcohol excessively (all the time or short-term “binge” drinking) You are seriously dehydrated (have lost a large amount of body fluids) You are going to have, within a few days, certain x-ray tests with injectable contrast agents You are going to have surgery You develop a serious condition such as a heart attack, severe infection, or a stroke You are 80 years of age or older and have NOT had your kidney function tested Q12. What are the symptoms of lactic acidosis ? Some of the symptoms include feeling very weak, tired or uncomfortable, unusual muscle pain, trouble breathing, unusual or unexpected stomach discomfort, feeling cold, feeling dizzy or lightheaded, or suddenly developing a slow or irregular heartbeat. If you notice these symptoms, or if your medical condition has suddenly changed, stop taking FORTAMET® and call your doctor right away. Lactic acidosis is a medical emergency that must be treated in a hospital. Q13. What does my doctor need to know to decrease my risk of lactic acidosis ? Tell your doctor if you have an illness that results in severe vomiting, diarrhea and/or fever, or if your intake of fluids is generally reduced. These situations can lead to severe dehydration, and it may be necessary to stop taking FORTAMET® temporarily. You should let your doctor know if you are going to have any surgery or specialized x-ray procedures that require injection of contrast agents. FORTAMET® therapy will need to be stopped temporarily in such instances. Q14. Can I take FORTAMET® with other medications ? Remind your doctor and/or pharmacist that you are taking FORTAMET® when any new drug is prescribed or a change is made in how you take a drug already prescribed. FORTAMET® may interfere with the way some drugs work and some drugs may interfere with the action of FORTAMET®. Q15. What if I become pregnant while taking FORTAMET® ? Tell your doctor if you plan to become pregnant or have become pregnant. As with other oral glucosecontrol medications, you should not take FORTAMET® during pregnancy. Usually your doctor will prescribe insulin while you are pregnant. Q16. How do I take FORTAMET® ? FORTAMET® tablets should not be cut, crushed, or chewed and should be taken whole with a full glass of water once daily with the evening meal. Occasionally, the inactive ingredients of FORTAMET® may be eliminated as a soft mass in your stool that may look like the original tablet; this is not harmful and will not affect the way FORTAMET® works to control diabetes. FORTAMET® should be taken once a day with food. You will be started on a low dose of FORTAMET® and your dosage will be increased gradually until your blood sugar is controlled. Q17. Where can I get more information about FORTAMET® ? This leaflet is a summary of the most important information about FORTAMET®. If you have any questions or problems, you should talk to your doctor or other healthcare provider about type 2 diabetes as well as FORTAMET® and its side effects.

Overdosage & Contraindications

OVERDOSE Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no casual association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see WARNINGS AND PRECAUTIONS]. 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. CONTRAINDICATIONS Riomet is contraindicated in patients with: Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥ 1.5 mg/dL [males], ≥ 1.4 mg/dL [females] or abnormal creatinine clearance) which may also result from  conditions such as cardiovascular collapse (shock), acute myocardial infarction, and  septicemia [see WARNINGS AND PRECAUTIONS]. Known hypersensitivity to metformin hydrochloride. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin. Riomet 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 WARNINGS AND PRECAUTIONS].

Overdosage & Contraindications

Overdosage & Contraindications

OVERDOSE Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases (see WARNINGS). Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected. CONTRAINDICATIONS GLUCOPHAGE and GLUCOPHAGE XR are contraindicated in patients with: Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥ 1.5 mg/dL [males], ≥ 1.4 mg/dL [females] or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia (see WARNINGS and PRECAUTIONS). Known hypersensitivity to metformin hydrochloride. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin. GLUCOPHAGE and GLUCOPHAGE XR 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.)

Overdosage & Contraindications

OVERDOSE Hypoglycemia has not been seen even with ingestion of up to 85 grams of immediate-release 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. CONTRAINDICATIONS FORTAMET® is contraindicated in patients with: Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥ 1.5 mg/dL [males], ≥ 1.4 mg/dL [females] or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia (see WARNINGS and PRECAUTIONS). Known hypersensitivity to metformin. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin. FORTAMET® 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).

Side Effects & Drug Interactions

SIDE EFFECTS Clinical Studies Experience In a U.S. double-blind clinical study of metformin in patients with type 2 diabetes, a total of 141 patients received metformin therapy (up to 2550 mg per day) and 145 patients received placebo. Adverse reactions reported in greater than 5% of the metformin patients, and that were more common in metformin- than placebo-treated patients, are listed in Table 1. Table 1: Most Common Adverse Reactions ( > 5.0 Percent) in a Placebo-Controlled Clinical Study of Metformin Monotherapy* Adverse Reaction Metformin Monotherapy (n = 141) Placebo (n = 145) % of patients Diarrhea 53.2 11.7 Nausea/ Vomiting 25.5 8.3 Flatulence 12.1 5.5 Asthenia 9.2 5.5 Indigestion 7.1 4.1 Abdominal Discomfort 6.4 4.8 Headache 5.7 4.8 *-Reactions that were more common in metformin-than placebo-treated patients. Diarrhea led to discontinuation of study medication in 6% of patients treated with metformin. Additionally, the following adverse reactions were reported in ≥ 1.0 to ≤ 5.0% of metformin patients and were more commonly reported with metformin than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation. Pediatric Patients In clinical trials with metformin in pediatric patients with type 2 diabetes, the profile of adverse reactions was similar to that observed in adults. DRUG INTERACTIONS Glyburide In a single-dose interaction study in type 2 diabetes patients, co-administration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and Cmax were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects, makes the clinical significance of this interaction uncertain [see DOSAGE AND ADMINISTRATION]. 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 Riomet 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 Riomet, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving Riomet, 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.

Side Effects & Drug Interactions

SIDE EFFECTS 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. Table 1: Treatment-Emergent Adverse Reactions Reported By >5H* of Patients for the Combined GLUMETZA Groups Venus Placebo Group Adverse Reaction GLUMETZA + Ghburide (n =431) Placebo + Glyburide (n = 144) Hypoglycemia 13.7% 4.9% Dianhea 12.5% 5.6% Nausea 6.7% 4.2% * ARs that were more common in the GLUMETZA-treated than in the placebo- treated patients Laboratory Tests Vitamin B12 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) DRUG INTERACTIONS Carbonic Anhydrase Inhibitors Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently decrease serum bicarbonate and induce nonunion 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. 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 recommendedin patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system. 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.

Side Effects & Drug Interactions

SIDE EFFECTS In a US double-blind clinical study of GLUCOPHAGE in patients with type 2 diabetes, a total of 141 patients received GLUCOPHAGE therapy (up to 2550 mg per day) and 145 patients received placebo. Adverse reactions reported in greater than 5% of the GLUCOPHAGE patients, and that were more common in GLUCOPHAGE- than placebo-treated patients, are listed in Table 11. Table 11: Most Common Adverse Reactions ( > 5.0 Percent) in a Placebo-Controlled Clinical Study of GLUCOPHAGE Monotherapy* Adverse Reaction GLUCOPHAGE Monotherapy (n=141) Placebo (n=145) % of Patients Diarrhea 53.2 11.7 Nausea/Vomiting 25.5 8.3 Flatulence 12.1 5.5 Asthenia 9.2 5.5 Indigestion 7.1 4.1 Abdominal Discomfort 6.4 4.8 Headache 5.7 4.8 * Reactions that were more common in GLUCOPHAGE- than placebo-treated patients Diarrhea led to discontinuation of study medication in 6% of patients treated with GLUCOPHAGE. Additionally, the following adverse reactions were reported in ≥ 1.0% to ≤ 5.0% of GLUCOPHAGE patients and were more commonly reported with GLUCOPHAGE than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation. In worldwide clinical trials over 900 patients with type 2 diabetes have been treated with GLUCOPHAGE XR in placebo- and active-controlled studies. In placebo-controlled trials, 781 patients were administered GLUCOPHAGE XR and 195 patients received placebo. Adverse reactions reported in greater than 5% of the GLUCOPHAGE XR patients, and that were more common in GLUCOPHAGE XR- than placebo-treated patients, are listed in Table 12. Table 12: Most Common Adverse Reactions ( > 5.0 Percent) in Placebo-Controlled Studies of GLUCOPHAGE XR* Adverse Reaction GLUCOPHAGE XR (n=781) Placebo (n=195) % of Patients Diarrhea 9.6 2.6 Nausea/Vomiting 6.5 1.5 * Reactions that were more common in GLUCOPHAGE XR- than placebo-treated patients. Diarrhea led to discontinuation of study medication in 0.6% of patients treated with GLUCOPHAGE XR. Additionally, the following adverse reactions were reported in ≥ 1.0% to ≤ 5.0% of GLUCOPHAGE XR patients and were more commonly reported with GLUCOPHAGE XR than placebo: abdominal pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance. Liver function test abnormalities or hepatitis, resolving upon metformin discontinuation, have been reported very rarely. Pediatric Patients In clinical trials with GLUCOPHAGE in pediatric patients with type 2 diabetes, the profile of adverse reactions was similar to that observed in adults. DRUG INTERACTIONS (Clinical Evaluation of Drug Interactions Conducted with GLUCOPHAGE) Glyburide In a single-dose interaction study in type 2 diabetes patients, coadministration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and Cmax were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects, makes the clinical significance of this interaction uncertain (see DOSAGE AND ADMINISTRATION: Concomitant GLUCOPHAGE or GLUCOPHAGE XR and Oral Sulfonylurea Therapy in Adult Patients). Furosemide A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by coadministration. 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 coadministered chronically. Nifedipine A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that coadministration 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 GLUCOPHAGE or GLUCOPHAGE XR 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 GLUCOPHAGE or GLUCOPHAGE XR, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving GLUCOPHAGE or GLUCOPHAGE XR, 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 coadministered 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.

Side Effects & Drug Interactions

SIDE EFFECTS FORTAMET® Clinical Studies In the controlled clinical studies of FORTAMET® in patients with type 2 diabetes, a total of 424 patients received FORTAMET® therapy (up to 2500 mg/day) and 430 patients received immediaterelease metformin. Adverse reactions reported in ≥ 5% of the FORTAMET® or immediate-release metformin patients are listed in Table 6. These pooled results show that the most frequently reported adverse reactions in the FORTAMET® group were infection, diarrhea, and nausea. Similar incidences of these adverse reactions were seen in the immediate-release metformin group. Table 6 : Number and Percentage of Patients With the Most Common (Incidence ≥ 5%)Treatment- Emergent Signs or Symptoms by Body System and PreferredTerm - Pooled Phase II and III Studies FORTAMET® (N=424) Immediate-Release Metformin (N=430) Body System Preferred Term n(%) n(%) Body as a Whole Accidental Injury 31(7.3) 24(5.6) Headache 20(4.7) 22(5.1) Infection 87(20.5) 90(20.9) Digestive System Diarrhea 71(16.7) 51(11.9) Dyspepsia 18(4.2) 22(5.1) Nausea 36(8.5) 32(7.4) Respiratory System Rhinitis 18(4.2) 24(5.6) The most frequent adverse events thought to be related to FORTAMET® were diarrhea, nausea, dyspepsia, flatulence, and abdominal pain. The frequency of dyspepsia was 4.2% in the FORTAMET® group compared to 5.1% in the immediate-release group, the frequency of flatulence was 3.5% in the FORTAMET® group compared to 3.7% in the immediate-release group, and the frequency of abdominal pain was 3.3% in the FORTAMET® group compared to 4.4% in the immediate-release group. In the controlled studies, 4.7% of patients treated with FORTAMET® and 4.9% of patients treated with immediate-release metformin were discontinued due to adverse events. Immediate-Release Metformin Immediate-Release Metformin Phase III Clinical Studies In a U.S. double-blind clinical study of immediate-release metformin in patients with type 2 diabetes, a total of 141 patients received immediate-release metformin therapy (up to 2550 mg per day) and 145 patients received placebo. Adverse reactions reported in greater than 5% of the immediate-release metformin patients, and that were more common in immediate-release metformin than placebo-treated patients, are listed in Table 7. Table 7 : Most Common Adverse Reactions ( > 5.0%) in a Placebo-Controlled Clinical Study of Immediate-Release Metformin Monotherapy* Adverse Reaction Immediate-Release Metformin Monotherapy (n = 141) Placebo (n = 145) % of Patients Diarrhea 53.2 11.7 Nausea/Vomiting 25.5 8.3 Flatulence 12.1 5.5 Asthenia 9.2 5.5 Indigestion 7.1 4.1 Abdominal Discomfort 6.4 4.8 Headache 5.7 4.8 *Reactions that were more common in immediate-release metformin than placebo-treated patients Diarrhea led to discontinuation of study medication in 6% of patients treated with immediate-release metformin. Additionally, the following adverse reactions were reported in ≥ 1.0 - ≤ 5.0% of immediaterelease metformin patients and were more commonly reported with immediate-release metformin than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation. Pediatric Patients No pediatric clinical studies have been conducted with FORTAMET®. In clinical trials with immediaterelease metformin in pediatric patients with type 2 diabetes, the profile of adverse reactions was similar to that observed in adults. DRUG INTERACTIONS Drug Interactions (Clinical Evaluation Of Drug Interactions Conducted With Immediate-Release Metformin) Glyburide In a single-dose interaction study in type 2 diabetes patients, co-administration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and Cmax were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects, makes the clinical significance of this interaction uncertain (see DOSAGE AND ADMINISTRATION: Concomitant FORTAMET® and Oral Sulfonylurea Therapy in Adult Patients). 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 FORTAMET® 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 FORTAMET®, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving FORTAMET®, 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 coadministered 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.

Warnings & Precautions

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Lactic Acidosis Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with Riomet; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels ( > 5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels > 5 μg/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking Riomet and by use of the minimum effective dose of Riomet. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Riomet treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, Riomet 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, Riomet should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking Riomet, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, Riomet should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure [see Radiologic Studies Involving the Use of Intravascular Iodinated Contrast Materials]. The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur. Riomet should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and, if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of Riomet, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease. Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking Riomet 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 Riomet, 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]. Impaired Hepatic Function Since impaired hepatic function has been associated with some cases of lactic acidosis, Riomet should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Monitoring Of Renal Function Metformin is known to be 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 Riomet. In patients with advanced age, Riomet 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, generally, Riomet should not be titrated to the maximum dose [see DOSAGE AND ADMINISTRATION]. Before initiation of Riomet 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 Riomet 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, should be used with caution [see DRUG INTERACTIONS]. Radiologic Studies Involving The Use Of Intravascular Iodinated Contrast Materials 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, Riomet 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. Vitamin B12 Levels In controlled clinical trials of metformin of 29 weeks duration, 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 metformin or Vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on Riomet and any apparent abnormalities should be appropriately investigated and managed [see 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. 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 Riomet [see Radiologic Studies Involving the Use of Intravascular Iodinated Contrast Materials]. Surgical Procedures Riomet 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. Change In Clinical Status Of Patients With Previously Controlled Type 2 Diabetes A patient with type 2 diabetes previously well controlled on Riomet 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, Riomet must be stopped immediately and other appropriate corrective measures initiated [see CONTRAINDICATIONS]. 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. 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 Riomet therapy, the drug should be promptly discontinued. 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 Riomet and temporarily administer insulin. Riomet 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 Riomet or sulfonylurea monotherapy, combined therapy with Riomet and sulfonylurea may result in a response. Should secondary failure occur with combined Riomet /sulfonylurea therapy, it may be necessary to consider therapeutic alternatives including initiation of insulin therapy. Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Riomet or any other oral anti-diabetic drug. 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 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 [see Vitamin B12 Levels]. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks), at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately four times 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 mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day. There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative. Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons. Use In Specific Populations Pregnancy Teratogenic Effects Pregnancy Category B Recent information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities. Most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Because animal reproduction studies are not always predictive of human response, Riomet should not be used during pregnancy unless clearly needed. There are no adequate and well-controlled studies in pregnant women with metformin. Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about two and six times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin. 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. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If Riomet is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered. Pediatric Use The safety and effectiveness of metformin for the treatment of type 2 diabetes have been established in pediatric patients ages 10 to 16 years (studies have not been conducted in pediatric patients below the age of 10 years). Use of metformin in this age group is supported by evidence from adequate and well-controlled studies of metformin in adults with additional data from a controlled clinical study in pediatric patients ages 10 to 16 years with type 2 diabetes, which demonstrated a similar response in glycemic control to that seen in adults [see Clinical Studies]. In this study, adverse effects were similar to those described in adults [see ADVERSE REACTIONS]. A maximum daily dose of 2000 mg is recommended [see DOSAGE AND ADMINISTRATION]. Geriatric Use Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients. Metformin is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, Riomet should only be used in patients with normal renal function [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]. Because aging is associated with reduced renal function, Riomet should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of Riomet [see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION].

Warnings & Precautions

WARNINGS Lactic Acidosis Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with GLUMETZA (metformin hcl) ; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels ( > 5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels > 5 μg/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking GLUMETZA (metformin hcl) and by use of the minimum effective dose of GLUMETZA (metformin hcl) . In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. GLUMETZA (metformin hcl) treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, GLUMETZA (metformin hcl) 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 (metformin hcl) should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking GLUMETZA (metformin hcl) , since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, GLUMETZA (metformin hcl) should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see also PRECAUTIONS). The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. These may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose and, if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of GLUMETZA (metformin hcl) , gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease. Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking GLUMETZA (metformin hcl) do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling. (See also PRECAUTIONS.) Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia). Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking GLUMETZA (metformin hcl) , the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery. (See also CONTRAINDICATIONS and PRECAUTIONS.) PRECAUTIONS General There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with GLUMETZA (metformin hcl) 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 (metformin hcl) . In patients with advanced age, GLUMETZA (metformin hcl) 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 (metformin hcl) should generally not be titrated to the maximum dose (see WARNINGS and DOSAGE AND ADMINISTRATION). Before initiation of GLUMETZA (metformin hcl) 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 (metformin hcl) 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 (metformin hcl) 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 (metformin hcl) therapy, the drug should be promptly discontinued. Surgical procedures — GLUMETZA (metformin hcl) 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 (metformin hcl) . Impaired hepatic function — Since impaired hepatic function has been associated with some cases of lactic acidosis GLUMETZA (metformin hcl) 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 (metformin hcl) or Vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on GLUMETZA (metformin hcl) 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 (metformin hcl) 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 (metformin hcl) 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 (metformin hcl) and temporarily administer insulin. GLUMETZA (metformin hcl) 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 (metformin hcl) or sulfonylurea monotherapy, combined therapy with GLUMETZA (metformin hcl) and sulfonylurea may result in a response. Should secondary failure occur with combined GLUMETZA (metformin hcl) /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 (metformin hcl) 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 (metformin hcl) sections, should be explained to patients. Patients should be advised to discontinue GLUMETZA (metformin hcl) 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 (metformin hcl) , 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 (metformin hcl) 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 (metformin hcl) 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 (metformin hcl) 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.)

Warnings & Precautions

WARNINGS Lactic Acidosis: Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with GLUCOPHAGE or GLUCOPHAGE XR; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels ( > 5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels > 5 μg/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases /1000 patient-years, with approximately 0.015 fatal cases /1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking GLUCOPHAGE or GLUCOPHAGE XR and by us e of the minimum effective dose of GLUCOPHAGE or GLUCOPHAGE XR. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. GLUCOPHAGE or GLUCOPHAGE XR 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 lacticacidosis. In addition, GLUCOPHAGE and GLUCOPHAGE XR 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, GLUCOPHAGE and GLUCOPHAGE XR should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking GLUCOPHAGE or GLUCOPHAGE XR, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, GLUCOPHAGE and GLUCOPHAGE XR should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see also PRECAUTIONS). The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur (see also PRECAUTIONS). GLUCOPHAGE and GLUCOPHAGE XR should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of GLUCOPHAGE or GLUCOPHAGE XR, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease. Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking GLUCOPHAGE or GLUCOPHAGE XR do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling. (See also PRECAUTIONS.) Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia). Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking GLUCOPHAGE or GLUCOPHAGE XR, 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 res ultsin prompt reversal of symptoms and recovery. (See also CONTRAINDICATIONS and PRECAUTIONS.) PRECAUTIONS General Macrovascular Outcomes - There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with GLUCOPHAGE or GLUCOPHAGE XR or any other antidiabetic drug. Monitoring of renal function - Metformin is known to be 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 GLUCOPHAGE or GLUCOPHAGE XR. In patients with advanced age, GLUCOPHAGE and GLUCOPHAGE XR 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, generally, GLUCOPHAGE and GLUCOPHAGE XR should not be titrated to the maximum dose (see WARNINGS and DOSAGE AND ADMINISTRATION). Before initiation of GLUCOPHAGE or GLUCOPHAGE XR 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 GLUCOPHAGE or GLUCOPHAGE XR 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 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, GLUCOPHAGE or GLUCOPHAGE XR 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 GLUCOPHAGE or GLUCOPHAGE XR therapy, the drug should be promptly discontinued. Surgical procedures - GLUCOPHAGE or GLUCOPHAGE XR 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 GLUCOPHAGE or GLUCOPHAGE XR. Impaired hepatic function - Since impaired hepatic function has been associated with some cases of lactic acidosis, GLUCOPHAGE and GLUCOPHAGE XR should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Vitamin B12 levels - In controlled clinical trials of GLUCOPHAGE of 29 weeks duration, 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 GLUCOPHAGE or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on GLUCOPHAGE or GLUCOPHAGE XR 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 2- to 3-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 GLUCOPHAGE or GLUCOPHAGE XR 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, GLUCOPHAGE or GLUCOPHAGE XR must be stopped immediately and other appropriate corrective measures initiated (see also WARNINGS). Hypoglycemia - Hypoglycemia does not occur in patients receiving GLUCOPHAGE or GLUCOPHAGE XR 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 GLUCOPHAGE or GLUCOPHAGE XR and temporarily administer insulin. GLUCOPHAGE or GLUCOPHAGE XR 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 GLUCOPHAGE or GLUCOPHAGE XR or sulfonylurea monotherapy, combined therapy with GLUCOPHAGE or GLUCOPHAGE XR and sulfonylurea may result in a response. Should secondary failure occur with combined GLUCOPHAGE/sulfonylurea therapy or GLUCOPHAGE XR/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 GLUCOPHAGE or GLUCOPHAGE XR 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 WARNINGS and PRECAUTIONS sections, should be explained to patients. Patients should be advised to discontinue GLUCOPHAGE or GLUCOPHAGE XR 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 GLUCOPHAGE or GLUCOPHAGE XR, 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 GLUCOPHAGE or GLUCOPHAGE XR. GLUCOPHAGE or GLUCOPHAGE XR alone does not usually cause hypoglycemia, although it may occur when GLUCOPHAGE or GLUCOPHAGE XR 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. (See PATIENT INFORMATION.) Patients should be informed that GLUCOPHAGE XR 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. 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 GLUCOPHAGE therapy, if this is suspected, vitamin B12 deficiency should be excluded. Carcinogenesis, Mutagenesis, Impairment Of Fertility Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately 4 times 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 mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day. There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative. Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately 3 times the maximum recommended human daily dose based on body surface area comparisons. Pregnancy Teratogenic Effects Recent information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities. Most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Because animal reproduction studies are not always predictive of human response, GLUCOPHAGE and GLUCOPHAGE XR should not be used during pregnancy unless clearly needed. There are no adequate and well-controlled studies in pregnant women with GLUCOPHAGE or GLUCOPHAGE XR. Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 6 times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin. 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. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If GLUCOPHAGE or GLUCOPHAGE XR is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered. Pediatric Use The safety and effectiveness of GLUCOPHAGE for the treatment of type 2 diabetes have been established in pediatric patients ages 10 to 16 years (studies have not been conducted in pediatric patients below the age of 10 years). Use of GLUCOPHAGE in this age group is supported by evidence from adequate and well-controlled studies of GLUCOPHAGE in adults with additional data from a controlled clinical study in pediatric patients ages 10 to 16 years with type 2 diabetes, which demonstrated a similar response in glycemic control to that seen in adults. (See CLINICAL PHARMACOLOGY: Pediatric Clinical Studies.) In this study, adverse effects were similar to those described in adults. (See ADVERSE REACTIONS: Pediatric Patients.) A maximum daily dose of 2000 mg is recommended. (See DOSAGE AND ADMINISTRATION: Recommended Dosing Schedule: Pediatrics .) Safety and effectiveness of GLUCOPHAGE XR in pediatric patients have not been established. Geriatric Use Controlled clinical studies of GLUCOPHAGE and GLUCOPHAGE XR did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients. Metformin is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, GLUCOPHAGE and GLUCOPHAGE XR should only be used in patients with normal renal function (see CONTRAINDICATIONS, WARNINGS, and CLINICAL PHARMACOLOGY: Pharmacokinetics ). Because aging is associated with reduced renal function, GLUCOPHAGE or GLUCOPHAGE XR should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of GLUCOPHAGE or GLUCOPHAGE XR (see also WARNINGS and DOSAGE AND ADMINISTRATION).

Warnings & Precautions

WARNINGS Lactic Acidosis Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with FORTAMET® (metformin hydrochloride) Extended-Release Tablets; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels ( > 5 mmol/ L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels > 5 μg/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases /1000 patient-years , with approximately 0.015 fatal cases /1000 patient-years). Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/ surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking FORTAMET® (metformin hydrochloride) Extended-Release Tablets and by use of the minimum effective dose of FORTAMET®. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. FORTAMET® treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, FORTAMET® 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, FORTAMET® should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking FORTAMET®, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, FORTAMET® should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see also PRECAUTIONS). The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur (see also PRECAUTIONS). FORTAMET® should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose and, if indicated, blood pH, lactate levels , and even blood metformin levels may be useful. Once a patient is stabilized on any dos e level of FORTAMET®, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lacticacidos is or other serious disease. Levels of fasting venous plasma lactate above the upper limit of normal but les s than 5 mmol/L in patients taking FORTAMET® 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 s ample handling (see also PRECAUTIONS). Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia). Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking FORTAMET®, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery (see also CONTRAINDICATIONS and PRECAUTIONS). PRECAUTIONS General Monitoring Of Renal Function Metformin is known to be 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 FORTAMET®. In patients with advanced age, FORTAMET® 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, generally, FORTAMET® should not be titrated to the maximum dose (see WARNINGS and DOSAGE AND ADMINISTRATION). Before initiation of FORTAMET® 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 FORTAMET® discontinued if evidence of renal impairment is present. Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with FORTAMET® or any other anti-diabetic drug. 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), 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, FORTAMET® 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 reevaluated 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 FORTAMET® therapy, the drug should be promptly discontinued. Surgical procedures - FORTAMET® 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 FORTAMET®. Impaired hepatic function - Since impaired hepatic function has been associated with some cases of lactic acidosis, FORTAMET® should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Vitamin B12 levels - In controlled clinical trials of immediate-release metformin of 29 weeks duration, 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 immediate-release metformin or Vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on FORTAMET® 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 FORTAMET® 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, FORTAMET® must be stopped immediately and other appropriate corrective measures initiated (see also WARNINGS). Hypoglycemia - Hypoglycemia does not occur in patients receiving FORTAMET® 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 FORTAMET® and temporarily administer insulin. FORTAMET® 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 FORTAMET® or sulfonylurea monotherapy, combined therapy with FORTAMET® and sulfonylurea may result in a response. Should secondary failure occur with combined FORTAMET® /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 FORTAMET® 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 WARNINGS and PRECAUTIONS sections, should be explained to patients. Patients should be advised to discontinue FORTAMET® 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 FORTAMET®, 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 FORTAMET®. FORTAMET® alone does not usually cause hypoglycemia, although it may occur when FORTAMET® 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 (see PATIENT INFORMATION). Patients should be informed that FORTAMET® must be swallowed whole and not chewed, cut, or crushed, 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 immediate-release metformin therapy, if this is suspected, Vitamin B12 deficiency should be excluded. Carcinogenesis, Mutagenesis, Impairment Of Fertility Long-term carcinogenicity studies with metformin have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately four times 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 mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day. There was no evidence of mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative. Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons. Pregnancy Teratogenic Effects Pregnancy Category B Recent information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities. Most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Because animal reproduction studies are not always predictive of human response, FORTAMET® should not be used during pregnancy unless clearly needed. There are no adequate and well-controlled studies in pregnant women with immediate-release metformin or FORTAMET®. Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about two and six times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin. 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. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If FORTAMET® is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered. Pediatric Use No pediatric clinical studies have been conducted with FORTAMET®. The safety and effectiveness of immediate-release metformin for the treatment of type 2 diabetes have been established in pediatric patients ages 10 to 16 years (studies have not been conducted in pediatric patients below the age of 10 years). Use of immediate-release metformin in this age group is supported by evidence from adequate and well-controlled studies of immediate-release metformin in adults with additional data from a controlled clinical study in pediatric patients ages 10-16 years with type 2 diabetes, which demonstrated a similar response in glycemic control to that seen in adults (see CLINICAL PHARMACOLOGY: Pediatric Clinical Studies ). In this study, adverse effects were similar to those described in adults (see ADVERSE REACTIONS: Pediatric Patients ). A maximum daily dose of 2000 mg of immediaterelease metformin is recommended. The safety and efficacy of FORTAMET® has not been evaluated in pediatric patients. Geriatric Use Of the 389 patients who received FORTAMET® in controlled Phase III clinical studies, 26.5% [103/389] were 65 years and older. No overall differences in effectiveness or safety were observed between these patients and younger patients. Controlled clinical studies of immediate-release metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients. Metformin is known to be substantially excreted by the kidney and because of the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, immediaterelease metformin should only be used in patients with normal renal function (see CONTRAINDICATIONS, WARNINGS, and CLINICAL PHARMACOLOGY: Pharmacokinetics ). Because aging is associated with reduced renal function, immediate-release metformin should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of immediate-release metformin (see also WARNINGS and DOSAGE AND ADMINISTRATION).

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