ADVERSE REACTIONS SECTION.


For GLUCOPHAGE/GLUCOPHAGE XR, the most common adverse reactions (>5.0%) are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

BOXED WARNING SECTION.


WARNING: LACTIC ACIDOSIS. Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions (5.1)].Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided [see Dosage and Administration (2.3), (2.7), Contraindications (4), Warnings and Precautions (5.1)].If metformin-associated lactic acidosis is suspected, immediately discontinue GLUCOPHAGE or GLUCOPHAGE XR and institute general supportive measures in hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1)].. WARNING: LACTIC ACIDOSIS See full prescribing information for complete boxed warning. Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL. (5.1)Risk factors include renal impairment, concomitant use of certain drugs, age >65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information. (5.1)If lactic acidosis is suspected, discontinue GLUCOPHAGE/ GLUCOPHAGE XR and institute general supportive measures in hospital setting. Prompt hemodialysis is recommended. (5.1). Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL. (5.1). Risk factors include renal impairment, concomitant use of certain drugs, age >65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information. (5.1). If lactic acidosis is suspected, discontinue GLUCOPHAGE/ GLUCOPHAGE XR and institute general supportive measures in hospital setting. Prompt hemodialysis is recommended. (5.1).

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type diabetes mellitus, 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. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.. 12.3 Pharmacokinetics. AbsorptionThe absolute bioavailability of 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 lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. 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 ug/mL.Following single oral dose of GLUCOPHAGE XR, Cmax is achieved with median value of hours and range of to 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 comparable 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 mcg/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 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.Effect of food: Food decreases the extent of absorption and slightly delays the absorption of metformin, as shown by approximately 40% lower mean peak plasma concentration (Cmax), 25% lower area under the plasma concentration versus time curve (AUC), and 35-minute prolongation of time to peak plasma concentration (Tmax) following administration of single 850 mg tablet of GLUCOPHAGE with food, compared to the same tablet strength administered fasting.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.DistributionThe 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. Metformin partitions into erythrocytes, most likely as function of time.MetabolismIntravenous 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. Elimination 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 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 compartment of distribution.Specific PopulationsRenal ImpairmentIn patients with decreased renal function the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased (see Table 3) [See Dosage and Administration (2.3), Contraindications (4), Warnings and Precautions (5.1) and Use in Specific Populations (8.6)] Hepatic Impairment No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment [See Warnings and Precautions (5.1) and Use in Specific Populations (8.7)]GeriatricsLimited 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. It appears that the change in metformin pharmacokinetics with aging is primarily accounted for by change in renal function (see Table 4). [See Warnings and Precautions (5.1) and Use in Specific Populations (8.5)]Table 4: Select Mean (+-S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of GLUCOPHAGE Subject Groups: GLUCOPHAGE dosea (number of subjects) Cmax (mcg/mL) Tmax (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 diabetes mellitus: 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) All doses given fasting except the first 18 doses of the multiple dose studies Peak plasma concentration Time to peak plasma concentration Combined results (average means) of five studies: mean age 32 years (range 23-59 years) Kinetic study done following dose 19, given fasting Elderly subjects, mean age 71 years (range 65-81 years) CLcr creatinine clearance normalized to body surface area of 1.73 m2 PediatricsAfter administration of single oral GLUCOPHAGE 500 mg tablet with food, geometric mean metformin Cmax and AUC differed less than 5% between pediatric type diabetic patients (12-16 years of age) and gender- and weight-matched healthy adults (20-45 years of age), all with normal renal function.GenderMetformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type diabetes mellitus when analyzed according to gender (males=19, females=16).RaceNo studies of metformin pharmacokinetic parameters according to race have been performed.Drug InteractionsIn Vivo Assessment of Drug InteractionsTable 5: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure Coadministered Drug Dose of CoadministeredDrugDose of MetforminGeometric Mean Ratio(ratio with/without coadministered drug)No Effect 1.00 AUC Cmax No dosing adjustments required for the following: Glyburide mg 850 mg metformin 0.91 0.93 Furosemide 40 mg 850 mg metformin 1.09 1.22 Nifedipine 10 mg 850 mg metformin 1.16 1.21 Propranolol 40 mg 850 mg metformin 0.90 0.94 Ibuprofen 400 mg 850 mg metformin 1.05 1.07 Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination [See Warnings and Precautions (5.9) and Drug Interactions (7.2)] Cimetidine 400 mg850 mg metformin 1.40 1.61 Carbonic anhydrase inhibitors may cause metabolic acidosis [See Warnings and Precautions (5.9) and Drug Interactions (7.1)] Topiramate 100 mg 500 mg metformin 1.25 1.17 All metformin and coadministered drugs were given as single doses AUC AUC(INF) Ratio of arithmetic means At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC AUC0-12hTable 6: Effect of Metformin on Coadministered Drug Systemic Exposure Coadministered Drug Dose ofCoadministered Drug Dose of MetforminGeometric Mean Ratio(ratio with/without metformin)No Effect 1.00 AUC+ Cmax No dosing adjustments required for the following: Glyburide mg 850 mg glyburide 0.78 0.63 Furosemide 40 mg 850 mg furosemide 0.87 0.69 Nifedipine 10 mg 850 mg nifedipine 1.10 1.08 Propranolol 40 mg 850 mg propranolol 1.01 1.02 Ibuprofen 400 mg 850 mg ibuprofen 0.97 1.01 Cimetidine 400 mg 850 mg cimetidine 0.95 1.01 All metformin and coadministered drugs were given as single doses+ AUC AUC(INF) unless otherwise noted Ratio of arithmetic means, p-value of difference <0.05 AUC(0-24 hr) reported Ratio of arithmetic means.

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES. 14.1 GLUCOPHAGE. Adult Clinical StudiesA double-blind, placebo-controlled, multicenter US clinical trial involving obese patients with type diabetes mellitus whose hyperglycemia was not adequately controlled with dietary management alone (baseline fasting plasma glucose [FPG] of approximately 240 mg/dL) was conducted. Patients were treated with GLUCOPHAGE (up to 2550 mg/day) or placebo for 29 weeks. The results are presented in Table 7.Table 7: Mean Change in Fasting Plasma Glucose and HbA1c at Week 29 Comparing GLUCOPHAGE vs Placebo in Patients with Type Diabetes Mellitus GLUCOPHAGE(n=141) Placebo(n=145) p-Value FPG (mg/dL)BaselineChange at FINULLL VISIT 241.553.0 237.76.3 NS0.001 Hemoglobin A1c (%)BaselineChange at FINULLL VISIT 8.41.4 8.20.4 NS0.001 Not statistically significantMean baseline body weight was 201 lbs and 206 lbs in the GLUCOPHAGE and placebo arms, respectively. Mean change in body weight from baseline to week 29 was -1.4 lbs and -2.4 lbs in the GLUCOPHAGE and placebo arms, respectively. 29-week, double-blind, placebo-controlled study of GLUCOPHAGE and glyburide, alone and in combination, was conducted in obese patients with type diabetes mellitus who had failed to achieve adequate glycemic control while on maximum doses of glyburide (baseline FPG of approximately 250 mg/dL). 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 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) discontinued glyburide and followed the same titration schedule. Patients in the glyburide arm continued the same dose of glyburide. 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. The results are displayed in Table 8.Table 8: Mean Change in Fasting Plasma Glucose and HbA1c at Week 29 Comparing GLUCOPHAGE/Glyburide (Comb) vs Glyburide (Glyb) vs GLUCOPHAGE (GLU): in Patients with Type Diabetes Mellitus with Inadequate Glycemic Control on Glyburide p-Values Comb(n=213) Glyb(n=209) GLU(n=210) Glyb vs Comb GLU vs Comb GLU vs GlybFasting Plasma Glucose (mg/dL) BaselineChange at FINULLL VISIT 250.5-63.5247.513.7 253.9-0.9NS0.001NS0.001NS0.025 Hemoglobin A1c (%) BaselineChange at FINULLL VISIT 8.8-1.7 8.50.2 8.9-0.4 NS0.001 NS0.0010.0070.001 Not statistically significant Mean baseline body weight was 202 lbs, 203 lbs, and 204 lbs in the GLUCOPHAGE/glyburide, glyburide, and GLUCOPHAGE arms, respectively. Mean change in body weight from baseline to week 29 was 0.9 lbs, -0.7 lbs, and -8.4 lbs in the GLUCOPHAGE/glyburide, glyburide, and GLUCOPHAGE arms, respectively.Pediatric Clinical StudiesA double-blind, placebo-controlled study in pediatric patients aged 10 to 16 years with type diabetes mellitus (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) was conducted. The results are displayed in Table 9. Table 9: Mean Change in Fasting Plasma Glucose at Week 16 Comparing GLUCOPHAGE vs Placebo in Pediatric Patientsa with Type Diabetes MellitusGLUCOPHAGE Placebo p-ValueFPG (mg/dL)(n=37) (n=36) BaselineChange at FINULLL VISIT 162.442.9 192.321.4<0.001a Pediatric patients mean age 13.8 years (range 10-16 years)Mean baseline body weight was 205 lbs and 189 lbs in the GLUCOPHAGE and placebo arms, respectively. Mean change in body weight from baseline to week 16 was -3.3 lbs and -2.0 lbs in the GLUCOPHAGE and placebo arms, respectively.. 14.2 GLUCOPHAGE XR. 24-week, double-blind, placebo-controlled study of GLUCOPHAGE XR, taken once daily with the evening meal, was conducted in patients with type diabetes mellitus who had failed to achieve glycemic control with diet and exercise. Patients entering the study had mean baseline HbA1c of 8.0% and mean baseline FPG of 176 mg/dL. The treatment dose was increased to 1500 mg once daily if at Week 12 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 diabetes mellitus who had failed to achieve glycemic control with diet and exercise. The results are shown in Table 10.Table 10: Mean Changes from Baseline in HbA1c and Fasting Plasma Glucose at Week 16 Comparing GLUCOPHAGE XR vs Placebo in Patients with Type Diabetes Mellitus GLUCOPHAGE XR 500 mgOnceDaily 1000 mgOnce Daily 1500 mgOnceDaily 2000 mgOnceDaily 1000 mgTwiceDaily Placebo 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 8.4Change at FINULLL VISIT -0.4 -0.6 -0.9 -0.8 -1.1 0.1p-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 FINULLL 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 <0.001a All comparisons versus Placebo Mean baseline body weight was 193 lbs, 192 lbs, 188 lbs, 196 lbs, 193 lbs and 194 lbs in the GLUCOPHAGE XR 500 mg, 1000 mg, 1500 mg, and 2000 mg once daily, 1000 mg twice daily and placebo arms, respectively. Mean change in body weight from baseline to week 16 was -1.3 lbs, -1.3 lbs, -0.7 lbs, -1.5 lbs, -2.2 lbs and -1.8 lbs, respectively.A 24-week, double-blind, randomized study of GLUCOPHAGE XR, taken once daily with the evening meal, and GLUCOPHAGE, taken twice daily (with breakfast and evening meal), was conducted in patients with type diabetes mellitus who had been treated with GLUCOPHAGE 500 mg twice daily for at least weeks prior to study entry. The results are shown in Table 11.Table 11: Mean Changes from Baseline in HbA1c and Fasting Plasma Glucose at Week 24 Comparing GLUCOPHAGE XR vs GLUCOPHAGE in Patients with Type Diabetes Mellitus GLUCOPHAGE500 mgTwice DailyGLUCOPHAGE XR 1000 mg Once Daily 1500 mgOnce Daily Hemoglobin A1c (%)(n=67) (n=72) (n=66) Baseline 7.06 6.99 7.02 Change at FINULLL 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 FINULLL VISIT 14.0 11.5 7.6 (95% CI) (7.0,21.0) (4.4,18.6) (1.0,14.2)a n=68Mean baseline body weight was 210 lbs, 203 lbs and 193 lbs in the GLUCOPHAGE 500 mg twice daily, and GLUCOPHAGE XR 1000 mg and 1500 mg once daily arms, respectively. Mean change in body weight from baseline to week 24 was 0.9 lbs, 1.1 lbs and 0.9 lbs, respectively.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS. Severe renal impairment (eGFR below 30 mL/min/1.73 m2) (4, 5.1)Hypersensitivity to metformin (4) Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. (4) Severe renal impairment (eGFR below 30 mL/min/1.73 m2) (4, 5.1). Hypersensitivity to metformin (4) Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. (4) . GLUCOPHAGE and GLUCOPHAGE XR are contraindicated in patients with:Severe renal impairment (eGFR below 30 mL/min/1.73 m2) [see Warnings and Precautions (5.1)].Hypersensitivity to metformin.Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.. Severe renal impairment (eGFR below 30 mL/min/1.73 m2) [see Warnings and Precautions (5.1)].. Hypersensitivity to metformin.. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.

DESCRIPTION SECTION.


11 DESCRIPTION. GLUCOPHAGE/GLUCOPHAGE XR contain the antihyperglycemic agent metformin, which is biguanide, in the form of monohydrochloride. The chemical name of metformin hydrochloride is N,N-dimethylimidodicarbonimidic diamide hydrochloride. The structural formula is as shown below: Metformin hydrochloride is white to off-white crystalline compound with molecular formula of C4H11N5 HCl and molecular weight of 165.63. It is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of 1% aqueous solution of metformin hydrochloride is 6.68.GLUCOPHAGE tablets contain 500 mg, 850 mg, or 1000 mg of metformin hydrochloride, which is equivalent to 389.93 mg, 662.88 mg, 779.86 mg metformin base, respectively. 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, which is equivalent to 389.93 mg, 584.90 mg metformin base, respectively.GLUCOPHAGE XR 500 mg tablets contain the inactive ingredients hypromellose, microcrystalline cellulose, sodium carboxymethyl cellulose, and magnesium stearate.GLUCOPHAGE XR 750 mg tablets contain the inactive ingredients hypromellose, sodium carboxymethyl cellulose, magnesium stearate and iron oxide pigment red.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION. Adult Dosage for GLUCOPHAGE:Starting dose: 500 mg orally twice day or 850 mg once day, with mealsIncrease the dose in increments of 500 mg weekly or 850 mg every weeks, up to maximum dose of 2550 mg per day, given in divided doses (2.1) Doses above 2000 mg may be better tolerated given times day with meals (2.1) Adult Dosage for GLUCOPHAGE XR:Swallow GLUCOPHAGE XR tablets whole and never crush, cut or chew (2.1) Starting dose: 500 mg orally once daily with the evening meal (2.1) Increase the dose in increments of 500 mg weekly, up to maximum of 2000 mg once daily with the evening meal (2.1) Patients receiving GLUCOPHAGE may be switched to GLUCOPHAGE XR once daily at the same total daily dose, up to 2000 mg once daily (2.1) Pediatric Dosage for GLUCOPHAGE:Starting dose: 500 mg orally twice day, with meals (2.2) Increase dosage in increments of 500 mg weekly up to maximum of 2000 mg per day, given in divided doses twice daily (2.2) Renal Impairment:Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) (2.3) Do not use in patients with eGFR below 30 mL/minute/1.73 m2 (2.3) Initiation is not recommended in patients with eGFR between 30-45 mL/minute/1.73 m2 (2.3) Assess risk/benefit of continuing if eGFR falls below 45 mL/minute/1.73 m2 (2.3) Discontinue if eGFR falls below 30 mL/minute/1.73 m2 (2.3) Discontinuation for Iodinated Contrast Imaging Procedures:GLUCOPHAGE/GLUCOPHAGE XR may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures (2.4) Starting dose: 500 mg orally twice day or 850 mg once day, with meals. Increase the dose in increments of 500 mg weekly or 850 mg every weeks, up to maximum dose of 2550 mg per day, given in divided doses (2.1) Doses above 2000 mg may be better tolerated given times day with meals (2.1) Swallow GLUCOPHAGE XR tablets whole and never crush, cut or chew (2.1) Starting dose: 500 mg orally once daily with the evening meal (2.1) Increase the dose in increments of 500 mg weekly, up to maximum of 2000 mg once daily with the evening meal (2.1) Patients receiving GLUCOPHAGE may be switched to GLUCOPHAGE XR once daily at the same total daily dose, up to 2000 mg once daily (2.1) Starting dose: 500 mg orally twice day, with meals (2.2) Increase dosage in increments of 500 mg weekly up to maximum of 2000 mg per day, given in divided doses twice daily (2.2) Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) (2.3) GLUCOPHAGE/GLUCOPHAGE XR may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures (2.4) 2.1 Adult Dosage. GLUCOPHAGEThe recommended starting dose of GLUCOPHAGE is 500 mg orally twice day or 850 mg once day, given with meals.Increase the dose in increments of 500 mg weekly or 850 mg every weeks on the basis of glycemic control and tolerability, up to maximum dose of 2550 mg per day, given in divided doses.Doses above 2000 mg may be better tolerated given times day with meals.GLUCOPHAGE XRSwallow GLUCOPHAGE XR tablets whole and never crush, cut or chew.The recommended starting dose of GLUCOPHAGE XR is 500 mg orally once daily with the evening meal.Increase the dose in increments of 500 mg weekly on the basis of glycemic control and tolerability, up to maximum of 2000 mg once daily with the evening meal.If glycemic control is not achieved with GLUCOPHAGE XR 2000 mg once daily, consider trial of GLUCOPHAGE XR 1000 mg twice daily. If higher doses are required, switch to GLUCOPHAGE at total daily doses up to 2550 mg administered in divided daily doses, as described above.Patients receiving GLUCOPHAGE may be switched to GLUCOPHAGE XR once daily at the same total daily dose, up to 2000 mg once daily.. The recommended starting dose of GLUCOPHAGE is 500 mg orally twice day or 850 mg once day, given with meals.. Increase the dose in increments of 500 mg weekly or 850 mg every weeks on the basis of glycemic control and tolerability, up to maximum dose of 2550 mg per day, given in divided doses.. Doses above 2000 mg may be better tolerated given times day with meals.. Swallow GLUCOPHAGE XR tablets whole and never crush, cut or chew.. The recommended starting dose of GLUCOPHAGE XR is 500 mg orally once daily with the evening meal.. Increase the dose in increments of 500 mg weekly on the basis of glycemic control and tolerability, up to maximum of 2000 mg once daily with the evening meal.. If glycemic control is not achieved with GLUCOPHAGE XR 2000 mg once daily, consider trial of GLUCOPHAGE XR 1000 mg twice daily. If higher doses are required, switch to GLUCOPHAGE at total daily doses up to 2550 mg administered in divided daily doses, as described above.. Patients receiving GLUCOPHAGE may be switched to GLUCOPHAGE XR once daily at the same total daily dose, up to 2000 mg once daily.. 2.2 Pediatric Dosage for GLUCOPHAGE. The recommended starting dose of GLUCOPHAGE for pediatric patients 10 years of age and older is 500 mg orally twice day, given with meals.Increase dosage in increments of 500 mg weekly on the basis of glycemic control and tolerability, up to maximum of 2000 mg per day, given in divided doses twice daily.. The recommended starting dose of GLUCOPHAGE for pediatric patients 10 years of age and older is 500 mg orally twice day, given with meals.. Increase dosage in increments of 500 mg weekly on the basis of glycemic control and tolerability, up to maximum of 2000 mg per day, given in divided doses twice daily.. 2.3 Recommendations for Use in Renal Impairment. Assess renal function prior to initiation of GLUCOPHAGE/GLUCOPHAGE XR and periodically thereafter.GLUCOPHAGE/GLUCOPHAGE XR is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m2.Initiation of GLUCOPHAGE/GLUCOPHAGE XR in patients with an eGFR between 30 45 mL/minute/1.73 m2 is not recommended.In patients taking GLUCOPHAGE/GLUCOPHAGE XR whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit risk of continuing therapy.Discontinue GLUCOPHAGE/GLUCOPHAGE XR if the patients eGFR later falls below 30 mL/minute/1.73 m2 [see Warnings and Precautions (5.1) ]. 2.4 Discontinuation for Iodinated Contrast Imaging Procedures. Discontinue GLUCOPHAGE/GLUCOPHAGE XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart GLUCOPHAGE/GLUCOPHAGE XR if renal function is stable.

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS. GLUCOPHAGE Tablets: 500 mg, 850 mg, and 1000 mg (3) GLUCOPHAGE XR Extended-Release Tablets: 500 mg and 750 mg (3) GLUCOPHAGE Tablets: 500 mg, 850 mg, and 1000 mg (3) GLUCOPHAGE XR Extended-Release Tablets: 500 mg and 750 mg (3) GLUCOPHAGE is available as:Tablets: 500 mg round, white to off-white, film-coated debossed with BMS 6060 around the periphery on one side and 500 debossed across the face of the other side. Tablets: 850 mg round, white to off-white, film-coated debossed with BMS 6070 around the periphery on one side and 850 debossed across the face of the other side.Tablets: 1000 mg white, oval, biconvex, film-coated with BMS 6071 debossed on one side and 1000 debossed on the opposite side and with bisect line on both sides.GLUCOPHAGE XR is available as:Extended-release tablets: 500 mg white to off-white, capsule shaped, biconvex, with BMS 6063 debossed on one side and 500 debossed across the face of the other side.Extended-release tablets: 750 mg pale red and may have mottled appearance, capsule shaped, biconvex, with BMS 6064 debossed on one side and 750 debossed on the other side.. Tablets: 500 mg round, white to off-white, film-coated debossed with BMS 6060 around the periphery on one side and 500 debossed across the face of the other side. Tablets: 850 mg round, white to off-white, film-coated debossed with BMS 6070 around the periphery on one side and 850 debossed across the face of the other side.. Tablets: 1000 mg white, oval, biconvex, film-coated with BMS 6071 debossed on one side and 1000 debossed on the opposite side and with bisect line on both sides.. Extended-release tablets: 500 mg white to off-white, capsule shaped, biconvex, with BMS 6063 debossed on one side and 500 debossed across the face of the other side.. Extended-release tablets: 750 mg pale red and may have mottled appearance, capsule shaped, biconvex, with BMS 6064 debossed on one side and 750 debossed on the other side.

DRUG INTERACTIONS SECTION.


Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring (7) Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the accumulation of metformin. Consider the benefits and risks of concomitant use (7) Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake (7) Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring (7) Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the accumulation of metformin. Consider the benefits and risks of concomitant use (7) Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake (7).

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. Table 12: GLUCOPHAGE/GLUCOPHAGE XR Available Strengths, Units, and Appearance GLUCOPHAGE Tablets 500 mg Bottles of 100 NDC 0087-6060-05 round, white to off-white, film-coated debossed with BMS 6060 around the periphery on one side and 500 debossed across the face of the other side 850 mgBottles of 100 NDC 0087-6070-05 round, white to off-white, film-coated debossed with BMS 6070 around the periphery on one side and 850 debossed across the face of the other side 1000 mg Bottles of 100 NDC 0087-6071-11 white, oval, biconvex, film-coated with BMS 6071 debossed on one side and 1000 debossed on the opposite side and with bisect line on both sidesGLUCOPHAGE XR Extended-Release Tablets 500 mgBottles of 100 NDC 0087-6063-13 white to off-white, capsule shaped, biconvex, with BMS 6063 debossed on one side and 500 debossed across the face of the other side750 mgBottles of 100 NDC 0087-6064-13 pale red and may have mottled appearance, capsule shaped, biconvex, with BMS 6064 debossed on one side and 750 debossed on the other side. 16.2 Storage. Store at 20-25C (68-77F); excursions permitted to 15-30C (59-86F). [See USP Controlled Room Temperature]Dispense in light-resistant containers.

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE. GLUCOPHAGE is indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients 10 years of age and older with type diabetes mellitus.GLUCOPHAGE XR is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus.. GLUCOPHAGE is biguanide indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients 10 years of age and older with type diabetes mellitus. (1) GLUCOPHAGE XR is biguanide indicated as an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus. (1).

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information). Lactic Acidosis: Explain the risks of lactic acidosis, its symptoms, and conditions that predispose to its development. Advise patients to discontinue GLUCOPHAGE/GLUCOPHAGE XR immediately and to promptly notify their healthcare provider if unexplained hyperventilation, myalgias, malaise, unusual somnolence or other nonspecific symptoms occur. Counsel patients against excessive alcohol intake and inform patients about importance of regular testing of renal function while receiving GLUCOPHAGE/GLUCOPHAGE XR. Instruct patients to inform their doctor that they are taking GLUCOPHAGE/GLUCOPHAGE XR prior to any surgical or radiological procedure, as temporary discontinuation may be required [see Warnings and Precautions (5.1)].Hypoglycemia:Inform patients that hypoglycemia may occur when GLUCOPHAGE/GLUCOPHAGE XR is coadministered with oral sulfonylureas and insulin. Explain to patients receiving concomitant therapy the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development [see Warnings and Precautions (5.3)].Vitamin B12 Deficiency:Inform patients about importance of regular hematological parameters while receiving GLUCOPHAGE/GLUCOPHAGE XR [see Warnings and Precautions (5.2)].Females of Reproductive Age:Inform females that treatment with GLUCOPHAGE/GLUCOPHAGE XR may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy [see Use in Specific Populations (8.3)].GLUCOPHAGE XR Administration Information:Inform patients that GLUCOPHAGE XR must be swallowed whole and not crushed, cut, or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as soft mass that may resemble the original tablet.Distributed by:Bristol-Myers Squibb CompanyPrinceton, NJ 08543 USAGLUCOPHAGE(R) is registered trademark of Merck Sante S.A.S., subsidiary of Merck KGaA of Darmstadt, Germany, licensed to Bristol-Myers Squibb Company.Rev December 2019.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY. 13.1 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 times the maximum recommended human daily dose of 2550 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 times the maximum recommended human daily dose of 2550 mg based on body surface area comparisons.

OVERDOSAGE SECTION.


10 OVERDOSAGE. 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 has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.1)]. Metformin is dialyzable with 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


-----------------------------------------REPRESENTATIVE PACKAGINGSee How Supplied section for complete list of available packages of GLUCOPHAGE and GLUCOPHAGE XR.100 TabletsNDC 0087-6060-05GLUCOPHAGE(R)(metformin hydrochloride) TabletsRx only500 mgBristol-Myers Squibb. glucophage-500mg-btl-lbl.

SPL UNCLASSIFIED SECTION.


The recommended starting dose of GLUCOPHAGE for pediatric patients 10 years of age and older is 500 mg orally twice day, given with meals.Increase dosage in increments of 500 mg weekly on the basis of glycemic control and tolerability, up to maximum of 2000 mg per day, given in divided doses twice daily.. The recommended starting dose of GLUCOPHAGE for pediatric patients 10 years of age and older is 500 mg orally twice day, given with meals.. Increase dosage in increments of 500 mg weekly on the basis of glycemic control and tolerability, up to maximum of 2000 mg per day, given in divided doses twice daily.

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS. Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. (8.3) Geriatric Use: Assess renal function more frequently. (8.5) Hepatic Impairment: Avoid use in patients with hepatic impairment. (8.7) Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. (8.3) Geriatric Use: Assess renal function more frequently. (8.5) Hepatic Impairment: Avoid use in patients with hepatic impairment. (8.7) 8.1 Pregnancy. Risk SummaryLimited data with GLUCOPHAGE/GLUCOPHAGE XR in pregnant women are not sufficient to determine drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported clear association with metformin and major birth defect or miscarriage risk [see Data]. There are risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy [see Clinical Considerations].No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2- and 5- times, respectively, 2550 mg clinical dose, based on body surface area [see Data].The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes mellitus with an HbA1C >7 and has been reported to be as high as 20-25% in women with HbA1C >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.Clinical ConsiderationsDisease-associated maternal and/or embryo/fetal riskPoorly-controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.DataHuman DataPublished data from post-marketing studies have not reported clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups.Animal DataMetformin hydrochloride did not adversely affect development outcomes when administered to pregnant rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about and times 2550 mg clinical dose based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated partial placental barrier to metformin.. 8.2 Lactation. Risk SummaryLimited published studies report that metformin is present in human milk [see Data]. However, there is insufficient information to determine the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for GLUCOPHAGE/GLUCOPHAGE XR and any potential adverse effects on the breastfed child from GLUCOPHAGE/GLUCOPHAGE XR or from the underlying maternal condition.DataPublished clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants.. 8.3 Females and Males of Reproductive Potential. Discuss the potential for unintended pregnancy with premenopausal women as therapy with GLUCOPHAGE/GLUCOPHAGE XR may result in ovulation in some anovulatory women.. 8.4 Pediatric Use. GLUCOPHAGEThe safety and effectiveness of GLUCOPHAGE for the treatment of type diabetes mellitus have been established in pediatric patients 10 to 16 years old. Safety and effectiveness of GLUCOPHAGE have not been established in pediatric patients less than 10 years old.Use of GLUCOPHAGE in pediatric patients 10 to 16 years old for the treatment of type diabetes mellitus is supported by evidence from adequate and well-controlled studies of GLUCOPHAGE in adults with additional data from controlled clinical study in pediatric patients 10 to 16 years old with type diabetes mellitus, which demonstrated similar response in glycemic control to that seen in adults [see Clinical Studies (14.1)]. In this study, adverse reactions were similar to those described in adults. maximum daily dose of 2000 mg of GLUCOPHAGE is recommended. [See Dosage and Administration (2.2)]GLUCOPHAGE XRSafety and effectiveness of GLUCOPHAGE XR in pediatric patients have not been established.. 8.5 Geriatric Use. Controlled clinical studies of GLUCOPHAGE/GLUCOPHAGE XR did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients [see Warnings and Precautions (.1 5)].. 8.6 Renal Impairment. Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. GLUCOPHAGE/GLUCOPHAGE XR is contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2 [see Dosage and Administration (2.3), Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].. 8.7 Hepatic Impairment. Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. GLUCOPHAGE/GLUCOPHAGE XR is not recommended in patients with hepatic impairment [see Warnings and Precautions (5.1)].

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS. Lactic Acidosis: See boxed warning. (5.1)Vitamin B12 Deficiency: Metformin may lower vitamin B12 levels. Measure hematological parameters annually and vitamin B12 at to year intervals and manage any abnormalities. (5.2) Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues: Increased risk of hypoglycemia when used in combination with insulin and/or an insulin secretagogue. Lower dose of insulin or insulin secretagogue may be required (5.3). Lactic Acidosis: See boxed warning. (5.1). Vitamin B12 Deficiency: Metformin may lower vitamin B12 levels. Measure hematological parameters annually and vitamin B12 at to year intervals and manage any abnormalities. (5.2) Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues: Increased risk of hypoglycemia when used in combination with insulin and/or an insulin secretagogue. Lower dose of insulin or insulin secretagogue may be required (5.3). 5.1 Lactic Acidosis. There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels were generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in hospital setting, along with immediate discontinuation of GLUCOPHAGE/GLUCOPHAGE XR. In GLUCOPHAGE/GLUCOPHAGE XR treated patients with diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable with clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.Educate patients and their families about the symptoms of lactic acidosis and, if these symptoms occur, instruct them to discontinue GLUCOPHAGE/GLUCOPHAGE XR and report these symptoms to their healthcare provider.For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:Renal impairment--The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment.The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patients renal function include [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)]Before initiating GLUCOPHAGE/GLUCOPHAGE XR, obtain an estimated glomerular filtration rate (eGFR).GLUCOPHAGE/GLUCOPHAGE XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see Contraindications (4)]Initiation of GLUCOPHAGE/GLUCOPHAGE XR is not recommended in patients with eGFR between 30-45 mL/min/1.73 m2.Obtain an eGFR at least annually in all patients taking GLUCOPHAGE/ GLUCOPHAGE XR. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.In patients taking GLUCOPHAGE/GLUCOPHAGE XR whose eGFR falls below 45 mL/min/1.73 m2, assess the benefit and risk ofcontinuing therapy. Drug interactions -- The concomitant use of GLUCOPHAGE/GLUCOPHAGE XR with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation. Consider more frequent monitoring of patients.Age 65 or greater -- The risk of metformin-associated lactic acidosis increases with the patients age because elderly patients have greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.Radiologic studies with contrast -- Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop GLUCOPHAGE/GLUCOPHAGE XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2 in patients with history of hepatic impairment, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart GLUCOPHAGE/GLUCOPHAGE XR if renal function is stable.Surgery and other procedures -- Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment. GLUCOPHAGE/GLUCOPHAGE XR should be temporarily discontinued while patients have restricted food and fluid intake.Hypoxic states -- Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may cause prerenal azotemia. When such an event occurs, discontinue GLUCOPHAGE/GLUCOPHAGE XR.Excessive alcohol intake -- Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving GLUCOPHAGE/GLUCOPHAGE XR.Hepatic impairment -- Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of GLUCOPHAGE/GLUCOPHAGE XR in patients with clinical or laboratory evidence of hepatic disease. Renal impairment--The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment.. Before initiating GLUCOPHAGE/GLUCOPHAGE XR, obtain an estimated glomerular filtration rate (eGFR).. GLUCOPHAGE/GLUCOPHAGE XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see Contraindications (4)]. Initiation of GLUCOPHAGE/GLUCOPHAGE XR is not recommended in patients with eGFR between 30-45 mL/min/1.73 m2.. Obtain an eGFR at least annually in all patients taking GLUCOPHAGE/ GLUCOPHAGE XR. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.. In patients taking GLUCOPHAGE/GLUCOPHAGE XR whose eGFR falls below 45 mL/min/1.73 m2, assess the benefit and risk ofcontinuing therapy. Drug interactions -- The concomitant use of GLUCOPHAGE/GLUCOPHAGE XR with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation. Consider more frequent monitoring of patients.. Age 65 or greater -- The risk of metformin-associated lactic acidosis increases with the patients age because elderly patients have greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.. Radiologic studies with contrast -- Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop GLUCOPHAGE/GLUCOPHAGE XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2 in patients with history of hepatic impairment, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart GLUCOPHAGE/GLUCOPHAGE XR if renal function is stable.. Surgery and other procedures -- Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment. GLUCOPHAGE/GLUCOPHAGE XR should be temporarily discontinued while patients have restricted food and fluid intake.. Hypoxic states -- Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may cause prerenal azotemia. When such an event occurs, discontinue GLUCOPHAGE/GLUCOPHAGE XR.. Excessive alcohol intake -- Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving GLUCOPHAGE/GLUCOPHAGE XR.. Hepatic impairment -- Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of GLUCOPHAGE/GLUCOPHAGE XR in patients with clinical or laboratory evidence of hepatic disease. 5.2 Vitamin B12 Deficiency. In GLUCOPHAGE clinical trials of 29-week duration, decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of GLUCOPHAGE or vitamin B12 supplementation. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis and vitamin B12 at to year intervals in patients on GLUCOPHAGE/GLUCOPHAGE XR and manage any abnormalities [see Adverse Reactions (6.1)].. 5.3 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues. Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. GLUCOPHAGE/GLUCOPHAGE XR may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue. Therefore, lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with GLUCOPHAGE/GLUCOPHAGE XR [see Drug Interactions (7)].. 5.4 Macrovascular Outcomes. There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with GLUCOPHAGE/GLUCOPHAGE XR.