tic impairment. steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided (see dosage and administration, contraindications, andprecautions). if metformin-associated lactic acidosis is suspected, immediately discontinue metformin hydrochloride extended-release tablets and institute general supportive measures in a hospital setting. prompt hemodialysis is recommended (see precautions).

sed to determine the therapeutic response to metformin hydrochloride extended-release tablets 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 metformin hydrochloride extended-release tablets, either when used as monotherapy or in combination with sulfonylurea or insulin. monitoring of blood glucose and glycosylated hemoglobin will also permit detection of primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication, and secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period of effectiveness. short-term administration of metformin hydrochloride extended-release tablets may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone. metformin hydrochloride extended-release tablets must be swallowed whole and never crushed or chewed. occasionally, the inactive ingredients of metformin hydrochloride extended-release tablets will be eliminated in the feces as a soft, hydrated mass. (see patient information printed below.) recommended dosing schedule adults the usual starting dose of metformin hydrochloride extended-release tablets are 500 mg once daily with the evening meal. in general, clinically significant responses are not seen at doses below 1500 mg per day. dosage increases should be made in increments of 500 mg weekly, up to a maximum of 2000 mg once daily with the evening meal. the dosage of metformin hydrochloride extended-release tablets must be individualized on the basis of both effectiveness and tolerability. if glycemic control is not achieved on metformin hydrochloride extended-release tablets 2000 mg once daily, a trial of metformin hydrochloride extended-release tablets 1000 mg twice daily should be considered. (see clinical pharmacology:clinical studies.) patients receiving metformin hydrochloride tablet treatment may be safely switched to metformin hydrochloride extended-release tablets once daily at the same total daily dose, up to 2000 mg once daily. following a switch from metformin hydrochloride tablets to metformin hydrochloride extended-release tablets, glycemic control should be closely monitored and dosage adjustments made accordingly (see clinical pharmacology: clinical studies). pediatrics safety and effectiveness of metformin hydrochloride extended-release tablets in pediatric patients have not been established. recommendations for use in renal impairment assess renal function prior to initiation of metformin hydrochloride extended-release tablets and periodically thereafter. metformin hydrochloride extended-release tablets are contraindicated in patients with an estimated glomerular filtration rate (egfr) below 30 ml/minute/1.73 m2. initiation of metformin hydrochloride extended-release tablet in patients with an egfr between 30 to 45 ml/minute/1.73 m2 is not recommended. in patients taking metformin hydrochloride extended-release tablets whose egfr later falls below 45 ml/min/1.73 m2, assess the benefit risk of continuing therapy. discontinue metformin hydrochloride extended-release tablets if the patient's egfr later falls below 30 ml/minute/1.73 m2 (see warnings and precautions). discontinuation for iodinated contrast imaging procedures discontinue metformin hydrochloride extended-release tablets 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 a 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 metformin hydrochloride extended-release tablets if renal function is stable. concomitant metformin hydrochloride extended-release tablets and oral sulfonylurea therapy in adult patients if patients have not responded to 4 weeks of the maximum dose of metformin hydrochloride extended-release tablets monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing metformin hydrochloride extended-release tablets 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 hydrochloride extended-release tablets 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 metformin hydrochloride extended-release tablets 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 metformin hydrochloride extended - release tablets and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without metformin hydrochloride extended-release tablets. concomitant metformin hydrochloride extended-release tablets and insulin therapy in adult patients the current insulin dose should be continued upon initiation of metformin hydrochloride extended-release tablets therapy. metformin hydrochloride extended-release tablets therapy should be initiated at 500 mg once daily in patients on insulin therapy. for patients not responding adequately, the dose of metformin hydrochloride extended-release tablets 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 2000 mg for metformin hydrochloride extended-release tablets. it is recommended that the insulin dose be decreased by 10% to 25% when fasting plasma glucose concentrations decrease to less than 120 mg/dl in patients receiving concomitant insulin and metformin hydrochloride extended-release tablets. further adjustment should be individualized based on glucose-lowering response. specific patient populations metformin hydrochloride extended-release tablets are not recommended for use in pregnancy. metformin hydrochloride extended-release tablets are not recommended in pediatric patients (below the age of 17 years). the initial and maintenance dosing of metformin hydrochloride extended-release tablets 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.

hea led to discontinuation of study medication in 0.6% of patients treated with metformin hydrochloride extended-release tablets. additionally, the following adverse reactions were reported in ≥ 1% to ≤ 5% of metformin hydrochloride extended-release tablets patients and were more commonly reported with metformin hydrochloride extended-release tablets than placebo: abdominal pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance. cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin.

median value of 7 hours and a range of 4 hours to 8 hours. at steady state, the auc and cmax are less than dose proportional for metformin hydrochloride extended-release tablets within the range of 500 mg to 2000 mg administered once daily. peak plasma levels are approximately 0.6, 1.1, 1.4, and 1.8 mcg/ml for 500 mg, 1000 mg, 1500 mg, and 2000 mg once-daily doses, respectively. the extent of metformin absorption (as measured by auc) from metformin hydrochloride extended-release tablets at a 2000 mg once-daily dose is similar to the same total daily dose administered as metformin hydrochloride tablets 1000 mg twice daily. after repeated administration of metformin hydrochloride extended-release tablets, metformin did not accumulate in plasma. within-subject variability in cmax and auc of metformin from metformin hydrochloride extended-release tablets is comparable to that with metformin hydrochloride tablets. although the extent of metformin absorption (as measured by auc) from the metformin hydrochloride extended-release 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 metformin hydrochloride extended-release tablets. distribution the apparent volume of distribution (v/f) of metformin following single oral doses of metformin hydrochloride tablets 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 hydrochloride tablets, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 mcg/ml. during controlled clinical trials of metformin hydrochloride tablets, maximum metformin plasma levels did not exceed 5 mcg/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. 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 metformin hydrochloride extended-release tablets in patients with type 2 diabetes are comparable to those in healthy normal adults. renal impairment in patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased (see table 1; also see contraindications, warnings, precautions and dosage and administration). hepatic impairment no pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency (see precautions). geriatrics limited data from controlled pharmacokinetic studies of metformin hydrochloride tablets 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; also see warnings, precautions, and dosage and administration). table 1: select mean (±s.d.) metformin pharmacokinetic parameters following single or multiple oral doses of metformin hydrochloride tablets * 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 to 59 years) ¶ kinetic study done following dose 19, given fasting # elderly subjects, mean age 71 years (range 65 to 81 years) Þ cl cr = creatinine clearance normalized to body surface area of 1.73 m 2 subject groups: metformin hydrochloride tablets dose*(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)§ 1.6 (±0.38) 2.64 (±0.82) 552 (±139) 850 mg three times daily for 19 doses¶(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 doses¶ (9) 1.9 (±0.62) 2.01 (±1.22) 550 (±160) elderly#, healthy nondiabetic adults: 850 mg single dose (12) 2.45 (±0.7) 2.71 (±1.05) 412 (±98) renal-impaired adults: 850 mg single dose mild (clcrÞ 61 to 90 ml/min) (5) 1.86 (±0.52) 3.2 (±0.45) 384 (±122) moderate (clcr 31 to 60 ml/min) (4) 4.12 (±1.83) 3.75 (±0.5) 108 (±57) severe (clcr 10 to 30 ml/min) (6) 3.93 (±0.92) 4.01 (±1.1) 130 (±90) pediatrics no pharmacokinetic data from studies of pediatric patients are currently available 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 hydrochloride tablets 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 hydrochloride tablets in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and hispanics (n=24). clinical studies metformin hydrochloride extended-release tablets a 24-week, double-blind, placebo-controlled study of metformin hydrochloride extended-release tablets, 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% to 10%, fpg 126 to 270 mg/dl). patients entering the study had a mean baseline hba1c of 8% 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 metformin hydrochloride extended-release tablets 1000 mg once daily. subsequently, the treatment dose was increased to 1500 mg once daily if hba1c was ≥7% but <8% (patients with hba1c ≥8% 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 metformin hydrochloride extended-release tablets. a 16-week, double-blind, placebo-controlled, dose-response study of metformin hydrochloride extended-release tablets, 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% to 11%, fpg 126 to 280 mg/dl). changes in glycemic control and body weight are shown in table 2. table 2: summary of mean changes from baseline* in hba1c, fasting plasma glucose, and body weight at final visit (16-week study) * all patients on diet therapy at baseline † all comparisons versus placebo ‡ not statistically significant metformin hydrochloride extended-release tablets placebo 500 mg once daily 1000 mg once daily 1500 mg once daily 2000 mg once daily 1000 mg twice daily hemoglobin a1c (%) baseline change at final visit p–value† (n = 115) 8.2 -0.4 <0.001 (n = 115) 8.4 -0.6 <0.001 (n = 111) 8.3 -0.9 <0.001 (n = 125) 8.4 -0.8 <0.001 (n = 112) 8.4 -1.1 <0.001 (n = 111) 8.4 0.1 - fpg (mg/dl) baseline change at final visit p–value† (n = 126) 182.7 -15.2 <0.001 (n = 118) 183.7 -19.3 <0.001 (n = 120) 178.9 -28.5 <0.001 (n = 132) 181 -29.9 <0.001 (n=122) 181.6 -33.6 <0.001 (n = 113) 179.6 7.6 - body weight (lbs) baseline change at final visit p–value† (n = 125) 192.9 -1.3 ns‡ (n = 119) 191.8 -1.3 ns‡ (n = 117) 188.3 -0.7 ns‡ (n = 131) 195.4 -1.5 ns‡ (n =119) 192.5 -2.2 ns‡ (n = 113) 194.3 -1.8 - compared with placebo, improvement in glycemic control was seen at all dose levels of metformin hydrochloride extended-release tablets and treatment was not associated with any significant change in weight (see dosage and administration for dosing recommendations for metformin hydrochloride extended-release tablets). a 24-week, double-blind, randomized study of metformin hydrochloride extended-release tablets, taken once daily with the evening meal, and metformin hydrochloride tablets, taken twice daily (with breakfast and evening meal), was conducted in patients with type 2 diabetes who had been treated with metformin hydrochloride tablets, 500 mg twice daily for at least 8 weeks prior to study entry. the metformin hydrochloride tablets 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 3. table 3: summary of mean changes from baseline in hba1c, fasting plasma glucose, and body weight at week 12 and at final visit (24-week study) metformin hydrochloride extended-release tablets 1000 mg once daily 1500 mg once daily hemoglobin a1c (%) (n = 72) (n = 66) baseline 6.99 7.02 change at 12 weeks 0.23 0.04 (95% ci) (0.1, 0.36) (-0.08, 0.15) change at final visit 0.27 0.13 (95% ci) (0.11, 0.43) (-0.02, 0.28) fpg (mg/dl) (n = 72) (n = 70) baseline 131 131.4 change at 12 weeks 9.5 3.7 (95% ci) (4.4, 14.6) (-0.4, 7.8) change at final visit 11.5 7.6 (95% ci) (4.4, 18.6) (1, 14.2) body weight (lbs) (n = 74) (n = 71) baseline 202.8 192.7 change at 12 weeks 0.9 0.7 (95% ci) (0, 2) (-0.4, 1.8) change at final visit 1.1 0.9 (95% ci) (-0.2, 2.4) (-0.4, 2) after 12 weeks of treatment, there was an increase in mean hba1c in all groups; in the metformin hydrochloride extended-release tablets 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 metformin hydrochloride extended-release tablets are shown in table 4. table 4: summary of mean percent changes from baseline* in major lipid variables at final visit (16-week study) metformin hydrochloride extended-release tablets 500 mg once daily 1000 mg once daily 1500 mg once daily 2000 mg once daily 1000 mg twice daily placebo total cholesterol (mg/dl) baseline mean % change at final visit (n = 120) 210.3 1% (n = 113) 218.1 1.7% (n = 110) 214.6 0.7% (n = 126) 204.4 - 1.6% (n = 117) 208.2 - 2.6% (n = 110) 208.6 2.6% total triglycerides (mg/dl) baseline mean % change at final visit (n = 120) 220.2 14.5% (n = 113) 211.9 9.4% (n = 110) 198 15.1% (n = 126) 194.2 14.9% (n = 117) 179 9.4% (n = 110) 211.7 10.9% ldl–cholesterol (mg/dl) baseline mean % change at final visit (n = 119) 131 -1.4% (n = 113) 134.9 -1.6% (n = 109) 135.8 -3.5% (n = 126) 125.8 -3.3% (n = 117) 131.4 -5.5% (n = 107) 131.9 3.2% hdl–cholesterol (mg/dl) baseline mean % change at final visit (n = 120) 40.8 6.2% (n = 108) 41.6 8.6% (n = 108) 40.6 5.5% (n = 125) 40.2 6.1% (n = 117) 42.4 7.1% (n = 108) 39.4 5.8% changes in lipid parameters in the previously described study of metformin hydrochloride extended-release tablets are shown in table 5. table 5: summary of mean percent changes from baseline in major lipid variables at final visit (24-week study) metformin hydrochloride extended-release tablets 1000 mg once daily 1500 mg once daily total cholesterol (mg/dl) baseline mean % change at final visit (n = 70) 201.9 1.3% (n = 66) 201.6 0.1% total triglycerides (mg/dl) baseline mean % change at final visit (n = 70) 169.2 25.3% (n = 66) 206.8 33.4% ldl–cholesterol (mg/dl) baseline mean % change at final visit (n = 70) 126.2 -3.3% (n = 66) 115.7 -3.7% hdl–cholesterol (mg/dl) baseline mean % change at final visit (n = 70) 41.7 1% (n = 65) 44.6 -2.1%