to metformin hydrochloride tablets 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 metformin hydrochloride 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 tablets may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone. recommended dosing schedule adults – the usual starting dose of metformin hydrochloride tablets usp is 500 mg twice a day or 850 mg once a day, given with meals. 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 or 850 mg every 2 weeks, up to a total of 2000 mg per day, given in divided doses. the dosage of metformin hydrochloride tablets must be individualized on the basis of both effectiveness and tolerability. 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, metformin hydrochloride tablets 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. pediatrics – the usual starting dose of metformin hydrochloride tablets 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. the dosage of metformin hydrochloride tablets must be individualized on the basis of both effectiveness and tolerability. recommendations for use in renal impairment assess renal function prior to initiation of metformin hydrochloride tablets and periodically thereafter. metformin hydrochloride tablets are contraindicated in patients with an estimated glomerular filtration rate (egfr) below 30 ml/minute/1.73 m2. initiation of metformin hydrochloride tablets in patients with an egfr between 30 to 45 ml/min/1.73 m2 is not recommended. in patients taking metformin hydrochloride tablets whose egfr later falls below 45 ml/min/1.73 m2, assess the benefit risk of continuing therapy. discontinue metformin hydrochloride tablets if the patient's egfr later falls below 30 ml/min/1.73 m2 (see warnings and precautions ). discontinuation for iodinated contrast imaging procedures discontinue metformin hydrochloride 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 if renal function is stable. concomitant metformin hydrochloride tablets and oral sulfonylurea therapy in adult patients if patients have not responded to four weeks of the maximum dose of metformin hydrochloride tablet monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing metformin hydrochloride 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 tablet 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 hydrochloride tablets 500 mg and glyburide 20 mg were titrated to 1000/20 mg, 1500/20 mg, 2000/20 mg or 2500/20 mg of metformin hydrochloride tablets and glyburide, respectively, to reach the goal of glycemic control as measured by fpg, hba1c and plasma glucose response (see clinical pharmacology: clinical studies). however, attempts should be made to identify the minimum effective dose of each drug to achieve this goal. with concomitant metformin hydrochloride 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 one to three months of concomitant therapy with the maximum dose of metformin hydrochloride tablets and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without metformin hydrochloride tablets. concomitant metformin hydrochloride tablet and insulin therapy in adult patients the current insulin dose should be continued upon initiation of metformin hydrochloride tablet therapy. metformin hydrochloride tablet therapy should be initiated at 500 mg once daily in patients on insulin therapy. for patients not responding adequately, the dose of metformin hydrochloride tablet 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 metformin hydrochloride 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 tablets. further adjustment should be individualized based on glucose-lowering response. specific patient populations metformin hydrochloride tablet is not recommended for use in pregnancy. metformin hydrochloride tablets are not recommended in patients below the age of 10 years. the initial and maintenance dosing of metformin hydrochloride 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.

n clinical trials with metformin hydrochloride tablets in pediatric patients with type 2 diabetes, the profile of adverse reactions was similar to that observed in adults. to report suspected adverse reactions, please call metcure pharmaceuticals, inc at 1-833-755-8327 or fda at 1-800-fda-1088 or www.fda.gov/medwatch.

tions is approximately 50% to 60%. studies using single oral doses of metformin hydrochloride 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. 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. 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. 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. 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 contraindications , warnings , precautions and dosage and administration). dosage and administration hepatic insufficiency 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). dosage and administration pediatrics after administration of a single oral metformin hydrochloride 500 mg tablet 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 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 tablets 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 hydrochloride tablets (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: metformin hydrochloride tablets vs placebo summary of mean changes from baseline* in fasting plasma glucose, hba1c, and body weight, at final visit (29-week study) *all patients on diet therapy at baseline **not statistically significant metformin hydrochloride tablets (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 a 1c (%) 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** a 29-week, double-blind, placebo-controlled study of metformin hydrochloride tablets 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 metformin hydrochloride tablets 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 hydrochloride tablets 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 hydrochloride tablets 2500 mg. patients in the metformin hydrochloride tablets 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 hydrochloride tablets 2000 mg/glyburide 20 mg or metformin hydrochloride tablets 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 hydrochloride tablets (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 hydrochloride tablets 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 metformin hydrochloride tablets/glyburide (comb) vs glyburide (glyb) or metformin hydrochloride tablets (met) monotherapy: summary of mean changes from baseline* in fasting plasma glucose, hba1c, and body weight, at final visit (29-week study) *all patients on glyburide, 20 mg/day, at baseline **not statistically significant p-values comb (n=213) glyb (n=209) met (n=210) 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 a 1c (%) 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 the magnitude of the decline in fasting blood glucose concentration following the institution of metformin hydrochloride 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, metformin hydrochloride tablets, 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) metformin hydrochloride tablets vs placebo combined metformin hydrochloride tablets/glyburide vs monotherapy metformin hydrochloride tablets (n=141) placebo (n=145) metformin hydrochloride tablets (n=210) metformin hydrochloride tablets/ 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 hydrochloride tablets tended to remain stable or even decrease somewhat (see tables 2 and 3). a 24-week, double-blind, placebo-controlled study of metformin hydrochloride tablets 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 metformin hydrochloride tablets 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 hydrochloride tablets plus insulin versus insulin plus placebo, respectively, p=0.04. table 5: combined metformin hydrochloride tablets/insulin vs placebo/insulin summary of mean changes from baseline in hba1c and daily insulin dose 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) metformin hydrochloride tablets/ insulin (n=26) placebo/ insulin (n=28) treatment difference mean ± se hemoglobin a 1c (%) 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 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 hydrochloride tablets maintained similar glycemic control (hba1c 7.15 ± 0.61 versus 6.97 ± 0.62 for metformin hydrochloride tablets 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 hydrochloride tablets plus insulin and placebo plus insulin, p<0.01). in addition, this study demonstrated that the combination of metformin hydrochloride tablets 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. a 24-week, double-blind, randomized study of 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 500 mg tablets 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 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) * all patients on metformin hydrochloride tablets 500 mg twice daily at baseline a n=68 metformin hydrochloride tablets metformin hydrochloride extended release tablets 500 mg twice daily 1000 mg once daily 1500 mg once daily hemoglobin a 1c (%) (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) after 12 weeks of treatment, there was an increase in mean hba1c in all groups. changes in lipid parameters in the previously described study of metformin hydrochloride extended release tablets are shown in table 9. table 9: summary of mean percent changes from baseline* in major lipid variables at final visit (24-week study) * all patients on metformin hydrochloride tablets 500 mg twice daily at baseline metformin hydrochloride tablets metformin hydrochloride extended release tablets 500 mg twice daily 1000 mg once 1500 mg once 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% 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 hydrochloride tablets (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: metformin hydrochloride tablets vs placebo (pediatrics a) summary of mean changes from baseline* in plasma glucose and body weight at final visit a pediatric patients mean age 13.8 years (range 10 to 16 years) * all patients on diet therapy at baseline ** not statistically significant metformin hydrochloride tablets 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**

ing 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.

e 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.

moglobin a 1c (%) 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** a 29-week, double-blind, placebo-controlled study of metformin hydrochloride tablets 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 metformin hydrochloride tablets 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 hydrochloride tablets 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 hydrochloride tablets 2500 mg. patients in the metformin hydrochloride tablets 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 hydrochloride tablets 2000 mg/glyburide 20 mg or metformin hydrochloride tablets 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 hydrochloride tablets (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 hydrochloride tablets 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 metformin hydrochloride tablets/glyburide (comb) vs glyburide (glyb) or metformin hydrochloride tablets (met) monotherapy: summary of mean changes from baseline* in fasting plasma glucose, hba1c, and body weight, at final visit (29-week study) *all patients on glyburide, 20 mg/day, at baseline **not statistically significant p-values comb (n=213) glyb (n=209) met (n=210) 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 a 1c (%) 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 the magnitude of the decline in fasting blood glucose concentration following the institution of metformin hydrochloride 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, metformin hydrochloride tablets, 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) metformin hydrochloride tablets vs placebo combined metformin hydrochloride tablets/glyburide vs monotherapy metformin hydrochloride tablets (n=141) placebo (n=145) metformin hydrochloride tablets (n=210) metformin hydrochloride tablets/ 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 hydrochloride tablets tended to remain stable or even decrease somewhat (see tables 2 and 3). a 24-week, double-blind, placebo-controlled study of metformin hydrochloride tablets 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 metformin hydrochloride tablets 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 hydrochloride tablets plus insulin versus insulin plus placebo, respectively, p=0.04. table 5: combined metformin hydrochloride tablets/insulin vs placebo/insulin summary of mean changes from baseline in hba1c and daily insulin dose 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) metformin hydrochloride tablets/ insulin (n=26) placebo/ insulin (n=28) treatment difference mean ± se hemoglobin a 1c (%) 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 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 hydrochloride tablets maintained similar glycemic control (hba1c 7.15 ± 0.61 versus 6.97 ± 0.62 for metformin hydrochloride tablets 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 hydrochloride tablets plus insulin and placebo plus insulin, p<0.01). in addition, this study demonstrated that the combination of metformin hydrochloride tablets 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. a 24-week, double-blind, randomized study of 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 500 mg tablets 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 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) * all patients on metformin hydrochloride tablets 500 mg twice daily at baseline a n=68 metformin hydrochloride tablets metformin hydrochloride extended release tablets 500 mg twice daily 1000 mg once daily 1500 mg once daily hemoglobin a 1c (%) (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) after 12 weeks of treatment, there was an increase in mean hba1c in all groups. changes in lipid parameters in the previously described study of metformin hydrochloride extended release tablets are shown in table 9. table 9: summary of mean percent changes from baseline* in major lipid variables at final visit (24-week study) * all patients on metformin hydrochloride tablets 500 mg twice daily at baseline metformin hydrochloride tablets metformin hydrochloride extended release tablets 500 mg twice daily 1000 mg once 1500 mg once 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% 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 hydrochloride tablets (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: metformin hydrochloride tablets vs placebo (pediatrics a) summary of mean changes from baseline* in plasma glucose and body weight at final visit a pediatric patients mean age 13.8 years (range 10 to 16 years) * all patients on diet therapy at baseline ** not statistically significant metformin hydrochloride tablets 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**

ul 2017 m.l.no.: 37/rr/ap/2003/f/r

ug 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 metformin hydrochloride tablets. metformin hydrochloride tablets alone does not usually cause hypoglycemia, although it may occur when metformin hydrochloride tablets are 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 printed below.)