change in metformin renal clearance. when administered with metformin, the c max and auc of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. no information is available about the interaction of metformin and furosemide when coadministered chronically. nifedipine - a single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that coadministration of nifedipine increased plasma metformin c max and auc by 20% and 9%, respectively, and increased the amount excreted in the urine. t max and half-life were unaffected. nifedipine appears to enhance the absorption of metformin. metformin had minimal effects on nifedipine. cationic drugs - cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin auc. there was no change in elimination half-life in the single-dose study. metformin had no effect on cimetidine pharmacokinetics. although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of metformin hydrochloride and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system. other - certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. these drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. when such drugs are administered to a patient receiving metformin hydrochloride, the patient should be closely observed for loss of blood glucose control. when such drugs are withdrawn from a patient receiving metformin hydrochloride, the patient should be observed closely for hypoglycemia. in healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when coadministered in single-dose interaction studies. metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.

n ). before initiation of metformin hydrochloride therapy and at least annually hereafter, renal function should be assessed and verified as normal. in patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and metformin hydrochloride discontinued if evidence of renal impairment is present. use of concomitant medications that may affect renal function or metformin disposition - concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion (see precautions: drug interactions ), should be used with caution. radiologic studies involving the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (ct) scans with intravascular contrast materials) - intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin (see contraindications ). therefore, in patients in whom any such study is planned, metformin hydrochloride should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal. hypoxic states - cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. when such events occur in patients on metformin hydrochloride therapy, the drug should be promptly discontinued. surgical procedures - metformin hydrochloride therapy should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal. alcohol intake - alcohol is known to potentiate the effect of metformin on lactate metabolism. patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving metformin hydrochloride. impaired hepatic function - since impaired hepatic function has been associated with some cases of lactic acidosis, metformin hydrochloride should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. vitamin b 12 levels - in controlled clinical trials of metformin hydrochloride tablets of 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin b 12 levels, without clinical manifestations, was observed in approximately 7% of patients. such decrease, possibly due to interference with b 12 absorption from the b 12 -intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin hydrochloride tablets or vitamin b 12 supplementation. measurement of hematologic parameters on an annual basis is advised in patients on metformin hydrochloride and any apparent abnormalities should be appropriately investigated and managed (see precautions: laboratory tests ). certain individuals (those with inadequate vitamin b 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin b 12 levels. in these patients, routine serum vitamin b 12 measurements at two- to three year intervals may be useful. change in clinical status of patients with previously controlled type 2 diabetes - a patient with type 2 diabetes previously well controlled on metformin hydrochloride who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood ph, lactate, pyruvate, and metformin levels. if acidosis of either form occurs, metformin hydrochloride must be stopped immediately and other appropriate corrective measures initiated (see also warnings ). hypoglycemia - hypoglycemia does not occur in patients receiving metformin hydrochloride extended-release tablets alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs. loss of control of blood glucose - when a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. at such times, it may be necessary to withhold metformin hydrochloride and temporarily administer insulin. metformin hydrochloride may be reinstituted after the acute episode is resolved. the effectiveness of oral antidiabetic drugs in lowering blood glucose to a targeted level decreases in many patients over a period of time. this phenomenon, which may be due to progression of the underlying disease or to diminished responsiveness to the drug, is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective during initial therapy. should secondary failure occur with either metformin hydrochloride or sulfonylurea monotherapy, combined therapy with metformin hydrochloride and sulfonylurea may result in a response. should secondary failure occur with combined metformin hydrochloride/sulfonylurea therapy, it may be necessary to consider therapeutic alternatives including initiation of insulin therapy.

used 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.)

ntinuation of study medication in 6% of patients treated with metformin hydrochloride tablets. additionally, the following adverse reactions were reported in ≥1.0% to ≤5.0% of metformin hydrochloride tablets patients and were more commonly reported with metformin hydrochloride tablets than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder,chest discomfort, chills, flu syndrome, flushing, palpitation. in worldwide clinical trials over 900 patients with type 2 diabetes have been treated with metformin hydrochloride extended-release tablets in placebo- and active-controlled studies. in placebo-controlled trials, 781 patients were administered metformin hydrochloride extended-release tablets and 195 patients received placebo. adverse reactions reported in greater than 5% of the metformin hydrochloride extended-release tablets patients, and that were more common in metformin hydrochloride extended-release tablets - than placebo-treated patients, are listed in table 12. table 12: most common adverse reactions (>5.0 percent) in placebo-controlled studies of metformin hydrochloride extended-release tablets reactions that were more common in metformin hydrochloride extended-release tablets - than placebo-treated patients. metformin hydrochloride extended-release tablets n=781) placebo (n=195) adverse reaction % of patients diarrhea 9.6 2.6 nausea/vomiting 6.5 1.5 diarrhea 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 ≥1.0% to ≤5.0% 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. liver function test abnormalities or hepatitis, resolving upon metformin discontinuation, have been reported very rarely.

change in metformin renal clearance. when administered with metformin, the c max and auc of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. no information is available about the interaction of metformin and furosemide when coadministered chronically. nifedipine - a single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that coadministration of nifedipine increased plasma metformin c max and auc by 20% and 9%, respectively, and increased the amount excreted in the urine. t max and half-life were unaffected. nifedipine appears to enhance the absorption of metformin. metformin had minimal effects on nifedipine. cationic drugs - cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin auc. there was no change in elimination half-life in the single-dose study. metformin had no effect on cimetidine pharmacokinetics. although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of metformin hydrochloride and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system. other - certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. these drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. when such drugs are administered to a patient receiving metformin hydrochloride, the patient should be closely observed for loss of blood glucose control. when such drugs are withdrawn from a patient receiving metformin hydrochloride, the patient should be observed closely for hypoglycemia. in healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when coadministered in single-dose interaction studies. metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.

se tablets in pediatric patients have not been established.

let, c max is achieved with a median value of 7 hours and a range of 4 to 8 hours. peak plasma levels are approximately 20% lower compared to the same dose of metformin hydrochloride tablet, however, the extent of absorption (as measured by auc) is similar to metformin hydrochloride tablet. at steady state, the auc and c max are less than dose proportional for metformin hydrochloride extended-release tablets 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 metformin hydrochloride extended-release tablet 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 c max 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 tablets increased by approximately 50% when given with food, there was no effect of food on c max and t max of metformin. both high and low fat meals had the same effect on the pharmacokinetics of metformin hydrochloride extended-release tablets.

ale 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.

nge at final visit 8.4 -1.4 8.2 0.4 ns 0.001 body weight (lbs) baseline change at final visit 201.0 -1.4 206.0 -2.4 ns 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 maximumdoses of glyburide (baseline fpg of approximately 250 mg/dl) (see table 3). patients randomized to the combination armstarted therapy with metformin hydrochloride tablets 500 mgand glyburide 20 mg. at the end of each week of the first 4 weeks of the trial, these patients had theirdosages of metformin hydrochloride tablets 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 toexceed 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 glycemiccontrol, with mean increases in fpg, ppg, and hba1c of 14 mg/dl, 3 mg/dl, and 0.2%, respectively. incontrast, 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 all patients on glyburide, 20 mg/day, at baseline in fasting plasma glucose, hba 1c and body weight, at final visit (29-week study) 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 change at final visit 250.5 -63.5 247.5 13.7 253.9 -0.9 ns not statistically significant 0.001 ns 0.001 ns 0.025 hemoglobin a 1c (%) baseline change at final visit 8.8 -1.7 8.5 0.2 8.9 -0.4 ns 0.001 ns 0.001 0.007 0.001 body weight (lbs) baseline change at final visit 202.2 0.9 203.0 -0.7 204.0 -8.4 ns 0.011 ns 0.001 ns 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 withtype 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 fastingserum triglycerides, total cholesterol, and ldl cholesterol levels, and had no adverse effects on otherlipid levels (see table 4 ). table 4. summary of mean percent change from baseline of major serum lipid variables at final visit (29-week study) 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 oreven decrease somewhat (see tables 2 and 3 ). a 24-week, double-blind, placebo-controlled study of metformin hydrochloride tablets plus insulin versus insulin plusplacebo was conducted in patients with type 2 diabetes who failed to achieve adequate glycemic controlon insulin alone (see table 5 ). patients randomized to receive metformin hydrochloride tablets plus insulin achieved a reduction in hba 1c of 2.10%, compared to a 1.56% reduction in hba 1c achieved by insulin plusplacebo. 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 hba 1c and daily insulin dose metformin hydrochloride tablets/ insulin (n=26) placebo/ insulin (n=28) treatment difference mean ± se hemoglobin a 1c (%) baseline change at final visit 8.95 -2.10 9.32 -1.56 -0.54 ± 0.43 statistically significant using analysis of covariance with baseline as covariate (p=0.04) not significant using analysis of variance (values shown in table) insulin dose (u/day) baseline change at final visit 93.12 -0.15 94.64 15.93 -16.08 ± 7.77 statistically significant for insulin (p=0.04) a second double-blind, placebo-controlled study (n=51), with 16 weeks of randomized treatment, emonstrated that in patients with type 2 diabetes controlled on insulin for 8 weeks with an average hba 1c of 7.46 ± 0.97%, the addition of metformin hydrochloride tablets maintained similar glycemic control (hba 1c 7.15 ± 0.61 vs 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 vs 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. 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 (hba ic 7.0%-10.0%, fpg 126-270 mg/dl). patients entering the study had a mean baseline hba ic of 8.0% and a mean baseline fpg of 176 mg/dl. after 12 weeks treatment, mean hba1c had increased from baseline by 0.1% and mean fpg decreased from baseline by 2 mg/dl in the placebo group, compared with a decrease in mean hba ic of 0.6% and a decrease in mean fpg of 23 mg/dl in patients treated with metformin hydrochloride extended-release 1000 mg tablet once daily. subsequently, the treatment dose was increased to 1500 mg once daily if hba ic was ≥7.0% but <8.0% (patients with hba ic ≥8.0% were discontinued from the study). at the final visit (24-week), mean hba ic 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 (hba 1c 7.0%-11.0%, fpg 126-280 mg/dl). changes in glycemic control and body weight are shown in table 6 . table 6: summary of mean changes from baseline all patients on diet therapy at baseline in hba 1c , fasting plasma glucose, and body weight 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 hemoglobin a 1 c (%) baseline change at final visit p-value all comparisons versus placebo ( 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 ) 181.0 -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 not statistically significant ( 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 500 mg tablet twice daily for at least 8 weeks prior to study entry. the metformin hydrochloride dose had not necessarily been titrated to achieve a specific level of glycemic control prior to study entry. patients qualified for the study if hba 1c 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 all patients on metformin hydrochloride tablets 500 mg twice daily at baseline in hba 1c , fasting plasma glucose, and body weight at week 12 and at final visit (24-week study) metformin hydrochloride metformin hydrochloride extended-release tablets 500 mg twice daily 1000 mg once daily 1500 mg once daily hemoglobin a 1 c (%) baseline change at 12 weeks (95% ci) change at final visit (95% ci) ( n = 67 ) 7.06 0.14 (-0.03, 0.31) 0.14 n=68 (-0.04, 0.31) ( n = 72 ) 6.99 0.23 (0.10, 0.36) 0.27 (0.11, 0.43) ( n = 66 ) 7.02 0.04 (-0.08, 0.15) 0.13 (-0.02, 0.28) fpg ( mg / dl ) baseline change at 12 weeks (95% ci) change at final visit (95% ci) ( n = 69 ) 127.2 12.9 (6.5, 19.4) 14.0 (7.0, 21.0) ( n = 72 ) 131.0 9.5 (4.4, 14.6) 11.5 (4.4, 18.6) ( n = 70 ) 131.4 3.7 (-0.4, 7.8) 7.6 (1.0, 14.2) body weight ( lbs ) baseline change at 12 weeks (95% ci) change at final visit (95% ci) ( n = 71 ) 210.3 0.4 (-0.4, 1.5) 0.9 (-0.4, 2.2) ( n = 74 ) 202.8 0.9 (0.0, 2.0) 1.1 (-0.2, 2.4) ( n = 71 ) 192.7 0.7 (-0.4, 1.8) 0.9 (-0.4, 2.0) after 12 weeks of treatment, there was an increase in mean hba 1c 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 8. table 8: summary of mean percent changes from baseline all patients on diet therapy at 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 1.0% ( 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 ) 198.0 15.1% ( n = 126 ) 194.2 14.9% ( n = 117 ) 179.0 9.4% ( n = 110 ) 211.7 10.9% ldl - cholesterol ( mg / dl ) baseline mean % change at final visit ( n = 119 ) 131.0 -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 tablets and metformin hydrochloride extended-release tablets are shown in table 9. table 9: summary of mean percent changes from baseline all patients on metformin hydrochloride tablets 500 mg twice daily at baseline in major lipid variables at final visit (24-week study) metformin hydrochloride tablets metformin hydrochloride extended-release tablets 500 mg twice daily 1000 mg once daily 1500 mg once daily total cholesterol ( mg / dl ) baseline mean % change at final visit ( n = 68 ) 199.0 0.1% ( n = 70 ) 201.9 1.3% ( n = 66 ) 201.6 0.1% total triglycerides ( mg / dl ) baseline mean % change at final visit ( n = 68 ) 178.0 6.3% ( n = 70 ) 169.2 25.3% ( n = 66 ) 206.8 33.4% ldl - cholesterol ( mg / dl ) baseline mean %change at final visit ( n = 68 ) 122.1 -1.3% ( n = 70 ) 126.2 -3.3% ( n = 66 ) 115.7 -3.7% hdl - cholesterol ( mg / dl ) baseline mean % change at final visit ( n = 68 ) 41.9 4.8% ( n = 70 ) 41.7 1.0% ( n = 65 ) 44.6 -2.1%

ence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease. patients should be counselled against excessive alcohol intake, either acute or chronic, while receiving metformin hydrochloride. metformin hydrochloride alone does not usually cause hypoglycemia, although it may occur when metformin hydrochloride 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.) patients should be informed that metformin hydrochloride extended-release tablets must be swallowed whole and not crushed or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.

sugar to a normal level. high blood sugar can be lowered by diet and exercise, by a number of medicines taken by mouth, and by insulin shots. before you take metformin hydrochloride, try to control your diabetes by exercise and weight loss. while you take your diabetes medicine, continue to exercise and follow the diet advised for your diabetes. no matter what your recommended diabetes management plan is, studies have shown that maintaining good blood sugar control can prevent or delay complications of diabetes, such as blindness. this medicine helps control your blood sugar in a number of ways. these include helping your body respond better to the insulin it makes naturally, decreasing the amount of sugar your liver makes, and decreasing the amount of sugar your intestines absorb. metformin hydrochloride does not cause your body to make more insulin. because of this, when taken alone, they rarely cause hypoglycemia (low blood sugar), and usually do not cause weight gain. however, when they are taken with a sulfonylurea or with insulin, hypoglycemia is more likely to occur, as is weight gain. warning: a small number of people who have taken metformin hydrochloride have developed a serious condition called lactic acidosis. lactic acidosis is caused by a buildup of lactic acid in the blood. this happens more often in people with kidney problems. most people with kidney problems should not take metformin hydrochloride. (see " what are the side effects of metformin hydrochloride? ") who should not take metformin hydrochloride? some conditions increase your chance of getting lactic acidosis, or cause other problems if you take either of these medicines. most of the conditions listed below can increase your chance of getting lactic acidosis. do not take metformin hydrochloride if you: have kidney problems have liver problems have heart failure that is treated with medicines, such as digoxin or furosemide drink a lot of alcohol. this means you binge drink for short periods or drink all the time are seriously dehydrated (have lost a lot of water from your body) are going to have an x-ray procedure with injection of dyes (contrast agents) are going to have surgery develop a serious condition, such as heart attack, severe infection, or a stroke are 80 years or older and you have not had your kidney function tested tell your doctor if you are pregnant or plan to become pregnant. metformin hydrochloride may not be right for you. talk with your doctor about your choices. you should also discuss your choices with your doctor if you are nursing a child. can metformin hydrochloride extended-release tablets usp be used in children? metformin hydrochloride extended-release tablets usp have not been studied in children. how should i take metformin hydrochloride? your doctor will tell you how much medicine to take and when to take it. you will probably start out with a low dose of the medicine. your doctor may slowly increase your dose until your blood sugar is better controlled. you should take metformin hydrochloride with meals. your doctor may have you take other medicines along with metformin hydrochloride to control your blood sugar. these medicines may include insulin shots. taking metformin hydrochloride with insulin may help you better control your blood sugar while reducing the insulin dose. continue your exercise and diet program and test your blood sugar regularly while taking metformin hydrochloride. your doctor will monitor your diabetes and may perform blood tests on you from time to time to make sure your kidneys and your liver are functioning normally. there is no evidence that metformin hydrochloride cause harm to the liver or kidneys. tell your doctor if you: have an illness that causes severe vomiting, diarrhea or fever, or if you drink a much lower amount of liquid than normal. these conditions can lead to severe dehydration (loss of water in your body). you may need to stop taking metformin hydrochloride for a short time. plan to have surgery or an x-ray procedure with injection of dye (contrast agent). you may need to stop taking metformin hydrochloride for a short time. start to take other medicines or change how you take a medicine. metformin hydrochloride can affect how well other drugs work, and some drugs can affect how well metformin hydrochloride extended-release tablets work. some medicines may cause high blood sugar. metformin hydrochloride extended-release tablets usp must be swallowed whole and never crushed or chewed. occasionally, the inactive ingredients of metformin hydrochloride extended-release tablets usp may be eliminated as a soft mass in your stool that may look like the original tablet; this is not harmful and will not affect the way metformin hydrochloride extended-release tablets usp work to control your diabetes. what should i avoid while taking metformin hydrochloride? do not drink a lot of alcoholic drinks while taking metformin hydrochloride. this means you should not binge drink for short periods, and you should not drink a lot of alcohol on a regular basis. alcohol can increase the chance of getting lactic acidosis.