inical pharmacology (12.3)]. intervention: consider the benefits and risks of concomitant use with metformin hydrochloride. examples: ranolazine, vandetanib, dolutegravir, and cimetidine. alcohol clinical impact: alcohol is known to potentiate the effect of metformin on lactate metabolism. intervention: warn patients against excessive alcohol intake while receiving metformin hydrochloride. insulin secretagogues or insulin clinical impact: coadministration of metformin hydrochloride with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia. intervention: patients receiving an insulin secretagogue or insulin may require lower doses of the insulin secretagogue or insulin. drugs affecting glycemic control clinical impact: certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. intervention: when such drugs are administered to a patient receiving metformin hydrochloride, observe the patient closely for loss of blood glucose control. when such drugs are withdrawn from a patient receiving metformin hydrochloride tablets, observe the patient closely for hypoglycemia. examples: thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid.

etformin hydrochloride tablets treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable with a clearance of up to 170 ml/min under good hemodynamic conditions). hemodialysis has often resulted in reversal of symptoms and recovery. educate patients and their families about the symptoms of lactic acidosis and, if these symptoms occur, instruct them to discontinue metformin hydrochloride tablets and report these symptoms to their healthcare provider. for each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: renal impairment—the postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. the risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. clinical recommendations based upon the patient’s renal function include [see dosage and administration (2.1), clinical pharmacology (12.3)]: before initiating metformin hydrochloride, obtain an estimated glomerular filtration rate (egfr). metformin hydrochloride is contraindicated in patients with an egfr less than 30 ml/min/1.73 m2 [see contraindications (4)]. initiation of metformin hydrochloride is not recommended in patients with egfr between 30-45 ml/min/1.73 m2. obtain an egfr at least annually in all patients taking metformin hydrochloride. in patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. in patients taking metformin hydrochloride whose egfr falls below 45 ml/min/1.73 m2, assess the benefit and risk of continuing therapy. drug interactions — the concomitant use of metformin hydrochloride with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation. consider more frequent monitoring of patients. age 65 or greater — the risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. assess renal function more frequently in elderly patients. radiologic studies with contrast — administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. stop metformin hydrochloride 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 hepatic impairment, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. re-evaluate egfr 48 hours after the imaging procedure, and restart metformin hydrochloride if renal function is stable. surgery and other procedures — withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment. metformin hydrochloride should be temporarily discontinued while patients have restricted food and fluid intake. hypoxic states — several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may cause prerenal azotemia. when such an event occurs, discontinue metformin hydrochloride tablets. excessive alcohol intake — alcohol potentiates the effect of metformin on lactate metabolism. patients should be warned against excessive alcohol intake while receiving metformin hydrochloride tablets. hepatic impairment — patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. this may be due to impaired lactate clearance resulting in higher lactate blood levels. therefore, avoid use of metformin hydrochloride tablets in patients with clinical or laboratory evidence of hepatic disease. 5.2 vitamin b12 deficiency in metformin hydrochloride clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin b12 levels was observed in approximately 7% of patients. such decrease, possibly due to interference with b12 absorption from the b12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin hydrochloride or vitamin b12 supplementation. certain individuals (those with inadequate vitamin b12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin b12 levels. measure hematologic parameters on an annual basis and vitamin b12 at 2 to 3 year intervals in patients on metformin hydrochloride and manage any abnormalities [see adverse reactions (6.1)]. 5.3 hypoglycemia with concomitant use with insulin and insulin secretagogues insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. metformin hydrochloride tablets may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue. therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with metformin hydrochloride tablets [see drug interactions (7)]. 5.4 macrovascular outcomes there have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin hydrochloride tablets.

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 – 45 ml/minute/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/minute/1.73 m2 [see warnings and precautions (5.1)]. 2.4 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 tablets if renal function is stable.

rochloride occurring >5% and more common than placebo in patients with type 2 diabetes mellitus metformin hydrochloride (n=141) placebo (n=145) diarrhea 53% 12% nausea/vomiting 26% 8% flatulence 12% 6% asthenia 9% 6% indigestion 7% 4% abdominal discomfort 6% 5% headache 6% 5% diarrhea led to discontinuation of metformin hydrochloride in 6% of patients. additionally, the following adverse reactions were reported in ≥1% to ≤5% of metformin hydrochloride treated patients and were more commonly reported with metformin hydrochloride than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation. in metformin hydrochloride clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin b12 levels was observed in approximately 7% of patients. pediatric patients in clinical trials with metformin hydrochloride tablets in pediatric patients with type 2 diabetes mellitus, the profile of adverse reactions was similar to that observed in adults. 6.2 postmarketing experience the following adverse reactions have been identified during post approval use of metformin. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin.

inical pharmacology (12.3)]. intervention: consider the benefits and risks of concomitant use with metformin hydrochloride. examples: ranolazine, vandetanib, dolutegravir, and cimetidine. alcohol clinical impact: alcohol is known to potentiate the effect of metformin on lactate metabolism. intervention: warn patients against excessive alcohol intake while receiving metformin hydrochloride. insulin secretagogues or insulin clinical impact: coadministration of metformin hydrochloride with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia. intervention: patients receiving an insulin secretagogue or insulin may require lower doses of the insulin secretagogue or insulin. drugs affecting glycemic control clinical impact: certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. intervention: when such drugs are administered to a patient receiving metformin hydrochloride, observe the patient closely for loss of blood glucose control. when such drugs are withdrawn from a patient receiving metformin hydrochloride tablets, observe the patient closely for hypoglycemia. examples: thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid.

for the indicated population is unknown. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk poorly-controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications. poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. data human data published data from post-marketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. however, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. animal data metformin hydrochloride did not adversely affect development outcomes when administered to pregnant rats and rabbits at doses up to 600 mg/kg/day. this represents an exposure of about 2 and 5 times a 2550 mg clinical dose based on body surface area comparisons for rats and rabbits, respectively. determination of fetal concentrations demonstrated a partial placental barrier to metformin. 8.2 lactation risk summary limited published studies report that metformin is present in human milk [see data]. however, there is insufficient information to determine the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for metformin hydrochloride and any potential adverse effects on the breastfed child from metformin hydrochloride or from the underlying maternal condition. data published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. however, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants. 8.3 females and males of reproductive potential discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin hydrochloride tablets may result in ovulation in some anovulatory women. 8.4 pediatric use metformin hydrochloride tablets the safety and effectiveness of metformin hydrochloride tablets for the treatment of type 2 diabetes mellitus have been established in pediatric patients 10 to 16 years old. safety and effectiveness of metformin hydrochloride have not been established in pediatric patients less than 10 years old. use of metformin hydrochloride tablets in pediatric patients 10 to 16 years old for the treatment of type 2 diabetes mellitus is supported by evidence from adequate and well-controlled studies of metformin hydrochloride tablets in adults with additional data from a controlled clinical study in pediatric patients 10 to 16 years old with type 2 diabetes mellitus, which demonstrated a similar response in glycemic control to that seen in adults [see clinical studies (14.1)]. in this study, adverse reactions were similar to those described in adults. a maximum daily dose of 2000 mg of metformin hydrochloride tablets are recommended. [see dosage and administration (2.2).] 8.5 geriatric use controlled clinical studies of metformin hydrochloride tablets did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients. in general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. assess renal function more frequently in elderly patients [see warnings and precautions (5.1)]. 8.6 renal impairment metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. metformin hydrochloride is contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (egfr) below 30 ml/min/1.73 m2 [see dosage and administration (2.3), contraindications (4), warnings and precautions (5.1), and clinical pharmacology (12.3)]. 8.7 hepatic impairment use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. metformin hydrochloride is not recommended in patients with hepatic impairment. [see warnings and precautions (5.1)].

de, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 μg/ml. effect of food: food decreases the extent of absorption 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 hydrochloride with food, compared to the same tablet strength administered fasting. distribution the apparent volume of distribution (v/f) of metformin following single oral doses of metformin hydrochloride 850 mg averaged 654 ± 358 l. metformin is negligibly bound to plasma proteins. metformin partitions into erythrocytes, most likely as a function of time. metabolism 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. elimination renal clearance (see table 4) is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. in blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. specific populations renal impairment in patients with decreased renal function the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased (see table 3) [see dosage and administration (2.3), contraindications (4), warnings and precautions (5.1) and use in specific populations (8.6)]. hepatic impairment no pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment [see warnings and precautions (5.1) and use in specific populations (8.7)]. geriatrics limited data from controlled pharmacokinetic studies of metformin hydrochloride in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and cmax is increased, compared to healthy young subjects. it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see table 4). [see warnings and precautions (5.1) and use in specific populations (8.5)]. table 4: select mean (±s.d.) metformin pharmacokinetic parameters following single or multiple oral doses of metformin hydrochloride tablets a all doses given fasting except the first 18 doses of the multiple dose studies b peak plasma concentration c time to peak plasma concentration d combined results (average means) of five studies: mean age 32 years (range 23-59 years) e kinetic study done following dose 19, given fasting f elderly subjects, mean age 71 years (range 65-81 years) g clcr = creatinine clearance normalized to body surface area of 1.73 m2 subject groups: metformin hydrochloride tablets dosea (number of subjects) cmaxb (mcg/ml) tmaxc (hrs) renal clearance (ml/min) healthy, nondiabetic adults: 500 mg single dose (24) 850 mg single dose (74)d 850 mg three times daily for 19 dosese (9) 1.03 (±0.33) 1.60 (±0.38) 2.01 (±0.42) 2.75 (±0.81) 2.64 (±0.82) 1.79 (±0.94) 600 (±132) 552 (±139) 642 (±173) adults with type 2 diabetes mellitus: 850 mg single dose (23) 850 mg three times daily for 19 dosese (9) 1.48 (±0.5) 1.90 (±0.62) 3.32 (±1.08) 2.01 (±1.22) 491 (±138) 550 (±160) elderlyf , healthy nondiabetic adults: 850 mg single dose (12) 2.45 (±0.70) 2.71 (±1.05) 412 (±98) renal-impaired adults: 850 mg single dose mild (clcr g 61 to 90 ml/min) (5) moderate (clcr 31 to 60 ml/min) (4) severe (clcr 10 to 30 ml/min) (6) 1.86 (±0.52) 4.12 (±1.83) 3.93 (±0.92) 3.20 (±0.45) 3.75 (±0.50) 4.01 (±1.10) 384 (±122) 108 (±57) 130 (±90) 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 (12-16 years of age) and gender-and weight-matched healthy adults (20-45 years of age), all with normal renal function. gender metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes mellitus when analyzed according to gender (males=19, females=16). race no studies of metformin pharmacokinetic parameters according to race have been performed. drug interactions in vivo assessment of drug interactions table 5: effect of coadministered drug on plasma metformin systemic exposure coadministered drug dose of coadministered drug* dose of metformin* geometric mean ratio (ratio with/without coadministered drug) no effect = 1.00 auc† cmax no dosing adjustments required for the following: glyburide 5 mg 850 mg metformin 0.91‡ 0.93‡ furosemide 40 mg 850 mg metformin 1.09‡ 1.22‡ nifedipine 10 mg 850 mg metformin 1.16 1.21 propranolol 40 mg 850 mg metformin 0.90 0.94 ibuprofen 400 mg 850 mg metformin 1.05‡ 1.07‡ cationic drugs eliminated by renal tubular secretion may reduce metformin elimination cimetidine 400 mg 850 mg metformin 1.40 1.61 carbonic anhydrase inhibitors may cause metabolic acidosis [ see warnings and precautions (5.1) and drug interactions (7).] topiramate 100 mg§ 500 mg§ metformin 1.25§ 1.07 * all metformin and coadministered drugs were given as single doses † auc = auc(inf) ‡ ratio of arithmetic means § at steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; auc = auc0-12h table 6: effect of metformin on coadministered drug systemic exposure coadministered drug dose of coadministered drug* dose of metformin* geometric mean ratio (ratio with/without metformin) no effect = 1.00 auc† cmax no dosing adjustments required for the following: glyburide 5 mg 850 mg glyburide 0.78‡ 0.63‡ furosemide 40 mg 850 mg furosemide 0.87‡ 0.69‡ nifedipine 10 mg 850 mg nifedipine 1.10§ 1.08 propranolol 40 mg 850 mg propranolol 1.01§ 1.02 ibuprofen 400 mg 850 mg ibuprofen 0.97¶ 1.01¶ cimetidine 400 mg 850 mg cimetidine 0.95§ 1.01 * all metformin and coadministered drugs were given as single doses † auc = auc(inf) unless otherwise noted ‡ ratio of arithmetic means, p-value of difference <0.05 § auc(0-24 hr) reported ¶ ratio of arithmetic means

ale rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately 2 times the maximum recommended human daily dose of 2550 mg based on body surface area comparisons.

rms, respectively. mean change in body weight from baseline to week 29 was -1.4 lbs and -2.4 lbs in the metformin hydrochloride tablets and placebo arms, respectively. 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 mellitus who had failed to achieve adequate glycemic control while on maximum doses of glyburide (baseline fpg of approximately 250 mg/dl). patients randomized to the combination arm started therapy with metformin hydrochloride tablets 500 mg and glyburide 20 mg. at the end of each week of the first 4 weeks of the trial, these patients had their dosages of 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 to exceed metformin hydrochloride tablets 2500 mg. patients in the metformin hydrochloride tablets only arm (metformin plus placebo) discontinued glyburide and followed the same titration schedule. patients in the glyburide arm continued the same dose of glyburide. at the end of the trial, approximately 70% of the patients in the combination group were taking metformin hydrochloride tablets 2000 mg/glyburide 20 mg or metformin hydrochloride tablets 2500 mg/glyburide 20 mg. the results are displayed in table 8. table 8: mean change in fasting plasma glucose and hba1c at week 29 comparing metformin /glyburide (comb) vs glyburide (glyb) vs metformin (met): in patients with type 2 diabetes mellitus with inadequate glycemic control on glyburide comb (n=213) glyb (n=209 ) glu (n=210) p-values 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* 0.001 ns* 0.001 ns* 0.025 hemoglobin a1c (%) 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 * not statistically significant mean baseline body weight was 202 lbs, 203 lbs, and 204 lbs in the metformin/glyburide, glyburide, and metformin arms, respectively. mean change in body weight from baseline to week 29 was 0.9 lbs, -0.7 lbs, and -8.4 lbs in the metformin/ glyburide, glyburide, and metformin arms, respectively. pediatric clinical studies a double-blind, placebo-controlled study in pediatric patients aged 10 to 16 years with type 2 diabetes mellitus (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) was conducted. the results are displayed in table 9. table 9: mean change in fasting plasma glucose at week 16 comparing metformin hydrochloride tablets vs placebo in pediatric patientsa with type 2 diabetes mellitus metformin hydrochloride tablets placebo p-value fpg (mg/dl) baseline change at final visit (n=37) 162.4 –42.9 (n=36) 192.3 21.4 <0.001 a pediatric patients mean age 13.8 years (range 10-16 years) mean baseline body weight was 205 lbs and 189 lbs in the metformin hydrochloride tablets and placebo arms, respectively. mean change in body weight from baseline to week 16 was -3.3 lbs and -2.0 lbs in the metformin hydrochloride tablets and placebo arms, respectively.

trolled room temperature.]