DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS Metformin hydrochloride extended release tablets are available as:oTablets: 500 mg white, oblong, biconvex tablets, debossed E4416 on one side and plain on the other side.. oTablets: 500 mg white, oblong, biconvex tablets, debossed E4416 on one side and plain on the other side.. oMetformin Hydrochloride Extended Release Tablets: 500 mg (3) oMetformin Hydrochloride Extended Release Tablets: 500 mg (3).

ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS The following adverse reactions are also discussed elsewhere in the labeling: oLactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1)] oVitamin B12 Deficiency [see Warnings and Precautions (5.2)]oHypoglycemia [see Warnings and Precautions (5.3)] oLactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1)] oVitamin B12 Deficiency [see Warnings and Precautions (5.2)]. oHypoglycemia [see Warnings and Precautions (5.3)] For metformin hydrochloride extended release tablets, the most common adverse reactions (>5.0%) are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Sandoz, Inc., at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Metformin hydrochloride extended release tablets In placebo-controlled trials, 781 patients were administered metformin hydrochloride extended release tablets. 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 2.Table 2. Adverse Reactions From Clinical Trials of Metformin Hydrochloride Extended Release Tablets Occurring >5% and More Common Than Placebo in Patients With Type Diabetes MellitusMetformin hydrochloride extended release tablets(n=781)Placebo(n=195)Diarrhea 10% 3% Nausea/Vomiting 7% 2% Diarrhea led to discontinuation of metformin hydrochloride extended release tablets in 0.6% of patients. 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.. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of metformin. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin.

BOXED WARNING SECTION.


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

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately times the maximum recommended human daily dose of 2550 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day. There was no evidence of mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative. Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately times the maximum recommended human daily dose of 2550 mg based on body surface area comparisons.

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.. 12.3 Pharmacokinetics Absorption. Following single oral dose of metformin hydrochloride extended release tablets, Cmax is achieved with median value of hours and range of to hours. Peak plasma levels are approximately 20% lower compared to the same dose of metformin hydrochloride immediate release tablets, however, the extent of absorption (as measured by AUC) is comparable to metformin hydrochloride immediate release tablets. At steady state, the AUC and Cmax 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 tablets at 2000 mg once-daily dose is similar to the same total daily dose administered as metformin hydrochloride immediate release tablets 1000 mg twice daily. After repeated administration of metformin hydrochloride extended release tablets, metformin did not accumulate in plasma.Effect of foodFood decreases the extent of absorption and slightly delays the absorption of metformin, as shown by approximately 40% lower mean peak plasma concentration (Cmax), 25% lower area under the plasma concentration versus time curve (AUC). 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 Cmax and Tmax of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of metformin hydrochloride extended release tablets.. Distribution. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as 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 plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be compartment of distribution.. Specific Population. 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)]. Gender. Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 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 VivoAssessment of Drug InteractionsTable 5. Effect of Coadministered Drug on Plasma Metformin Systemic ExposureCoadministered Drug Dose of Coadministered DrugAll metformin and coadministered drugs were given as single dosesDose of MetforminGeometric Mean Ratio(ratio with/without coadministered drug) No Effect 1.00AUCAUC AUC(INF)Cmax No dosing adjustments required for the following: Glyburide mg 850 mg metformin 0.91Ratio of arithmetic means 0.93 Furosemide 40 mg 850 mg metformin 1.09 1.22 Nifedipine 10 mg 850 mg metformin 1.16 1.21 Propranolol 40 mg 850 mg metformin 0.90 0.94 Ibuprofen 400 mg 850 mg metformin 1.05 1.07 Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination [See Warnings and Precautions (5.9) and Drug Interactions (7.2).] Cimetidine 400 mg 850 mg metformin 1.40 1.61 Carbonic anhydrase inhibitors may cause metabolic acidosis [See Warnings and Precautions (5.1) and Drug Interactions (7.1).] Topiramate 100 mgAt steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC AUC0-12h 500 mg metformin 1.25 1.17 Table 6. Effect of Metformin on Coadministered Drug Systemic ExposureCoadministered Drug Dose of Coadministered DrugAll metformin and coadministered drugs were given as single dosesDose of MetforminGeometric Mean Ratio (ratio with/without metformin) No Effect 1.00 AUCAUC AUC(INF) unless otherwise notedCmax No dosing adjustments required for the following: Glyburide mg 850 mg glyburide 0.78Ratio of arithmetic means, p-value of difference <0.05 0.63 Furosemide 40 mg 850 mg furosemide 0.87 0.69 Nifedipine 10 mg 850 mg nifedipine 1.10AUC(0-24 hr) reported 1.08 Propranolol 40 mg 850 mg propranolol 1.01 1.02 Ibuprofen 400 mg 850 mg ibuprofen 0.97Ratio of arithmetic means 1.01 Cimetidine 400 mg 850 mg cimetidine 0.95 1.01.

CLINICAL STUDIES SECTION.


6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Metformin hydrochloride extended release tablets In placebo-controlled trials, 781 patients were administered metformin hydrochloride extended release tablets. 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 2.Table 2. Adverse Reactions From Clinical Trials of Metformin Hydrochloride Extended Release Tablets Occurring >5% and More Common Than Placebo in Patients With Type Diabetes MellitusMetformin hydrochloride extended release tablets(n=781)Placebo(n=195)Diarrhea 10% 3% Nausea/Vomiting 7% 2% Diarrhea led to discontinuation of metformin hydrochloride extended release tablets in 0.6% of patients. 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.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS Metformin hydrochloride extended release tablets are contraindicated in patients with:oSevere renal impairment (eGFR below 30 mL/min/1.73 m2) [see Warnings and Precautions (5.1)]. oHypersensitivity to metformin. oAcute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. oSevere renal impairment (eGFR below 30 mL/min/1.73 m2) [see Warnings and Precautions (5.1)]. oHypersensitivity to metformin. oAcute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. oSevere renal impairment (eGFR below 30 mL/min/1.73 m2) (4, 5.1) oHypersensitivity to metformin (4) oAcute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. (4) oSevere renal impairment (eGFR below 30 mL/min/1.73 m2) (4, 5.1) oHypersensitivity to metformin (4) oAcute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. (4).

DESCRIPTION SECTION.


11 DESCRIPTION Metformin hydrochloride extended-release tablets, USP are oral antihyperglycemic, which are biguanides, in the form of monohydrochlorides. The chemical name of metformin hydrochloride is N,N-dimethylimidodicarbonimidic diamide hydrochloride. The structural formula is as shown below:Metformin hydrochloride, USP is white to off-white crystalline compound with molecular formula of C4H11N5 HCl and molecular weight of 165.63. It is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of 1% aqueous solution of metformin hydrochloride is 6.68.Metformin hydrochloride extended-release tablets, USP, 500 mg contain metformin hydrochloride as the active ingredient. In addition, each tablet contains the following inactive ingredients: carboxy methylcellulose sodium, colloidal silicon dioxide, hypromellose, magnesium stearate, and microcrystalline cellulose.. ChemicalStructure.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION Adult dosage forMetformin Hydrochloride Extended Release TabletsoSwallow metformin hydrochloride extended release tablets whole and never crush, cut or chew (2.1) oStarting dose: 500 mg orally once daily with the evening meal (2.1) oIncrease the dose in increments of 500 mg weekly, up to maximum of 2000 mg once daily with the evening meal (2.1) oPatients receiving metformin hydrochloride may be switched to metformin hydrochloride extended release once daily at the same total daily dose, up to 2000 mg once daily (2.1)Renal Impairment:oPrior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) (2.3)oDo not use in patients with eGFR below 30 mL/minute/1.73 m2 (2.3)oInitiation is not recommended in patients with eGFR between 30-45 mL/minute/1.73 m2 (2.3)oAssess risk/benefit of continuing if eGFR falls below 45 mL/minute/1.73 m2 (2.3)oDiscontinue if eGFR falls below 30 mL/minute/1.73 m2 (2.3) Discontinuation for Iodinated Contrast Imaging Procedures: oMetformin hydrochloride extended release tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures (2.4). oSwallow metformin hydrochloride extended release tablets whole and never crush, cut or chew (2.1) oStarting dose: 500 mg orally once daily with the evening meal (2.1) oIncrease the dose in increments of 500 mg weekly, up to maximum of 2000 mg once daily with the evening meal (2.1) oPatients receiving metformin hydrochloride may be switched to metformin hydrochloride extended release once daily at the same total daily dose, up to 2000 mg once daily (2.1). oPrior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) (2.3). oDo not use in patients with eGFR below 30 mL/minute/1.73 m2 (2.3). oInitiation is not recommended in patients with eGFR between 30-45 mL/minute/1.73 m2 (2.3). oAssess risk/benefit of continuing if eGFR falls below 45 mL/minute/1.73 m2 (2.3). oDiscontinue if eGFR falls below 30 mL/minute/1.73 m2 (2.3) oMetformin hydrochloride extended release tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures (2.4). 2.1 Adult Dosage Metformin Hydrochloride Extended Release TabletsoSwallow metformin hydrochloride extended release tablets whole and never crush, cut or chew. oThe recommended starting dose of metformin hydrochloride extended release tablets is 500 mg orally once daily with the evening meal. oIncrease the dose in increments of 500 mg weekly on the basis of glycemic control and tolerability, up to maximum of 2000 mg once daily with the evening meal. oIf glycemic control is not achieved with metformin hydrochloride extended release tablets 2000 mg once daily, consider trial of metformin hydrochloride extended release tablets 1000 mg twice daily. If higher doses are required, switch to metformin hydrochloride immediate release tablets total daily doses up to 2550 mg administered in divided daily doses, as described above. oPatients receiving metformin hydrochloride immediate release tablets may be switched to metformin hydrochloride extended release tablets once daily at the same total daily dose, up to 2000 mg once daily. oSwallow metformin hydrochloride extended release tablets whole and never crush, cut or chew. oThe recommended starting dose of metformin hydrochloride extended release tablets is 500 mg orally once daily with the evening meal. oIncrease the dose in increments of 500 mg weekly on the basis of glycemic control and tolerability, up to maximum of 2000 mg once daily with the evening meal. oIf glycemic control is not achieved with metformin hydrochloride extended release tablets 2000 mg once daily, consider trial of metformin hydrochloride extended release tablets 1000 mg twice daily. If higher doses are required, switch to metformin hydrochloride immediate release tablets total daily doses up to 2550 mg administered in divided daily doses, as described above. oPatients receiving metformin hydrochloride immediate release tablets may be switched to metformin hydrochloride extended release tablets once daily at the same total daily dose, up to 2000 mg once daily. 2.3 Recommendations for Use in Renal Impairment oAssess renal function prior to initiation of metformin hydrochloride extended release tablets and periodically thereafter. oMetformin hydrochloride extended release tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m2. oInitiation of metformin hydrochloride extended release tablets in patients with an eGFR between 30 to 45 mL/minute/1.73 m2 is not recommended. oIn patients taking metformin hydrochloride extended release tablets whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit risk of continuing therapy. oDiscontinue metformin hydrochloride extended release tablets if the patients eGFR later falls below 30 mL/minute/1.73 m2 [see Warnings and Precautions (5.1)]. oAssess renal function prior to initiation of metformin hydrochloride extended release tablets and periodically thereafter. oMetformin hydrochloride extended release tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m2. oInitiation of metformin hydrochloride extended release tablets in patients with an eGFR between 30 to 45 mL/minute/1.73 m2 is not recommended. oIn patients taking metformin hydrochloride extended release tablets whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit risk of continuing therapy. oDiscontinue metformin hydrochloride extended release tablets if the patients eGFR later falls below 30 mL/minute/1.73 m2 [see Warnings and Precautions (5.1)]. 2.4 Discontinuation for Iodinated Contrast Imaging Procedures Discontinue metformin hydrochloride extended release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart metformin hydrochloride extended release tablets if renal function is stable.

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS Table presents clinically significant drug interactions with metformin hydrochloride extended release tablets.Table 3. Clinically Significant Drug Interactions with Metformin Hydrochloride Extended Release TabletsCarbonic Anhydrase Inhibitors Clinical Impact: Carbonic anhydrase inhibitors frequently cause decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with metformin hydrochloride extended release tablets may increase the risk for lactic acidosis. Intervention: Consider more frequent monitoring of these patients. Examples: Topiramate, zonisamide, acetazolamide or dichlorphenamide. Drugs that Reduce Metformin Hydrochloride Extended Release Clearance Clinical Impact: Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology (12.3)]. Intervention: Consider the benefits and risks of concomitant use with metformin hydrochloride extended release tablets. 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 extended release tablets. Insulin Secretagogues or Insulin Clinical Impact: Coadministration of metformin hydrochloride extended release tablets 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 patient receiving metformin hydrochloride extended release tablets, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from patient receiving metformin hydrochloride extended release 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. oCarbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring (7) oDrugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the accumulation of metformin. Consider the benefits and risks of concomitant use (7) oAlcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake (7) oCarbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring (7) oDrugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the accumulation of metformin. Consider the benefits and risks of concomitant use (7) oAlcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake (7).

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.


8.3 Females and Males of Reproductive Potential Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin hydrochloride extended release tablets may result in ovulation in some anovulatory women.

GERIATRIC USE SECTION.


8.5 Geriatric Use Controlled clinical studies of metformin hydrochloride extended release 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)].

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Table 13. Metformin Hydrochloride Extended Release Tablets Available Strengths, Units, and AppearanceMetformin hydrochloride extended-release tablets, USP500 mgBottles of 100 NDC 0185-4416-01white, oblong, biconvex tablets, debossed E4416 on one side and plain on the other sideBottles of 500NDC 0185-4416-05Bottles of 750NDC 0185-4416-75. 16.2 Storage Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Dispense in light-resistant container as defined in the USP with child-resistant closure, as required.KEEP THIS AND ALL MEDICATION OUT OF THE REACH OF CHILDREN.

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE Metformin hydrochloride extended release tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus. Metformin hydrochloride extended release tablets are biguanide indicated as an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus. (1).

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Lactic Acidosis Explain the risks of lactic acidosis, its symptoms, and conditions that predispose to its development. Advise patients to discontinue metformin hydrochloride extended release tablets immediately and to promptly notify their healthcare provider if unexplained hyperventilation, myalgias, malaise, unusual somnolence or other nonspecific symptoms occur. Counsel patients against excessive alcohol intake and inform patients about importance of regular testing of renal function while receiving metformin hydrochloride extended release tablets. Instruct patients to inform their doctor that they are taking metformin hydrochloride extended release tablets prior to any surgical or radiological procedure, as temporary discontinuation may be required [see Warnings and Precautions (5.1)]. Hypoglycemia Inform patients that hypoglycemia may occur when metformin hydrochloride extended release tablets are coadministered with oral sulfonylureas and insulin. Explain to patients receiving concomitant therapy the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development [see Warnings and Precautions (5.3)]. Vitamin B12 Deficiency Inform patients about importance of regular hematological parameters while receiving metformin hydrochloride extended release tablets [see Warnings and Precautions (5.2)]. Females of Reproductive Age Inform females that treatment with metformin hydrochloride extended release tablets may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy [see Use in Specific Populations (8.3)]. Metformin Hydrochloride Extended Release Administration InformationInform patients that metformin hydrochloride extended release tablets must be swallowed whole and not crushed, cut, or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as soft mass that may resemble the original tablet.Metformin hydrochloride extended-release tablets, USP, 500 mg are manufactured by Cipla, Ltd.Kurkumbh, Indiafor Sandoz Inc.Princeton, NJ 08540.

LACTATION SECTION.


8.2 Lactation Risk SummaryLimited published studies report that metformin is present in human milk [see Data]. However, there is insufficient information to determine the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for metformin hydrochloride extended release tablets and any potential adverse effects on the breastfed child from metformin hydrochloride extended release tablets 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 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.

MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately times the maximum recommended human daily dose of 2550 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day. There was no evidence of mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative. Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately times the maximum recommended human daily dose of 2550 mg based on body surface area comparisons.

OVERDOSAGE SECTION.


10 OVERDOSAGE Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.1)]. Metformin is dialyzable with clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 0185-4416-01MetforminHydrochlorideExtended-ReleaseTablets USP500 mgRx only100 TabletsSandoz. 500mg100tabslabel.

PATIENT MEDICATION INFORMATION SECTION.


Patient Information. Metformin Hydrochloride Extended Release Tablets, USP(met FOR min)Read the Patient Information that comes with metformin hydrochloride extended release tablets before you start taking it and each time you get refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or treatment. What is the most important information should know about metformin hydrochloride extended release tablets Serious side effects can happen in people taking metformin hydrochloride extended release tablets, including: Lactic Acidosis. Metformin hydrochloride can cause rare, but serious, side effect called lactic acidosis (a build-up of lactic acid in the blood) that can cause death. Lactic acidosis is medical emergency and must be treated in hospital. Stop taking metformin hydrochloride extended release tablets and call your healthcare provider right away if you get any of the following symptoms of lactic acidosis:ofeel very weak and tired ohave unusual (not normal) muscle pain ohave trouble breathing ohave unusual sleepiness or sleep longer than usual ohave unexplained stomach or intestinal problems with nausea and vomiting, or diarrhea ofeel cold, especially in your arms and legs ofeel dizzy or lightheaded ohave slow or irregular heartbeat You have higher chance of getting lactic acidosis if you: ohave kidney problems. People whose kidneys are not working properly should not take metformin hydrochloride extended release tablets. ohave liver problems. ohave congestive heart failure that requires treatment with medicines. odrink lot of alcohol (very often or short-term binge drinking). oget dehydrated (lose large amount of body fluids). This can happen if you are sick with fever, vomiting, or diarrhea. Dehydration can also happen when you sweat lot with activity or exercise and do not drink enough fluids. ohave certain x-ray tests with injectable dyes or contrast agents. ohave surgery. ohave heart attack, severe infection, or stroke. oare 80 years of age or older and have not had your kidney function tested. What are metformin hydrochloride extended release tablets ometformin hydrochloride extended release tablets are prescription medicines. Metformin hydrochloride extended release tablets are used with diet and exercise to help control high blood sugar (hyperglycemia) in adults with type diabetes. ometformin hydrochloride extended release tablets are not for people with type diabetes. ometformin hydrochloride extended release tablets are not for people with diabetic ketoacidosis (increased ketones in your blood or urine).oMetformin hydrochloride extended release tablets work longer in your body. This medicine helps control your blood sugar in 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 extended release tablets do not cause your body to make more insulin.Who should not take metformin hydrochloride extended release tablets Some conditions increase your chance of getting lactic acidosis, or cause other problems if you take this medicine. Most of the conditions listed below can increase your chance of getting lactic acidosis. Do not take metformin hydrochloride extended release tablets if you: ohave kidney problems oare allergic to the metformin hydrochloride in metformin hydrochloride extended release tablets or any of the ingredients in metformin hydrochloride extended release tablets. See the end of this leaflet for complete list of ingredients in metformin hydrochloride extended release tablets. oare going to get an injection of dye or contrast agents for an x-ray procedure or if you are going to have surgery and not able to eat or drink much. In these situations, metformin hydrochloride extended release tablets will need to be stopped for short time. Talk to your healthcare provider about when you should stop metformin hydrochloride extended release tablets and when you should start metformin hydrochloride extended release tablets again. See What is the most important information should know about metformin hydrochloride extended release tabletsWhat should tell my healthcare provider before taking metformin hydrochloride extended release tabletsBefore taking metformin hydrochloride extended release tablets, tell your healthcare provider if you:ohave type diabetes. Metformin hydrochloride extended release tablets should not be used to treat people with type diabetes.ohave history or risk for diabetic ketoacidosis (high levels of certain acids, known as ketones, in the blood or urine). Metformin hydrochloride extended release tablets should not be used for the treatment of diabetic ketoacidosis.ohave kidney problems.ohave liver problems.ohave heart problems, including congestive heart failure.oare older than 80 years. If you are over 80 years old you should not take metformin hydrochloride extended release tablets unless your kidneys have been checked and they are normal.odrink alcohol very often, or drink lot of alcohol in short-term binge drinking.oare taking insulin.ohave any other medical conditions.oare pregnant or plan to become pregnant. It is not known if metformin hydrochloride extended release tablets will harm your unborn baby. If you are pregnant, talk with your healthcare provider about the best way to control your blood sugar while you are pregnant.oare breast-feeding or plan to breast-feed. It is not known if metformin hydrochloride passes into your breast milk. Talk with your healthcare provider about the best way to feed your baby while you take metformin hydrochloride extended release tablets.Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine.oMetformin hydrochloride extended release tablets may affect the way other medicines work, and other medicines may affect how metformin hydrochloride extended release tablets work.Can metformin hydrochloride extended release tablets be used in children Metformin hydrochloride extended release tablets have not been studied in children.How should take metformin hydrochloride extended release tablets oTake metformin hydrochloride extended release tablets exactly as your healthcare provider tells you. oMetformin hydrochloride extended release tablets should be taken with meals to help lessen an upset stomach side effect. oSwallow metformin hydrochloride extended release tablets whole. Do not crush, cut, or chew metformin hydrochloride extended release tablets. oYou may sometimes pass soft mass in your stools (bowel movement) that looks like metformin hydrochloride extended release tablets. This is not harmful and will not affect the way metformin hydrochloride extended release tablets work to control your diabetes. oWhen your body is under some types of stress, such as fever, trauma (such as car accident), infection, or surgery, the amount of diabetes medicine that you need may change. Tell your healthcare provider right away if you have any of these problems. oYour healthcare provider should do blood tests to check how well your kidneys are working before and during your treatment with metformin hydrochloride extended release tablets. oYour healthcare provider will check your diabetes with regular blood tests, including your blood sugar levels and your hemoglobin A1C. oFollow your healthcare providers instructions for treating blood sugar that is too low (hypoglycemia). Talk to your healthcare provider if low blood sugar is problem for you. See What are the possible side effects of metformin hydrochloride extended release tablets oCheck your blood sugar as your healthcare provider tells you to. oStay on your prescribed diet and exercise program while taking metformin hydrochloride extended release tablets. oIf you miss dose of metformin hydrochloride extended release tablets, take your next dose as prescribed unless your healthcare provider tells you differently. Do not take an extra dose the next day. oIf you take too many metformin hydrochloride extended release tablets, call your healthcare provider, local Poison Control Center, or go to the nearest hospital emergency room right away. What should avoid while taking metformin hydrochloride extended release tablets Do not drink lot of alcoholic drinks while taking metformin hydrochloride extended release tablets. This means you should not binge drink for short periods, and you should not drink lot of alcohol on regular basis. Alcohol can increase the chance of getting lactic acidosis. What are the side effects of metformin hydrochloride extended release tablets oLactic acidosis. Metformin can cause rare but serious condition called lactic acidosis (a buildup of an acid in the blood) that can cause death. Lactic acidosis is medical emergency and must be treated in the hospital. Call your doctor right away if you have any of the following symptoms, which could be signs of lactic acidosis: oyou feel cold in your hands or feet oyou feel dizzy or lightheaded oyou have slow or irregular heartbeat oyou feel very weak or tired oyou have trouble breathing oyou feel sleepy or drowsy oyou have stomach pains, nausea or vomiting Most people who have had lactic acidosis with metformin have other things that, combined with the metformin, led to the lactic acidosis. Tell your doctor if you have any of the following, because you have higher chance for getting lactic acidosis with metformin hydrochloride extended release tablets if you: ohave severe kidney problems, or your kidneys are affected by certain x-ray tests that use injectable dye ohave liver problems odrink alcohol very often, or drink lot of alcohol in short-term binge drinking oget dehydrated (lose large amount of body fluids). This can happen if you are sick with fever, vomiting, or diarrhea. Dehydration can also happen when you sweat lot with activity or exercise and do not drink enough fluids ohave surgery ohave heart attack, severe infection, or stroke Common side effects of metformin hydrochloride extended release tablets include diarrhea, nausea, and upset stomach. These side effects generally go away after you take the medicine for while. Taking your medicine with meals can help reduce these side effects. Tell your doctor if the side effects bother you lot, last for more than few weeks, come back after theyve gone away, or start later in therapy. You may need lower dose or need to stop taking the medicine for short period or for good. About out of every 100 people who take metformin hydrochloride extended release tablets have an unpleasant metallic taste when they start taking the medicine. It lasts for short time. Metformin hydrochloride extended release tablets rarely cause hypoglycemia (low blood sugar) by themselves. However, hypoglycemia can happen if you do not eat enough, if you drink alcohol, or if you take other medicines to lower blood sugar. How should store metformin hydrochloride extended release tablets Store metformin hydrochloride extended release tablets at 68F to 77F (20C to 25C). KEEP OUT OF THE REACH OF CHILDREN. General information about the use of metformin hydrochloride extended release tablets If you have questions or problems, talk with your doctor or other healthcare provider. You can ask your doctor or pharmacist for the information about metformin hydrochloride extended release tablets that is written for healthcare professionals. Medicines are sometimes prescribed for purposes other than those listed in patient information leaflet. Do not use metformin hydrochloride extended release tablets for condition for which they were not prescribed. Do not share your medicine with other people. What are the ingredients of metformin hydrochloride extended release tablets Active ingredients: metformin hydrochloride. Inactive ingredients in each tablet of metformin hydrochloride extended release tablets: carboxy methylcellulose sodium, colloidal silicon dioxide, hypromellose, magnesium stearate, and microcrystalline cellulose. What is type diabetes Type diabetes is condition in which your body does not make enough insulin, and the insulin that your body produces does not work as well as it should. Your body can also make too much sugar. When this happens, sugar (glucose) builds up in the blood. This can lead to serious medical problems. The main goal of treating diabetes is to lower your blood sugar to normal level. High blood sugar can be lowered by diet and exercise, and by certain medicines when necessary. Talk to your healthcare provider about how to prevent, recognize, and take care of low blood sugar (hypoglycemia), high blood sugar (hyperglycemia), and problems you have because of your diabetes.Metformin hydrochloride extended-release tablets, USP, 500 mg are manufactured by Cipla, Ltd.Kurkumbh, Indiafor Sandoz Inc.Princeton, NJ 08540. ofeel very weak and tired ohave unusual (not normal) muscle pain ohave trouble breathing ohave unusual sleepiness or sleep longer than usual ohave unexplained stomach or intestinal problems with nausea and vomiting, or diarrhea ofeel cold, especially in your arms and legs ofeel dizzy or lightheaded ohave slow or irregular heartbeat ohave kidney problems. People whose kidneys are not working properly should not take metformin hydrochloride extended release tablets. ohave liver problems. ohave congestive heart failure that requires treatment with medicines. odrink lot of alcohol (very often or short-term binge drinking). oget dehydrated (lose large amount of body fluids). This can happen if you are sick with fever, vomiting, or diarrhea. Dehydration can also happen when you sweat lot with activity or exercise and do not drink enough fluids. ohave certain x-ray tests with injectable dyes or contrast agents. ohave surgery. ohave heart attack, severe infection, or stroke. oare 80 years of age or older and have not had your kidney function tested. ometformin hydrochloride extended release tablets are prescription medicines. Metformin hydrochloride extended release tablets are used with diet and exercise to help control high blood sugar (hyperglycemia) in adults with type diabetes. ometformin hydrochloride extended release tablets are not for people with type diabetes. ometformin hydrochloride extended release tablets are not for people with diabetic ketoacidosis (increased ketones in your blood or urine).. oMetformin hydrochloride extended release tablets work longer in your body. This medicine helps control your blood sugar in 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 extended release tablets do not cause your body to make more insulin.. ohave kidney problems oare allergic to the metformin hydrochloride in metformin hydrochloride extended release tablets or any of the ingredients in metformin hydrochloride extended release tablets. See the end of this leaflet for complete list of ingredients in metformin hydrochloride extended release tablets. oare going to get an injection of dye or contrast agents for an x-ray procedure or if you are going to have surgery and not able to eat or drink much. In these situations, metformin hydrochloride extended release tablets will need to be stopped for short time. Talk to your healthcare provider about when you should stop metformin hydrochloride extended release tablets and when you should start metformin hydrochloride extended release tablets again. See What is the most important information should know about metformin hydrochloride extended release tablets. ohave type diabetes. Metformin hydrochloride extended release tablets should not be used to treat people with type diabetes.. ohave history or risk for diabetic ketoacidosis (high levels of certain acids, known as ketones, in the blood or urine). Metformin hydrochloride extended release tablets should not be used for the treatment of diabetic ketoacidosis.. ohave kidney problems.. ohave liver problems.. ohave heart problems, including congestive heart failure.. oare older than 80 years. If you are over 80 years old you should not take metformin hydrochloride extended release tablets unless your kidneys have been checked and they are normal.. odrink alcohol very often, or drink lot of alcohol in short-term binge drinking.. oare taking insulin.. ohave any other medical conditions.. oare pregnant or plan to become pregnant. It is not known if metformin hydrochloride extended release tablets will harm your unborn baby. If you are pregnant, talk with your healthcare provider about the best way to control your blood sugar while you are pregnant.. oare breast-feeding or plan to breast-feed. It is not known if metformin hydrochloride passes into your breast milk. Talk with your healthcare provider about the best way to feed your baby while you take metformin hydrochloride extended release tablets.. oMetformin hydrochloride extended release tablets may affect the way other medicines work, and other medicines may affect how metformin hydrochloride extended release tablets work.. oTake metformin hydrochloride extended release tablets exactly as your healthcare provider tells you. oMetformin hydrochloride extended release tablets should be taken with meals to help lessen an upset stomach side effect. oSwallow metformin hydrochloride extended release tablets whole. Do not crush, cut, or chew metformin hydrochloride extended release tablets. oYou may sometimes pass soft mass in your stools (bowel movement) that looks like metformin hydrochloride extended release tablets. This is not harmful and will not affect the way metformin hydrochloride extended release tablets work to control your diabetes. oWhen your body is under some types of stress, such as fever, trauma (such as car accident), infection, or surgery, the amount of diabetes medicine that you need may change. Tell your healthcare provider right away if you have any of these problems. oYour healthcare provider should do blood tests to check how well your kidneys are working before and during your treatment with metformin hydrochloride extended release tablets. oYour healthcare provider will check your diabetes with regular blood tests, including your blood sugar levels and your hemoglobin A1C. oFollow your healthcare providers instructions for treating blood sugar that is too low (hypoglycemia). Talk to your healthcare provider if low blood sugar is problem for you. See What are the possible side effects of metformin hydrochloride extended release tablets oCheck your blood sugar as your healthcare provider tells you to. oStay on your prescribed diet and exercise program while taking metformin hydrochloride extended release tablets. oIf you miss dose of metformin hydrochloride extended release tablets, take your next dose as prescribed unless your healthcare provider tells you differently. Do not take an extra dose the next day. oIf you take too many metformin hydrochloride extended release tablets, call your healthcare provider, local Poison Control Center, or go to the nearest hospital emergency room right away. oLactic acidosis. Metformin can cause rare but serious condition called lactic acidosis (a buildup of an acid in the blood) that can cause death. Lactic acidosis is medical emergency and must be treated in the hospital. oyou feel cold in your hands or feet oyou feel dizzy or lightheaded oyou have slow or irregular heartbeat oyou feel very weak or tired oyou have trouble breathing oyou feel sleepy or drowsy oyou have stomach pains, nausea or vomiting ohave severe kidney problems, or your kidneys are affected by certain x-ray tests that use injectable dye ohave liver problems odrink alcohol very often, or drink lot of alcohol in short-term binge drinking oget dehydrated (lose large amount of body fluids). This can happen if you are sick with fever, vomiting, or diarrhea. Dehydration can also happen when you sweat lot with activity or exercise and do not drink enough fluids ohave surgery ohave heart attack, severe infection, or stroke.

PEDIATRIC USE SECTION.


8.4 Pediatric Use Metformin Hydrochloride Extended Release TabletsSafety and effectiveness of metformin hydrochloride extended release tablets in pediatric patients have not been established.

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics Absorption. Following single oral dose of metformin hydrochloride extended release tablets, Cmax is achieved with median value of hours and range of to hours. Peak plasma levels are approximately 20% lower compared to the same dose of metformin hydrochloride immediate release tablets, however, the extent of absorption (as measured by AUC) is comparable to metformin hydrochloride immediate release tablets. At steady state, the AUC and Cmax 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 tablets at 2000 mg once-daily dose is similar to the same total daily dose administered as metformin hydrochloride immediate release tablets 1000 mg twice daily. After repeated administration of metformin hydrochloride extended release tablets, metformin did not accumulate in plasma.Effect of foodFood decreases the extent of absorption and slightly delays the absorption of metformin, as shown by approximately 40% lower mean peak plasma concentration (Cmax), 25% lower area under the plasma concentration versus time curve (AUC). 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 Cmax and Tmax of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of metformin hydrochloride extended release tablets.. Distribution. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as 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 plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be compartment of distribution.. Specific Population. 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)]. Gender. Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 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 VivoAssessment of Drug InteractionsTable 5. Effect of Coadministered Drug on Plasma Metformin Systemic ExposureCoadministered Drug Dose of Coadministered DrugAll metformin and coadministered drugs were given as single dosesDose of MetforminGeometric Mean Ratio(ratio with/without coadministered drug) No Effect 1.00AUCAUC AUC(INF)Cmax No dosing adjustments required for the following: Glyburide mg 850 mg metformin 0.91Ratio of arithmetic means 0.93 Furosemide 40 mg 850 mg metformin 1.09 1.22 Nifedipine 10 mg 850 mg metformin 1.16 1.21 Propranolol 40 mg 850 mg metformin 0.90 0.94 Ibuprofen 400 mg 850 mg metformin 1.05 1.07 Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination [See Warnings and Precautions (5.9) and Drug Interactions (7.2).] Cimetidine 400 mg 850 mg metformin 1.40 1.61 Carbonic anhydrase inhibitors may cause metabolic acidosis [See Warnings and Precautions (5.1) and Drug Interactions (7.1).] Topiramate 100 mgAt steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC AUC0-12h 500 mg metformin 1.25 1.17 Table 6. Effect of Metformin on Coadministered Drug Systemic ExposureCoadministered Drug Dose of Coadministered DrugAll metformin and coadministered drugs were given as single dosesDose of MetforminGeometric Mean Ratio (ratio with/without metformin) No Effect 1.00 AUCAUC AUC(INF) unless otherwise notedCmax No dosing adjustments required for the following: Glyburide mg 850 mg glyburide 0.78Ratio of arithmetic means, p-value of difference <0.05 0.63 Furosemide 40 mg 850 mg furosemide 0.87 0.69 Nifedipine 10 mg 850 mg nifedipine 1.10AUC(0-24 hr) reported 1.08 Propranolol 40 mg 850 mg propranolol 1.01 1.02 Ibuprofen 400 mg 850 mg ibuprofen 0.97Ratio of arithmetic means 1.01 Cimetidine 400 mg 850 mg cimetidine 0.95 1.01.

PREGNULLNCY SECTION.


8.1 Pregnancy Risk SummaryLimited data with metformin hydrochloride extended release tablets in pregnant women are not sufficient to determine drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported clear association with metformin and major birth defect or miscarriage risk [see Data]. There are risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy [see Clinical Considerations]. No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2- and 5- times, respectively, 2550 mg clinical dose, based on body surface area [see Data]. The estimated background risk of major birth defects is to 10% in women with pre-gestational diabetes mellitus with an HbA1C >7 and has been reported to be as high as 20 to 25% in women with HbA1C >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 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 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 and times 2550 mg clinical dose based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated partial placental barrier to metformin.

SPL UNCLASSIFIED SECTION.


2.1 Adult Dosage Metformin Hydrochloride Extended Release TabletsoSwallow metformin hydrochloride extended release tablets whole and never crush, cut or chew. oThe recommended starting dose of metformin hydrochloride extended release tablets is 500 mg orally once daily with the evening meal. oIncrease the dose in increments of 500 mg weekly on the basis of glycemic control and tolerability, up to maximum of 2000 mg once daily with the evening meal. oIf glycemic control is not achieved with metformin hydrochloride extended release tablets 2000 mg once daily, consider trial of metformin hydrochloride extended release tablets 1000 mg twice daily. If higher doses are required, switch to metformin hydrochloride immediate release tablets total daily doses up to 2550 mg administered in divided daily doses, as described above. oPatients receiving metformin hydrochloride immediate release tablets may be switched to metformin hydrochloride extended release tablets once daily at the same total daily dose, up to 2000 mg once daily. oSwallow metformin hydrochloride extended release tablets whole and never crush, cut or chew. oThe recommended starting dose of metformin hydrochloride extended release tablets is 500 mg orally once daily with the evening meal. oIncrease the dose in increments of 500 mg weekly on the basis of glycemic control and tolerability, up to maximum of 2000 mg once daily with the evening meal. oIf glycemic control is not achieved with metformin hydrochloride extended release tablets 2000 mg once daily, consider trial of metformin hydrochloride extended release tablets 1000 mg twice daily. If higher doses are required, switch to metformin hydrochloride immediate release tablets total daily doses up to 2550 mg administered in divided daily doses, as described above. oPatients receiving metformin hydrochloride immediate release tablets may be switched to metformin hydrochloride extended release tablets once daily at the same total daily dose, up to 2000 mg once daily.

STORAGE AND HANDLING SECTION.


16.2 Storage Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Dispense in light-resistant container as defined in the USP with child-resistant closure, as required.KEEP THIS AND ALL MEDICATION OUT OF THE REACH OF CHILDREN.

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS oFemales and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. (8.3) oGeriatric Use: Assess renal function more frequently. (8.5) oHepatic Impairment: Avoid use in patients with hepatic impairment. (8.7). oFemales and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. (8.3) oGeriatric Use: Assess renal function more frequently. (8.5) oHepatic Impairment: Avoid use in patients with hepatic impairment. (8.7). 8.1 Pregnancy Risk SummaryLimited data with metformin hydrochloride extended release tablets in pregnant women are not sufficient to determine drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported clear association with metformin and major birth defect or miscarriage risk [see Data]. There are risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy [see Clinical Considerations]. No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2- and 5- times, respectively, 2550 mg clinical dose, based on body surface area [see Data]. The estimated background risk of major birth defects is to 10% in women with pre-gestational diabetes mellitus with an HbA1C >7 and has been reported to be as high as 20 to 25% in women with HbA1C >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 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 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 and times 2550 mg clinical dose based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated partial placental barrier to metformin.. 8.2 Lactation Risk SummaryLimited published studies report that metformin is present in human milk [see Data]. However, there is insufficient information to determine the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for metformin hydrochloride extended release tablets and any potential adverse effects on the breastfed child from metformin hydrochloride extended release tablets 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 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 extended release tablets may result in ovulation in some anovulatory women.. 8.4 Pediatric Use Metformin Hydrochloride Extended Release TabletsSafety and effectiveness of metformin hydrochloride extended release tablets in pediatric patients have not been established.. 8.5 Geriatric Use Controlled clinical studies of metformin hydrochloride extended release 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 extended release tablets are 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 extended release tablets are not recommended in patients with hepatic impairment. [see Warnings and Precautions (5.1)].

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS oLactic Acidosis: See boxed warning. (5.1)oVitamin B12 Deficiency: Metformin may lower vitamin B12 levels. Measure hematological parameters annually and vitamin B12 at to year intervals and manage any abnormalities. (5.2)oHypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues: Increased risk of hypoglycemia when used in combination with insulin and/or an insulin secretagogue. Lower dose of insulin or insulin secretagogue may be required (5.3). oLactic Acidosis: See boxed warning. (5.1). oVitamin B12 Deficiency: Metformin may lower vitamin B12 levels. Measure hematological parameters annually and vitamin B12 at to year intervals and manage any abnormalities. (5.2). oHypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues: Increased risk of hypoglycemia when used in combination with insulin and/or an insulin secretagogue. Lower dose of insulin or insulin secretagogue may be required (5.3). 5.1 Lactic Acidosis There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels were generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in hospital setting, along with immediate discontinuation of metformin hydrochloride extended release tablets. In metformin hydrochloride extended release tablets treated patients with diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable with clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery. Educate patients and their families about the symptoms of lactic acidosis and, if these symptoms occur, instruct them to discontinue metformin hydrochloride extended release 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:oRenal impairment--The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patients renal function include [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)]: Before initiating metformin hydrochloride extended release tablets, obtain an estimated glomerular filtration rate (eGFR). Metformin hydrochloride extended release tablets are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see Contraindications (4)]. Initiation of metformin hydrochloride extended release tablets are not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m2. Obtain an eGFR at least annually in all patients taking metformin hydrochloride extended release tablets. 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 extended release tablets whose eGFR falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy. oDrug interactions -- The concomitant use of metformin hydrochloride extended release tablets 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. oAge 65 or greater -- The risk of metformin-associated lactic acidosis increases with the patients age because elderly patients have greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients. oRadiologic 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 extended release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with 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 extended release tablets if renal function is stable. oSurgery 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 extended release tablets should be temporarily discontinued while patients have restricted food and fluid intake. oHypoxic 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 extended release tablets. oExcessive alcohol intake -- Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving metformin hydrochloride extended release tablets. oHepatic 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 extended release tablets in patients with clinical or laboratory evidence of hepatic disease. oRenal impairment--The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patients renal function include [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)]: Before initiating metformin hydrochloride extended release tablets, obtain an estimated glomerular filtration rate (eGFR). Metformin hydrochloride extended release tablets are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see Contraindications (4)]. Initiation of metformin hydrochloride extended release tablets are not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m2. Obtain an eGFR at least annually in all patients taking metformin hydrochloride extended release tablets. 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 extended release tablets whose eGFR falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy. Before initiating metformin hydrochloride extended release tablets, obtain an estimated glomerular filtration rate (eGFR). Metformin hydrochloride extended release tablets are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see Contraindications (4)]. Initiation of metformin hydrochloride extended release tablets are not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m2. Obtain an eGFR at least annually in all patients taking metformin hydrochloride extended release tablets. 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 extended release tablets whose eGFR falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy. oDrug interactions -- The concomitant use of metformin hydrochloride extended release tablets 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. oAge 65 or greater -- The risk of metformin-associated lactic acidosis increases with the patients age because elderly patients have greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients. oRadiologic 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 extended release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with 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 extended release tablets if renal function is stable. oSurgery 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 extended release tablets should be temporarily discontinued while patients have restricted food and fluid intake. oHypoxic 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 extended release tablets. oExcessive alcohol intake -- Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving metformin hydrochloride extended release tablets. oHepatic 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 extended release tablets in patients with clinical or laboratory evidence of hepatic disease. 5.2 Vitamin B12 Deficiency In metformin hydrochloride immediate release tablet clinical trials of 29-week duration, decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin hydrochloride immediate release tablets or vitamin B12 supplementation. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis and vitamin B12 at to year intervals in patients on metformin hydrochloride extended release tablets 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 extended release may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue. Therefore, lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with metformin hydrochloride extended release 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 extended release tablets.