Metformin Hydrochloride Extended-Release Tablets, USP 8207201/0817 Rx only

Metformin hydrochloride (HCl) extended-release tablets, USP are oral antihyperglycemic drugs used in the management of type 2 diabetes. Metformin HCl, USP ( N, N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. The structural formula is as shown:

Metformin Hydrochloride Structural Formula

Metformin HCl, USP is a white to off-white crystalline compound with a molecular formula of C ₄H ₁₁N ₅ • HCl and a molecular weight of 165.63. Metformin HCl, USP is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pK _a of metformin is 12.4. The pH of a 1% aqueous solution of metformin HCl, USP is 6.68.

Metformin HCl extended-release tablets, USP contain 500 mg or 750 mg of metformin HCl, USP as the active ingredient.

Metformin HCl extended-release tablets, USP 500 mg contain the inactive ingredients; colloidal silicon dioxide, hypromellose, magnesium stearate and microcrystalline cellulose.

Metformin HCl extended-release tablets, USP 750 mg contain the inactive ingredients; colloidal silicon dioxide, hypromellose and magnesium stearate.

Dissolution Method: Test 10

System Components and Performance – Metformin HCl extended-release tablets comprise a dual hydrophilic polymer matrix system. Metformin HCl is combined with a drug release controlling polymer to form an "inner" phase, which is then incorporated as discrete particles into an "external" phase of a second polymer. After administration, fluid from the gastrointestinal (GI) tract enters the tablet, causing the polymers to hydrate and swell. Drug is released slowly from the dosage form by a process of diffusion through the gel matrix that is essentially independent of pH. The hydrated polymer system is not rigid and is expected to be broken up by normal peristalsis in the GI tract. The biologically inert components of the tablet may occasionally remain intact during GI transit and will be eliminated in the feces as a soft, hydrated mass.

Mechanism of Action
Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see PRECAUTIONS) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

Pharmacokinetics
Absorption and Bioavailability
Following a single oral dose of metformin HCl extended-release tablets, C _max is achieved with a median value of 7 hours and a range of 4 hours to 8 hours.

At steady-state, the AUC and C _max are less than dose proportional for metformin HCl extended-release tablets within the range of 500 mg to 2,000 mg administered once daily. Peak plasma levels are approximately 0.6, 1.1, 1.4, and 1.8 mcg/mL for 500, 1,000, 1,500, and 2,000 mg once-daily doses, respectively. After repeated administration of metformin HCl extended-release tablets, metformin did not accumulate in plasma.

Although the extent of metformin absorption (as measured by AUC) from the metformin HCl extended-release tablets increased by approximately 50% when given with food, there was no effect of food on C _max and T _max of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of metformin HCl extended-release tablets.

Metabolism and Elimination
Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion. Renal clearance 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
Patients with Type 2 Diabetes
In the presence of normal renal function, there are no differences between single- or multiple-dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects nor is there any accumulation of metformin in either group at usual clinical doses.

The pharmacokinetics of metformin HCl extended-release tablets in patients with type 2 diabetes are comparable to those in healthy normal adults.

Renal Impairment
In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased (see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).

Hepatic Impairment
No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency (see PRECAUTIONS).

Gender
Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males = 19, females = 16).

Race
No studies of metformin pharmacokinetic parameters according to race have been performed.

Clinical Studies
Metformin HCl Extended-Release Tablets
A 24-week, double-blind, placebo-controlled study of metformin HCl extended-release tablets, taken once daily with the evening meal, was conducted in patients with type 2 diabetes who had failed to achieve glycemic control with diet and exercise (HbA _1c 7% to 10%, FPG 126 to 270 mg/dL). Patients entering the study had a mean baseline HbA _1c of 8% and a mean baseline FPG of 176 mg/dL. After 12 weeks treatment, mean HbA _1c had increased from baseline by 0.1% and mean FPG decreased from baseline by 2 mg/dL in the placebo group, compared with a decrease in mean HbA _1c of 0.6% and a decrease in mean FPG of 23 mg/dL in patients treated with metformin HCl extended-release tablets 1,000 mg once daily. Subsequently, the treatment dose was increased to 1,500 mg once daily if HbA _1c was ≥7% but <8% (patients with HbA _1c ≥8% were discontinued from the study). At the final visit (24-week), mean HbA _1c had increased 0.2% from baseline in placebo patients and decreased 0.6% with metformin HCl extended-release tablets.

A 16-week, double-blind, placebo-controlled, dose-response study of metformin HCl extended-release tablets, taken once daily with the evening meal or twice daily with meals, was conducted in patients with type 2 diabetes who had failed to achieve glycemic control with diet and exercise (HbA _1c 7% to 11%, FPG 126 to 280 mg/dL). Changes in glycemic control and body weight are shown in Table 6.

Compared with placebo, improvement in glycemic control was seen at all dose levels of metformin HCl extended-release tablets and treatment was not associated with any significant change in weight (see DOSAGE AND ADMINISTRATION) for dosing recommendations for metformin HCl extended-release tablets.

A 24-week, double-blind, randomized study of metformin HCl extended-release tablets, taken once daily with the evening meal, was conducted in patients with type 2 diabetes who had been treated with metformin HCl 500 mg twice daily for at least 8 weeks prior to study entry. The metformin HCl dose had not necessarily been titrated to achieve a specific level of glycemic control prior to study entry. Patients qualified for the study if HbA _1c was ≤8.5% and FPG was ≤200 mg/dL. Changes in glycemic control and body weight are shown in Table 7.

After 12 weeks of treatment, there was an increase in mean HbA _1c in all groups; in the metformin HCl extended-release tablets 1,000 mg group, the increase from baseline of 0.23% was statistically significant (see DOSAGE AND ADMINISTRATION).

Changes in lipid parameters in the previously described placebo-controlled dose-response study of metformin HCl extended-release tablets are shown in Table 8.

Changes in lipid parameters in the previously described study of metformin HCl extended-release tablets are shown in Table 9.

Metformin HCl extended-release tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Metformin HCl, extended-release tablets are contraindicated in patients with:

1. Severe renal impairment (eGFR below 40 mL/min/1.73 m ²) (see WARNINGS and PRECAUTIONS).
2. Known hypersensitivity to metformin HCl.
3. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

General

• Lactic acidosis – There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a 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 a hospital setting, along with immediate discontinuation of metformin HCl extended-release tablets. In metformin HCl extended-release 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 HCl 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:
• 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, CLINICAL PHARMACOLOGY):
• Before initiating metformin HCl extended-release tablets, obtain an estimated glomerular filtration rate (eGFR)
• Metformin HCl extended-release tablets is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m ² (see CONTRAINDICATIONS).
• Initiation of metformin HCl extended-release tablets is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m ².
• Obtain an eGFR at least annually in all patients taking metformin HCl 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 HCl extended-release tablets whose eGFR falls below 45 mL/min/1.73 m ², assess the benefit and risk of continuing therapy.
• Drug interactions – The concomitant use of metformin HCl 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.
• 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 HCl 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 m ²; 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 HCl extended-release tablets 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 HCl extended-release tablets 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 HCl extended-release tablets.
• Excessive alcohol intake – Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving metformin HCl extended-release 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 HCl extended-release tablets in patients with clinical or laboratory evidence of hepatic disease.

Vitamin B ₁₂ levels – Measurement of hematologic parameters on an annual basis is advised in patients on metformin HCl extended-release tablets and any apparent abnormalities should be appropriately investigated and managed (see PRECAUTIONS: Laboratory Tests).

Certain individuals (those with inadequate Vitamin B ₁₂ or calcium intake or absorption) appear to be predisposed to developing subnormal Vitamin B ₁₂ levels. In these patients, routine serum Vitamin B ₁₂ measurements at two- to three-year intervals may be useful.

Hypoglycemia – Hypoglycemia does not occur in patients receiving metformin HCl extended-release tablets alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol.

Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs.

Macrovascular outcomes – There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin HCl extended-release tablets or any other antidiabetic drug.

Information for Patients
Patients should be informed of the potential risks and benefits of metformin HCl extended-release tablets and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose, glycosylated hemoglobin, renal function, and hematologic parameters.

The risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in the WARNINGS and PRECAUTIONS sections, should be explained to patients. Patients should be advised to discontinue metformin HCl extended-release tablets immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of metformin HCl extended-release tablets, gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving metformin HCl extended-release tablets.

Metformin HCl extended-release tablets alone do not usually cause hypoglycemia, although it may occur when metformin HCl extended-release tablets are used in conjunction with oral sulfonylureas and insulin. When initiating combination therapy, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. (See Patient Information printed below.)

Patients should be informed that metformin HCl extended-release tablets must be swallowed whole and not crushed or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.

Laboratory Tests
Response to all diabetic therapies should be monitored by periodic measurements of fasting blood glucose and glycosylated hemoglobin levels, with a goal of decreasing these levels toward the normal range. During initial dose titration, fasting glucose can be used to determine the therapeutic response. Thereafter, both glucose and glycosylated hemoglobin should be monitored. Measurements of glycosylated hemoglobin may be especially useful for evaluating long-term control (see also DOSAGE AND ADMINISTRATION).

Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis.

Instruct patients to inform their doctor that they are taking metformin HCl extended-release tablets prior to any surgical or radiological procedure, as temporary discontinuation of metformin HCl extended-release tablets may be required until renal function has been confirmed to be normal (see PRECAUTIONS).

Drug Interactions (Clinical Evaluation of Drug Interactions Conducted with Metformin HCl)
Glyburide – In a single-dose interaction study in type 2 diabetes patients, co-administration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and C _max were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects, makes the clinical significance of this interaction uncertain (see DOSAGE AND ADMINISTRATION: Concomitant Metformin HCl Extended-Release Tablets and Oral Sulfonylurea Therapy in Adult Patients).

Furosemide – A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. Furosemide increased the metformin plasma and blood C _max by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the C _max and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when co-administered chronically.

Nifedipine – A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma metformin C _max and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. T _max and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.

Drugs that reduce metformin clearance – 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 such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics.

In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when co-administered in single-dose interaction studies.

Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.

Other – Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving metformin HCl extended-release tablets, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin HCl extended-release tablets, the patient should be observed closely for hypoglycemia.

Carbonic anhydrase inhibitors – Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with metformin HCl extended-release tablets may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.

Alcohol – Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving metformin HCl extended-release tablets.

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 1,500 mg/kg/day, respectively. These doses are both approximately four times the maximum recommended human daily dose of 2,000 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 a 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 three times the maximum recommended human daily dose based on body surface area comparisons.

Pregnancy
Teratogenic Effects: Pregnancy Category B
Recent information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities. Most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Because animal reproduction studies are not always predictive of human response, metformin HCl extended-release tablets should not be used during pregnancy unless clearly needed.

There are no adequate and well-controlled studies in pregnant women with metformin HCl extended-release tablets. Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about two and six times the maximum recommended human daily dose of 2,000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.

Nursing Mothers
Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If metformin HCl extended-release tablets are discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

Pediatric Use
Safety and effectiveness of metformin HCl extended-release tablets in pediatric patients have not been established.

Geriatric Use
Controlled clinical studies of metformin HCl extended-release tablets did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and 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, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).

In worldwide clinical trials over 900 patients with type 2 diabetes have been treated with metformin HCl extended-release tablets in placebo- and active-controlled studies. In placebo-controlled trials, 781 patients were administered metformin HCl extended-release tablets and 195 patients received placebo. Adverse reactions reported in greater than 5% of the metformin HCl extended-release tablets patients, and that were more common in metformin HCl extended-release tablets - than placebo-treated patients, are listed in Table 12.

Diarrhea led to discontinuation of study medication in 0.6% of patients treated with metformin HCl extended-release tablets. Additionally, the following adverse reactions were reported in ≥1% to ≤5% of metformin HCl extended-release tablets patients and were more commonly reported with metformin HCl extended-release tablets than placebo: abdominal pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance.

Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin.

Overdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin HCl has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases (see WARNINGS). Metformin is dialyzable with a 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.

There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with metformin HCl extended-release tablets or any other pharmacologic agent. Dosage of metformin HCl extended-release tablets must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily doses. The maximum recommended daily dose of metformin HCl extended-release tablets in adults is 2,000 mg.

Metformin HCl extended-release tablets should generally be given once daily with the evening meal. Metformin HCl extended-release tablets should be started at a low dose, with gradual dose escalation, both to reduce gastrointestinal side effects and to permit identification of the minimum dose required for adequate glycemic control of the patient.

During treatment initiation and dose titration (see Recommended Dosing Schedule), fasting plasma glucose should be used to determine the therapeutic response to metformin HCl extended-release tablets and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately three months. The therapeutic goal should be to decrease both fasting plasma glucose and glycosylated hemoglobin levels to normal or near normal by using the lowest effective dose of metformin HCl extended-release tablets, either when used as monotherapy or in combination with sulfonylurea or insulin.

Monitoring of blood glucose and glycosylated hemoglobin will also permit detection of primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication, and secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period of effectiveness.

Short-term administration of metformin HCl extended-release tablets may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone.

Metformin HCl extended-release tablets must be swallowed whole and never crushed or chewed. Occasionally, the inactive ingredients of metformin HCl extended-release tablets, USP will be eliminated in the feces as a soft, hydrated mass. (See Patient Information printed below.)

Recommended Dosing Schedule
Adults
The usual starting dose of metformin HCl extended-release tablets is 500 mg once daily with the evening meal. In general, clinically significant responses are not seen at doses below 1,500 mg per day. Dosage increases should be made in increments of 500 mg weekly, up to a maximum of 2,000 mg once daily with the evening meal. The dosage of metformin HCl extended-release tablets must be individualized on the basis of both effectiveness and tolerability. If glycemic control is not achieved on metformin HCl extended-release tablets 2,000 mg once daily, a trial of metformin HCl extended-release tablets 1,000 mg twice daily should be considered. (See CLINICAL PHARMACOLOGY, Clinical Studies. )

Pediatrics - Safety and effectiveness of metformin HCl extended-release tablets in pediatric patients have not been established.

Recommendations for Use in Renal Impairment
Assess renal function prior to initiation of metformin HCl extended-release tablets and periodically thereafter.

Metformin HCl extended-release tablets is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m ².

Initiation of metformin HCl extended-release tablets in patients with an eGFR between 30 to 45 mL/minute/1.73 m ² is not recommended.

In patients taking metformin HCl extended-release tablets whose eGFR later falls below 45 mL/min/1.73 m ², assess the benefit risk of continuing therapy.

Discontinue metformin HCl extended-release tablets if the patient’s eGFR later falls below 30 mL/minute/1.73 m ² (See WARNINGS and PRECAUTIONS).

Discontinuation for Iodinated Contrast Imaging Procedures
Discontinue metformin HCl 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 m ²; 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 HCl extended-release tablets if renal function is stable.

Concomitant Metformin HCl Extended-Release Tablets and Oral Sulfonylurea Therapy in Adult Patients
If patients have not responded to four weeks of the maximum dose of metformin HCl extended-release tablets monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing metformin HCl extended-release tablets at the maximum dose, even if prior primary or secondary failure to a sulfonylurea has occurred. Clinical and pharmacokinetic drug-drug interaction data are currently available only for metformin plus glyburide (glibenclamide).

With concomitant metformin HCl extended-release tablets and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. With concomitant metformin HCl extended-release tablets and sulfonylurea therapy, the risk of hypoglycemia associated with sulfonylurea therapy continues and may be increased. Appropriate precautions should be taken. (See Package Insert of the respective sulfonylurea.)

If patients have not satisfactorily responded to one to three months of concomitant therapy with the maximum dose of metformin HCl extended-release tablets and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without metformin HCl extended-release tablets.

Concomitant Metformin HCl Extended-Release Tablets and Insulin Therapy in Adult Patients
The current insulin dose should be continued upon initiation of metformin HCl extended-release tablet therapy. Metformin HCl extended-release tablet therapy should be initiated at 500 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of metformin HCl extended-release tablets should be increased by 500 mg after approximately 1 week and by 500 mg every week thereafter until adequate glycemic control is achieved. The maximum recommended daily dose is 2,000 mg for metformin HCl extended-release tablets. It is recommended that the insulin dose be decreased by 10% to 25% when fasting plasma glucose concentrations decrease to less than 120 mg/dL in patients receiving concomitant insulin and metformin HCl extended-release tablets. Further adjustment should be individualized based on glucose-lowering response.

Specific Patient Populations
Metformin HCl extended-release tablets, USP are not recommended for use in pregnancy. Metformin HCl extended-release tablets are not recommended in pediatric patients (below the age of 17 years).

The initial and maintenance dosing of metformin HCl extended-release tablets should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment should be based on a careful assessment of renal function.

Metformin HCl Extended-Release Tablets, USP 500 mg are white, capsule shaped, biconvex tablets debossed "IP 178" on one side and plain on the other side.

They are available as follows:
Unit dose packages of 100 (10 x 10) NDC 68084-072-01

Storage
Store at 20° to 25° C (68° to 77° F); excursions permitted to 15° to 30° C (59° to 86° F) [See USP Controlled Room Temperature].

FOR YOUR PROTECTION: Do not use if blister is torn or broken.

American Health Packaging unit dose blisters (see How Supplied section) contain drug product from Amneal Pharmaceuticals LLC as follows:
(500 mg / 100 UD) NDC 68084-072-01 packaged from NDC 53746-178

Distributed by:
American Health Packaging
Columbus, OH 43217

8207201/0817

8207201/0817
Metformin (met-FORE-min) Hydrochloride
Extended-Release Tablets

Read this information carefully before you start taking this medicine and each time you refill your prescription. There may be new information. This information does not take the place of your doctor's advice. Ask your doctor or pharmacist if you do not understand some of this information or if you want to know more about this medicine.

What is metformin HClextended-release tablets?
Metformin HCl extended-release tablets are used to treat type 2 diabetes. This is also known as noninsulin-dependent diabetes mellitus. People with type 2 diabetes are not able to make enough insulin or respond normally to the insulin their bodies make. When this happens, sugar (glucose) builds up in the blood. This can lead to serious medical problems including kidney damage, amputations, and blindness. Diabetes is also closely linked to heart disease. The main goal of treating diabetes is to lower your blood sugar to a normal level.

High blood sugar can be lowered by diet and exercise, by a number of medicines taken by mouth, and by insulin shots. Before you take metformin HCl extended-release tablets, try to control your diabetes by exercise and weight loss. While you take your diabetes medicine, continue to exercise and follow the diet advised for your diabetes. No matter what your recommended diabetes management plan is, studies have shown that maintaining good blood sugar control can prevent or delay complications of diabetes, such as blindness.

Metformin HCl extended-release tablets work longer in your body. Metformin HCl helps control your blood sugar in a number of ways. These include helping your body respond better to the insulin it makes naturally, decreasing the amount of sugar your liver makes, and decreasing the amount of sugar your intestines absorb. Metformin HCl does not cause your body to make more insulin. Because of this, when taken alone, they rarely cause hypoglycemia (low blood sugar), and usually do not cause weight gain. However, when they are taken with a sulfonylurea or with insulin, hypoglycemia is more likely to occur, as is weight gain.

Tell your doctor if you are pregnant or plan to become pregnant. Metformin HCl extended-release tablets may not be right for you. Talk with your doctor about your choices. You should also discuss your choices with your doctor if you are nursing a child.

Can metformin HCl extended-release tablets be used in children?
Metformin HCl extended-release tablets have not been studied in children.

How should I take metformin HClextended-release tablets?
Your doctor will tell you how much medicine to take and when to take it. You will probably start out with a low dose of the medicine. Your doctor may slowly increase your dose until your blood sugar is better controlled. You should take metformin HCl extended-release tablets with meals.

Your doctor may have you take other medicines along with metformin HCl extended-release tablets to control your blood sugar. These medicines may include insulin shots. Taking metformin HCl extended-release tablets with insulin may help you better control your blood sugar while reducing the insulin dose.

Continue your exercise and diet program and test your blood sugar regularly while taking metformin HCl extended-release tablets. Your doctor will monitor your diabetes and may perform blood tests on you from time to time to make sure your kidneys and your liver are functioning normally. There is no evidence that metformin HCl causes harm to the liver or kidneys.

Tell your doctor if you:

• have an illness that causes severe vomiting, diarrhea or fever, or if you drink a much lower amount of liquid than normal. These conditions can lead to severe dehydration (loss of water in your body). You may need to stop taking metformin HCl extended-release tablets for a short time.
• plan to have surgery or an x-ray procedure with injection of dye (contrast agent). You may need to stop taking metformin HCl extended-release tablets for a short time.
• start to take other medicines or change how you take a medicine. Metformin HCl extended-release tablets can affect how well other drugs work, and some drugs can affect how well metformin HCl extended-release tablets works. Some medicines may cause high blood sugar.

Metformin HCl extended-release tablets must be swallowed whole and never crushed or chewed. Occasionally, the inactive ingredients of metformin HCl extended-release tablets may be eliminated as a soft mass in your stool that may look like the original tablet; this is not harmful and will not affect the way metformin HCl extended-release tablets works to control your diabetes.

What should I avoid while taking metformin HClextended-release tablets?
Do not drink a lot of alcoholic drinks while taking metformin HCl extended-release tablets. This means you should not binge drink for short periods, and you should not drink a lot of alcohol on a regular basis. Alcohol can increase the chance of getting lactic acidosis.

What are the side effects of Metformin HCl?
Lactic Acidosis. Metformin, the active ingredient in metformin HCl extended-release tablets, can cause a rare but serious condition called lactic acidosis (a buildup of an acid in the blood) that can cause death. Lactic acidosis is a 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:

• you feel cold in your hands or feet
• you feel dizzy or lightheaded
• you have a slow or irregular heartbeat
• you feel very weak or tired
• you have unusual (not normal) muscle pain
• you have trouble breathing
• you feel sleepy or drowsy
• you 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 a higher chance for getting lactic acidosis with metformin HCl extended-release tablets if you:

• have severe kidney problems, or your kidneys are affected by certain x-ray tests that use injectable dye
• have liver problems
• drink alcohol very often, or drink a lot of alcohol in short-term "binge" drinking
• get dehydrated (lose a large amount of body fluids). This can happen if you are sick with a fever, vomiting, or diarrhea. Dehydration can also happen when you sweat a lot with activity or exercise and do not drink enough fluids
• have surgery
• have a heart attack, severe infection, or stroke

The best way to keep from having a problem with lactic acidosis from metformin is to tell your doctor if you have any of the problems in the list above. Your doctor may decide to stop your metformin HCl extended-release tablets for a while if you have any of these things.

Other Side Effects.
Common side effects of metformin HCl extended-release tablets include diarrhea, nausea, and upset stomach. These side effects generally go away after you take the medicine for a while. Taking your medicine with meals can help reduce these side effects. Tell your doctor if the side effects bother you a lot, last for more than a few weeks, come back after they've gone away, or start later in therapy. You may need a lower dose or need to stop taking the medicine for a short period or for good.

About 3 out of every 100 people who take metformin HCl extended-release tablets have an unpleasant metallic taste when they start taking the medicine. It lasts for a short time.

Metformin HCl 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.

General advice about prescription medicines
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 HCl extended-release tablets that is written for health care professionals. Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use metformin HCl extended-release tablets for a condition for which it was not prescribed. Do not share your medicine with other people.

Questions or comments?
Call 1-877-835-5472 Monday through Friday 9AM to 5PM EST.

Distributed by:
American Health Packaging
Columbus, OH 43217

8207201/0817

500 mg Metformin HCl ER Tablets Carton

NDC 68084-072-01

Metformin Hydrochloride
Extended-Release Tablets, USP

500 mg

100 Tablets (10 x 10)

PHARMACIST: Dispense with the accompanying Patient
Information Leaflet to each patient.

Each Extended-Release Tablet Contains:
Metformin Hydrochloride, USP .............................................. 500 mg

Usual Dosage: See enclosed package insert for full prescribing information.

Store at 20° to 25°C (68° to 77°F); excursions permitted between
15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Keep this and all drugs out of reach of children.

FOR YOUR PROTECTION: Do not use if blister is torn or broken.

Rx Only

The drug product contained in this packaged is from
NDC # 53746-178, Amneal Pharmaceuticals.

Distributed by:
American Health Packaging
Columbus, Ohio 43217

007201
0207201/0617OS

500 mg Metformin HCl ER Tablet Blister

Metformin Hydrochloride
Extended-Release
Tablet, USP

500 mg