Label: METFORMIN HYDROCHLORIDE - metformin hydrochloride tablet, extended release

  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: Abbreviated New Drug Application

Drug Label Information

Updated 02/15

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  • BOXED WARNING(What is this?)

    Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with metformin HCl extended release tablets; when it occurs, it is fatal in approximately 50%of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 mcg/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin HCl is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient’s age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin HCl extended release tablets and by use of the minimum effective doses of metformin hydrochloride extended release tablets. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin HCl extended release tablets treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, metformin HCl extended release tablets should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, metformin HCl extended release tablets should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking metformin HCl extended release tablets, since alcohol potentiates the effects of metformin HCl on lactate metabolism. In addition, metformin HCl extended release tablets should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see also PRECAUTIONS).

    The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur (see also PRECAUTIONS). Metformin HCl extended release tablets should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of metformin HCl extended release tablets, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease. Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking metformin HCl extended release tablets do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling. (See also PRECAUTIONS.)

    Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).

    Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking metformin HCl extended release tablets, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin HCl is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery. (See also CONTRAINDICATIONS and PRECAUTIONS.)

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  • DESCRIPTION

    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:

    b52f6092-figure-01

    Metformin HCl is a white to off-white crystalline compound with a molecular formula of C4H11N5 • HCl and a molecular weight of 165.63. Metformin HCl is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of Metformin HCl is 6.68.

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

    Metformin HCl extended release tablets 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, USP comprises 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.

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  • CLINICAL PHARMACOLOGY

    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, Cmax is achieved with a median value of 7 hours and a range of 4 hours to 8 hours.

    At steady state, the AUC and Cmax are less than dose proportional for metformin HCl extended release tablets within the range of 500 mg 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. 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 Cmax and Tmax 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) nor 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.

    Special Populations

    Patients with Type 2 Diabetes

    In the presence of normal renal function, there are no differences between single- or multiple-dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects 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 Insufficiency

    In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (see WARNINGS).

    Hepatic Insufficiency

    No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency.

    Geriatrics

    Metformin HCl extended release tablets treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced (see WARNINGS and DOSAGE AND ADMINISTRATION).

    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 (HbA1c 7.0 to 10.0%, FPG 126 to 70 mg/dL). Patients entering the study had a mean baseline HbA1c of 8% and a mean baseline FPG of 176 mg/dL. After 12 weeks treatment, mean HbA1c had increased from baseline by 0.1% and mean FPG decreased from baseline by 2 mg/dL in the placebo group, compared with a decrease in mean HbA1c of 0.6% and a decrease in mean FPG of 23 mg/dL in patients treated with metformin HCl extended release tablets 1000 mg once daily.

    Subsequently, the treatment dose was increased to 1500 mg once daily if HbA1c was ≥7% but <% (patients with HbA1c>8% were discontinued from the study). At the final visit (24-week), mean HbA1c 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 (HbA1c 7% to 11%, FPG 126 to 280 mg/dL).

    Changes in glycemic control and body weight are shown in Table 1.

    Table 1: Summary of Mean Changes from Baseline* in HbA1c, Fasting Plasma, Glucose, and Body Weight at Final Visit (16-week study)
    Metformin Hydrochloride Extended-Release Tablets Placebo
    500 mg
    Once Daily
    1000 mg
    Once Daily
    1500 mg
    Once Daily
    2000 mg
    Once Daily
    1000 mg
    Twice Daily
    Hemoglobin A1c (%) (n=115) (n=115) (n=111) (n=125) (n=112) (n=111)
    Baseline 8.2 8.4 8.3 8.4 8.4 8.4
    Change at FINAL VISIT -0.4 -0.6 -0.9 -0.8 -1.1 0.1
    p-valuea <0.001 <0.001 <0.001 <0.001 <0.001 -
    FPG (mg/dL) (n=126) (n=118) (n=120) (n=132) (n=122) (n=113)
    Baseline 182.7 183.7 178.9 181 181.6 179.6
    Change at FINAL VISIT -15.2 -19.3 -28.5 -29.9 -33.6 7.6
    p-valuea <0.001 <0.001 <0.001 <0.001 <0.001 -
    Body Weight (lbs) (n=125) (n=119) (n=117) (n=131) (n=119) (n=113)
    Baseline 192.9 191.8 188.3 195.4 192.5 194.3
    Change at FINAL VISIT -1.3 -1.3 -0.7 -1.5 -2.2 -1.8
    p-valuea NS** NS** NS** NS** NS** -

    * All patients on diet therapy at Baseline

    a All comparisons versus Placebo

    ** Not statistically significant

    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 HbA1c was <8.5% and FPG was <200 mg/dL. Changes in glycemic control and body weight are shown in Table 2

    Table 2: Summary of Mean Changes from Baseline in HbA1c, Fasting Plasma, Glucose, and Body Weight at Week 12 and at Final Visit (24-week study)
    Metformin HCl Extended-Release Tablets
    1000 mg
    Once Daily
    1500 mg
    Once Daily
    Hemoglobin A1c (%) (n=72) (n=66)
    Baseline 6.99 7.02
    Change at 12 Weeks 0.23 0.04
    (95% CI) (0.10, 0.36) (-0.08, 0.15)
    Change at FINAL VISIT 0.27 0.13
    (95 % CI) (0.11, 0.43) (-0.02, 0.28)
    FPG (mg/dL) (n=72) (n=70)
    Baseline 131 131.4
    Change at 12 Weeks 9.5 3.7
    (95% CI) (4.4, 14.6) (-0.4, 7.8)
    Change at FINAL VISIT 11.5 7.6
    (95% CI) (4.4, 18.6) (1, 14.2)
    Body Weight (lbs) (n=74) (n=71)
    Baseline 202.8 192.7
    Change at 12 Weeks 0.9 0.7
    (95% CI) (0, 2) (-0.4, 1.8)
    Change at FINAL VISIT 1.1 0.9
    (95 % CI) (-0.2, 2.4) (-0.4, 2)

    After 12 weeks of treatment, there was an increase in mean HbA1c in all groups; in the metformin HCl extended release tablets 1000 mg group, the increase from baseline of 0.23% was statistically significant (see DOSAGE AND ADMINISTRATION).

    Changes in lipid parameters in the previously described placebo controlled dose-response study of metformin HCl extended release tablets are shown in Table 3.

    Table 3: Summary of Mean Percent Changes from Baseline* in Major Lipid Variables at  Final Visit (16-week study)
    Metformin HCl Extended-Release Tablets Placebo
    500 mg
    Once Daily
    1000 mg
    Once Daily
    1500 mg
    Once Daily
    2000 mg
    Once Daily
    1000 mg
    Twice Daily
    Total Cholesterol mg/dL) (n=120) (n=113) (n=110) (n=126) (n=117) (n=110)
    Baseline 210.3 218.1 214.6 204.4 208.2 208.6
    Mean % Change at FINAL VISIT 1% 1.7% 0.7% -1.6% -2.6% 2.6%
    Total Triglycerides mg/dL) (n=120) (n=113) (n=110) (n=126) (n=117) (n=110)
    Baseline 220.2 211.9 198 194.2 179 211.7
    Mean % Change at FINAL VISIT 14.5% 9.4% 15.1% 14.9% 9.4% 10.9%
    LDL Cholesterol mg/dL) (n=119) (n=113) (n=109) (n=126) (n=117) (n=107)
    Baseline 131 134.9 135.8 125.8 131.4 131.9
    Mean % Change at FINAL VISIT -1.4% -1.6% -3.5% -3.3% -5.5% 3.2%
    HDL Cholesterol mg/dL) (n=120) (n=108) (n=108) (n=125) (n=117) (n=108)
    Baseline 40.8 41.6 40.6 40.2 42.4 39.4
    Mean % Change at FINAL VISIT 6.2% 8.6% 5.5% 6.1% 7.1% 5.8%

    *All patients on diet therapy at Baseline

    Changes in lipid parameters in the previously described study of metformin HCl extended release tablets are shown in Table 4.

    Table 4: Summary of Mean Percent Changes from Baseline - in Major Lipid Variables  at Final Visit (24-week study)
    Metformin HCl Extended-Release Tablets
    1000 mg
    Once Daily
    1500 mg
    Once Daily
    Total Cholesterol mg/dL) (n=70) (n=66)
    Baseline 201.9 201.6
    Mean % Change at FINAL VISIT 1.3% 0.1%
    Total Triglycerides mg/dL) (n=70) (n=66)
    Baseline 169.2 206.8
    Mean % Change at FINAL VISIT 25.3% 33.4%
    LDL Cholesterol mg/dL) (n=70) (n=66)
    Baseline 126.2 115.7
    Mean % Change at FINAL VISIT -3.3% -3.7%
    HDL Cholesterol mg/dL) (n=70) (n=65)
    Baseline 41.7 44.6
    Mean % Change at FINAL VISIT 1% -2.1%
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  • INDICATIONS AND USE

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

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  • CONTRAINDICATIONS

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

    1. Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females] or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia (see WARNINGS and PRECAUTIONS).

    2. Known hypersensitivity to metformin HCl, USP.

    3. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, without coma. Diabetic ketoacidosis should be treated with insulin.

    Metformin HCl extended release tablets, USP should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function. (See also PRECAUTIONS.)

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  • WARNINGS

    Lactic Acidosis:

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  • ADVERSE REACTIONS

    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 5.

    Table 5: Most Common Adverse Reactions (> 5 Percent) in Placebo-Controlled Studies of Metformin HCl Extended Release Tablets*
    Metformin Hydrochloride
    Extended Release Tablets
    N=781
    Placebo
    N=195
    Adverse Reactions % of Patients
    Diarrhea 9.6 2.6
    Nausea / Vomiting 6.5 1.5

    *Reactions that were more common in metformin HCl extended release tablets-than placebo-treated patients.

    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 ≥1.0% to ≥5.0% 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.

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  • OVERDOSAGE

    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.

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  • DOSAGE AND ADMINISTRATION

    There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with metformin HCl extended release tablets, USP or any other pharmacologic agent. Dosage of metformin HCl extended release tablets, USP must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily doses. The maximum daily dose of metformin hydrochloride extended release tablets, USP in adults is 2000 mg. Metformin HCl extended release tablets, USP should generally be given once daily with the evening meal. Metformin HCl extended release tablets, USP 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, USP 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, USP 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, USP may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone.

    Metformin HCl extended release tablets, USP 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 - In general, clinically significant responses are not seen at doses below 1500 mg per day.

    However, a lower recommended starting dose and gradually increased dosage is advised to minimize gastrointestinal symptoms.

    The usual starting dose of metformin HCl extended release tablets, USP is 500 mg once daily with the evening meal. Dosage increases should be made in increments of 500 mg weekly, up to a maximum of 2000 mg once daily with the evening meal. If glycemic control is not achieved on metformin HCl extended release tablets, USP 2000 mg once daily, a trial of metformin HCl extended release tablets, USP 1000 mg twice daily should be considered. (See CLINICAL PHARMACOLOGY, Clinical Studies.)

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

    Transfer From Other Antidiabetic Therapy

    When transferring patients from standard oral hypoglycemic agents other than chlorpropamide to metformin HCl extended release tablets, USP no transition period generally is necessary. When transferring patients from chlorpropamide, care should be exercised during the first two weeks because of the prolonged retention of chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia.

    Concomitant Metformin HCl Extended Release Tablets, USP 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, USP monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing metformin HCl extended release tablets, USP 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, USP 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, USP 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, USP and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without metformin HCl extended release tablets, USP.

    Concomitant Metformin HCl Extended Release Tablets, USP and Insulin Therapy in Adult Patients

    The current insulin dose should be continued upon initiation of metformin HCl extended release tablets, USP therapy. Metformin HCl extended release tablets, USP 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, USP 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 2000 mg for metformin HCl extended release tablets, USP. 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, USP. Further adjustment should be individualized based on glucose-lowering response.

    Specific Patient Populations

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

    The initial and maintenance dosing of metformin HCl extended release tablets, USP 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. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of metformin HCl extended release tablets, USP.

    Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly. (See WARNINGS.)

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  • HOW SUPPLIED

    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:

    NDC 42291-610-90 Bottle of 90
    NDC 42291-610-18 Bottle of 180
    NDC 42291-610-36 Bottle of 360
    NDC 42291-610-10 Bottle of 1000

    Metformin HCl Extended Release Tablets, USP 750 mg are white, capsule shaped, biconvex tablets debossed "IP 179" on one side and plain on the other side.

    They are available as follows:

    NDC 42291-611-18 Bottle of 180
    NDC 42291-611-90  Bottles of 90
    NDC 42291-611-27  Bottles of 270
    NDC 42291-611-50  Bottles of 500

    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].

    Dispense in tight, light-resistant containers as defined in the USP.

    Manufactured for:

    AvKARE, Inc.

    Pulaski, TN 38478

    Mfg. Rev. 06/12
    AV Rev 11/14 (N)

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  • PATIENT INFORMATION

    Metformin 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 HCl Extended Release Tablets?

    Metformin HCl is 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, 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 works 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.

    WARNING: Most people with kidney problems should not take Metformin HCl. (See "What are the side effects of metformin HCl?")

    Who should not take metformin HCl?

    Some conditions increase your chance of getting lactic acidosis, or cause other problems if you take either of these medicines. A small number of people who have taken metformin HCl have developed a serious condition called lactic acidosis. Lactic acidosis is caused by a buildup of lactic acid in the blood. This happens more often in people with kidney problems. Most of the conditions listed below can increase your chance of getting lactic acidosis.

    Do not take Metformin HCl if you:

    • have kidney problems
    • have liver problems
    • have heart failure that is treated with medicines, such as Lanoxin® (digoxin) or Lasix® (furosemide)
    • drink a lot of alcohol. This means you binge drink for short periods or drink all the time
    • are seriously dehydrated (have lost a lot of water from your body)
    • are going to have an x-ray procedure with injection of dyes (contrast agents)
    • are going to have surgery
    • develop a serious condition, such as heart attack, severe infection, or a stroke
    • are 80 years or older and you have NOT had your kidney function tested

    Tell your doctor if you are pregnant or plan to become pregnant.

    Metformin HCl 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?

    MetforminHCl extended release tablets have not been studied in children.

    How should I take Metformin HCl?

    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 with meals.

    Your doctor may have you take other medicines along with metformin HCl to control your blood sugar. These medicines may include insulin shots. Taking metformin HCl 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.

    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 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 for a short time.
    • start to take other medicines or change how you take a medicine. Metformin HCl can affect how well other drugs work, and some drugs can affect how well metformin HCl 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 HCl?

    Do not drink a lot of alcoholic drinks while taking metformin HCl. 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. In rare cases, metformin HCl can cause a serious side effect called lactic acidosis. This is caused by a buildup of lactic acid in your blood. This build-up can cause serious damage.  Lactic acidosis caused by metformin HCl is rare and has occurred mostly in people whose kidneys were not working normally. Although rare, if lactic acidosis does occur, it can be fatal in up to half the people who develop it.

    It is also important for your liver to be working normally when you take metformin HCl. Your liver helps remove lactic acid from your blood.

    Make sure you tell your doctor before you use metformin hydrochloride extended release tablets if you have kidney or liver problems. You should also stop using metformin USP and call your doctor right away if you have signs of lactic acidosis. Lactic acidosis is a medical emergency that must be treated in a hospital.

    Signs of lactic acidosis are:

    • feeling very weak, tired, or uncomfortable
    • unusual muscle pain
    • trouble breathing
    • unusual or unexpected stomach discomfort
    • feeling cold
    • feeling dizzy or lightheaded
    • suddenly developing a slow or irregular heartbeat

    If your medical condition suddenly changes, stop taking metformin HCl and call your doctor right away. This may be a sign of lactic acidosis or another serious side effect.

    Other Side Effects.

    Common side effects of metformin HCl 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 have an unpleasant metallic taste when they start taking the medicine. It lasts for a short time.

    Metformin HCl 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 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 for a condition for which it was not prescribed. Do not share your medicine with other people.

    Questions or comments? Call 1-855-361-3993 Monday through Friday 9AM to 5PM EST.

    Manufactured for:

    AvKARE, Inc.

    Pulaski, TN 38478

    Mfg. Rev. 06/12
    AV Rev. 10/14 (N)

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  • PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

    AvKARE
    NDC 42291-610-36
    Metformin Hydrochloride Extended-Release Tablets, USP.

    500 mg

    360 Tablets        Rx Only

    PHARMACIST: PLEASE DISPENSE WITH ATTACHED PATIENT INFORMATION LEAFLET.

    Each extended-release tablet contains:
    Metformin Hydrochloride..........................500mg

    Usual Dosage: See enclosed package insert for dosage information.

    Store at 20o to 25oC (68o to 77oF) excursions permitted to 15o to 30oC (59o to 86oF). [See USP Controlled Room Temperature].

    Dispense in tight, light-resistant container as defined in USP.

    Keep out of the reach of children.

    Manufactured for:
    AvKARE, Inc.
    Pulaski, TN 38478

    Mfg. Rev. 06-2012     
    AV Rev. 10/14 (N)

    3 42291 61036 1

    label 1

    AvKARE
    NDC 42291-611-18

    Metformin Hydrochloride Extended-Release Tablets, USP

    750 mg

    180 Tablets        Rx Only

    PHARMACIST: PLEASE DISPENSE WITH ATTACHED PATIENT INFORMATIN LEAFLET.

    Each extended-release tablet contains:
    Metformin Hydrochloride..........................750mg

    Usual Dosage: See enclosed package insert for dosage information.

    Store at 20o to 25oC (68o to 77oF) excursions permitted to 15o to 30oC (59o to 86oF). [See USP Controlled Room Temperature].

    Dispense in tight, light-resistant container as defined in USP.

    Keep out of the reach of children.

    Manufactured for:
    AvKARE, Inc.
    Pulaski, TN 38478

    Mfg. Rev. 06-2012     
    AV Rev. 10/14 (N)

    N3   42291 61118   4

    label

     

    Close
  • INGREDIENTS AND APPEARANCE
    METFORMIN HYDROCHLORIDE  
    metformin hydrochloride tablet, extended release
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:42291-610(NDC:53746-178)
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    METFORMIN HYDROCHLORIDE (UNII: 786Z46389E) (METFORMIN - UNII:9100L32L2N) METFORMIN HYDROCHLORIDE 500 mg
    Inactive Ingredients
    Ingredient Name Strength
    Silicon Dioxide (UNII: ETJ7Z6XBU4)  
    Hypromelloses (UNII: 3NXW29V3WO)  
    Magnesium Stearate (UNII: 70097M6I30)  
    Cellulose, Microcrystalline (UNII: OP1R32D61U)  
    Product Characteristics
    Color WHITE Score no score
    Shape CAPSULE (Biconvex) Size 19mm
    Flavor Imprint Code IP;178
    Contains     
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:42291-610-90 90 in 1 BOTTLE
    2 NDC:42291-610-18 180 in 1 BOTTLE
    3 NDC:42291-610-36 360 in 1 BOTTLE
    4 NDC:42291-610-10 1000 in 1 BOTTLE
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    ANDA ANDA078596 12/02/2009
    METFORMIN HYDROCHLORIDE  
    metformin hydrochloride tablet, extended release
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:42291-611(NDC:53746-179)
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    METFORMIN HYDROCHLORIDE (UNII: 786Z46389E) (METFORMIN - UNII:9100L32L2N) METFORMIN HYDROCHLORIDE 750 mg
    Inactive Ingredients
    Ingredient Name Strength
    Silicon Dioxide (UNII: ETJ7Z6XBU4)  
    Hypromelloses (UNII: 3NXW29V3WO)  
    Magnesium Stearate (UNII: 70097M6I30)  
    Product Characteristics
    Color WHITE Score no score
    Shape CAPSULE (Biconvex) Size 19mm
    Flavor Imprint Code IP;179
    Contains     
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:42291-611-18 180 in 1 BOTTLE
    2 NDC:42291-611-90 90 in 1 BOTTLE
    3 NDC:42291-611-27 270 in 1 BOTTLE
    4 NDC:42291-611-50 500 in 1 BOTTLE
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    ANDA ANDA078596 12/02/2009
    Labeler - AvKARE, Inc. (796560394)
    Close