metFORMIN HCl 500 MG 24HR Extended Release Oral Tablet

Details

Generic Name: METFORMIN HYDROCHLORIDE

Brand Name: Metformin Hydrochloride

Substance Name(s):
METFORMIN HYDROCHLORIDE

DRUG INTERACTIONS

Drug Interactions (Clinical Evaluation of Drug Interactions Conducted with metformin hydrochloride tablets, USP) 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 Hydrochloride Tablets, USP or Metformin Hydrochloride Extended-release Tablets, USP and Oral Sulfonylurea Therapy ). Furosemide: A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by coadministration. 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. Cationic drugs: Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system. Other: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP, the patient should be observed closely for hypoglycemia. In healthy volunteers, the pharmacokinetics of metformin and propranolol and metformin and ibuprofen were not affected when 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.

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 hydrochloride 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.

DESCRIPTION

Metformin hydrochloride tablets, USP and metformin hydrochloride extended-release tablets, USP are oral antihyperglycemic drugs used in the management of type 2 diabetes. Metformin hydrochloride (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 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 hydrochloride 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 hydrochloride is 6.68. Metformin hydrochloride tablets, USP contain 500 mg, 850 mg, or 1000 mg of metformin hydrochloride. Each tablet contains the inactive ingredients magnesium stearate, microcrystalline cellulose and povidone. In addition, the coating for the 500 mg, 850 mg and 1000 mg tablets contains hypromellose 2910, polyethylene glycol 400 and titanium dioxide. Metformin hydrochloride extended-release tablets, USP contain 500 mg or 750 mg of metformin hydrochloride as the active ingredient. Metformin hydrochloride extended-release 500 mg tablets, USP contain the inactive ingredients hypromellose 2208, colloidal silicon dioxide, and magnesium stearate. Metformin hydrochloride extended-release 750 mg tablets, USP contain the inactive ingredients hypromellose 2208, colloidal silicon dioxide, D&C yellow #10 aluminum lake, and magnesium stearate. Label

CLINICAL STUDIES

METFORMIN HYDROCHLORIDE TABLETS, USP In a double-blind, placebo-controlled, multicenter U.S. clinical trial involving obese patients with type 2 diabetes whose hyperglycemia was not adequately controlled with dietary management alone (baseline fasting plasma glucose [FPG] of approximately 240 mg/dL), treatment with metformin hydrochloride tablets, USP (up to 2550 mg/day) for 29 weeks resulted in significant mean net reductions in fasting and postprandial plasma glucose (PPG) and hemoglobin A 1c (HbA 1c) of 59 mg/dL, 83 mg/dL, and 1.8%, respectively, compared to the placebo group (see Table 2). Table 2. Metformin Hydrochloride vs. Placebo Summary of Mean Changes from Baseline* in Plasma Glucose HbA1c and Body Weight, at Final Visit (29-week study) * All patients on diet therapy at Baseline ** Not statistically significant Metformin Hydrochloride (n =141) Placebo (n=145) P-Value FPG (mg/dL) Baseline 241.5 237.7 NS** Change at FINAL VISIT -53.0 6.3 0.001 Hemoglobin A 1c (%) Baseline 8.4 8.2 NS** Change at FINAL VISIT -1.4 0.4 0.001 Body Weight (lbs) Baseline 201.0 206.0 NS** Change at FINAL VISIT -1.4 -2.4 NS** A 29-week, double-blind, placebo-controlled study of metformin hydrochloride tablets, USP and glyburide, alone and in combination, was conducted in obese patients with type 2 diabetes who had failed to achieve adequate glycemic control while on maximum doses of glyburide (baseline FPG of approximately 250 mg/dL) (see Table 3). Patients randomized to the combination arm started therapy with metformin hydrochloride tablets, USP 500 mg and glyburide 20 mg. At the end of each week of the first four weeks of the trial, these patients had their dosages of metformin hydrochloride tablets, USP increased by 500 mg if they had failed to reach target fasting plasma glucose. After week four, such dosage adjustments were made monthly, although no patient was allowed to exceed metformin hydrochloride tablets, USP 2500 mg. Patients in the metformin hydrochloride tablets, USP only arm (metformin plus placebo) followed the same titration schedule. At the end of the trial, approximately 70% of the patients in the combination group were taking metformin hydrochloride tablets, USP 2000 mg/glyburide 20 mg or metformin hydrochloride tablets, USP 2500 mg/glyburide 20 mg. Patients randomized to continue on glyburide experienced worsening of glycemic control, with mean increases in FPG, PPG and HbA 1c of 14 mg/dL, 3 mg/dL and 0.2%, respectively. In contrast, those randomized to metformin hydrochloride tablets, USP (up to 2500 mg/day) experienced a slight improvement, with mean reductions in FPG, PPG and HbA 1c of 1 mg/dL, 6 mg/dL and 0.4%, respectively. The combination of metformin hydrochloride tablets, USP and glyburide was effective in reducing FPG, PPG and HbA 1c levels by 63 mg/dL, 65 mg/dL, and 1.7%, respectively. Compared to results of glyburide treatment alone, the net differences with combination treatment were -77 mg/dL, -68 mg/dL and -1.9%, respectively (see Table 3). Table 3. Combined Metformin/Glyburide (Comb) vs. Glyburide (Glyb) or Metformin Hydrochloride (MET) Monotherapy: Summary of Mean Changes from Baseline* in Fasting Plasma Flucose, HbA1c and Body Weight, at Final Visit (29-week study) *All patients on glyburide, 20 mg/day, at Baseline **Not statically significant Comb (n=213) Glyb (n=209) MET (n=210) p-values Glyb vs. Comb MET vs. Comb MET vs. Glyb Fasting Plasma Glucose (mg/dL) Baseline 250.5 247.5 253.9 NS** NS** NS** Change at FINAL VISIT -63.5 13.7 -0.9 0.001 0.001 0.025 Hemoglobin A 1c (%) Baseline 8.8 8.5 8.9 NS** NS** 0.007 Change at FINAL VISIT -1.7 0.2 -0.4 0.001 0.001 0.001 Body Weight (lbs.) Baseline 202.2 203.0 204.0 NS** NS** NS** Change at FINAL VISIT 0.9 -0.7 -8.4 0.011 0.001 0.001 The magnitude of the decline in fasting blood glucose concentration following the institution of metformin hydrochloride tablets, USP therapy was proportional to the level of fasting hyperglycemia. Patients with type 2 diabetes with higher fasting glucose concentrations experienced greater declines in plasma glucose and glycosylated hemoglobin. In clinical studies, metformin hydrochloride tablets, USP, alone or in combination with a sulfonylurea, lowered mean fasting serum triglycerides, total cholesterol and LDL cholesterol levels and had no adverse effects on other lipid levels (see Table 4). Table 4. Summary of Mean Percent Change from Baseline of Major Serum Lipid Variables at Final Visit (29-week studies) Metformin Hydrochloride vs. Placebo Combined Metformin/ Glyburide vs. Monotherapy Metformin Hydrochloride (n=141) Placebo (n=145) Metformin Hydrochloride (n=141) Metformin Hydrochloride/ Glyburide (n=213) Glyburide (n=209) Total Cholesterol (mg/dL) Baseline 211.0 212.3 213.1 215.6 219.6 Mean % change at FINAL VISIT -5% 1% -2% -4% 1% Total Triglycerides (mg/dL) Baseline 236.1 203.5 242.5 215.0 266.1 Mean % change at FINAL VISIT -16% 1% -3% -8% 4% LDL-Cholesterol (mg/dL) Baseline 135.4 138.5 134.3 136.0 137.5 Mean % change at FINAL VISIT -8% 1% -4% -6% 3% HDL-Cholesterol (mg/dL) Baseline 39.0 40.5 37.2 39.0 37.0 Mean % change at FINAL VISIT 2% -1% 5% 3% 1% In contrast to sulfonylureas, body weight of individuals on metformin hydrochloride tablets, USP tended to remain stable or even decrease somewhat (see Tables 2 and 3). A 24-week, double-blind, placebo-controlled study of metformin hydrochloride tablets, USP plus insulin versus insulin plus placebo was conducted in patients with type 2 diabetes who failed to achieve adequate glycemic control on insulin alone (see Table 5). Patients randomized to received metformin hydrochloride tablets, USP plus insulin achieved a reduction in HbA 1c of 2.10%, compared to 1.56% reduction in HbA 1c achieved by insulin plus placebo. The improvement in glycemic control was achieved at the final study visit with 16% less insulin, 93.0 U/day vs. 110.6 U/day, metformin hydrochloride tablets, USP plus insulin versus insulin plus placebo, respectively P = 0.04. Table 5. Combined Metformin Hydrochloride/Insulin vs. Placebo/Insulin Summary of Mean Changes from Baseline in HbA 1c and Daily Insulin Dose ªStatistically significant using analysis of covariance with baseline as covariate (p=0.04) Not significant using analysis of variance (values shown in table) b Statistically significant for insulin (p=0.04) Metformin Hydrochloride/Insulin (n=26) Placebo/Insulin (n=28) Treatment Difference Mean ± SE Hemoglobin A 1c (%) Baseline 8.95 9.32 Change at FINAL VISIT -2.10 -1.56 -0.54 ± 0.43ª Insulin Dose (U/day) Baseline 93.12 94.64 Change at FINAL VISIT -0.15 15.93 -16.08 ± 7.77 b A second double-blind, placebo-controlled study (n=51), with 16 weeks of randomized treatment, demonstrated that in patients with type 2 diabetes controlled on insulin for 8 weeks with an average HbA 1c of 7.46 ± 0.97%, the addition of metformin hydrochloride tablets, USP maintained similar glycemic control (HbA 1c 7.15 ± 0.61 versus 6.97 ± 0.62 for metformin hydrochloride tablets, USP plus insulin and placebo plus insulin respectively) with 19% less insulin versus baseline (reduction of 23.68 ± 30.22 versus an increase of 0.43 ± 25.20 units for metformin hydrochloride tablets, USP plus insulin and placebo plus insulin, p<0.01). In addition, this study demonstrated that the combination of metformin hydrochloride tablets, USP plus insulin resulted in reduction in body weight of 3.11 ± 4.30 lbs, compared to an increase of 1.30 ± 6.08 lbs for placebo plus insulin, p=0.01. METFORMIN HYDROCHLORIDE EXTENDED-RELEASE TABLETS, USP A 24-week, double-blind, placebo-controlled study of metformin hydrochloride extended-release tablets, USP, 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 7.0-10.0%, FPG 126-270 mg/dL). Patients entering the study had a mean baseline HbA 1c of 8.0% 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 hydrochloride extended-release tablets, USP 1000 mg once daily. Subsequently, the treatment dose was increased to 1500 mg once daily if HbA 1c was ≥ 7.0 % but <8.0% (patients with HbA 1c ≥ 8.0% 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 hydrochloride extended-release tablets, USP. A 16-week, double-blind, placebo-controlled, dose-response study of metformin hydrochloride extended-release tablets, USP, taken once daily with the evening meal, or twice daily with meals, was conducted in patients with type 2 diabetes who had failed to achieve glycemic control with diet and exercise (HbA 1c 7.0-11.0%, FPG 126-280 mg/dL). Changes in glycemic control and body weight are shown in Table 6. Table 6. Summary of Mean Changes from Baseline* in HbA 1c, Fasting Plasma Glucose, and Body Weight at Final Visit (16-week study) * All patients on diet therapy at Baseline ª All comparisons versus Placebo ** Not statistically significant Metformin hydrochloride extended-release 500 mg Once Daily 1000 mg Once Daily 1500 mg Once Daily 2000 mg Once Daily 1000 mg Twice Daily Placebo Hemoglobin A 1c (%) (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 182.7 183.7 178.9 181.0 181.6 179.6 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** – Compared with placebo, improvement in glycemic control was seen at all dose levels of metformin hydrochloride extended-release tablets, USP and treatment was not associated with any significant change in weight (see DOSAGE AND ADMINISTRATION for dosing recommendations for metformin hydrochloride tablets, USP and metformin hydrochloride extended-release tablets, USP). A 24-week, double-blind, randomized study of metformin hydrochloride extended-release tablets, USP, taken once daily with the evening meal, and metformin hydrochloride tablets, USP, taken twice daily (with breakfast and evening meal), was conducted in patients with type 2 diabetes who had been treated with metformin hydrochloride tablets, USP 500 mg twice daily for at least 8 weeks prior to study entry. The metformin hydrochloride tablets, USP dose had not necessarily been titrated to achieve a specific level of glycemic control prior to study entry. Patients qualified for the study if HbA 1c was ≤ 8.5 % and FPG was ≤ 200 mg/dL. Changes in glycemic control and body weight are shown in Table 7. Table 7. Summary of Mean Changes from Baseline* in HbA 1c, Fasting Plasma Glucose, and Body Weight at Week 12 and at Final Visit (24-week study) *All patients on metformin hydrochloride tablets, USP 500 mg twice daily at Baseline ª n=68 Metformin Metformin Hydrochloride Extended-release Tablets, USP Hydrochloride Tablets, USP 500 mg Twice Daily 1000 mg Once Daily 1500 mg Once Daily Hemoglobin A 1c (%) (n=67) (n=72) (n=66) Baseline 7.06 6.99 7.02 Change at 12 Weeks 0.14 0.23 0.04 (95% CI) (-0.03, 0.31) (0.10, 0.36) (-0.08, 0.15) Change at FINAL VISIT 0.14ª 0.27 0.13 (95%) (-0.04, 0.31) (0.11, 0.43) (-0.02, 0.28) FPG (mg/dL) (n=69) (n=72) (n=70) Baseline 127.2 131.0 131.4 Change at 12 Weeks 12.9 9.5 3.7 (95% CI) (6.5, 19.4) (4.4, 14.6) (-0.4, 7.8) Change at FINAL VISIT 14.0 11.5 7.6 (95%) (7.0, 21.0) (4.4, 18.6) (1.0, 14.2) Body Weight (lbs) (n=71) (n=74) (n=71) Baseline 210.3 202.8 192.7 Change at 12 Weeks 0.4 0.9 0.7 (95% CI) (-0.04, 1.5) (0.0, 2.0) (-0.04, 1.8) Change at FINAL VISIT 0.9 1.1 0.9 (95%) (-0.04, 2.2) (-0.2, 2.4) (-0.4, 2.0) After 12 weeks of treatment, there was an increase in mean HbA 1c in all groups; in the metformin hydrochloride extended-release tablets, USP 1000 mg group, the increase from baseline of 0.23% was statistically significant (see DOSAGE AND ADMINISTRATION ). Changes in lipid parameters in the previously described placebo-controlled dose-response study of metformin hydrochloride extended-release tablets, USP are shown in Table 8. Table 8. Summary of Mean Percent Changes from Baseline* in Major Lipid Variables at Final Visit (16-week study) *All patients on diet therapy at Baseline Metformin Hydrochloride Extended-release Tablets, USP 500 mg Once Daily 1000 mg Once Daily 1500 mg Once Daily 2000 mg Once Daily 1000 mg Twice Daily Placebo Total Cholesterol (mg/dL) (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 1.0% 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 220.2 211.9 198.0 194.2 179.0 211.7 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 131.0 134.9 135.8 125.8 131.4 131.9 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% Changes in lipid parameters in the previously described study of metformin hydrochloride tablets, USP and metformin hydrochloride extended-release tablets, USP are shown in Table 9. Table 9. Summary of Mean Percent Changes from Baseline* in Major Lipid Variables at Final Visit (24-week study) *All patients on metformin hydrochloride tablets, USP 500 mg twice daily at Baseline Metformin Hydrochloride Tablets, USP Metformin Hydrochloride Extended-release Tablets, USP 500 mg Twice Daily 1000 mg Once Daily 1500 mg Once Daily Total Cholesterol (mg/dL) (n=68) (n=70) (n=66) Baseline 199.0 201.9 201.6 Mean % change at FINAL VISIT 0.1% 1.3% 0.1% Total Triglycerides (mg/dL) (n=68) (n=70) (n=66) Baseline 178.0 169.2 206.8 Mean % change at FINAL VISIT 6.3% 25.3% 33.4% LDL-Cholesterol (mg/dL) (n=68) (n=70) (n=66) Baseline 122.1 126.2 115.7 Mean % change at FINAL VISIT -1.3% -3.3% -3.7% HDL-Cholesterol (mg/dL) (n=68) (n=70) (n=65) Baseline 41.9 41.7 44.6 Mean % change at FINAL VISIT 4.8% 1.0% -2.1% Pediatric Clinical Studies In a double-blind, placebo-controlled study in pediatric patients aged 10 to 16 years with type 2 diabetes (mean FPG 182.2 mg/dL), treatment with metformin hydrochloride tablets, USP (up to 2000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks) resulted in a significant mean net reduction in FPG of 64.3 mg/dL, compared with placebo (see Table 10). Table 10. Metformin Hydrochloride Tablets, USP vs. Placebo (Pediatricsª) Summary of Mean Changes from Baseline* in Plasma Glucose and Body Weight at Final Visit ª Pediatric patients mean age 13.8 years (range 10-16 years) * All patients on diet therapy at Baseline ** Not statistically significant Metformin Hydrochloride Tablets, USP Placebo p-Value FPG (mg/dL) (n=37) (n=36) Baseline 162.4 192.3 Change at FINAL VISIT -42.9 21.4 <0.001 Body Weight (lbs) (n=39) (n=38) Baseline 205.3 189.0 Change at FINAL VISIT -3.3 -2.0 NS**

HOW SUPPLIED

Metformin hydrochloride tablets, USP are available as: 500 mg Bottles of 100 NDC 62037-674-01 500 mg Bottles of 500 NDC 62037-674-05 500 mg Bottles of 1000 NDC 62037-674-10 850 mg Bottles of 100 NDC 62037-675-01 850 mg Bottles of 500 NDC 62037-675-05 850 mg Bottles of 1000 NDC 62037-675-10 1000 mg Bottles of 100 NDC 62037-676-01 1000 mg Bottles of 500 NDC 62037-676-05 1000 mg Bottles of 1000 NDC 62037-676-10 Metformin hydrochloride 500 mg tablets, USP are round, white to off-white, film coated tablets debossed with “Andrx 674” on one side and “500” debossed on the other side. Metformin hydrochloride 850 mg tablets, USP are round, white to off-white, film coated tablets debossed with “Andrx 675” on one side and “850” debossed on the other side. Metformin hydrochloride 1000 mg tablets, USP are oval, white to off-white, film coated tablets with “Andrx 676” debossed on one side and bisected “1000” on the other side. Metformin hydrochloride extended-release tablets, USP are available as: 500 mg Bottles of 90 NDC 62037-571-90 500 mg Bottles of 100 NDC 62037-571-01 500 mg Bottles of 500 NDC 62037-571-05 500 mg Bottles of 1000 NDC 62037-571-10 750 mg Bottles of 100 NDC 62037-577-01 750 mg Bottles of 500 NDC 62037-577-05 750 mg Bottles of 1000 NDC 62037-577-10 Metformin hydrochloride extended-release 500 mg tablets, USP are white to off-white, capsule shaped tablets, debossed with the and “571” on one side and “500” on the other side. Metformin hydrochloride extended-release 750 mg tablets, USP are light yellow, capsule shaped tablets, debossed with and “577” on one side and “750” on opposite side. Logo Logo Storage Store at controlled room temperature 20°-25°C (68°-77°F). [See USP.] Dispense in light-resistant containers. Metformin hydrochloride tablets, USP are manufactured by: Patheon Puerto Rico, Inc. Caguas, Puerto Rico 00725, USA Distributed by: Watson Pharma, Inc. Metformin hydrochloride extended-release tablets, USP are manufactured by: Watson Laboratories, Inc. Corona, CA 92880 USA Distributed by: Watson Pharma, Inc. Rev. date 05/09 190733

GERIATRIC USE

Geriatric Use Controlled clinical studies of metformin hydrochloride tablets, USP and metformin hydrochloride extended-release tablets, USP 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. Metformin is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, metformin hydrochloride tablets, USP, and metformin hydrochloride extended-release tablets, USP should only be used in patients with normal renal function (see CONTRAINDICATIONS, WARNINGS and CLINICAL PHARMACOLOGY: Pharmacokinetics ). Because aging is associated with reduced renal function, metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP (see also WARNINGS and DOSAGE AND ADMINISTRATION ).

MECHANISM OF ACTION

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.

INDICATIONS AND USAGE

Metformin hydrochloride tablets, USP is indicated as an adjunct to diet and exercise to improve glycemic control in adults and children with type 2 diabetes mellitus. Metformin hydrochloride extended-release tablets, USP is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

PEDIATRIC USE

Pediatric Use The safety and effectiveness of metformin hydrochloride tablets, USP for the treatment of type 2 diabetes have been established in pediatric patients ages 10 to 16 years (studies have not been conducted in pediatric patients below the age of 10 years). Use of metformin hydrochloride tablets, USP in this age group is supported by evidence from adequate and well-controlled studies of metformin hydrochloride tablets, USP in adults with additional data from a controlled clinical study in pediatric patients ages 10 to 16 years with type 2 diabetes, which demonstrated a similar response in glycemic control to that seen in adults. (See CLINICAL PHARMACOLOGY: Pediatric Clinical Studies. ) In this study, adverse effects were similar to those described in adults. (See ADVERSE REACTIONS: Pediatric Patients. ) A maximum daily dose of 2000 mg is recommended. (See DOSAGE AND ADMINISTRATION: Recommended Dosing Schedule: Pediatrics. ) Safety and effectiveness of metformin hydrochloride extended-release tablets, USP in pediatric patients have not been established.

PREGNANCY

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 hydrochloride tablets, USP and metformin hydrochloride extended-release tablets, USP should not be used during pregnancy unless clearly needed. There are no adequate and well-controlled studies in pregnant women with metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP. 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 2000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.

NUSRING MOTHERS

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 hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP are discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

BOXED WARNING

WARNINGS Lactic Acidosis: Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP; 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 μg/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin hydrochloride 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 hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP and by use of the minimum effective dose of metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP 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 hydrochloride tablets, USP and metformin hydrochloride extended-release tablets, USP 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 hydrochloride tablets, USP and metformin hydrochloride extended-release tablets, USP 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 hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, metformin hydrochloride tablets, USP and metformin hydrochloride extended-release tablets, USP 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 hydrochloride tablets, USP and metformin hydrochloride extended-release tablets, USP 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 hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP, 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 hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP 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 hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride 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.)

INFORMATION FOR PATIENTS

Information for Patients Patients should be informed of the potential risks and benefits of metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP 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 hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP 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 hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP, 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 hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP. Metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP alone does not usually cause hypoglycemia, although it may occur when metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP 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. (See Patient Information Printed Separately.) Patients should be informed that metformin hydrochloride extended-release tablets, USP 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.

DOSAGE AND ADMINISTRATION

There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP or any other pharmacologic agent. Dosage of metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily dose. The maximum recommended daily dose of metformin hydrochloride tablets, USP is 2550 mg in adults and 2000 mg in pediatric patients (10-16 years of age); the maximum recommended daily dose of metformin hydrochloride extended-release tablets, USP in adults is 2000 mg. Metformin hydrochloride tablets, USP should be given in divided doses with meals while metformin hydrochloride extended-release tablets, USP should generally be given once daily with the evening meal. Metformin hydrochloride tablets, USP or metformin hydrochloride 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 hydrochloride tablets, USP or metformin hydrochloride 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 hydrochloride tablets, USP or metformin hydrochloride 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 hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone. Metformin hydrochloride extended-release tablets, USP must be swallowed whole and never crushed or chewed. Occasionally, the inactive ingredients of metformin hydrochloride extended-release will be eliminated in the feces as a soft, hydrated mass. (See Patient Information printed separately.) 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 hydrochloride tablets, USP is 500 mg twice a day or 850 mg once a day, given with meals. Dosage increases should be made in increment of 500 mg weekly or 850 mg every 2 weeks, up to a total of 2000 mg per day, given in divided doses. Patients can also be titrated from 500 mg twice a day to 850 mg twice a day after 2 weeks. For those patients requiring additional glycemic control, metformin hydrochloride tablets, USP may be given to a maximum daily dose of 2550 mg per day. Doses above 2000 mg may be better tolerated given three times a day with meals. The usual starting dose of metformin hydrochloride 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 hydrochloride extended-release tablets, USP 2000 mg once daily, a trial of metformin hydrochloride extended-release tablets, USP 1000 mg twice daily should be considered. If higher doses of metformin hydrochloride tablets, USP are required, metformin hydrochloride tablets, USP should be used at total daily doses up to 2550 mg administered in divided daily doses, as described above. (See CLINICAL PHARMACOLOGY, Clinical Studies .) In a randomized trial, patients currently treated with metformin hydrochloride tablets, USP were switched to metformin hydrochloride extended-release tablets, USP. Results of this trial suggest that patients receiving metformin hydrochloride tablets, USP treatment may be safely switched to metformin hydrochloride extended-release tablets, USP once daily at the same total daily dose, up to 2000 mg once daily. Following a switch from metformin hydrochloride tablets, USP to metformin hydrochloride extended-release tablets, USP glycemic control should be closely monitored and dosage adjustments made accordingly (see CLINICAL PHARMACOLOGY, Clinical Studies ). Pediatrics – The usual starting dose of metformin hydrochloride tablets, USP is 500 mg twice a day, given with meals. Dosage increases should be made in increments of 500 mg weekly up to a maximum of 2000 mg per day, given in divided doses. Safety and effectiveness of metformin hydrochloride 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 hydrochloride tablets, USP or metformin hydrochloride 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 Hydrochloride Tablets, USP or Metformin Hydrochloride 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 hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing metformin hydrochloride tablets, USP or metformin hydrochloride extendedrelease 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 hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. In a clinical trial of patients with type 2 diabetes and prior failure on glyburide, patients started on metformin hydrochloride tablets, USP 500 mg and glyburide 20 mg were titrated to 1000/20mg, 1500/20 mg, 2000/20 mg or 2500/20 mg of metformin hydrochloride tablets, USP and glyburide, respectively, to reach the goal of glycemic control as measured by FPG, HbA 1c and plasma glucose response (see CLINICAL PHARMACOLOGY: Clinical Studies). However, attempts should be made to identify the minimum effective dose of each drug to achieve this goal. With concomitant metformin hydrochloride tablets, USP or metformin hydrochloride 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 hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP. Concomitant Metformin Hydrochloride Tablets, USP or Metformin Hydrochloride Extended-release Tablets, USP and Insulin Therapy in Adult Patients The current insulin dose should be continued upon initiation of metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP therapy. Metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP should be initiated at 500 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of metformin hydrochloride tablets, USP or metformin hydrochloride 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 2500 mg for metformin hydrochloride tablets, USP and 2000 mg for metformin hydrochloride 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 hydrochloride tablets, USP or metformin hydrochlorideextended-release tablets, USP. Further adjustment should be individualized based on glucose-lowering response. Specific Patient Populations Metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP are not recommended for use in pregnancy. Metformin hydrochloride tablets, USP are not recommended in patients below the age of 10 years. Metformin hydrochloride extended-release tablets, USP are not recommended in pediatric patients (below the age of 17 years). The initial and maintenance dosing of metformin hydrochloride tablets, USP or metformin hydrochloride 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 hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP. Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly. (See WARNINGS .)