Metformin Er 500 Mg

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

DOSAGE & ADMINISTRATION There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with metformin hydrochloride extended-release tablets, USP or any other pharmacologic agent. Dosage of metformin hydrochloride 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 recommended daily dose of metformin hydrochloride extended-release tablets, USP in adults is 2000 mg. Metformin hydrochloride extended-release tablets, USP should generally be given once daily with the evening meal. 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 extended-release tablets, USP and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately 3 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 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 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 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 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. (See CLINICAL PHARMACOLOGY : Clinical Studies .) In a randomized trial, patients currently treated with metformin hydrochloride tablets were switched to metformin hydrochloride extended-release tablets. Results of this trial suggest that patients receiving metformin hydrochloride tablets treatment may be safely switched to metformin hydrochloride extended-release tablets once daily at the same total daily dose, up to 2000 mg once daily. Following a switch from metformin hydrochloride tablets to metformin hydrochloride extended-release tablets, glycemic control should be closely monitored and dosage adjustments made accordingly (see CLINICAL PHARMACOLOGY : Clinical Studies ). Pediatrics Safety and effectiveness of metformin hydrochloride extended-release tablets, USP in pediatric patients have not been established. Recommendations for Use in Renal Impairment Assess renal function prior to initiation of metformin hydrochloride extended-release tablets and periodically thereafter. Metformin hydrochloride extended-release tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m2. Initiation of metformin hydrochloride extended-release tablets in patients with an eGFR between 30 to 45 mL/minute/1.73 m2 is not recommended. In patients taking metformin hydrochloride extended-release tablets whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit risk of continuing therapy. Discontinue metformin hydrochloride extended-release tablets if the patients eGFR later falls below 30 mL/minute/1.73 m2 (See WARNINGS and PRECAUTIONS ). Discontinuation for Iodinated Contrast Imaging Procedures Discontinue metformin hydrochloride extended-release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart metformin hydrochloride extended-release tablets if renal function is stable. Concomitant Metformin Hydrochloride Extended-Release Tablets, USP and Oral Sulfonylurea Therapy in Adult Patients If patients have not responded to 4 weeks of the maximum dose of metformin hydrochloride extended-release tablets monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing metformin hydrochloride 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 hydrochloride extended-release tablets 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 500 mg and glyburide 20 mg were titrated to 1000/20 mg, 1500/20 mg, 2000/20 mg or 2500/20 mg of metformin hydrochloride tablets and glyburide, respectively, to reach the goal of glycemic control as measured by FPG, HbA1c 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 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 1 to 3 months of concomitant therapy with the maximum dose of metformin hydrochloride extended-release tabletsand the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without metformin hydrochloride extended-release tablets. Concomitant Metformin Hydrochloride Extended-Release Tablets and Insulin Therapy in Adult Patients The current insulin dose should be continued upon initiation of metformin hydrochloride extended-release tablets therapy. Metformin hydrochloride extended-release tablets therapy should be initiated at 500 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of metformin hydrochloride 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 2000 mg for metformin hydrochloride extended-release tablets. It is recommended that the insulin dose be decreased by 10% to 25% when fasting plasma glu

WARNINGS LACTIC ACIDOSIS: Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension and resistant bradyarrhythmias. The onset of metformin associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin associated lactic acidosis was characterized by elevated blood lactate levels(>5 mmol/Liter), anion gap acidosis (without evidenceof ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL (see Error! Hyperlink reference not valid.). Risk factors for metformin associated lactic acidosis include renal impairment, concamitent use of certain drugs (e.g carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided (see Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. , AND Error! Hyperlink reference not valid. ). If metformin associated lactic acidosis is suspected, immediately discontinue metformin hydrochloride extend release tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended (see Error! Hyperlink reference not valid. ).

CONTRAINDICATIONS Metformin hydrochloride extended-release tablets, USP are contraindicated in patients with: 1. Severe Renal Impairment (eGFR below 30mL/min/1.73m2) (see Error! Hyperlink reference not valid. and Error! Hyperlink reference not valid. ). 2.Known hypersensitivity to metformin hydrochloride, USP. 3.Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

ADVERSE REACTIONS In A US double blind clinical study of metformin hydrochloride tablets in patients with type 2 diabetes, a total of 141 patients received metformin hydrochloride tablets therapy (up to 2550 mg per day) and 145 patients received placebo. Adverse reactions reported in greater than 5% of the metformin hydrochloride tablets patients, and that were more common in metformin hydrochloride tablets than placebo treated patients, are listed in Table 6. Table 6: Most Common Adverse Reactions (>5 Percent) in a Placebo-Controlled Clinical Study of Metformin Hydrochloride Tablets Monotherapy* Adverse Reaction Metformin Hydrochloride Tablets (n=141) Placebo (n=145) % of Patients Diarrhea 53.2 11.7 Nausea/Vomiting 25.5 8.3 Flatulence 12.1 5.5 Asthenia 9.2 5.5 Indigestion 7.1 4.1 Abdominal Discomfort 6.4 4.8 Headache 5.7 4.8 *Reactions that were more common in metformin hydrochloride tablets than placebo treated patients. Diarrhea led to discontinuation of study medication in 6% of patients treated with metformin hydrochloride tablets. Additionally, the following adverse reactions were reported in ≥1 - ≤5% of metformin hydrochloride tablets patients and myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, and palpitation. In worldwide clinical trials over 900 patients with type 2 diabetes have been treated with metformin hydrochloride extended-release tablets in placebo and active controlled studies. In placebo controlled trails, 781 patients were administered metformin hydrochloride extended-release tablets and 195 patients received placebo. Adverse reactions reported in greater than 5% of the metformin hydrochloride extended release tablets patients, and that were more common in metformin hydrochloride extended-release tablets than placebo treated patients are listed in Table 7. Table 7: Most Common Adverse Reactions (>5 Percent) in Placebo-Controlled Studies of Metformin Hydrochloride 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 Diarrhea led to discontinuation of study medication in 0.6% of patients treated with metformin hydrochloride extended-release tablets. Additionally, the following adverse reactions were reported in ≥1 - ≤5% of metformin hydrochloride extended-release tablets patients and were more commonly reported with metformin hydrochloride extended-release tablets than placebo: abdominal pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance.*Reactions that were more common in metformin hydrochloride extended-release tablets than placebo treated patients.

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 Hydrochloride Extended-Release Tablets, C max is achieved with a median value of 7 hours and a range of 4 to 8 hours.Peak plasma levels are approximately 20% lower compared to the same dose of metformin hydrochloride tablets, however, the extent of absorption (as measured by AUC) is similar to metformin hydrochloride tablets. At steady state, the AUC and C max are less than dose proportional for metformin hydrochloride extended-release tablets within the range of 500 to 2000 mg administered once daily. Peak plasma levels are approximately 0.6, 1.1, 1.4, and 1.8 mcg/mL for 500, 1000, 1500, and 2000 mg once-daily doses, respectively. The extent of metformin absorption (as measured by AUC) from metformin hydrochloride extended-release tablets at a 2000 mg once-daily dose is similar to the same total daily dose administered as metformin hydrochloride tablets 1000 mg twice daily. After repeated administration of metformin hydrochloride extended-release tablets, metformin did not accumulate in plasma. Within-subject variability in C max and AUC of metformin from metformin hydrochloride extended-release tablets is comparable to that with metformin hydrochloride tablets. Although the extent of metformin absorption (as measured by AUC) from the metformin hydrochloride extended-release tablets increased by approximately 50% when given with food, there was no effect of food on C max and T max of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of metformin hydrochloride extended-release tablets. Distribution The apparent volume of distribution (V/F) of metformin following single oral doses of metformin hydrochloride 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin hydrochloride tablets, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 mcg/mL. During controlled clinical trials of metformin hydrochloride tablets, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses. 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 (see Table 1 ) 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 Population 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 (see Table 1) nor is there any accumulation of metformin in either group at usual clinical doses. The pharmacokinetics of metformin hydrochloride extended-release tablets in patients with type 2 diabetes is comparable to those in healthy normal adults. Renal Impairment 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 Table 1: also see also see CONTRAINDICATIONS , WARNINGS , PRECAUTIONS , and DOSAGE AND ADMINISTRATION ). Hepatic Impairment No parmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency (see PRECAUTIONS ). Geriatrics Limited data from controlled pharmacokinetic studies of metformin hydrochloride tablets in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 1; also see WARNINGS , PRECAUTIONS , and DOSAGE AND ADMINISTRATION ). Metformin hydrochloride 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 ). Table 1: Select Mean ( ± S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin Hydrochloride Tablets Subject Groups: Metformin Hydrochloride Tablet dose a (number of subjects) Cmax b (mcg/mL) Tmax c (hrs) Renal Clearance (mL/min) Healthy, nondiabetic adults: 500 mg single dose (24) 1.03 (±0.33) 2.75 (±0.81) 600 (±132) 850 mg single dose (74)d 1.60 (±0.38) 2.64 (±0.82) 552 (±139) 850 mg three times daily for 19 doses e (9) 2.01 (±0.42) 1.79 (±0.94) 642 (±173) Adults with type 2 diabetes: 850 mg single dose (23) 1.48 (±0.5) 3.32 (±1.08) 491 (±138) 850 mg three times daily for 19 dosese (9) 1.90 (±0.62) 2.01 (±1.22) 550 (±160) Elderly f , healthy nondiabetic adults: 850 mg single dose (12) 2.45 (±0.70) 2.71 (±1.05) 412 (±98) Renal-impaired adults: 850 mg single dose Mild (CL cr g 61-90 mL/min) (5) 1.86 (±0.52) 3.20 (±0.45) 384 (±122) Moderate (CL cr 31-60 mL/min) (4) 4.12 (±1.83) 3.75 (±0.50) 108 (±57) Severe (CL cr 10-30 mL/min) (6) 3.93 (±0.92) 4.01 (±1.10) 130 (±90) a All doses given fasting except the first 18 doses of the multiple dose studies b Peak plasma concentration c Time to peak plasma concentration d Combined results (average means) of five studies: mean age 32 years (range 23-59 years) e Kinetic study done following dose 19, given fasting f Elderly subjects, mean age 71 years (range 65-81 years) g CLcr = creatinine clearance normalized to body surface area of 1.73 m 2 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 Hydrochloride Extended-Release Tablets A 24-week, double-blind, placebo-controlled study of metformin hydrochloride 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 to 10%, FPG 126 to 270 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 HbA 1c had increased from baseline by 0.1% and mean FPG decreased from baseline by 2 mg/dL in the placebo