Dosage Form: tablet, extended release
Metformin Hydrochloride Extended-Release Tablets, USP
Metformin Extended Release Description
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 C4H11N5 • 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 extended-release tablets, USP contain 500 mg or 750 mg of metformin hydrochloride as the active ingredient. Each tablet contains the inactive ingredients hypromellose, silicified microcrystalline cellulose, xanthan gum, maltodextrin, colloidal silicon dioxide and stearic acid.
Dissolution Method: USP dissolution test is pending.
System Components and Performance - Metformin hydrochloride extended-release tablets, USP comprises a drug releasing 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.
Metformin Extended Release - 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, Cmax is achieved with a median value of 7 hours and a range of 4 to 8 hours.
At steady state, the AUC and Cmax are less than dose proportional for Metformin hydrochloride extended-release tablets within the range of 500 to 2000 mg administered once daily. Peak plasma levels are approximately 0.6, 1.1, 1.4, and 1.8 µg/mL for 500, 1000, 1500, and 2000 mg once-daily doses, respectively. After repeated administration of Metformin hydrochloride extended-release tablets, metformin did not accumulate in plasma.
Although the extent of metformin absorption (as measured by AUC) from the Metformin hydrochloride extended-release tablets increased by approximately 50% when given with food, there was no effect of food on Cmax and Tmax of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of Metformin hydrochloride extended-release tablets.
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 hydrochloride 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 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).
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 7.0%-10.0%, FPG 126-270 mg/dL). Patients entering the study had a mean baseline HbA1c of 8.0% 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 hydrochloride extended-release tablets 1000 mg once daily.
Subsequently, the treatment dose was increased to 1500 mg once daily if HbA1c was ≥7.0% but <8.0% (patients with HbA1c ≥8.0% 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 hydrochloride extended-release tablets. A 16-week, double-blind, placebo-controlled, dose-response study of Metformin hydrochloride 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 7.0%-11.0%, FPG 126-280 mg/dL). Changes in glycemic control and body weight are shown in Table 6.
| 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 | ||
| * All patients on diet therapy at Baseline | ||||||
| a All comparisons versus Placebo | ||||||
| ** Not statistically significant | ||||||
| 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 | 181.0 | 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 and treatment was not associated with any significant change in weight (see DOSAGE AND ADMINISTRATION for dosing recommendations for Metformin hydrochloride extended-release tablets.
A 24-week, double-blind, randomized study of Metformin hydrochloride extended-release tablets, taken once daily with the evening meal, was conducted in patients with type 2 diabetes who had been treated with Metformin hydrochloride 500 mg twice daily for at least 8 weeks prior to study entry. The Metformin hydrochloride 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 7.
| Metformin hydrochloride 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) | (0.1, 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 hydrochloride 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 hydrochloride extended-release tablets are shown in Table 8.
| 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 | ||
| * All patients on diet therapy at Baseline | ||||||
| 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% |
Changes in lipid parameters in the previously described study of Metformin hydrochloride extended-release tablets, USP are shown in Table 9.
| 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 | 1.0% | –2.1% |
Indications and Usage for Metformin Extended Release
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.
Contraindications
Metformin hydrochloride extended-release tablets are contraindicated in patients with:
- 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).
- Known hypersensitivity to metformin hydrochloride.
- Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.
Metformin hydrochloride extended-release tablets 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.)
Warnings
Lactic Acidosis:
Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with Metformin hydrochloride 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 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 extended release tablets and by use of the minimum effective dose of Metformin hydrochloride extended release tablets. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. 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, as these patients are more susceptible to developing lactic acidosis. In addition, Metformin hydrochloride 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 hydrochloride 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 hydrochloride extended release tablets, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, Metformin hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride extended release tablets, 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.)
Precautions
General
Macrovascular Outcomes—There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Metformin hydrochloride extended release tablets or any other antidiabetic drug.
Monitoring of renal function—Metformin is known to be substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive Metformin hydrochloride extended release tablets. In patients with advanced age, Metformin hydrochloride extended release tablets should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, particularly those ≥80 years of age, renal function should be monitored regularly and, generally, Metformin hydrochloride extended release tablets should not be titrated to the maximum dose (see WARNINGS and DOSAGE AND ADMINISTRATION).
Before initiation of Metformin hydrochloride extended-release tablets therapy and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and Metformin hydrochloride extended-release tablets discontinued if evidence of renal impairment is present.
Use of concomitant medications that may affect renal function or metformin disposition—Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion (see PRECAUTIONS: Drug Interactions), should be used with caution.
Radiologic studies involving the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast materials)—Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin (see CONTRAINDICATIONS). Therefore, in patients in whom any such study is planned, Metformin hydrochloride extended-release tablets should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.
Hypoxic states—Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on Metformin hydrochloride extended-release tablets therapy, the drug should be promptly discontinued.
Surgical procedures—Metformin hydrochloride extended-release tablets therapy should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.
Alcohol intake—Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving Metformin hydrochloride extended-release tablets.
Impaired hepatic function—Since impaired hepatic function has been associated with some cases of lactic acidosis, Metformin hydrochloride extended-release tablets should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.
Vitamin B12 levels—Measurement of hematologic parameters on an annual basis is advised in patients on Metformin hydrochloride extended-release tablets and any apparent abnormalities should be appropriately investigated and managed (see PRECAUTIONS: Laboratory Tests).
Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at 2- to 3-year intervals may be useful.
Change in clinical status of patients with previously controlled type 2 diabetes—A patient with type 2 diabetes previously well controlled on Metformin hydrochloride extended-release tablets who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, Metformin hydrochloride extended-release tablets must be stopped immediately and other appropriate corrective measures initiated (see also WARNINGS).
Hypoglycemia—Hypoglycemia does not occur in patients receiving Metformin hydrochloride extended-release tablets alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol.
Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs.
Loss of control of blood glucose—When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold Metformin hydrochloride extended-release tablets and temporarily administer insulin. Metformin hydrochloride extended-release tablets may be reinstituted after the acute episode is resolved.
The effectiveness of oral antidiabetic drugs in lowering blood glucose to a targeted level decreases in many patients over a period of time. This phenomenon, which may be due to progression of the underlying disease or to diminished responsiveness to the drug, is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective during initial therapy. Should secondary failure occur with either Metformin hydrochloride extended-release tablets or sulfonylurea monotherapy, combined therapy with Metformin hydrochloride extended-release tablets and sulfonylurea may result in a response. Should secondary failure occur with combined Metformin hydrochloride extended-release tablets/sulfonylurea therapy, it may be necessary to consider therapeutic alternatives including initiation of insulin therapy.
Information for Patients
Patients should be informed of the potential risks and benefits of Metformin hydrochloride extended-release tablets and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose, glycosylated hemoglobin, renal function, and hematologic parameters.
The risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in the WARNINGS and PRECAUTIONS sections, should be explained to patients. Patients should be advised to discontinue Metformin hydrochloride extended-release tablets immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of Metformin hydrochloride extended-release tablets, gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.
Patients should be counselled against excessive alcohol intake, either acute or chronic, while receiving Metformin hydrochloride extended-release tablets.
Metformin hydrochloride extended-release tablets alone does not usually cause hypoglycemia, although it may occur when Metformin hydrochloride extended-release tablets is used in conjunction with oral sulfonylureas and insulin. When initiating combination therapy, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. (See Patient Information printed below.)
Patients should be informed that Metformin hydrochloride extended-release tablets must be swallowed whole and not crushed or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.
Laboratory Tests
Response to all diabetic therapies should be monitored by periodic measurements of fasting blood glucose and glycosylated hemoglobin levels, with a goal of decreasing these levels toward the normal range. During initial dose titration, fasting glucose can be used to determine the therapeutic response. Thereafter, both glucose and glycosylated hemoglobin should be monitored. Measurements of glycosylated hemoglobin may be especially useful for evaluating long-term control (see also DOSAGE AND ADMINISTRATION).
Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis.
Glyburide—In a single-dose interaction study in type 2 diabetes patients, coadministration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and Cmax 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 extended-release tablets and Oral Sulfonylurea Therapy in Adult Patients).
Furosemide—A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by coadministration. Furosemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the Cmax 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 coadministered chronically.
Nifedipine—A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that coadministration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. Tmax and half-life were unaffected. Nifedipine appears to enhance the absorption of metformi
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