Glumetza Information
Glumetza () Indications And Usage
Glumetza () is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Glumetza () Dosage Forms And Strengths
Glumetza () (metformin hydrochloride extended-release tablets) 500 mg are available as blue, film coated, oval-shaped tablets debossed with “GMZ” on one side and “500” on the other side.
Glumetza () (metformin hydrochloride extended-release tablets) 1000 mg are available as white, film coated, oval-shaped tablets with “M1000” on one side.
Glumetza () Contraindications
Glumetza () is contraindicated in patients with:
Glumetza () Warnings And Precautions
Lactic acidosis is a serious, metabolic complication that can occur due to metformin accumulation during treatment with Glumetza () and 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 concentrations (>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 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 impairment, 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, particularly when accompanied by hypoperfusion and hypoxemia due to unstable or acute failure, 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 Glumetza () . In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Glumetza () treatment should not be initiated in any patient unless measurement of creatinine clearance demonstrates that renal function is not reduced. In addition, Glumetza () 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, Glumetza () should generally be avoided in patients with clinical or laboratory evidence of hepatic impairment. Patients should be cautioned against excessive alcohol intake when taking Glumetza () , because alcohol potentiates the effects of metformin on lactate metabolism. In addition, Glumetza () should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure necessitating restricted intake of food or fluids. Use of topiramate, a carbonic anhydrase inhibitor, in epilepsy and migraine prophylaxis may frequently cause dose-dependent metabolic acidosis (In controlled trials, 32% and 67% for adjunctive treatment in adults and pediatric patients, respectively, and 15 to 25% for monotherapy of epilepsy, with decrease in serum bicarbonate to less than 20 mEq/L; 3% and 11% for adjunctive treatment in adults and pediatric patients, respectively, and 1 to 7% for monotherapy of epilepsy, with decrease in serum bicarbonate to less than 17 mEq/L) and may exacerbate the risk of metformin-induced lactic acidosis. (See Drug Interactions and Clinical Pharmacology) 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.
Patients should be educated to promptly report these symptoms should they occur. If present, Glumetza () should be withdrawn until lactic acidosis is ruled out. Serum electrolytes, ketones, blood glucose, blood pH, lactate levels, and blood metformin levels may be useful. Once a patient is stabilized on any dose level of Glumetza () , gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to recur. 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 Glumetza () 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. 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 Glumetza () , 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 CONTRAINDICATIONS ())
Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Therefore Glumetza () is contraindicated in patients with renal impairment.
Before initiation of Glumetza () and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated (e.g., elderly), renal function should be assessed more frequently and Glumetza () discontinued if evidence of renal impairment is present. Metformin 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.
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Radiological studies and surgical procedures:
Radiologic studies involving the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography) can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin. Therefore, in patients in whom any such study is planned, Glumetza () 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.
Glumetza () 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.
Glumetza () Adverse Reactions
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
In clinical trials conducted in the U.S., over 1000 patients with type 2 diabetes mellitus have been treated with Glumetza () 1500–2000 mg/day in active-controlled and placebo-controlled studies with the 500 mg dosage form.
In the 24-week monotherapy trial comparing Glumetza () to immediate-release metformin, serious adverse reactions were reported in 3.6% (19/528) of the Glumetza () -treated patients compared to 2.9% (5/174) of the patients treated with immediate-release metformin. In the add-on to sulfonylurea study, patients receiving background glyburide therapy were randomized to receive add-on treatment of either one of three different regimens of Glumetza () or placebo. In total, 431 patients received Glumetza () and glyburide and 144 patients received placebo and glyburide. A serious adverse reaction was reported in 2.1% (9/431) of the Glumetza () and glyburide-treated patients compared to 1.4% (2/144) of the placebo and glyburide-treated patients. When the data from the monotherapy and add-on to sulfonylurea clinical trials were combined, the most frequently (incidence ≥ 0.5 %) reported serious adverse reactions classified by system organ class were gastrointestinal disorders (1.0% of Glumetza () -treated patients compared to 0% of patients not treated with Glumetza () ) and cardiac disorders (0.4% of Glumetza () -treated patients compared to 0.5% of patients not treated with Glumetza () ). Only 2 serious adverse reactions (unstable angina [n=2] and pancreatitis [n=2]) were reported in more than one Glumetza () -treated patient.
Adverse reactions reported in greater than 5% of patients treated with Glumetza () that were more common in the combined Glumetza () and glyburide group than in the placebo and glyburide group are shown in .
In 0.7% of patients treated with Glumetza () and glyburide, diarrhea was responsible for discontinuation of study medication compared to no patients in the placebo and glyburide group : Adverse Reactions Occurring in 1% or More of Patients on Omeprazole Therapy from U.S. Studies
Glumetza () Use In Specific Populations
Teratogenic Effects: Pregnancy Category B
Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day, which represent 3 and 6 times the maximum recommended human daily dose of 2000 mg based on body surface area comparison for rats and rabbits, respectively. However, because animal reproduction studies are not always predictive of human response, Metformin HCl should not be used during pregnancy unless clearly needed.
Glumetza () Overdosage
No cases of overdose were reported during Glumetza () clinical trials. It would be expected that adverse reactions of a more intense character including epigastric discomfort, nausea, and vomiting followed by diarrhea, drowsiness, weakness, dizziness, malaise and headache might be seen. Should those symptoms persist, lactic acidosis should be excluded.
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 ()) 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.
Glumetza () Description
Glumetza () (metformin hydrochloride) extended release tablet is an oral antihyperglycemic medication 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 of metformin hydrochloride (metformin HCl) is as shown:
Metformin HCl is a white to off-white crystalline compound with a molecular formula of CHN•HCl and a molecular weight of 165.63. Metformin HCl is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. Glumetza () tablets are modified release dosage forms that contain 500 mg or 1000 mg of metformin HCl. Each 500 mg tablet contains coloring, hypromellose, magnesium stearate, microcrystalline cellulose and polyethylene oxide. Each 1000 mg tablet contains colloidal silicon dioxide, polyvinyl alcohol, crospovidone, glyceryl behenate, polyacrylate dispersion, hypromellose, talc, polyethylene glycol, eudragit, titanium dioxide, simethicone emulsion, polysorbate and coloring. Glumetza () 500 mg and 1000 mg tablets are formulated to gradually release metformin to the upper gastrointestinal (GI) tract.
Glumetza () Clinical Studies
Glumetza () has been studied as monotherapy and in combination with a sulfonylurea and insulin. Other formulations of metformin have been studied with other classes of antihyperglycemic agents, either as immediate or as extended release tablets.
In a multicenter, randomized, double-blind, active-controlled, dose-ranging, parallel group trial Glumetza () 1500 mg once daily, Glumetza () 1500 per day in divided doses (500 mg in the morning and 1000 mg in the evening), and Glumetza () 2000 mg once daily were compared to immediate-release metformin 1500 mg per day in divided doses (500 mg in the morning and 1000 mg in the evening). This trial enrolled patients (n = 338) who were newly diagnosed with diabetes, patients treated only with diet and exercise, patients treated with a single anti-diabetic medication (sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, or meglinitides ), and patients (n = 368) receiving metformin up to 1500 mg/day plus a sulfonylurea at a dose equal to or less than one-half the maximum dose. Patients who were enrolled on monotherapy or combination anti-diabetic therapy underwent a 6-week washout. Patients randomized to Glumetza () began titration from 1000 mg/day up to their assigned treatment dose over 3 weeks. Patients randomized to immediate-release metformin initiated 500 mg twice daily for 1 week followed by 500 mg with breakfast and 1000 mg with dinner for the second week. The 3-week treatment period was followed by an additional 21-week period at the randomized dose. For HbA and fasting plasma glucose, each of the Glumetza () regimens was at least as effective as immediate-release metformin. Additionally, once daily dosing of Glumetza () was as effective as twice daily dosing of the immediate release metformin formulation.
In a double-blind, randomized, placebo-controlled (glyburide add-on) multicenter trial, patients with type 2 diabetes mellitus who were newly diagnosed or treated with diet and exercise (n = 144), or who were receiving monotherapy with metformin, sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, or meglinitides, or treated with combination therapy consisting of metformin/glyburide at doses up to 1000 mg metformin + 10 mg glyburide per day (or equivalent doses of glipizide or glimepiride up to half the maximum therapeutic dose) (n = 431) were enrolled. All patients were stabilized on glyburide for a 6-week run-in period, and then randomized to 1 of 4 treatments: placebo + glyburide (glyburide alone); Glumetza () 1500 mg once a day + glyburide, Glumetza () 2000 mg once a day + glyburide, or Glumetza () 1000 mg twice a day + glyburide. A 3-week Glumetza () titration phase was followed by a 21-week maintenance treatment phase. Use of insulin and oral hypoglycemic agents other than the study drugs were prohibited. The difference in the change from Baseline in HbA levels between the combined Glumetza () + glyburide groups and the glyburide only group was statistically significant at week 24 (p
A 24-week, double-blind, placebo-controlled trial of immediate release metformin plus insulin versus insulin plus placebo was conducted in patients with type 2 diabetes who failed to achieve adequate glycemic control on insulin alone. Patients randomized to receive metformin plus insulin achieved a mean reduction in HbA of 2.10%, compared to a 1.56% reduction in HbA 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 plus insulin versus insulin plus placebo, respectively, p=0.04.
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 of 7.46 ± 0.97%, the addition of metformin maintained similar glycemic control (HbA1c 7.15 ± 0.61 versus 6.97 ± 0.62 for metformin 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 plus insulin and placebo plus insulin, p
Glumetza () How Supplied/storage And Handling
Glumetza () tablets - 500 mg are available as blue, film coated, oval-shaped tablets debossed with “GMZ” on one side and “500” on the other side.
Glumetza () tablets 1000 mg are available as white, film coated, oval-shaped tablets with “M1000” on one side.
They are supplied as follows:
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F); see [USP Controlled Room Temperature].
Glumetza () Patient Counseling Information
See FDA-Approved Patient Labeling.
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