Metformin hydrochloride Extended release
Extended release, Film coated, oral, Tablets: 500 mg and 750 mg,
Indication & Usage
Gly-Once (Metformin hydrochloride extended-release tablets), as monotherapy, are indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes.
Gly-Once may be used concomitantly with a sulfonylurea or insulin to improve glycemic control.
Dosage & Administration
There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with Gly-Once or any other pharmacologic agent. Dosage of Gly-Once must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily dose of 2000 mg for Gly-Once.
Gly-Once should generally be given once daily with the evening meal. Gly-Once 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 Gly-Once 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 Gly-Once, 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 Gly-Once may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone.
Recommended Dosing Schedule
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 Gly-Once (metformin hydrochloride extended- release tablets) 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 Gly-Once 2000 mg once daily, a trial of Gly-Once 1000 mg twice daily should be considered. If higher doses of are required, Metformin should be used at total daily doses up to 2550 mg administered in divided daily doses, as described above.
In a randomized trial, patients currently treated with Metformin were switched to Gly-Once. Results of this trial suggest that patients receiving Metformin treatment may be safely switched to Gly-Once, once daily at the same total daily dose, up to 2000 mg once daily. Following a switch from Metformin to Gly-Once, glycemic control should be closely monitored and dosage adjustments made accordingly.
In worldwide clinical trials over 900 patients with type 2 diabetes have been treated with Metformin XR in placebo- and active-controlled studies. In placebo-controlled trials, 781 patients were administered Metformin XR and 195 patients received placebo. Adverse reactions reported in greater than 5% of the Metformin XR patients, and that were more common in Metformin XR- than placebo-treated patients, are listed in Table 1.
Table 1. Most Common Adverse Reactions (>5.0%) in Placebo-Controlled Studies of Metformin XR*
Metformin XR n=781
% of Patients
* Reactions that were more common in Metformin XR- than placebo-treated patients.
Diarrhea led to discontinuation of study medication in 0.6% of patients treated with Metformin XR. Additionally, the following adverse reactions were reported in 1.0% - 5.0% of Metformin XR patients and were more commonly reported with Metformin XR than placebo: abdominal pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance.
Gly-Once 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
- Congestive heart failure requiring pharmacologic treatment.
- Known hypersensitivity to hydrochloride.
- Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.
Gly-Once 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.
Glyburide---In a single-dose interaction study in type 2 diabetes patients, co-administration of and glyburide did not result in any changes in either 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.
Furosemide---A single-dose, -furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. Furosemide increased the plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in renal clearance. When administered with, 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 and furosemide when co- administered chronically.
Nifedipine---A single-dose, -nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma 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. 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 by competing for common renal tubular transport systems. Such interaction between and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, -cimetidine drug interaction studies, with a 60% increase in peak plasma and whole blood concentrations and a 40% increase in plasma and whole blood AUC. There was no change in elimination half-life in the single-dose study. Had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of Metformin or Gly-Once 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 or Gly-Once, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving Metformin or Gly-Once, the patient should be observed closely for hypoglycemia.
In healthy volunteers, the pharmacokinetics of and propranolol, and ibuprofen were not affected when co-administered in single-dose interaction studies.
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.
Warning & Precaution
Monitoring of renal function— is known to be substantially excreted by the kidney, and the risk of 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 Gly-Once. In patients with advanced age, Gly-Once 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, Gly-Once should not be titrated to the maximum dose.
Before initiation of or Gly-Once 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 Gly-Once discontinued if evidence of renal impairment is present.
Use of concomitant medications that may affect renal function or disposition—Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of , such as cationic drugs that are eliminated by renal tubular secretion, 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. Therefore, in patients in whom any such study is planned, Gly-Once 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 Gly-Once therapy, the drug should be promptly discontinued.
Surgical procedures— Gly-Once 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 on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving Gly-Once.
Impaired hepatic function—Since impaired hepatic function has been associated with some cases of lactic acidosis, Gly-Once should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.
Vitamin B12 levels—In controlled clinical trials of Metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum Vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of Metformin or Vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on Gly-Once and any apparent abnormalities should be appropriately investigated and managed
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 two- to three-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 Gly-Once 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 levels. If acidosis of either form occurs, Gly-Once must be stopped immediately and other appropriate corrective measures initiated.
Hypoglycemia—Hypoglycemia does not occur in patients receiving Gly-Once 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 Gly-Once and temporarily administer insulin. Gly-Once 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 Gly-Once or sulfonylurea monotherapy, combined therapy with Gly-Once and sulfonylurea may result in a response. Should secondary failure occur with combined Gly-Once /sulfonylurea therapy, it may be necessary to consider therapeutic alternatives including initiation of insulin therapy.
Pregnancy & Lactation
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, Gly-Once should not be used during pregnancy unless clearly needed.
There are no adequate and well-controlled studies in pregnant women with Metformin XR. 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.
Studies in lactating rats show that 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 Gly-Once is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.
Keep out of the reach of children.
Store below 25° and protect from moisture.
Glyonce 500 mg: Carton containing 1 HDPE Bottle of 100 tablets each.
Glyonce 750 mg: Carton containing 1 HDPE Bottle of 60 tablets each.
Marketing Authorization Holder
Marketing Authorization Holder