METFORMIN HYDROCHLORIDE- metformin hydrochloride tablet, film coated
Dr. Reddy’s Laboratories Limited
Metformin hydrochloride tablets 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, USP is a white crystalline compound with a molecular formula of C4 H11 N5 • HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water, slightly soluble in alcohol and is practically insoluble in acetone, and methylene chloride. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.
Metformin hydrochloride tablets, for oral administration contains, 500 mg, 850 mg, or 1000 mg of metformin hydrochloride. Each tablet contains the inactive ingredients povidone and magnesium stearate. In addition, the coating for the 500 mg, 850 mg and 1000 mg tablets contains hypromellose, titanium dioxide and macrogol.
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.
The absolute bioavailability of a metformin hydrochloride 500 mg tablet given under fasting conditions is approximately 50 to 60%. Studies using single oral doses of metformin hydrochloride 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (Cmax ), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (Tmax ) following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.
The apparent volume of distribution (V/F) of metformin following single oral doses of metformin hydrochloride tablets 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 µg/mL. During controlled clinical trials of metformin hydrochloride tablets, maximum metformin plasma levels did not exceed 5 µg/mL, even at maximum doses.
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.
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.
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 WARNINGS).
No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency.
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). Metformin hydrochloride 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).
|Subject Groups: Metformin hydrochloride tablets dose * (number of subjects)||Cmax †(µg/mL)||Tmax ‡(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)§||1.60 (±0.38)||2.64 (±0.82)||552 (±139)|
|850 mg three times daily for 19 doses ¶ (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 doses ¶ (9)||1.90 (±0.62)||2.01 (±1.22)||550 (±160)|
|Elderly # ,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 (CLcr Þ 61-90 mL/min) (5)||1.86 (±0.52)||3.20 (±0.45)||384 (±122)|
|Moderate (CLcr 31-60 mL/min) (4)||4.12 (±1.83)||3.75 (±0.50)||108 (±57)|
|Severe (CLcr 10-30 mL/min) (6)||3.93 (±0.92)||4.01 (±1.10)||130 (±90)|
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