Metformin Hydrochloride

METFORMIN HYDROCHLORIDE- metformin hydrochloride tablet, extended release
Actavis Elizabeth LLC

DESCRIPTION

Metformin hydrochloride extended-release tablets, USP are an oral antihyperglycemic drug 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:

Image from Drug Label Content

Metformin hydrochloride, USP is a white to off-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 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 750 mg of metformin hydrochloride as the active ingredient. Each tablet contains the following inactive ingredients: hypromellose, iron oxide red, iron oxide yellow, magnesium stearate, polydextrose, polyethylene glycol, povidone, titanium dioxide, and triacetin.

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 hours 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 Cmax are less than dose proportional for metformin hydrochloride extended-release within the range of 500 mg 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. The extent of metformin absorption (as measured by AUC) from metformin hydrochloride extended-release 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, metformin did not accumulate in plasma.

Within-subject variability in Cmax and AUC of metformin from metformin hydrochloride extended-release is comparable to that with metformin hydrochloride tablets.

Although the extent of metformin absorption (as measured by AUC) from the metformin hydrochloride extended-release tablet 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.

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 24-48 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.

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.

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 (see Table 1), nor is there any accumulation of metformin in either group at usual clinical doses.

The pharmacokinetics of metformin hydrochloride extended-release 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 s prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (see Table 1; also see WARNINGS).

Hepatic Insufficiency: No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency.

Geriatrics: Limited data from controlled pharmacokinetic studies of metformin 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 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
Subject Groups:Metformin HClDosea (number of subjects) Cmax b (µg/mL) Tmax c (hrs) Renal Clearance(mL/min)
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 yrs)
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 m2
Healthy, nondiabetic adults: 500 mg single dose (24)850 mg single dose (74)d 850 mg three times daily for 19 dosese (9) 1.03 (±0.33)1.60 (±0.38)2.01 (±0.42) 2.75 (±0.81)2.64 (±0.82)1.79 (±0.94) 600 (±132)552 (±139)642 (±173)
Adults with type 2 diabetes: 850 mg single dose (23)850 mg three times daily for 19 dosese (9) 1.48 (±0.5)1.90 (±0.62) 3.32 (±1.08)2.01 (±1.22) 491 (±138)550 (±160)
Elderlyf , healthy nondiabetic adults: 850 mg single dose (12) 2.45 (±0.70) 2.71 (±1.05) 412 (±98)
Renal-impaired adults:850 mg single doseMild(CLcr g 61-90 mL/min) (5)Moderate(CLcr 31-60 mL/min) (4)Severe(CLcr 10-30 mL/min) (6) 1.86 (±0.52)4.12 (±1.83)3.93 (±0.92) 3.20 (±0.45)3.75 (±0.50)4.01 (±1.10) 384 (±122)108 (±57)130 (±90)

Pediatrics:After administration of a single oral metformin hydrochloride 500 mg tablet with food, geometric mean metformin Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight- matched healthy adults (20 to 45 years of age), all with normal renal function.

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). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin hydrochloride tablets was comparable in males and females.

Race:No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n = 249), blacks (n = 51), and Hispanics

(n = 24).

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