Metformin Hydrochloride Extended Release

METFORMIN HYDROCHLORIDE EXTENDED RELEASE- metformin hydrochloride tablet, extended release
Major Pharmaceuticals

DESCRIPTION

Metformin Hydrochloride Tablets, USP and 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-structure

Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C4 H11 N5 •HCI 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.

Each Metformin Hydrochloride Tablet, USP for oral administration, contains 500 mg, 850 mg or 1000 mg of metformin hydrochloride. In addition, each film-coated tablet also contains the following inactive ingredients: methylcellulose, microcrystalline cellulose, polyethylene glycol, colloidal silicon dioxide, magnesium stearate, hypromellose, hydroxypropyl cellulose and titanium dioxide.

Each 500 mg Metformin Hydrochloride Extended-Release Tablet, USP for oral administration, contains 500 mg of metformin hydrochloride. In addition, each 500 mg tablet contains the following inactive ingredients: colloidal silicon dioxide, hypromellose, magnesium stearate and methylcellulose.

Each 750 mg Metformin Hydrochloride Extended-Release Tablet, USP for oral administration, contains 750 mg of metformin hydrochloride. In addition, each 750 mg tablet contains the following inactive ingredients: colloidal silicon dioxide, hypromellose and magnesium stearate.

Metformin Extended-Release Tablets, USP meet USP Dissolution Test 6.

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

The absolute bioavailability of a metformin hydrochloride 500 mg tablet given under fasting conditions is approximately 50-60%. Studies using single oral doses of metformin hydrochloride tablets 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.

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 tablets 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 mcg/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 tablets 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 tablets, metformin did not accumulate in plasma.

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

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.

Distribution

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 mcg/mL. During controlled clinical trials of metformin hydrochloride tablets, maximum metformin plasma levels did not exceed 5 mcg/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 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 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 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 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 Hydrochloride Tablets
Subject Groups: Metformin Hydrochloride Tablets dosea (number of subjects) Cmax b (µg/mL) Tmax c (hrs) Renal Clearance (mL/min)
All doses given fasting except the first 18 doses of the multiple dose studies
Peak plasma concentration
Time to peak plasma concentration
Combined results (average means) of five studies: mean age 32 years (range 23-59 years)
Kinetic study done following dose 19, given fasting
Elderly subjects, mean age 71 years (range 65-81 years)
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 dose Mild (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)

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2020. All Rights Reserved.