Metformin

METFORMIN- metformin hydrochloride tablet
Aphena Pharma Solutions — Tennessee, LLC

DESCRIPTION

Metformin Hydrochloride Extended-Release Tablets, USP

Metformin hydrochloride extended-release tablets, USP are oral antihyperglycemic drugs used in the management of type 2 diabetes. Metformin hydrochloride, USP (N,N-dimethyl-monohydrochloride,Imidodicarbonimidic diamide) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. The structural formula is as shown:

metformin
(click image for full-size original)

Metformin hydrochloride, USP is a white or almost white, crystalline powder with a molecular formula of C4H11N5•HCl and a molecular weight of 165.62. Metformin hydrochloride is freely soluble in water, slightly soluble in alcohol, practically insoluble in acetone and in Methylene chloride. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.35.
Metformin hydrochloride extended-release tablets, USP contain 500 mg or 750 mg of metformin hydrochloride as the active ingredient.
Metformin hydrochloride extended-release tablets, USP 500 mg and 750 mg tablets contain the inactive ingredients hypromellose, magnesium stearate, and polyvinyl pyrrolidone.
Dissolution Method: Test 10
System Components and Performance — Metformin hydrochloride extended-release tablets, USP comprises a dual hydrophilic polymer matrix system. Metformin hydrochloride, USP is combined with a drug release controlling polymer to form an “inner” phase, which is then incorporated as discrete particles into an “external” phase of a second polymer. After administration, fluid from the gastrointestinal (GI) tract enters the tablet, causing the polymers to hydrate and swell. Drug is released slowly from the dosage form by a process of diffusion through the gel matrix that is essentially independent of pH. The hydrated polymer system is not rigid and is expected to be broken up by normal peristalsis in the GI tract. The biologically inert components of the tablet may occasionally remain intact during GI transit and will be eliminated in the feces as a soft, hydrated mass.

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, C max is achieved with a median value of 7 hours and a range of 4 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 C max are less than dose proportional for metformin hydrochloride extended-release tablets within the range of 500 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 C max 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 C max and T max 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 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.

Specific Population

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 is comparable to those in healthy normal adults.

Renal Impairment

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 also see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).

Hepatic Impairment

No parmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency (see PRECAUTIONS).

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; also see WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION). Metformin hydrochloride extended-release 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).

Table 1: Select Mean ( ± S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin Hydrochloride Tablets
Subject Groups: Metformin Hydrochloride Tablet dose a (number of subjects) Cmax b (mcg/mL) Tmax c (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)d 1.60 (±0.38) 2.64 (±0.82) 552 (±139)
850 mg three times daily for 19 doses e (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 dosese (9) 1.90 (±0.62) 2.01 (±1.22) 550 (±160)
Elderly f , 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 (CL cr g 61-90 mL/min) (5) 1.86 (±0.52) 3.20 (±0.45) 384 (±122)
Moderate (CL cr 31-60 mL/min) (4) 4.12 (±1.83) 3.75 (±0.50) 108 (±57)
Severe (CL cr 10-30 mL/min) (6) 3.93 (±0.92) 4.01 (±1.10) 130 (±90)

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 years)

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 m 2

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). Race

No studies of metformin pharmacokinetic parameters according to race have been performed.

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