Metformin Hydrochloride

METFORMIN HYDROCHLORIDE- metformin hydrochloride tablet
Contract Pharmacy Services-PA

DESCRIPTION

Metformin Hydrochloride 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:

5fec0b40-figure-01

Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C 4 H 11 N 5 • 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 tablets , USP contains 500 mg, 850 mg, or 1000 mg of Metformin hydrochloride. Each tablet contains the inactive ingredients povidone (K-30), povidone (K-90), pregelatinized starch, and magnesium stearate. In addition, the coating for the tablets contains artificial blackberry flavor, hypromellose, macrogol and titanium dioxide.

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% to 60%. Studies using single oral doses of metformin hydrochloride tablets 500 to 1500 mg, and 850 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 (C max ), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (T max ) 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.

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 µg/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.

Renal Insufficiency

In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased (see Table 1 ; also see CONTRAINDICATIONS , WARNINGS , PRECAUTIONS and DOSAGE AND ADMINISTRATION ).

Hepatic Impairment

No pharmacokinetic 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 C max 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 ).

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) C max b (mcg/mL) T max 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 doses e (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 to 90 mL/min) (5) 1.86 (±0.52) 3.20 (±0.45) 384 (±122)
Moderate (CL cr 31 to 60 mL/min) (4) 4.12 (±1.83) 3.75 (±0.50) 108 (±57)
Severe (CL cr 10 to 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 to 59 years)

e Kinetic study done following dose 19, given fasting

f Elderly subjects, mean age 71 years (range 65 to 81 years)

g CL cr = creatinine clearance normalized to body surface area of 1.73 m 2

Pediatrics

After administration of a single oral metformin hydrochloride 500 mg tablet with food, geometric mean metformin C max 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 hydrochloride tablets 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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