METFORMIN HYDROCHLORIDE

METFORMIN HYDROCHLORIDE- metformin hydrochloride tablet, extended release
H. J. Harkins Company Inc.

Metformin hydrochloride extended-release 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:

http://medlibrary.org/lib/images-rx/metformin-hydrochloride-83/metformin.jpg

Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C4H11N5• 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 500 mg or 750 mg of metformin hydrochloride USP as the active ingredient.

Metformin hydrochloride extended-release tablets 500 mg contain the inactive ingredients xanthan gum, hypromellose, sodium carbonate, povidone, talc, colloidal silicon dioxide and magnesium stearate.

Metformin hydrochloride extended-release tablets 750 mg contain the inactive ingredients xanthan gum, hypromellose, sodium carbonate, povidone, talc, colloidal silicon dioxide, magnesium stearate and ferric oxide (red).

Metformin hydrochloride extended-release tablets meet USP dissolution test 10.

System Components and Performance-Metformin hydrochloride extended-release tablets comprises a hydrophilic polymer matrix system. Metformin hydrochloride is combined with a drug release controlling polymers to form a monophasic matrix system. 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 tablet, Cmax is achieved with a median value of 7 hours and a range of 4 hours to 8 hours.

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 mg, 1000 mg, 1500 mg, 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 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 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.

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 Impairment

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 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).

Table 1: Select Mean (±S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin Hydrochloride Tablets

Subject Groups: Cmax† Tmax‡ Renel Clearance

Metformin Hydrochloride (mcg/mL) (hrs) (mL/min)

Tablets dose*(number of subjects)

Healthy, nondiabetic adults:

500 mg single dose (24) 1.03 (±0.33) 2.75 (±0.81) 600 (±132)


850 mg single dose(74)§ 1.6 (±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). 1.9 (±0.62). 2.01 (±1.22). 550 (±160)

Elderly#, healthy nondiabetic adults:

850 mg single dose (12) 2.45 (±0.7). 2.71 (±1.05). 412 (±98)

Renal-impaired adults:

850 mg single dose

Mild (CLcrÞ 61 to 90 mL/min) (5) 1.86 (±0.52). 3.2 (±0.45) 384 (±122)

Moderate (CLcr 31 to 60 mL/min) (4) 4.12 (±1.83) 3.75 (±0.5) 108 (±57)

Severe (CLcr 10 to 30 mL/min) (6) 3.93 (±0.92) 4.01 (±1.1). 130 (±90)

*

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 to 59 years)

Kinetic study done following dose 19, given fasting

#

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

Þ

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

Pediatrics

No pharmacokinetic data from studies of pediatric patients are currently available

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).

Clinical Studies

METFORMIN HYDROCHLORIDE EXTENDED-RELEASE TABLETS
A 24-week, double-blind, placebo-controlled study of metformin hydrochloride extended-release tablets, taken once daily with the evening meal, was conducted in patients with type 2 diabetes who had failed to achieve glycemic control with diet and exercise (HbA1c 7% to 10%, FPG 126 to 270 mg/dL). Patients entering the study had a mean baseline HbA1c of 8% and a mean baseline FPG of 176 mg/dL. After 12 weeks treatment, mean HbA1c had increased from baseline by 0.1% and mean FPG decreased from baseline by 2 mg/dL in the placebo group, compared with a decrease in mean HbA1c of 0.6% and a decrease in mean FPG of 23 mg/dL in patients treated with metformin hydrochloride extended-release tablets 1000 mg once daily. Subsequently, the treatment dose was increased to 1500 mg once daily if HbA1c was ≥7% but <8% (patients with HbA1c ≥8% were discontinued from the study). At the final visit (24-week), mean HbA1c had increased 0.2% from baseline in placebo patients and decreased 0.6% with metformin hydrochloride extended-release tablets.
A 16-week, double-blind, placebo-controlled, dose-response study of metformin hydrochloride extended-release tablets, taken once daily with the evening meal or twice daily with meals, was conducted in patients with type 2 diabetes who had failed to achieve glycemic control with diet and exercise (HbA1c 7% to 11%, FPG 126 to 280 mg/dL). Changes in glycemic control and body weight are shown in Table 2.

Table 2: Summary of Mean Changes from Baseline* in HbA1c, Fasting Plasma Glucose,

and Body Weight at Final Visit (16-week study)

Metformin Hydrochloride Extended-Release Tablet

500mg 1000mg 1500mg 2000mg 1000 mg Placebo
Once Once Once Once Twice
Daily. Daily Daily Daily Daily

Hemoglobin A1c (%) (n=115) (n=115) (n=111) (n=125) (n=112) (n=111)
Baseline 8.2 8.4 8.3 8.4 8.4 8.4
Change at FINAL VISIT -0.4 -0.6 -0.9 -0.8 1.1 0.1
p–value† <0.001 <0.001 <0.001 <0.001 <0.001 —

FPG (mg/dL) (n = 126) (n = 118) (n = 120) (n = 132) (n = 122) (n = 113)

Baseline 182.7 183.7 178.9 181 181.6 179.6
Change at FINAL VISIT 15.2 -19.3 -28.5 -29.9 -33.6 7.6

p–value† <0.001 <0.001 <0.001 <0.001 <0.001 –

Body Weight (lbs) (n = 125) (n = 125) (n = 125) (n = 125) (n = 125) (n-115)

Baseline 192.9 191.8 188.3 195.4 192.5 194.3

Change at FINAL VISIT -1.3 -1.3 -0.7 -1.5 — 2.2 -1.8
p–value† NS‡ NS‡ NS‡ NS‡ NS‡

*

All patients on diet therapy at Baseline

All comparisons versus Placebo

Not statistically significant

Compared with placebo, improvement in glycemic control was seen at all dose levels of metformin hydrochloride extended-release tablets and treatment was not associated with any significant change in weight (see DOSAGE AND ADMINISTRATION for dosing recommendations for metformin hydrochloride extended-release tablets).
A 24-week, double-blind, randomized study of metformin hydrochloride extended-release tablets, taken once daily with the evening meal, and metformin hydrochloride tablets, taken twice daily (with breakfast and evening meal), was conducted in patients with type 2 diabetes who had been treated with metformin hydrochloride tablets, 500 mg twice daily for at least 8 weeks prior to study entry. The metformin hydrochloride tablets dose had not necessarily been titrated to achieve a specific level of glycemic control prior to study entry. Patients qualified for the study if HbA1c was ≤8.5% and FPG was ≤200 mg/dL. Changes in glycemic control and body weight are shown in Table 3.


Table 3: Summary of Mean Changes from Baseline in HbA1c, Fasting Plasma Glucose, and Body Weight at Week 12 and at Final Visit (24-week study) Metformin Hydrochloride Extended-Release Tablets

1000 mg 1500mg
Once Daily Once Daily

Hemoglobin A1c (%) (n = 72) (n = 66)

Baseline 6.99 7.02

Change at 12 Weeks 0.23 0.04

(95% CI) (0.1, 0.36) (-0.08, 0.15)

Change at FINAL VISIT 0.27 0.13

(95% CI) (0.11, 0.43) (-0.02, 0.28)

FPG (mg/dL) (n = 72) (n = 70)

Baseline 131 131.4

Change at 12 Weeks 9.5 3.7

(95% CI) (4.4, 14.6) (-0.4, 7.8)

Change at FINAL VISIT 11.5 7.6

(95% CI) (4.4, 18.6) (1, 14.2)

Body Weight (lbs) (n = 74) (n = 71)

Baseline 202.8 192.7

Change at 12 Weeks 0.9 0.7

(95% CI) (0, 2) (-0.4, 1.8)

Change at FINAL VISIT 1.1 0.9

(95% CI) (-0.2, 2.4) (-0.4, 2)

After 12 weeks of treatment, there was an increase in mean HbA1c in all groups; in the metformin hydrochloride extended-release tablets 1000 mg group, the increase from baseline of 0.23% was statistically significant (see DOSAGE AND ADMINISTRATION).
Changes in lipid parameters in the previously described placebo-controlled dose-response study of metformin hydrochloride extended-release tablets are shown in Table 4.

Table 4: Summary of Mean Percent Changes from Baseline* in Major Lipid Variables at Final Visit (16-week study) Metformin Hydrochloride Extended-Release Tablets

500 mg. 1000mg 1500mg 2000mg 1000mg Placebo
Once Once Once Once Twice Once
Daily. Daily Daily Daily Daily Daily

1

Total Cholesterol (n =120) (n =113) (n = 110) (n = 126) (n=117) (n=110)
(mg/dl) 210.3 218.1 214.6 204.4 208.2 208.6

Baseline 1% 1.7% 0.7% -1.6% -2.6% -2.6%
Mean % Change at FINAL VISIT

Total Triglycerides (n =120) (n =113) (n = 110) (n = 126) (n=117) (n=110)

(mg/dL) 220.2 211.9 198 194.2 179 211.7

Baseline 14.5% 9.4% 15.1% 14.9% 9.4% 10.9%

Mean % Change at FINAL VISIT

LDL–Cholesterol (n =119) (n =113) (n = 109) (n = 126) (n=117) (n=107)

(mg/dL) 131 134.9 135.8 125.8 131.4 131.9

Baseline -1.4% -1.6% -3.5% -3.3% -5.5% 3.2%

Mean % Change at FINAL VISIT

HDL–Cholesterol (n =120) (n =108) (n = 108) (n = 125) (n=117) (n=108)

(mg/dL) 40.8 41.6 40.6 40.2 42.4 39.4

Baseline 6.2% 8.6% 5.5% 6.1% 7.1% 5.8%

Mean % Change at FINAL VISIT

Changes in lipid parameters in the previously described study of metformin hydrochloride extended-release tablets are shown in Table 5.


Table 5: Summary of Mean Percent Changes from Baseline in Major Lipid Variables at Final Visit (24-week study)

Metformin Hydrochloride Extended-Release Tablets

1000 mg 1500mg
Once Daily Once Daily

Total Cholesterol (n = 70) (n = 66)

(mg/dL) 201.9 201.6
Baseline 1.3% 0.1%
Mean % Change at FINAL VISIT

Total Triglycerides (n = 70) (n = 66)

(mg/dL) 169.2 206.8

Baseline 25.3% 33.4%

Mean % Change at FINAL VISIT

LDL–Cholesterol (n = 70) (n = 66)

(mg/dL) 126.2 115.7

Baseline -3.3% -3.7%

Mean % Change at FINAL VISIT

HDL–Cholesterol (n = 70) (n = 65)

(mg/dL) 41.7 44.6

Baseline 1% -2.1%

Mean % Change at FINAL VISIT

Table 5: Summary of Mean Percent Changes from Baseline in Major Lipid Variables at Final Visit (24-week study)

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