GLUCOPHAGE (metforminhydrochloride) Tablets GLUCOPHAGE XR(metforminhydrochloride) Extended-Release Tablets

GLUCOPHAGE (metforminhydrochloride) Tablets and GLUCOPHAGE XR (metforminhydrochloride) Extended-Release Tablets are oral antihyperglycemic drugs usedin the management of type 2 diabetes. Metformin hydrochloride (N,N-dimethylimidodicarbonimidicdiamide hydrochloride) is not chemically or pharmacologically related to anyother classes of oral antihyperglycemic agents. The structural formula isas shown:

Metformin hydrochloride is a white to off-white crystallinecompound with a molecular formula of CHN •HCl and a molecular weight of 165.63. Metformin hydrochloride is freely solublein water and is practically insoluble in acetone, ether, and chloroform. ThepK of metformin is 12.4. The pH of a 1% aqueous solutionof metformin hydrochloride is 6.68.

GLUCOPHAGE tabletscontain 500 mg, 850 mg, or 1000 mg of metformin hydrochloride. Each tabletcontains the inactive ingredients povidone and magnesium stearate. In addition,the coating for the 500 mg and 850 mg tablets contains hypromellose and thecoating for the 1000 mg tablet contains hypromellose andpolyethylene glycol.

GLUCOPHAGE XR contains 500 mgor 750 mg of metformin hydrochloride as the active ingredient.

GLUCOPHAGEXR 500 mg tablets contain the inactive ingredients sodium carboxymethyl cellulose,hypromellose, microcrystalline cellulose, and magnesium stearate.

GLUCOPHAGEXR 750 mg tablets contain the inactive ingredients sodium carboxymethyl cellulose,hypromellose, and magnesium stearate.

SystemComponents and Performance–GLUCOPHAGE XR comprises a dual hydrophilicpolymer matrix system. Metformin hydrochloride is combined with a drug releasecontrolling polymer to form an "inner" phase, which is then incorporated asdiscrete particles into an "external" phase of a second polymer. After administration,fluid from the gastrointestinal (GI) tract enters the tablet, causing thepolymers to hydrate and swell. Drug is released slowly from the dosage formby a process of diffusion through the gel matrix that is essentially independentof pH. The hydrated polymer system is not rigid and is expected to be brokenup by normal peristalsis in the GI tract. The biologically inert componentsof the tablet may occasionally remain intact during GI transit and will beeliminated in the feces as a soft, hydrated mass.

Metformin is an antihyperglycemic agentwhich improves glucose tolerance in patients with type 2 diabetes, loweringboth basal and postprandial plasma glucose. Its pharmacologic mechanisms ofaction are different from other classes of oral antihyperglycemic agents.Metformin decreases hepatic glucose production, decreases intestinal absorptionof glucose, and improves insulin sensitivity by increasing peripheral glucoseuptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemiain either patients with type 2 diabetes or normal subjects (except in specialcircumstances, see PRECAUTIONS ) and doesnot cause hyperinsulinemia. With metformin therapy, insulin secretion remainsunchanged while fasting insulin levels and day-long plasma insulin responsemay actually decrease.

The absolute bioavailability of a GLUCOPHAGE500 mg tablet given under fasting conditions is approximately 50% to 60%.Studies using single oral doses of GLUCOPHAGE 500 to 1500 mg,and 850 to 2550 mg, indicate that there is a lack of dose proportionalitywith increasing doses, which is due to decreased absorption rather than analteration in elimination. Food decreases the extent of and slightly delaysthe absorption of metformin, as shown by approximately a 40% lower mean peakplasma concentration (C), a 25% lower area underthe plasma concentration versus time curve (AUC), and a 35-minute prolongationof time to peak plasma concentration (T) followingadministration of a single 850 mg tablet of metformin with food, comparedto the same tablet strength administered fasting. The clinical relevance ofthese decreases is unknown.

Following a single oraldose of GLUCOPHAGE XR, C is achieved with a medianvalue of 7 hours and a range of 4 to 8 hours. Peak plasma levels are approximately20% lower compared to the same dose of GLUCOPHAGE, however, the extent ofabsorption (as measured by AUC) is similar to GLUCOPHAGE.

Atsteady state, the AUC and C are less than dose proportionalfor GLUCOPHAGE XR 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 µg/mL for 500,1000, 1500, and 2000 mg once-daily doses, respectively. The extent of metforminabsorption (as measured by AUC) from GLUCOPHAGE XR at a 2000 mg once-dailydose is similar to the same total daily dose administered as GLUCOPHAGE tablets1000 mg twice daily. After repeated administration of GLUCOPHAGE XR, metformindid not accumulate in plasma.

Within-subject variabilityin C and AUC of metformin from GLUCOPHAGE XR iscomparable to that with GLUCOPHAGE.

Although the extentof metformin absorption (as measured by AUC) from the GLUCOPHAGE XR tabletincreased by approximately 50% when given with food, there was no effect offood on C and T of metformin.Both high and low fat meals had the same effect on the pharmacokinetics ofGLUCOPHAGE XR.

The apparent volume of distribution (V/F) of metformin followingsingle oral doses of GLUCOPHAGE 850 mg averaged 654 ± 358 L. Metformin isnegligibly bound to plasma proteins, in contrast to sulfonylureas, which aremore than 90% protein bound. Metformin partitions into erythrocytes, mostlikely as a function of time. At usual clinical doses and dosing schedulesof GLUCOPHAGE, steady state plasma concentrations of metformin are reachedwithin 24 to 48 hours and are generally <1 µg/mL. During controlled clinicaltrials of GLUCOPHAGE, maximum metformin plasma levels did not exceed 5 µg/mL,even at maximum doses.

Intravenous single-dose studies in normal subjects demonstratethat metformin is excreted unchanged in the urine and does not undergo hepaticmetabolism (no metabolites have been identified in humans) nor biliary excretion.Renal clearance (see Table 1 ) isapproximately 3.5 times greater than creatinine clearance, which indicatesthat tubular secretion is the major route of metformin elimination. Followingoral administration, approximately 90% of the absorbed drug is eliminatedvia the renal route within the first 24 hours, with a plasma elimination half-lifeof approximately 6.2 hours. In blood, the elimination half-life is approximately17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

In the presence of normal renal function, there are no differencesbetween single- or multiple-dose pharmacokinetics of metformin between patientswith type 2 diabetes and normal subjects (see Table1 ), nor is there any accumulation of metformin in either groupat usual clinical doses.

The pharmacokinetics of GLUCOPHAGE XR in patients with type 2 diabetesare comparable to those in healthy normal adults.

In patients with decreased renal function (based on measured creatinineclearance), the plasma and blood half-life of metformin is prolonged and therenal clearance is decreased in proportion to the decrease in creatinine clearance(see Table 1 ; also see WARNINGS ).

No pharmacokinetic studies of metformin have been conducted inpatients with hepatic insufficiency.

Limited data from controlled pharmacokineticstudies of GLUCOPHAGE in healthy elderly subjects suggest that total plasmaclearance of metformin is decreased, the half-life is prolonged, and C isincreased, compared to healthy young subjects. From these data, it appearsthat the change in metformin pharmacokinetics with aging is primarily accountedfor by a change in renal function (see Table 1 ).GLUCOPHAGE (metformin hydrochloride) Tablets and GLUCOPHAGE XR (metforminhydrochloride) Extended-Release Tablets treatment should not be initiatedin patients ≥80 years of age unless measurement of creatinine clearance demonstratesthat renal function is not reduced (see WARNINGS and DOSAGE AND ADMINISTRATION ).

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

Metformin pharmacokinetic parameters did not differ significantlybetween normal subjects and patients with type 2 diabetes when analyzed accordingto gender (males = 19, females = 16). Similarly, in controlled clinical studiesin patients with type 2 diabetes, the antihyperglycemic effect of GLUCOPHAGEwas comparable in males and females.

No studies of metformin pharmacokinetic parameters according torace have been performed. In controlled clinical studies of GLUCOPHAGE inpatients with type 2 diabetes, the antihyperglycemic effect was comparablein whites (n=249), blacks (n=51), and Hispanics (n=24).

In a double-blind, placebo-controlled,multicenter US clinical trial involving obese patients with type 2 diabeteswhose hyperglycemia was not adequately controlled with dietary managementalone (baseline fasting plasma glucose [FPG] of approximately 240 mg/dL),treatment with GLUCOPHAGE (up to 2550 mg/day) for 29 weeks resulted in significantmean net reductions in fasting and postprandial plasma glucose (PPG) and hemoglobinA (HbA) of 59 mg/dL, 83mg/dL, and 1.8%, respectively, compared to the placebo group (see Table 2 ).

A 29-week, double-blind, placebo-controlled study of GLUCOPHAGEand glyburide, alone and in combination, was conducted in obese patients withtype 2 diabetes who had failed to achieve adequate glycemic control whileon maximum doses of glyburide (baseline FPG of approximately 250 mg/dL) (see Table 3 ). Patients randomized to the combinationarm started therapy with GLUCOPHAGE 500 mg and glyburide 20 mg. At the endof each week of the first 4 weeks of the trial, these patients had their dosagesof GLUCOPHAGE increased by 500 mg if they had failed to reachtarget fasting plasma glucose. After week 4, such dosage adjustments weremade monthly, although no patient was allowed to exceed GLUCOPHAGE 2500 mg.Patients in the GLUCOPHAGE only arm (metformin plus placebo) followed thesame titration schedule. At the end of the trial, approximately 70% of thepatients in the combination group were taking GLUCOPHAGE 2000 mg/glyburide20 mg or GLUCOPHAGE 2500 mg/glyburide 20 mg. Patients randomized to continueon glyburide experienced worsening of glycemic control, with mean increasesin FPG, PPG, and HbA of 14 mg/dL, 3 mg/dL,and 0.2%, respectively. In contrast, those randomized to GLUCOPHAGE (up to2500 mg/day) experienced a slight improvement, with meanreductions in FPG, PPG, and HbA of 1 mg/dL, 6 mg/dL,and 0.4%, respectively. The combination of GLUCOPHAGE and glyburide was effectivein reducing FPG, PPG, and HbA levels by 63 mg/dL,65 mg/dL, and 1.7%, respectively. Compared to results of glyburide treatmentalone, the net differences with combination treatment were –77 mg/dL, –68mg/dL, and –1.9%, respectively (see Table 3 ).

The magnitude of the decline in fasting blood glucoseconcentration following the institution of GLUCOPHAGE (metformin hydrochloride)Tablets therapy was proportional to the level of fasting hyperglycemia. Patientswith type 2 diabetes with higher fasting glucose concentrations experiencedgreater declines in plasma glucose and glycosylated hemoglobin.

Inclinical studies, GLUCOPHAGE, alone or in combination with a sulfonylurea,lowered mean fasting serum triglycerides, total cholesterol, and LDL cholesterollevels, and had no adverse effects on other lipid levels (see Table 4 ).

In contrast to sulfonylureas, body weight of individualson GLUCOPHAGE tended to remain stable or even decrease somewhat (see Tables 2 and 3 ).

A24-week, double-blind, placebo-controlled study of GLUCOPHAGE plus insulinversus insulin plus placebo was conducted in patients with type 2 diabeteswho failed to achieve adequate glycemic control on insulin alone (see Table 5 ). Patients randomized to receive GLUCOPHAGEplus insulin achieved a reduction in HbA of 2.10%,compared to a 1.56% reduction in HbA achieved byinsulin plus placebo. The improvement in glycemic control was achieved atthe final study visit with 16% less insulin, 93.0 U/day vs 110.6 U/day, GLUCOPHAGEplus insulin versus insulin plus placebo, respectively, p=0.04.

A second double-blind, placebo-controlled study (n=51),with 16 weeks of randomized treatment, demonstrated that in patients withtype 2 diabetes controlled on insulin for 8 weeks with an average HbA of7.46 ± 0.97%, the addition of GLUCOPHAGE maintained similar glycemic control(HbA 7.15 ± 0.61 vs 6.97 ± 0.62 for GLUCOPHAGE plusinsulin and placebo plus insulin, respectively) with 19% less insulin versusbaseline (reduction of 23.68 ± 30.22 vs an increase of 0.43 ± 25.20 unitsfor GLUCOPHAGE plus insulin and placebo plus insulin, p<0.01). In addition,this study demonstrated that the combination of GLUCOPHAGE plus insulin resultedin reduction in body weight of 3.11 ± 4.30 lbs, compared to an increase of1.30 ± 6.08 lbs for placebo plus insulin, p=0.01.

A 24-week, double-blind, placebo-controlledstudy of GLUCOPHAGE XR, taken once daily with the evening meal, was conductedin patients with type 2 diabetes who had failed to achieve glycemic controlwith diet and exercise (HbA 7.0%-10.0%, FPG 126-270mg/dL). Patients entering the study had a mean baseline HbA of8.0% and a mean baseline FPG of 176 mg/dL. After 12 weeks treatment, meanHbA had increased from baseline by 0.1% and meanFPG decreased from baseline by 2 mg/dL in the placebo group, compared witha decrease in mean HbA of 0.6% and a decrease inmean FPG of 23 mg/dL in patients treated with GLUCOPHAGE XR 1000 mg once daily.Subsequently, the treatment dose was increased to 1500 mg once daily if HbA was≥7.0% but <8.0% (patients with HbA ≥8.0% werediscontinued from the study). At the final visit (24-week), mean HbA hadincreased 0.2% from baseline in placebo patients and decreased 0.6% with GLUCOPHAGEXR.

A 16-week, double-blind, placebo-controlled, dose-responsestudy of GLUCOPHAGE XR, taken once daily with the evening meal or twice dailywith meals, was conducted in patients with type 2 diabetes who had failedto achieve glycemic control with diet and exercise (HbA 7.0%-11.0%,FPG 126-280 mg/dL). Changes in glycemic control and body weight are shownin Table 6 .

Compared with placebo, improvement in glycemic controlwas seen at all dose levels of GLUCOPHAGE XR (metformin hydrochloride) Extended-ReleaseTablets and treatment was not associated with any significant change in weight(see DOSAGE AND ADMINISTRATION for dosingrecommendations for GLUCOPHAGE and GLUCOPHAGE XR).

A24-week, double-blind, randomized study of GLUCOPHAGE XR, taken once dailywith the evening meal, and GLUCOPHAGE (metformin hydrochloride) Tablets, takentwice daily (with breakfast and evening meal), was conducted in patients withtype 2 diabetes who had been treated with GLUCOPHAGE 500 mg twice daily forat least 8 weeks prior to study entry. The GLUCOPHAGE dose had not necessarilybeen titrated to achieve a specific level of glycemic control prior to studyentry. Patients qualified for the study if HbA was≤8.5% and FPG was ≤200 mg/dL. Changes in glycemic control and body weightare shown in Table 7 .

After 12 weeks of treatment, there was anincrease in mean HbA in all groups; in the GLUCOPHAGEXR 1000 mg group, the increase from baseline of 0.23% was statistically significant(see DOSAGE AND ADMINISTRATION ).

Changesin lipid parameters in the previously described placebo-controlled dose-responsestudy of GLUCOPHAGE XR are shown in Table 8 .

Changes in lipid parameters in the previously describedstudy of GLUCOPHAGE and GLUCOPHAGE XR are shown in Table9 .