 XR
`GLUCOPHAGE® /GLUCOPHAGE
`Response to FDA Comments of 10 12 00.doc – CLEAN DRAFT 10 13 00
`
`Page 1 of 29
`
`Rx only
`
`GLUCOPHAGE
` (metformin hydrochloride tablets)
`GLUCOPHAGE XR (metformin hydrochloride
`extended-release tablets)
`
`DESCRIPTION
`GLUCOPHAGE®
`XR
`tablets) and GLUCOPHAGE
`(metformin hydrochloride
`(metformin hydrochloride extended-release tablets) are oral antihyperglycemic drugs used
`(N,N-
`in
`the management of
`type 2 diabetes. Metformin hydrochloride
`dimethylimidodicarbonimidic
`diamide
`hydrochloride)
`is
`not
`chemically
`or
`pharmacologically related to any other classes of oral antihyperglycemic agents. The
`structural formula is as shown:
`
`
`
` Metformin hydrochloride is a white to off-white crystalline compound with a
`molecular formula of C4H11N5 (cid:127) 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.
` GLUCOPHAGE tablets contain 500 mg, 850 mg, or 1000 mg of metformin
`hydrochloride. Each tablet contains the inactive ingredients povidone and magnesium
`stearate. In addition, the coating for the 500-mg and 850-mg tablets contains
`hydroxypropyl methylcellulose (hypromellose) and the coating for the 1000-mg tablet
`contains hydroxypropyl methylcellulose and polyethylene glycol.
` GLUCOPHAGE XR (metformin hydrochloride extended-release tablets) contains 500
`mg of metformin hydrochloride as the active ingredient. Each tablet contains the inactive
`ingredients
`sodium
`carboxymethyl
`cellulose,
`hydroxypropyl methylcellulose,
`microcrystalline cellulose, and magnesium stearate.
`System Components and Performance. GLUCOPHAGE XR
`(metformin
`hydrochloride extended-release tablets) comprises a dual hydrophilic polymer matrix
`system. Metformin hydrochloride is combined with a drug release controlling polymer to
`form an "inner" phase, which is then incorporated as discrete particles into an "external"
`
`AUROBINDO EX1012, 1
`
`

`

` XR
`GLUCOPHAGE® /GLUCOPHAGE
`Response to FDA Comments of 10 12 00.doc – CLEAN DRAFT 10 13 00
`
`Page 2 of 29
`
`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
`The absolute bioavailability of a GLUCOPHAGE 500-mg tablet given under fasting
`conditions is approximately 50-60%. Studies using single oral doses of GLUCOPHAGE
`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 GLUCOPHAGE XR, 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 GLUCOPHAGE, however, the extent of
`absorption (as measured by AUC) is similar to GLUCOPHAGE.
`less
`than dose proportional for
`the AUC and Cmax are
` At steady state,
`GLUCOPHAGE XR 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 µg/mL for 500, 1000, 1500,
`and 2000 mg once-daily doses, respectively. The extent of metformin absorption (as
`measured by AUC) from GLUCOPHAGE XR at a 2000 mg once-daily dose is similar to
`the same total daily dose administered as GLUCOPHAGE tablets 1000 mg twice daily.
`After repeated administration of GLUCOPHAGE XR, metformin did not accumulate in
`
`AUROBINDO EX1012, 2
`
`

`

` XR
`GLUCOPHAGE® /GLUCOPHAGE
`Response to FDA Comments of 10 12 00.doc – CLEAN DRAFT 10 13 00
`
`Page 3 of 29
`
`plasma.
`Within-subject variability in Cmax and AUC of metformin from GLUCOPHAGE XR
`is comparable to that with GLUCOPHAGE.
` Although the extent of metformin absorption (as measured by AUC) from the
`GLUCOPHAGE XR 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 GLUCOPHAGE XR.
`
`Distribution
`The apparent volume of distribution (V/F) of metformin following single oral doses of
`GLUCOPHAGE 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 GLUCOPHAGE, steady state plasma concentrations of metformin are
`reached within 24-48 hours and are generally <1 (cid:31)g/mL. During controlled clinical trials
`of GLUCOPHAGE, maximum metformin plasma levels did not exceed 5 (cid:31)g/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 GLUCOPHAGE XR 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.
`
`AUROBINDO EX1012, 3
`
`

`

` XR
`GLUCOPHAGE® /GLUCOPHAGE
`Response to FDA Comments of 10 12 00.doc – CLEAN DRAFT 10 13 00
`
`Page 4 of 29
`
`Geriatrics
`Limited data from controlled pharmacokinetic studies of GLUCOPHAGE 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). GLUCOPHAGE and
`GLUCOPHAGE XR 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).
`
`AUROBINDO EX1012, 4
`
`

`

` XR
`GLUCOPHAGE® /GLUCOPHAGE
`Response to FDA Comments of 10 12 00.doc – CLEAN DRAFT 10 13 00
`
`Page 5 of 29
`
`Table 1. Select Mean (±S.D.) Metformin Pharmacokinetic Parameters Following
` Single or Multiple Oral Doses of GLUCOPHAGE
`
`Subject Groups: GLUCOPHAGE
`dosea (number of subjects)
`Healthy, nondiabetic adults:
` 500 mg single dose (24)
` 850 mg single dose (74) d
` 850 mg three times daily for 19
`doses e (9)
`
`Adults with type 2 diabetes:
` 850 mg single dose (23)
` 850 mg three times daily for 19
`doses e (9)
`
`Elderly f, healthy nondiabetic adults:
` 850 mg single dose (12)
`
`b
`Cmax
`((cid:31)g/mL)
`
`c
`Tmax
`(hrs)
`
`Renal Clearance
`(mL/min)
`
`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)
`
`1.48 (±0.5)
` 1.90 (±0.62)
`
`3.32 (±1.08)
`2.01 (±1.22)
`
`491 (±138)
`550 (±160)
`
`2.45 (±0.70)
`
`2.71 (±1.05)
`
`412 (±98)
`
`Renal-impaired adults:
`850 mg single dose
` g 61-90 mL/min) (5)
` Mild (CLcr
` 384 (±122)
`3.20 (±0.45)
`1.86 (±0.52)
` Moderate (CLcr 31-60 mL/min) (4)
`108 (±57)
`3.75 (±0.50)
`4.12 (±1.83)
` Severe (CLcr 10-30 mL/min) (6)
`130 (±90)
`4.01 (±1.10)
`3.93 (±0.92)
`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 m2
`
`Pediatrics
`No pharmacokinetic studies of metformin in pediatric patients have been conducted.
`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 GLUCOPHAGE was comparable in males
`and females.
`Race
`No studies of metformin pharmacokinetic parameters according to race have been
`performed. In controlled clinical studies of GLUCOPHAGE in patients with type 2
`diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51),
`and Hispanics (n=24).
`
`AUROBINDO EX1012, 5
`
`

`

` XR
`GLUCOPHAGE® /GLUCOPHAGE
`Response to FDA Comments of 10 12 00.doc – CLEAN DRAFT 10 13 00
`
`Page 6 of 29
`
`Clinical Studies
`
`GLUCOPHAGE
`
`In a double-blind, placebo-controlled, multicenter U.S. clinical trial involving obese
`patients with type 2 diabetes whose hyperglycemia was not adequately controlled with
`dietary management alone (baseline fasting plasma glucose [FPG] of approximately 240
`mg/dL), treatment with GLUCOPHAGE (up to 2550 mg/day) for 29 weeks resulted in
`significant mean net reductions in fasting and postprandial plasma glucose (PPG) and
`hemoglobin A1c (HbA1c) of 59 mg/dL, 83 mg/dL, and 1.8%, respectively, compared to the
`placebo group (see Table 2).
`
`Table 2. GLUCOPHAGE vs Placebo
` Summary of Mean Changes from Baseline* in Fasting Plasma
`Glucose, HbA1c, and Body Weight, at Final Visit (29-week study)
`
`FPG (mg/dL)
` Baseline
` Change at FINAL VISIT
`
`Hemoglobin A1c (%)
` Baseline
` Change at FINAL VISIT
`
`Body Weight (lbs)
` Baseline
` Change at FINAL VISIT
`
`GLUCOPHAGE
`(n = 141)
`
`Placebo
`(n = 145)
`
`p–Value
`
`241.5
` –53.0
`
`237.7
` 6.3
`
`NS **
` 0.001
`
`8.4
` –1.4
`
`8.2
` 0.4
`
`NS **
` 0.001
`
`201.0
`–1.4
`
`206.0
`–2.4
`
`NS **
`NS **
`
`*All patients on diet therapy at Baseline **Not statistically significant
`
`AUROBINDO EX1012, 6
`
`

`

` XR
`GLUCOPHAGE® /GLUCOPHAGE
`Response to FDA Comments of 10 12 00.doc – CLEAN DRAFT 10 13 00
`
`Page 7 of 29
`
`A 29-week, double-blind, placebo-controlled study of GLUCOPHAGE and glyburide,
`alone and in combination, was conducted in obese patients with type 2 diabetes who had
`failed to achieve adequate glycemic control while on maximum doses of glyburide
`(baseline FPG of approximately 250 mg/dL) (see Table 3). Patients randomized to
`continue on glyburide experienced worsening of glycemic control, with mean increases in
`FPG, PPG, and HbA1c of 14 mg/dL, 3 mg/dL, and 0.2%, respectively. In contrast, those
`randomized to GLUCOPHAGE (up to 2500 mg/day) experienced a slight improvement,
`with mean reductions in FPG, PPG, and HbA1c of 1 mg/dL, 6 mg/dL, and 0.4%,
`respectively. The combination of GLUCOPHAGE and glyburide was effective in
`reducing FPG, PPG, and HbA1c levels by 63 mg/dL, 65 mg/dL, and 1.7%, respectively.
`Compared to results of glyburide treatment alone, the net differences with combination
`treatment were –77 mg/dL, –68 mg/dL, and –1.9%, respectively (see Table 3).
`
`Table 3. Combined GLUCOPHAGE/Glyburide (Comb) vs Glyburide (Glyb)
`or GLUCOPHAGE (GLU) Monotherapy: Summary of Mean Changes from Baseline*
`in Fasting Plasma Glucose, HbA1c, and Body Weight, at Final Visit (29-week study)
` p−−−−values
` Comb Glyb GLU Glyb vs GLU vs GLU vs
` (n = 213) (n = 209) (n = 210) Comb Comb Glyb
`
`Fasting Plasma
` Glucose (mg/dL)
` Baseline
` Change at FINAL VISIT
`
`Hemoglobin A1c (%)
` Baseline
` Change at FINAL VISIT
`
`Body Weight (lbs)
` Baseline
` Change at FINAL VISIT
`
`250.5
` –63.5
`
`247.5
` 13.7
`
`253.9
` –0.9
`
`NS**
` 0.001
`
`NS**
` 0.001
`
`NS**
` 0.025
`
`8.8
` –1.7
`
`8.5
` 0.2
`
`8.9
` –0.4
`
`NS**
` 0.001
`
`NS**
` 0.001
`
`0.007
`0.001
`
`202.2
` 0.9
`
`203.0
` -0.7
`
`204.0
` -8.4
`
`NS**
` 0.011
`
`NS**
` 0.001
`
`NS**
` 0.001
`
` *All patients on glyburide, 20 mg/day, at Baseline **Not statistically significant
`
`The magnitude of the decline in fasting blood glucose concentration following the
`institution of GLUCOPHAGE therapy was proportional to the level of fasting
`hyperglycemia. Patients with type 2 diabetes with higher fasting glucose concentrations
`experienced greater declines in plasma glucose and glycosylated hemoglobin.
` In clinical studies, GLUCOPHAGE, alone or in combination with a sulfonylurea,
`lowered mean fasting serum triglycerides, total cholesterol, and LDL cholesterol levels
`and had no adverse effects on other lipid levels (see Table 4).
`
`AUROBINDO EX1012, 7
`
`

`

` XR
`GLUCOPHAGE® /GLUCOPHAGE
`Response to FDA Comments of 10 12 00.doc – CLEAN DRAFT 10 13 00
`
`Page 8 of 29
`
`Table 4. Summary of Mean Percent Change From Baseline of Major Serum Lipid
`Variables at Final Visit (29-week studies)
`
`GLUCOPHAGE vs Placebo
`
`Combined GLUCOPHAGE/Glyburide
`vs Monotherapy
`
`GLUCOPHAGE
`(n = 141)
`
`Placebo
`(n = 145)
`
`GLUCOPHAGE
`(n = 210)
`
`GLUCOPHAGE/
`Glyburide
`(n = 213)
`
`Glyburide
`(n = 209)
`
`Total
`Cholesterol
`(mg/dL)
` Baseline
` Mean %
`Change at
`FINAL
`VISIT
`
`Total
`Triglycerides
`(mg/dL)
` Baseline
`Mean %
`Change at
`FINAL
`VISIT
`
`LDL-
`Cholesterol
`(mg/dL)
` Baseline
` Mean %
`Change at
`FINAL
`VISIT
`HDL-
`Cholesterol
`(mg/dL)
` Baseline
` Mean %
`Change at
`FINAL
`VISIT
`
`211.0
`
`-5%
`
`236.1
`
`-16%
`
`135.4
`
`-8%
`
`39.0
`
`2%
`
`212.3
`
`1%
`
`203.5
`
`1%
`
`138.5
`
`1%
`
`40.5
`
`-1%
`
`213.1
`
`-2%
`
`242.5
`
` -3%
`
`134.3
`
`-4%
`
`37.2
`
`5%
`
`215.6
`
`-4%
`
`215.0
`
`-8%
`
`136.0
`
`-6%
`
`39.0
`
`3%
`
`219.6
`
`1%
`
`266.1
`
`4%
`
`137.5
`
`3%
`
`37.0
`
`1%
`
`AUROBINDO EX1012, 8
`
`

`

` XR
`GLUCOPHAGE® /GLUCOPHAGE
`Response to FDA Comments of 10 12 00.doc – CLEAN DRAFT 10 13 00
`
`Page 9 of 29
`
`In contrast to sulfonylureas, body weight of individuals on GLUCOPHAGE tended to
`remain stable or even decrease somewhat (see Tables 2 and 3).
` A 24-week, double-blind, placebo-controlled study of GLUCOPHAGE plus insulin
`versus insulin plus placebo was conducted in patients with type 2 diabetes who failed to
`achieve adequate glycemic control on insulin alone (see Table 5). Patients randomized to
`receive GLUCOPHAGE plus insulin achieved a reduction in HbA1c of 2.10%, compared
`to a 1.56% reduction in HbA1c achieved by insulin plus placebo. The improvement in
`glycemic control was achieved at the final study visit with 16% less insulin, 93.0 U/day vs
`110.6 U/day, GLUCOPHAGE plus insulin versus insulin plus placebo, respectively,
`p=0.04.
`
`Table 5. Combined GLUCOPHAGE/Insulin vs Placebo/Insulin
`Summary of Mean Changes from Baseline in HbA1c and Daily Insulin Dose
`Treatment
`Difference
`Mean + SE
`
`GLUCOPHAGE/
`Insulin
`n = 26
`
`Placebo/
`Insulin
`n = 28
`
`Hemoglobin A1c (%)
` Baseline
` Change at FINAL VISIT
`
`Insulin Dose (U/day)
` Baseline
` Change at FINAL VISIT
`
`8.95
` - 2.10
`
` 9.32
` - 1.56
`
`0.54 + 0.43a
`
`93.12
` - 0.15
`
`94.64
`15.93
`
`- 16.08 + 7.77b
`
`a Statistically significant using analysis of covariance with baseline as covariate (p=0.04)
`Not significant using analysis of variance (values shown in table)
`b Statistically significant for insulin (p=0.04)
`
`A second double-blind, placebo-controlled study (n=51), with 16 weeks of
`randomized treatment, demonstrated that in patients with type 2 diabetes controlled on
`insulin for 8 weeks with an average HbA1c of 7.46 + 0.97%, the addition of
`GLUCOPHAGE maintained similar glycemic control (HbA1c 7.15 + 0.61 versus 6.97 +
`0.62 for GLUCOPHAGE plus insulin and placebo plus insulin, respectively) with 19%
`less insulin versus baseline (reduction of 23.68 + 30.22 versus an increase of 0.43 + 25.20
`units for GLUCOPHAGE plus insulin and placebo plus insulin, p<0.01). In addition, this
`study demonstrated that the combination of GLUCOPHAGE plus insulin resulted in
`reduction in body weight of 3.11 + 4.30 lbs, compared to an increase of 1.30 + 6.08 lbs for
`placebo plus insulin, p=0.01.
`
`AUROBINDO EX1012, 9
`
`

`

` XR
`GLUCOPHAGE® /GLUCOPHAGE
`Response to FDA Comments of 10 12 00.doc – CLEAN DRAFT 10 13 00
`
`Page 10 of 29
`
`GLUCOPHAGE XR
`A 24-week, double-blind, placebo-controlled study of GLUCOPHAGE XR, 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 7.0-10.0%, FPG 126-
`270 mg/dL). Patients entering the study had a mean baseline HbA1c of 8.0% 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 GLUCOPHAGE XR 1000 mg once daily.
`Subsequently, the treatment dose was increased to 1500 mg once daily if HbA1c was
`≥7.0% but <8.0% (patients with HbA1c ≥8.0% 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 GLUCOPHAGE XR.
`A 16-week, double-blind, placebo-controlled, dose-response study of GLUCOPHAGE
`XR, 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 7.0-11.0%, FPG 126-280 mg/dL). Changes in glycemic control and body
`weight are shown in Table 6.
`
`Table 6. Summary of Mean Changes from Baseline* in HbA1c,
`Fasting Plasma Glucose, and Body Weight at Final Visit (16-week study)
`GLUCOPHAGE XR
`1000mg
`1500mg
` 2000mg 1000mg
`Once
`Once
` Once Twice
`Daily
`Daily
`Daily Daily
`(n = 115)
`(n = 111)
`(n = 125)
`(n=112)
`8.4
`8.3
`8.4
`8.4
`-0.6
`-0.9
`-1.1
`-0.8
`<0.001
`<0.001
`<0.001
`<0.001
`
`500mg
`Once
`Daily
`(n = 115)
`8.2
`-0.4
`<0.001
`
`Hemoglobin A1C (%)
` Baseline
` Change at FINAL VISIT
` p – valuea
`
`FPG (mg/dL)
` Baseline
` Change at FINAL VISIT
` p – valuea
`
`Body Weight (lbs)
` Baseline
` Change at FINAL VISIT
` p – valuea
`
`(n = 126)
`182.7
`-15.2
`<0.001
`
`(n = 125)
`192.9
`-1.3
`NS**
`
`(n = 118)
`183.7
`-19.3
`<0.001
`
`(n = 119)
`191.8
`-1.3
`NS**
`
`(n = 120)
`178.9
`-28.5
`<0.001
`
`(n = 117)
`188.3
`-0.7
`NS**
`
`(n = 132)
`181.0
`-29.9
`<0.001
`
`(n = 131)
`195.4
`-1.5
` NS**
`
`(n=122)
`181.6
`-33.6
`<0.001
`
`(n=119)
`192.5
`-2.2
`NS**
`
` *All patients on diet therapy at Baseline
` a All comparisons versus Placebo
` ** Not statistically significant
`
`Placebo
`
`(n = 111)
`8.4
`0.1
`-
`
`(n = 113)
`179.6
`7.6
`-
`
`(n = 113)
`194.3
`-1.8
`-
`
`AUROBINDO EX1012, 10
`
`

`

` XR
`GLUCOPHAGE® /GLUCOPHAGE
`Response to FDA Comments of 10 12 00.doc – CLEAN DRAFT 10 13 00
`
`Page 11 of 29
`
`Compared with placebo, improvement in glycemic control was seen at all dose levels
`of GLUCOPHAGE XR and treatment was not associated with any significant change in
`weight (see DOSAGE AND ADMINISTRATION for dosing recommendations for
`GLUCOPHAGE and GLUCOPHAGE XR).
`A 24 week, double-blind, randomized study of GLUCOPHAGE XR, taken once daily
`with the evening meal, and GLUCOPHAGE, taken twice daily (with breakfast and
`evening meal), was conducted in patients with type 2 diabetes who had been treated with
`GLUCOPHAGE 500 mg twice daily for at least 8 weeks prior to study entry. The
`GLUCOPHAGE 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 7.
`
`Table 7. Summary of Mean Changes from Baseline* in HbA1c,
`Fasting Plasma Glucose, and Body Weight at Week 12 and at Final
`Visit (24-week study)
`GLUCOPHAGE XR
`GLUCOPHAGE
`500mg
`1000mg
`1500mg
`Twice Daily
`Once Daily
`Once Daily
`(n = 72)
`(n = 66)
`Hemoglobin A1c (%)
`(n = 67)
`6.99
`7.02
` Baseline
`7.06
`0.23
`0.04
` Change at 12 Weeks
`0.14
`(0.10, 0.36)
`(-0.08, 0.15)
` (95% CI)
`(-0.03, 0.31)
`0.14a
`0.27
`0.13
` Change at FINAL VISIT
`(-0.04, 0.31)
`(0.11, 0.43)
`(-0.02, 0.28)
` (95% CI)
`FPG (mg/dL)
`(n = 69)
`(n = 72)
`(n = 70)
` Baseline
`127.2
`131.0
`131.4
` Change at 12 Weeks
`12.9
`9.5
`3.7
` (95% CI)
`(6.5,19.4)
`(4.4, 14.6)
`(-0.4, 7.8)
` Change at FINAL VISIT
`14.0
`11.5
`7.6
` (95% CI)
`(7.0, 21.0)
`(4.4, 18.6)
`(1.0, 14.2)
`Body Weight (lbs)
`(n = 71)
`(n = 74)
`(n = 71)
` Baseline
`210.3
`202.8
`192.7
` Change at 12 Weeks
`0.4
`0.9
`0.7
` (95% CI)
`(-0.4, 1.5)
`(0.0, 2.0)
`(-0.4, 1.8)
` Change at FINAL VISIT
`0.9
`1.1
`0.9
` (95% CI)
`(-0.4, 2.2)
`(-0.2, 2.4)
`(-0.4, 2.0)
`* All patients on GLUCOPHAGE 500mg twice daily at Baseline
`a n = 68
`
`After 12 weeks of treatment, there was an increase in mean HbA1c in all groups; in the
`GLUCOPHAGE XR 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 GLUCOPHAGE XR are shown in Table 8.
`
`AUROBINDO EX1012, 11
`
`

`

` XR
`GLUCOPHAGE® /GLUCOPHAGE
`Response to FDA Comments of 10 12 00.doc – CLEAN DRAFT 10 13 00
`
`Page 12 of 29
`
`Table 8. Summary of Mean Percent Changes from Baseline* in Major Lipid Variables at
`Final Visit (16-week study)
`
`500mg
`
`Once
`Daily
`(n = 120)
`Total Cholesterol (mg/dL)
`210.3
` Baseline
`1.0%
` Mean % Change at FINAL VISIT
`(n = 120)
`Total Triglycerides (mg/dL)
`220.2
` Baseline
`14.5%
` Mean % Change at FINAL VISIT
`(n = 119)
`LDL – Cholesterol (mg/dL)
`131.0
` Baseline
`- 1.4%
` Mean % Change at FINAL VISIT
`(n = 120)
`HDL – Cholesterol (mg/dL)
`40.8
` Baseline
`6.2%
` Mean % Change at FINAL VISIT
`*All patients on diet therapy at Baseline
`
`GLUCOPHAGE XR
`
`1000mg
`Once
`Daily
`
`1500mg
`Once
`Daily
`
`(n = 113)
`218.1
`1.7%
`(n = 113)
`211.9
`9.4%
`(n = 113)
`134.9
`- 1.6%
`(n = 108)
`41.6
`8.6%
`
`(n = 110)
`214.6
`0.7%
`(n = 110)
`198.0
`15.1%
`(n = 109)
`135.8
`- 3.5%
`(n = 108)
`40.6
`5.5%
`
`2000mg
`
`Once
`Daily
`(n = 126)
`204.4
`- 1.6%
`(n = 126)
`194.2
`14.9%
`(n = 126)
`125.8
`- 3.3%
`(n = 125)
`40.2
`6.1%
`
`1000mg
`Twice
`Daily
`
`(n = 117)
`208.2
`- 2.6%
`(n = 117)
`179.0
`9.4%
`(n = 117)
`131.4
`- 5.5%
`(n = 117)
`42.4
`7.1%
`
`Placebo
`
`(n = 110)
`208.6
`2.6%
`(n = 110)
`211.7
`10.9%
`(n = 107)
`131.9
` 3.2%
`(n = 108)
`39.4
`5.8%
`
`Changes in lipid parameters in the previously described study of GLUCOPHAGE and
`GLUCOPHAGE XR are shown in Table 9.
`
`Table 9. Summary of Mean Percent Changes from Baseline* in Major
`Lipid Variables at Final Visit (24-week study)
`Glucophage
`Glucophage XR
`500mg
`1000mg
`1500mg
`Twice Daily
`Once Daily
`Once Daily
`(n = 68)
`(n = 70)
`(n = 66)
`Total Cholesterol (mg/dL)
`199.0
`201.9
`201.6
` Baseline
`0.1%
`1.3%
`0.1%
` Mean % Change at FINAL VISIT
`(n = 68)
`(n = 70)
`(n = 66)
`Total Triglycerides (mg/dL)
`178.0
`169.2
`206.8
` Baseline
`6.3%
`25.3%
`33.4%
` Mean % Change at FINAL VISIT
`(n = 68)
`(n = 70)
`(n = 66)
`LDL – Cholesterol (mg/dL)
`122.1
`126.2
`115.7
` Baseline
`- 1.3%
`- 3.3%
`- 3.7%
` Mean % Change at FINAL VISIT
`(n = 68)
`(n = 70)
`(n = 65)
`HDL – Cholesterol (mg/dL)
`41.9
` Baseline
`41.7
`44.6
`4.8%
` Mean % Change at FINAL VISIT
`1.0%
`- 2.1%
`*All patients on GLUCOPHAGE 500mg twice daily at Baseline
`
`AUROBINDO EX1012, 12
`
`

`

` XR
`GLUCOPHAGE® /GLUCOPHAGE
`Response to FDA Comments of 10 12 00.doc – CLEAN DRAFT 10 13 00
`
`Page 13 of 29
`
`INDICATIONS AND USE
`GLUCOPHAGE (metformin hydrochloride tablets) and GLUCOPHAGE XR (metformin
`hydrochloride extended-release tablets), as monotherapy, are indicated as an adjunct to
`diet and exercise to improve glycemic control in patients with type 2 diabetes.
` GLUCOPHAGE or GLUCOPHAGE XR may be used concomitantly with a
`sulfonylurea or insulin to improve glycemic control.
`
`CONTRAINDICATIONS
`GLUCOPHAGE and GLUCOPHAGE XR are contraindicated in patients with:
`1. Renal disease or renal dysfunction (e.g., as suggested by serum creatinine
` levels (cid:31)1.5 mg/dL [males], (cid:31)1.4 mg/dL [females] or abnormal creatinine
` clearance) which may also result from conditions such as cardiovascular
` collapse (shock), acute myocardial infarction, and septicemia
` (see WARNINGS and PRECAUTIONS).
` 2. Congestive heart failure requiring pharmacologic treatment.
` 3. Known hypersensitivity to metformin hydrochloride.
`4. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with
` or without coma. Diabetic ketoacidosis should be treated with insulin.
`
`
`
`GLUCOPHAGE and GLUCOPHAGE XR should be temporarily discontinued in
`patients undergoing radiologic studies involving intravascular administration of iodinated
`contrast materials, because use of such products may result in acute alteration of renal
`function. (See also PRECAUTIONS.)
`
`WARNINGS
`Lactic Acidosis:
`Lactic acidosis is a rare, but serious, metabolic complication that can occur due to
`metformin
`accumulation during
`treatment with GLUCOPHAGE
`or
`GLUCOPHAGE XR; when it occurs, it is fatal in approximately 50% of cases.
`Lactic acidosis may also occur in association with a number of pathophysiologic
`conditions, including diabetes mellitus, and whenever there is significant tissue
`hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood
`lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an
`increased anion gap, and an increased lactate/pyruvate ratio. When metformin is
`implicated as the cause of lactic acidosis, metformin plasma levels >5 µg/mL are
`generally found.
`The reported incidence of lactic acidosis in patients receiving metformin
`hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with
`approximately 0.015 fatal cases/1000 patient-years). Reported cases have occurred
`primarily in diabetic patients with significant renal insufficiency, including both
`intrinsic renal disease and renal hypoperfusion, often in the setting of multiple
`concomitant medical/surgical problems and multiple concomitant medications.
`
`AUROBINDO EX1012, 13
`
`

`

` XR
`GLUCOPHAGE® /GLUCOPHAGE
`Response to FDA Comments of 10 12 00.doc – CLEAN DRAFT 10 13 00
`
`Page 14 of 29
`
`Patients with congestive heart failure requiring pharmacologic management, in
`particular those with unstable or acute congestive heart failure who are at risk of
`hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of
`lactic acidosis increases with the degree of renal dysfunction and the patient's age.
`The risk of lactic acidosis may, therefore, be significantly decreased by regular
`monitoring of
`renal
`function
`in patients
`taking GLUCOPHAGE or
`GLUCOPHAGE XR and by use of the minimum effective dose of GLUCOPHAGE
`or GLUCOPHAGE XR. In particular, treatment of the elderly should be
`accompanied by careful monitoring of renal function. GLUCOPHAGE or
`GLUCOPHAGE XR treatment should not be initiated in patients (cid:31)80 years of age
`unless measurement of creatinine clearance demonstrates that renal function is not
`reduced, as these patients are more susceptible to developing lactic acidosis. In
`addition, GLUCOPHAGE and GLUCOPHAGE XR should be promptly withheld
`in the presence of any condition associated with hypoxemia, dehydration, or sepsis.
`Because impaired hepatic function may significantly limit the ability to clear
`lactate, GLUCOPHAGE and GLUCOPHAGE XR should generally be avoided in
`patients with clinical or laboratory evidence of hepatic disease. Patients should be
`cautioned against excessive alcohol intake, either acute or chronic, when taking
`GLUCOPHAGE or GLUCOPHAGE XR, since alcohol potentiates the effects of
`metformin hydrochloride on lactate metabolism. In addition, GLUCOPHAGE
`and GLUCOPHAGE XR should be temporarily discontinued prior to any
`intravascular radiocontrast study and for any surgical procedure (see also
`PRECAUTIONS).
`The onset of lactic acidosis often is subtle, and accompanied only by nonspecific
`symptoms such as malaise, myalgias, respiratory distress, increasing somnolence,
`and nonspecific abdominal distress. There may be associated hypothermia,
`hypotension, and resistant bradyarrhythmias with more marked acidosis. The
`patient and the patient's physician must be aware of the possible importance of
`such symptoms and the patient should be instructed to notify the physician
`immediately if they occur (see also PRECAUTIONS). GLUCOPHAGE and
`GLUCOPHAGE XR should be withdrawn until the situation is clarified. Serum
`electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels, and
`even blood metformin levels may be useful. Once a patient is stabilized on any dose
`level of GLUCOPHAGE or GLUCOPHAGE XR, gastrointestinal symptoms, which
`are common during initiation of therapy, are unlikely to be drug related. Later
`occurrence of gastrointestinal symptoms could be due to lactic acidosis or other
`serious disease.
` Levels of fasting venous plasma lactate above the upper limit of normal but less
`than 5 mmol/L in patients taking GLUCOPHAGE or GLUCOPHAGE XR do not
`necessarily indicate impending lactic acidosis and may be explainable by other
`mechanisms, such as poorly controlled diabetes or obesity, vigorous physical
`activity, or technical problems in sample handling. (See also PRECAUTIONS.)
`
`AUROBINDO EX1012, 14
`
`

`

` XR
`GLUCOPHAGE® /GLUCOPHAGE
`Response to FDA Comments of 10 12 00.doc – CLEAN DRAFT 10 13 00
`
`Page 15 of 29
`
` Lactic acidosis should be suspected in any diabetic patient with metabolic
`acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).
` Lactic acidosis is a medical emergency that must be treated in a hospital
`setting. In a patient with lactic acidosis who is taking GLUCOPHAGE or
`GLUCOPHAGE XR, the drug should be discontinued immediately and general
`supportive measures promptly instituted. Because metformin hydrochloride is
`dialyzable (with a clearance of up to 170 mL/min under good hemodynamic
`conditions), prompt hemodialysis is recommended to correct the acidosis and
`remove the accumulated metformin. Such management often results in prompt
`reversal of symptoms and recovery. (See also CONTRAINDICATIONS and
`PRECAUTIONS.)
`
`PRECAUTIONS
`General
`Monitoring of renal function—Metformin is known to be substantially excreted by the
`kidney, a