CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICATION NUMBER: 20-357/SO19
`
`FINAL PRINTED LABELING
`
`MYLAN Ex. 1004, Page 1
`
`

`
`Rx only
`GLUCOPHAGE®
`(metformin hydrochloride tablets)
`
`GLUCOPHAGE® XR
`(metformin hydrochloride extended-release tablets)
`DESCRIPTION
`GLUCOPHAGE• (metformin hydrochloride tablets) and GLUCOPHAGE" XR (metformin hydrochlo-
`ride extended-release tablets) are oral antihyperglycemic drugs used in the management of type 2
`diabetes. Metformin hydrochloride (N,N-dirnethylimidodicarbonimidic diamide hydrochloride) is not
`chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. The
`structural formula is as shown:
`
`H3C
`
`N - C-NH-C -NH2. HCI
`
`NH NH
`
`H3C
`
`Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of
`C41111N5•HCI 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 methylceffulose (hypromellose) and the
`coating for the 1000-mg contains hydroxypropyl methylcellulose and polyethylene glycol.
`GLUCOPHAGE XR contains 500 mg of metformin hydrochloride as the active ingredient. Each
`tablet contains the inactive ingredients sodium carboxymethyl cellulose, hydroxypropyl methylcel-
`lulose, microcrystalline cellulose, and magnesium stearate.
`System Components and Performance
`GLUCOPHAGE XR tablets comprise a dual hydrophilic polymer matrix system. Metforrnin hydrochlo-
`ride is combined with a drug release controlling polymer to form an "inner phase, which is then incor-
`porated 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 essen-
`tialty 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 wit 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 sen-
`sitivity by increasing peripheral glucose uptake arid 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 met-
`formin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plas-
`ma insulin response may actually decrease.
`
`Phannacokinetics
`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 (Sr."), a 25% lower area under the plasma concentration versus time curve
`(AUC), and a 35 minute prolongation of time to peak plasma concentration (T ,,,s„) following adminis-
`tration of a single 850-mg tablet of metformin with food, compared to the same tablet strength admin-
`istered fasting. The clinical relevance of these decreases is unknown.
`Following a single oral dose of GLUCOPHAGE XR, C 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 sim-
`ilar to GLUCOPHAGE.
`At steady state, the AUC and CTe1 are less than dose proportional for 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 pg/ml for 500, 1000, 1503, and 2000 mg once-daily doses, respectively. The extent of
`metformin absorption (as measured by Aug 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 plasma.
`Within-subject variability in C, 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 Cram
`and T (cid:9)
`of metformin. Both high and low tat meals had the same effect on the pharmecokinetics
`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 sulfonyiureas, 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 ug/mL During controlled clinical trials of GLUCOPHAGE, maximum met-
`formin plasma levels did not exceed 5 rag/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 iden-
`tified 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 approx-
`imately 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.
`
`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 C,,,s,
`
`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 (metformin hydrochloride extended-release
`tablets) treatment should not be initiated in patients > 80 years of age unless measurement of ere-
`atinine 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 GLUCOPHAGE
`Cab
`
`Tm.,,c
`(hrs)
`
`Renal Clearance
`(mUmin)
`
`Subject Groups: GLUCOPHAGE
`dose° (number of subjects)
`
`(119/m0
`
`Healthy, nondiabetic adults:
`500 mg single dose (24)
`850 mg single dose (74)d
`850 mg three times daily for
`19 doses° (9)
`
`Adults with type 2 diabetes:
`850 mg single dose (23)
`850 mg three times daily for
`19 dosesa (9)
`
`Elderlyf, healthy nondiabetic adults:
`850 mg single dose (12)
`
`Renal-impaired adults:
`850 mg single dose
`Mild (Clag 61-90 mUmin) (5)
`Moderate (CL,:, 31-60 mUmin) (4)
`Severe (CL.. 10-30 mUmin) (6)
`
`1.03 (±0.33)
`1.80 (10.38)
`2.01 (±0.42)
`
`2.75 (10.81)
`2.64 (±0.82)
`1.79 (±0.94)
`
`600 (±132)
`552 (±139)
`642 (±173)
`
`1.48 (±0.5)
`1.90 (10.62)
`
`3.32 (±1.08)
`2.01 (±1.22)
`
`491 (±138)
`550 (±160)
`
`2.45 (±0.70)
`
`2.71 (±1.05)
`
`412 (±98)
`
`1.86 (±0.52)
`4.12 (±1.83)
`3.93 (±0.92)
`
`3.20 (±0.45)
`3.75 (±0.50)
`4.01 (±1.10)
`
`384 (±122)
`108 (±57)
`130 (290)
`
`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)
`° Kinetic study done following dose 19, given fasting
`f Elderly subjects, mean age 71 years (range 65-81 years)
`g CL," = creatinine clearance normalized to body surface area of 1.73 m2
`
`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 GLUCOPHAGE (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 GLUCOPHAGE in patients with type 2 diabetes, the antihyperglycemic
`effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).
`
`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 tasting plasma glucose [FPGI 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 A15 (HbA.,) of 59 mg/dL,
`83 mg/dL, and 1.8%, respectively, compared to the placebo group (see Table 2).
`
`Table 2. GLUCOPHAGE ye Placebo
`Summary of Mean Changes from Baseline' In Fasting Plasma Glucose,
`HbA.,, and Body Weight, at Final Visit (29-week study)
`
`GLUCOPHAGE (cid:9)
`(n = 141) (cid:9)
`
`Placebo (cid:9)
`(n = 145)
`
`p-Value
`
`FPO (mg/dL)
`
`Baseline
`
`Change at FINAL VISIT
`
`Hemoglobin Ate (%)
`
`Baseline
`
`Change at FINAL VISIT
`
`Body Weight (Ibis)
`
`Baseline
`
`Change at FINAL VISIT
`
`241.5
`
`-53.0
`
`8.4
`
`-1.4
`
`201.0
`
`-1.4
`
`237.7
`
`6.3
`
`8.2
`
`0.4
`
`206.0
`
`-2.4
`
`NS"
`
`0.001
`
`NS-
`
`0.001
`
`NS"
`NS*"
`
`'All patients on diet therapy at Baseline
`
`**Not statistically significant
`
`MYLAN Ex. 1004, Page 2
`
`(cid:9)
`

`
`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 HbAjc 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 HbA., oft mg/dL, 6 mg/dL and 0.4%,
`respectively. The combination of GLUCOPHAGE and glyburide was effective in reducing FPG, PPG,
`and HbA.,c levels by 63 mg/dL, 65 mg/d1_, and 1.7%, respectively. Compared to results of glyburide
`treatment alone, the net differences with combination treatment were -77 mg/di, -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, HbA.i. and Body Weight, at Final Visit (29-week study)
`p-values
`GLU vs (cid:9) GLU vs
`Comb (cid:9)
`Glyb
`
`Comb (cid:9)
`(n = 213) (cid:9)
`
`GLU (cid:9)
`Glyb (cid:9)
`(n = 209) (n . 210) (cid:9)
`
`Glyb vs (cid:9)
`Comb (cid:9)
`
`Fasting Plasma
`Glucose (mg/dL)
`Baseline
`Change at FINAL VISIT
`Hemoglobin Ai. (./..)
`Baseline
`Change at FINAL VISIT
`Body Weight lb.)
`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
`
`-Not statistically significant
`'AN patients on glyburide, 20 mg/day, at Baseline (cid:9)
`The magnitude of the decline in fasting blood glucose concentration following the institution
`of GLUCOPHAGE (metformin hydrochloride tablets) 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 tailfonylurea, lowered mean fast-
`ing serum triglyceridee, total cholesterol, and LDL cholesterol levels and had no adverse effects on
`other lipid levels (see Table 4).
`
`GLUCOPHAGE vs Placebo
`
`Table 4. Summary of Mean Percent Change from Baseline
`of Major Serum Lipid Variables at Final Visit (29-week studies)
`Combined GLUCOPHAGE/Glyburlde
`vs Monotherapy
`OLUCOPHAGE/
`Glyburide
`(n . 213)
`
`GLUCOPHAGE
`In . 141)
`Total Cholesterol mg/dL)
`Baseline
`211.0
`Mean % change
`-5%
`at FINAL VISIT
`Total Triglycerides (mg/dL)
`Baseline
`236.1
`Mean % change
`-16%
`at FINAL VISIT
`LDL-Cholesterol (mg/dL)
`Baseline
`135.4
`Mean % change
`-8%
`at FINAL VISIT
`HDL-Cholesterol (mg/dL)
`Baseline
`39.0
`Mean % change
`at FINAL VISIT
`
`2%
`
`Placebo
`fn . 145)
`
`GLUCOPHAGE
`(n = 210)
`
`Glyburide
`(n .. 209)
`
`212.3
`
`1%
`
`203.5
`
`1%
`
`138.5
`
`1%
`
`40.5
`
`-1%
`
`213.1
`
`-2%
`
`242.5
`
`-3%
`
`134.3
`
`-4%
`
`37.2
`
`5%
`
`215.8
`
`-4%
`
`215.0
`
`-8%
`
`136.0
`
`-6%
`
`39.0
`
`3%
`
`219.6
`
`1%
`
`266.1
`
`4%
`
`137.5
`
`3%
`
`37.0
`
`1%
`
`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 HbAic of 2.10%, compared to a 1.58% reduction in HbAie 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 HbAi. and Daily Insulin Dose
`GLUCOPHAGE/Insulin
`Placebo/Insulin
`n=26
`n=28
`
`Treatment difference
`Mean s SE
`
`Hemoglobin Aft (%)
`Baseline
`Change at FINAL VISIT
`Insulin Dose (U/day)
`Baseline
`Change at FINAL VISIT
`
`8.95
`- 2.10
`
`93.12
`- 0.15
`
`9.32
`- 1.56
`
`94.64
`15.93
`
`- 0.54 t 0.43a
`
`- 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 aver-
`age HbAic of 7.46 ± 0.97%, the addition of GLUCOPHAGE maintained similar glycemic control
`
`(HbAic 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 t 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 (metformin hydrochloride tablets)
`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.
`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 (HbA„ 7.0-10.0%, FPG 126-270 mg/dL). Patients entering the study
`had a mean baseline HbAic of 8.0% and a mean baseline FPG of 176 mg/dL. After 12 weeks treat-
`ment, mean HbAft 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 HbA,, of 0.6% arid 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 HbAic was ..7.0% but
`<8.0% (patients with HbAic ?8.0% were discontinued from the study). At the final visit (24-week),
`mean HbAic had increased 0.2% from baseline in placebo patients and decreased 0.6% with
`GLUCOPHAGE XR (metformin hydrochloride extended-release tablets).
`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 (HbAic 7.0-11%, 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 HbAi.,
`Fasting Plasma Glucose, and Body Weight at Final Visit (16-week study)
`Placebo
`GLUCOPHAGE XR
`1000 mg (cid:9)
`1500 mg (cid:9)
`2000 mg (cid:9)
`Once (cid:9)
`Once (cid:9)
`Once (cid:9)
`Daily (cid:9)
`Daily (cid:9)
`Daily (cid:9)
`(n=111)
`(n=125)
`8.3
`8.4
`-0.9
`-0.8
`<0.001
`<0.001
`(n.132)
`(n.120)
`181.0
`178.9
`-28.5
`-29.9
`<0.001
`<0.001
`(n=131)
`(n=117)
`188.3
`195.4
`-0.7
`-1.5
`NS"
`NS-
`
`500 mg (cid:9)
`Once (cid:9)
`Daily (cid:9)
`(n=115)
`8.2
`-0.4
`<0.001
`(n=126)
`182.7
`-15.2
`<0.001
`(n=125)
`192.9
`-1.3
`NS-
`
`(n.115)
`8.4
`-0.8
`<0.001
`(n=118)
`183.7
`-19.3
`<0.001
`(n=119)
`191.8
`-1.3
`NS"
`
`Hemoglobin Aft (%)
`Baseline
`Change at FINAL VISIT
`p-values
`FPG (mg/dL)
`Baseline
`Change at FINAL VISIT
`p-valuea
`Body Weight (lbs)
`Baseline
`Change at FINAL VISIT
`p-valuea
`
`1000 mg
`Twice
`Daffy
`(n=112)
`8.4
`-1.1
`<0.001
`(rw122)
`181.6
`-33.6
`<0.001
`(n=119)
`192.5
`-2.2
`NS-
`
`(n=111)
`8.4
`0.1
`-
`(n=113)
`179.6
`7.8
`
`(n=113)
`194.3
`-1.8
`
`All patients on diet therapy at Baseline
`a All comparisons versus Placebo
`- Not statistically significant
`
`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), wee con-
`ducted 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 HbAio was 48.5% and FPG was 4200 mg/dL Changes in glycemic control and body
`weight are shown in Table 7.
`
`Table 7. Summary of Mean Changes from Baseline' in HbAft,
`Fasting Plasma Glucose, and Body Weight at Week 12 and at Final Visit
`(24-week study)
`GLUCOPHAGE
`500 mg Twice Daily
`(n.67)
`7.06
`0.14
`(-0.03, 0.31)
`0.141
`(-0.04, 0.31)
`
`GLUCOPHAGE XR
`1000 mg Once Daily 1500 mg Once Daily
`(m66)
`7.02
`0.04
`(-0.08, 0.15)
`0.13
`(-0.02, 0.28)
`(n.70)
`131.4
`3.7
`(-0.4, 7.8)
`7.6
`(1.0, 14.2)
`(n=71)
`192.7
`0.7
`(-0.4, 1.8)
`0.9
`(-0.4, 2.0)
`
`(n=72)
`6.99
`0.23
`(0.10, 0.36)
`0.27
`(0.11, 0.43)
`(n=72)
`131.0
`9.5
`(4.4, 14.6)
`11.5
`(4.4, 18.6)
`(n=74)
`202.8
`0.9
`(0.0, 2.0)
`1.1
`(-0.2, 2.4)
`
`1 69)
`127.2
`12.9
`(6.5, 19.4)
`14.0
`(7.0, 21.0)
`(n=71)
`210.3
`0.4
`(-0.4, 1.5)
`0.9
`(-0.4, 2.2)
`
`Hemoglobin At. (%)
`Baseline
`Change at 12 Weeks
`(95% CI)
`Change at FINAL VISIT
`(95% CI)
`FPG (mg/dL)
`Baseline
`Change at 12 Weeks
`(95% CI)
`Change at FINAL VISIT
`(95% Cr)
`Body Weight (ibs)
`Baseline
`Change at 12 Weeks
`(95% CI)
`Change at FINAL VISIT
`(95% CI)
`
`All patients on GLUCOPHAGE 500 mg twice daily at Baseline
`a n=68
`After 12 weeks of treatment, there was an increase in mean HbAtc in all groups; in the
`GLUCOPHAGE XR 1000 mg group, the increase from baseline of 0.23% was statistically signifi-
`cant (see DOSAGE AND ADMINISTRATION).
`
`MYLAN Ex. 1004, Page 3
`
`

`
`Changes in lipid parameters in the previously described placebo-controlled dose-response study
`of GLUCOPHAGE XR are shown in Table 8.
`
`Table 8. Summary of Mean Percent Changes from Baseline* in
`Major L. pid Variables at Final Visit (16-week study)
`
`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
`
`GLUCOPHAGE XR
`500 mg 1000 mg 1500 mg 2000 mg 1000 mg
`Once Once
`Once
`Once Rice
`Daily
`Daffy
`Daily
`Daily
`Daily Placebo
`(r=120) (n=113)
`(n=110)
`(n=126)
`210.3
`218.1
`214.6
`204.4
`1.0%
`1.7%
`0.7%
`-1.6%
`
`(n=117)
`208.2
`-2.6%
`
`(n=110)
`208.8
`2.8%
`
`(rm113)
`211.9
`9.4%
`
`(n=110)
`198.0
`15.1%
`
`(n=126)
`194.2
`14.9%
`
`(n=117)
`179.0
`9.4%
`
`(n=110)
`211.7
`10.9%
`
`(n=119) (ou113)
`131.0
`134.9
`-1.4%
`-1.6%
`
`(n=120) (rw108)
`40.8
`41.6
`8.6%
`6.2%
`
`(n=109)
`135.8
`-3.5%
`
`(rsc126)
`125.8
`-3.3%
`
`(n=117)
`131.4
`-5.5%
`
`(n=107)
`131.9
`3.2%
`
`(n=108)
`40.6
`5.5%
`
`(n=125)
`40.2
`6.1%
`
`(n=117)
`42.4
`7.1%
`
`(n=108)
`39.4
`5.8%
`
`Total Cholesterol (mg/dL)
`Baseline
`Mean % change at
`FINAL VISIT
`Total Triglycerides (mg/dL) (n=120)
`Baseline
`220.2
`Mean % change at
`14.5%
`FINAL VISIT
`LDL-Cholesterol (mg/dL)
`Baseline
`Mean % change at
`FINAL VISIT
`HDL-Cholesterol (mg/dL)
`Baseline
`Mean % change at
`FINAL VISIT
`
`• All patients on diet therapy at Baseline
`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
`500 mg Twice Daffy 1000 mg Once Daily 1500 mg Once Daily
`(m68)
`(n=70)
`(n=66)
`199.0
`201.9
`201.6
`0.1%
`1.3%
`0.1%
`
`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
`
`1r68)
`178.0
`6.3%
`
`(n=68)
`122.1
`-1.3%
`
`(n=68)
`41.9
`4.8%
`
`(n=70)
`169.2
`25.3%
`
`(n=70)
`126.2
`-3.3%
`
`(n=70)
`41.7
`1.0%
`
`1166)
`206.8
`33.4%
`
`(l 66)
`115.7
`-3.7%
`
`(n=65)
`44.6
`-21 %
`
`' All patients on GLUCOPHAGE 500 mg twice daily at Baseline
`Pediatric Clinical Studies
`In a double-blind, placebo-controlled study in pediatric patients aged 10 to 16 years with type 2
`diabetes (mean FPG 182.2 mg/d1), treatment with GLUCOPHAGE (up to 2000 mg/day) for up to
`16 weeks (mean duration of treatment 11 weeks) resulted in a significant mean net reduction in FPG
`of 64.3 mg/dL, compared with placebo (see Table loy
`
`Table 10, GLUCOPHAGE vs Placebo (Pediatricsa)
`Summary of Mean Changes from Baseline* In
`Plasma Glucose and Body Weight at Final Visit
`GLUCOPHAGE
`Placebo
`(rm37)
`162.4
`-42.9
`(n=39)
`205.3
`-3.3
`
`(n=36)
`192.3
`21.4
`(n=38)
`189.0
`-2.0
`
`FPG (mg/dL)
`Baseline
`Change at FINAL VISIT
`Body Weight (lbs)
`Baseline
`Change at FINAL VISIT
`
`p-Value
`
`< 0.001
`
`NS"
`
`a Pediatric patients mean age 13.8 years (range 10-16 years)
`All patients on diet therapy at Baseline
`" Not statistically significant
`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 is indicated in patients
`10 years of age and older, and GLUCOPHAGE XR is incficated in patients 17 years of age and older.
`GLUCOPHAGE or GLUCOPHAGE XR may be used concomitantly with a sulfonyfurea or insulin to
`improve *comic control in adults (17 years of age and older).
`CONTRAINDICATIONS
`GLUCOPHAGE and GLUCOPHAGE XR are contraindicated in patients with:
`1. Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels 2 1.5 mg/dL
`(males), 2 1.4 mg/dL (females) or abnormal creatinine clearance) which may also result from
`conditions such as cardiovascular collapse (shock), acute myocardial infarction, and sep-
`ticemia (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.
`
`Lactic Acidosis:
`Lactic acidosis is a rare, but serious, metabolic complication that can occur due to met-
`fonnin 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 asso-
`ciation with a number of pathophysiologic conditions, including diabetes mellitus, and
`whenever there Is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is char-
`acterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte
`disturbances with an increased anion gap, and en increased lactatelpyruvate ratio. When
`metfomffn is implicated as the cause of lactic acidosis, metformin plasma levels >6 pg/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 hypo-
`perfusion, often in the setting of multiple concomitant rnedicaVsurgical problems and mul-
`tiple concomitant medications. Patients with congestive heart failure requiring pharmsco-
`logic 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 register 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 280 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 addi-
`tion, 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, myelgies, respiratory distress, Increasing somnolence, and
`nonspecific abdominal distress. There may be associated hypothermia, hypotension, and
`resistant bradyarrhythmies 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 PRECAU-
`TIONS). GLUCOPHAGE and GLUCOPHAGE XR should be withdrawn until the situation is
`clarified. Serum electrolytes, ketones, blood glucose end, 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 mmoVL in patients taking GLUCOPHAGE or GLUCOPHAGE XR do not necessarily indi-
`cate 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.)
`Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lack-
`ing evidence of ketoacidosle (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 X11, the drug
`should be discontinued immediately and general supportive measures promptly instituted.
`Because rnetfonnin hydrochloride Is dialyzable (with a clearance of up to 170 miJmin under
`good hemodynamic conditions), prompt hemodialysis Is recommended to correct the aci-
`dosis and remove the accumulated metfonnin. 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,
`and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment
`of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for
`their age should not receive GLUCOPHAGE (metformin hydrochloride tablets) or GLUCOPHAGE
`XR (metformin hydrochloride extended-release tablets). In patients with advanced age,
`GLUCOPHAGE and GLUCOPHAGE XR should be carefully titrated to establish the minimum dose
`for adequate glycernic effect, because aging is associated with reduced renal function. In elderly
`patients, particularly those 280 years of age, renal function should be monitored regularly and, gen-
`er