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`
`
` GLUCOPHAGE®
`
`(metformin hydrochloride tablets)
`
`GLUCOPHAGE® XR
`
`(metformin hydrochloride extended-release tablets)
`
`DESCRIPTION
`tablets) and GLUCOPHAGE® XR (metformin
`GLUCOPHAGE® (metformin hydrochloride
`
`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:
`
`
`
`
`
`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.
`
`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 hypromellose and the coating for the 1000 mg tablet contains
`hypromellose and polyethylene glycol.
`
`
`
`GLUCOPHAGE XR contains 500 mg or 750 mg of metformin hydrochloride as the active ingredient.
`
`GLUCOPHAGE XR 500 mg tablets contain the inactive ingredients sodium carboxymethyl cellulose,
`hypromellose, microcrystalline cellulose, and magnesium stearate.
`
`
`
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`GLUCOPHAGE XR 750 mg tablets contain the inactive ingredients sodium carboxymethyl cellulose,
`
`hypromellose, and magnesium stearate.
`
`System Components and Performance - GLUCOPHAGE XR 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" 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% to 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 adminis­
`tration 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.
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` 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.
`
`
`
`At steady state, the AUC and Cmax 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 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 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 to 48 hours
`and are generally <1 µg/mL. During controlled clinical trials of GLUCOPHAGE, maximum
`metformin plasma levels did not exceed 5 µg/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.
`
`
`
`
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`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 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 (metformin hydrochloride tablets) and GLUCOPHAGE XR (metformin
`hydrochloride extended-release tablets) 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).
`
`
`
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`
`Table 1:
`
`Select Mean (±S.D.) Metformin Pharmacokinetic Parameters
`
`
`Following Single or Multiple Oral Doses of GLUCOPHAGE
`
`Renal
`Clearance
`
`(mL/min)
`
`600 (±132)
`552 (±139)
`642 (±173)
`
`
`491 (±138)
`550 (±160)
`
`
`412 (±98)
`
`
`
` 384 (±122)
`108 (±57)
`
`130 (±90)
`
`c
`
`Tmax
`(hrs)
`
`2.75 (±0.81)
`2.64 (±0.82)
`1.79 (±0.94)
`
`
`3.32 (±1.08)
`2.01 (±1.22)
`
`
`2.71 (±1.05)
`
`
`
`
`
`
`Healthy, nondiabetic adults:
`
`500 mg single dose (24)
`850 mg single dose (74)d
`
`
` 850 mg three times daily for 19 dosese (9)
`
`Adults with type 2 diabetes:
`
`850 mg single dose (23)
`850 mg three times daily for 19 dosese (9)
`
`
`Elderlyf, healthy nondiabetic adults:
`
`
`850 mg single dose (12)
`Renal-impaired adults:
`
` 850 mg single dose
`
`g 61-90 mL/min) (5)
`
`1.86 (±0.52)
`3.20 (±0.45)
`Mild (CLcr
`
`4.12 (±1.83)
`3.75 (±0.50)
`
`Moderate (CLcr 31-60 mL/min) (4)
`3.93 (±0.92)
`4.01 (±1.10)
`Severe (CLcr 10-30 mL/min) (6)
`
`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)
`
`2
`g
`CLcr = creatinine clearance normalized to body surface area of 1.73 m
`
`Pediatrics
`After administration of a single oral GLUCOPHAGE 500 mg tablet with food, geometric mean
` metformin Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16
`
`
`years of age) and gender- and weight-matched healthy adults (20 to 45 years of age), all with normal
`renal function.
`
`b
`
`Cmax
`(µg/mL)
`
`1.03 (±0.33)
`1.60 (±0.38)
`2.01 (±0.42)
`
`
`1.48 (±0.5)
`1.90 (±0.62)
`
`
`2.45 (±0.70)
`
`
`
`
` Subject Groups: GLUCOPHAGE dosea
`
`(number of subjects)
`
`
`
`
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`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).
`
`
`
`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:
`
`
`
`FPG (mg/dL)
`
`Baseline
`
`Change at FINAL VISIT
`
`
`241.5
`-53.0
`
`
`GLUCOPHAGE vs Placebo Summary of Mean Changes from
`
`Baseline* in Fasting Plasma Glucose, HbA1c, and Body Weight,
`at Final Visit (29-week study)
`GLUCOPHAGE
`
`(n=141)
`
`Placebo
`(n=145)
`
`237.7
`6.3
`
`p–Value
`
`
`NS**
`0.001
`
`Hemoglobin A1c (%)
`
`Baseline
`
`Change at FINAL VISIT
`
`Body Weight (lbs)
`
`
`Baseline
`
`
`Change at FINAL VISIT
` *All patients on diet therapy at Baseline
`
`
`
`8.4
`
`
` -1.4
`
`201.0
` -1.4
`
`
`
`
`
`
`8.2
`0.4
`
`206.0
` -2.4
`**Not statistically significant
`
`
`NS**
`0.001
`
`NS**
`NS**
`
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` 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 the combination arm started therapy with GLUCOPHAGE 500
`
`
` mg and glyburide 20 mg. At the end of each week of the first four weeks of the trial, these patients had
` their dosages of GLUCOPHAGE increased by 500 mg if they had failed to reach target fasting plasma
`
`
` glucose. After week four, such dosage adjustments were made monthly, although no patient was
` allowed to exceed GLUCOPHAGE 2500 mg. Patients in the GLUCOPHAGE only arm (metformin
`
`
`
`
` plus placebo) followed the same titration schedule. At the end of the trial, approximately 70% of the
` patients in the combination group were taking GLUCOPHAGE 2000 mg/glyburide 20 mg or
`
`
`GLUCOPHAGE 2500 mg/glyburide 20 mg. 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).
`
`
`
`
`
`
`
`
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`
`NDA 20-357/S-031
`NDA 21-202/S-016
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`
`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
`Glyb vs
`GLU vs
`Comb
`Glyb
`GLU
`
`
`
`
`
`Comb
`Comb
`(n=213)
`(n=209)
`(n=210)
`
`
`
`
`GLU vs
`
`Glyb
`
`
`
`
`
`
`Fasting Plasma
`
`Glucose (mg/dL)
`
`NS**
`0.025
`
`0.007
`0.001
`
`NS**
`0.001
`
`
`
`
`
`
`
`NS**
`NS**
`0.001
`0.001
`
`
`NS**
`NS**
`0.001
`0.001
`
`
`NS**
`NS**
`0.001
`0.011
`**Not statistically significant
`
`
`
`253.9
`-0.9
`
`
` 8.9
`
`-0.4
`
`204.0
`
`-8.4
`
`
`250.5
`Baseline
`
`-63.5
`Change at FINAL VISIT
`
`
`Hemoglobin A1c (%)
` 8.8
` Baseline
`
`-1.7
`
`Change at FINAL VISIT
`
`
`Body Weight (lbs)
`
`202.2
`Baseline
`
`
`0.9
`Change at FINAL VISIT
` *All patients on glyburide, 20 mg/day, at Baseline
`
`
` 247.5
`13.7
`
`8.5
`0.2
`
` 203.0
` -0.7
`
`
`
`
`
`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 sulfonylurea, lowered mean
`
`
`
`fasting serum triglycerides, total cholesterol, and LDL cholesterol levels and had no adverse effects on
`
`other lipid levels (see Table 4).
`
`
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`

`
`GLUCOPHAGE vs Placebo
`
`GLUCOPHAGE
`
`(n=141)
`
`Placebo
`(n=145)
`
`GLUCOPHAGE
`
`(n=210)
`
`
`
`
`
`
`
`Glyburide
`(n=209)
`
`
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`NDA 20-357/S-031
`NDA 21-202/S-016
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`
`Table 4:
`
`
`
`
`
`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
`
`Summary of Mean Percent Change From Baseline of Major
`
`Serum Lipid Variables at Final Visit (29-week studies)
`
`
`Combined GLUCOPHAGE/Glyburide
`
`vs Monotherapy
`GLUCOPHAGE/
`
`Glyburide
`(n=213)
`
`
`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
`
`219.6
`
`
`-4%
`
`
`
`
`1%
`
`
`
`215.0
`
`266.1
`
`-8%
`
`
`
`
`4%
`
`
`
`
`136.0
`
`137.5
`
`
`-6%
`
`
`
`39.0
`
`
`3%
`
`
`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 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.
`
`
`
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`Table 5:
`
`
`
`Hemoglobin A1c (%)
` Baseline
` Change at FINAL VISIT
`
`
`Combined GLUCOPHAGE/Insulin vs Placebo/Insulin
`Summary of Mean Changes from Baseline in HbA1c and Daily
`Insulin Dose
`GLUCOPHAGE/
`
`Insulin
` (n=26)
`
`Treatment
`Difference
`Mean ± SE
`
`
`Placebo/
`Insulin
` (n=28)
`
`9.32
`-1.56
`
`
`8.95
`-2.10
`
`
`
`-0.54 ± 0.43a
`
`
`
`
`-16.08 ± 7.77b
`
`
`
`
`
`
`Insulin Dose (U/day)
`94.64
`93.12
` Baseline
`15.93
`-0.15
` Change at FINAL VISIT
`
`
` 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.
`
`
`
`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
`
`
`
`increased 0.2% from baseline
`in placebo patients and decreased 0.6% with
`HbA1c had
`GLUCOPHAGE XR.
`
`
`
`Boehringer Ex. 2021
`Mylan v. Boehringer Ingelheim
`IPR2016-01564
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`

`
`NDA 20-357/S-031
`NDA 21-202/S-016
`Page 13
`
`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:
`
`
`
`
`
`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
`
`
`
`Summary of Mean Changes from Baseline* in HbA1c, Fasting
`Plasma Glucose, and Body Weight at Final Visit (16-week
`
`
`study)
`
`
`500 mg
`
`Once
`Daily
`
`
`(n=115)
`8.2
`
`
`-0.4
`<0.001
`
`(n=126)
`182.7
`
`-15.2
`
`<0.001
`
`
` GLUCOPHAGE XR
`1000 mg
`
`
`
`1500 mg
`2000 mg
`Once
`Once
`Once
`
`
`
`Daily
`Daily
`Daily
`
`(n=115)
`8.4
`
`
`-0.6
`<0.001
`
`(n=118)
`183.7
`
`-19.3
`
`<0.001
`
`(n=111)
`8.3
`
`
`-0.9
`<0.001
`
`(n=120)
`178.9
`
`-28.5
`
`<0.001
`
`(n=125)
`8.4
`
`
`-0.8
`<0.001
`
`(n=132)
`181.0
`
`-29.9
`
`<0.001
`
`
`1000 mg
`Twice
`
`Daily
`
`(n=112)
`8.4
`
`
`-1.1
`<0.001
`
`(n=122)
`181.6
`
`-33.6
`
`<0.001
`
`
`Placebo
`
`(n=111)
`8.4
`
`0.1
`-
`
`(n=113)
`179.6
`
`7.6
`
`-
`
`(n=125)
`192.9
`
`(n=119)
`191.8
`
`(n=117)
`188.3
`
`(n=131)
`195.4
`
`(n=119)
`192.5
`
`(n=113)
`194.3
`
`
`-1.3
`
`NS**
`
`
`-1.3
`
`NS**
`
`
`-0.7
`
`NS**
`
`
`-1.5
`
`NS**
`
`
`-2.2
`
`NS**
`
`
`-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 (metformin hydrochloride extended-release tablets) 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 (metformin hydrochloride tablets), 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.
`
`Boehringer Ex. 2021
`Mylan v. Boehringer Ingelheim
`IPR2016-01564
`Page 11
`
`

`
`NDA 20-357/S-031
`NDA 21-202/S-016
`Page 14
`
`
`
`
`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
`1000 mg
`1500 mg
`
`
`Once Daily
`Once Daily
`(n=72)
`(n=66)
`6.99
`7.02
`0.23
`0.04
`(0.10, 0.36)
`(-0.08, 0.15)
`0.27
`0.13
`(0.11, 0.43)
`(-0.02, 0.28)
`
`(n=72)
`131.0
`9.5
`(4.4, 14.6)
`11.5
`(4.4, 18.6)
`
`(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)
`
`
`
`
`
`Hemoglobin A1c (%)
`
`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% CI)
`
`
`
`GLUCOPHAGE
`
`500 mg
`
`Twice Daily
`
`(n=67)
`7.06
`0.14
`(-0.03, 0.31)
` 0.14a
`
`(-0.04, 0.31)
`
`(n=69)
`127.2
` 12.9
`(6.5, 19.4)
`14.0
`(7.0, 21.0)
`
`
`(n=74)
`(n=71)
`Body Weight (lbs)
`
`202.8
`210.3
`Baseline
`
`
`0.9
` 0.4
`Change at 12 Weeks
`
`(0.0, 2.0)
`(-0.4, 1.5)
` (95% CI)
`
`1.1
` 0.9
`Change at FINAL VISIT
`
`
`(-0.2, 2.4)
`(-0.4, 2.2)
` (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 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.
`
`
`Boehringer Ex. 2021
`Mylan v. Boehringer Ingelheim
`IPR2016-01564
`Page 12
`
`

`
`NDA 20-357/S-031
`NDA 21-202/S-016
`Page 15
`
`
`Table 8:
`
`Summary of Mean Percent Changes from Baseline* in Major
`
`Lipid Variables at Final Visit (16-week study)
`
`GLUCOPHAGE XR
`
`
`
`Total Cholesterol (mg/dL)
`
`Baseline
`
`
`Mean % Change at FINAL
`
`
`VISIT
`
`Total Triglycerides (mg/dL)
`
`Baseline
`
`
`Mean % Change at FINAL
`
`
`VISIT
`
`
`500 mg
`Once
`
`Daily
`
`(n=120)
`210.3
`
`
`1000 mg
`Once
`
`Daily
`
`(n=113)
`218.1
`
`
`1500 mg
`Once
`
`Daily
`
`
`2000 mg
`Once
`
`Daily
`
`
`1000 mg
`Twice
`
`Daily
`
`Placebo
`
`(n=110)
`214.6
`
`(n=126)
`204.4
`
`(n=117)
`208.2
`
`(n=110)
`208.6
`
`
`1.0%
`
`
`1.7%
`
`
`0.7%
`
`
`-1.6%
`
`
`-2.6%
`
`
`2.6%
`
`(n=120)
`220.2
`
`(n=113)
`211.9
`
`(n=110)
`198.0
`
`(n=126)
`194.2
`
`(n=117)
`179.0
`
`(n=110)
`211.7
`
`
`14.5%
`
`
`9.4%
`
`
`15.1%
`
`
`14.9%
`
`
`9.4%
`
`
`10.9%
`
`(n=119)
`131.0
`
`(n=113)
`134.9
`
`(n=109)
`135.8
`
`(n=126)
`125.8
`
`(n=117)
`131.4
`
`(n=107)
`131.9
`
`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
`
`the previously described study of GLUCOPHAGE and
`in
`lipid parameters
`in
`Changes
`GLUCOPHAGE XR are shown in Table 9.
`
` -1.4%
`
` -1.6%
`
` -3.5%
`
` -3.3%
`
` -5.5%
`
`
`3.2%
`
`(n=120)
`40.8
`
`(n=108)
`41.6
`
`(n=108)
`40.6
`
`(n=125)
`40.2
`
`(n=117)
`42.4
`
`(n=108)
`39.4
`
`
`6.2%
`
`
`8.6%
`
`
`5.5%
`
`
`6.1%
`
`
`7.1%
`
`
`5.8%
`
`
`
`Boehringer Ex. 2021
`Mylan v. Boehringer Ingelheim
`IPR2016-01564
`Page 13
`
`

`
`NDA 20-357/S-031
`NDA 21-202/S-016
`Page 16
`
`
`Table 9:
`
`
`
`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
`
`Summary of Mean Percent Changes from Baseline* in Major
`
`Lipid Variables at Final Visit (24-week study)
`
`GLUCOPHAGE XR
`GLUCOPHAGE
`
`500 mg
`
`1000 mg
`1500 mg
`
`
`Once Daily
`Once Daily
`Twice Daily
`
`(n=68)
`(n=70)
`(n=66)
`199.0
`201.9
`201.6
`
`0.1%
`
`
`(n=68)
`178.0
`
`6.3%
`
`
`(n=68)
`122.1
`
` -1.3%
`
`1.3%
`
`
`(n=70)
`169.2
`
`25.3%
`
`
`(n=70)
`126.2
`
` -3.3%
`
`0.1%
`
`
`(n=66)
`206.8
`
`33.4%
`
`
`(n=66)
`115.7
`
` -3.7%
`
`(n=68)
`41.9
`
`
`4.8%
`
`(n=70)
`41.7
`
`
`1.0%
`
`(n=65)
`44.6
`
` -2.1%
`
`HDL-Cholesterol (mg/dL)
` Baseline
`
` Mean % Change at FINAL
`
`VISIT
`*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/dL), 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 10).
`
`
`
`
`Boehringer Ex. 2021
`Mylan v. Boehringer Ingelheim
`IPR2016-01564
`Page 14
`
`

`
`GLUCOPHAGE vs Placebo (Pediatricsa) Summary of Mean
`Changes from Baseline* in Plasma Glucose and Body Weight
`
`at Final Visit
` GLUCOPHAGE
`
`
`
`Placebo
`
`p-Value
`
`
`
`<0.001
`
`(n=36)
`192.3
`21.4
`
`(n=37)
`162.4
` -42.9
`
`NDA 20-357/S-031
`NDA 21-202/S-016
`Page 17
`
`
`Table 10:
`
`
`
`FPG (mg/dL)
`Baseline
`
`Change at FINAL VISIT
`
`
`
`NS**
`
`(n=38)
`189.0
` -2.0
`
`
`
`
`(n=39)
`Body Weight (lbs)
`205.3
`Baseline
`
` -3.3
`Change at FINAL VISIT
` a Pediatric patients mean age 13.8 years (range 10-16 years)
`
` * All patients on diet therapy at Baseline
`
`
` ** Not statistically significant
`
`
`
`INDICATIONS AND USAGE
`GLUCOPHAGE (metformin hydrochloride tablets) is indicated as an adjunct to diet and exercise to
`improve glycemic control in adults and children with type 2 diabetes mellitus.
`
`
`
`GLUCOPHAGE XR (metformin hydrochloride extended-release tablets) is indicated as an adjunct to
`diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
`
`CONTRAINDICATIONS
`GLUCOPHAGE and GLUCOPHAGE XR are contraindicated in patients with:
`
`1. Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥1.5 mg/dL
`
`
`[males], ≥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. Known hypersensitivity to metformin hydrochloride.
`
`
`3. 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.)
`
`Boehringer Ex. 2021
`Mylan v. Boehringer Ingelheim
`IPR2016-01564
`Page 15
`
`

`
`NDA 20-357/S-031
`NDA 21-202/S-016
`Page 18
`
` 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). In more than 20,000 patient-years exposure to metformin in clinical trials, there
`were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients
`
`intrinsic renal disease and renal
`with significant renal
`insufficiency,
`including both
`
`hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and
`multiple concomitant medications. 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
`
`