CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICATION NUMBER: 20-357/S019
`
`FINAL PRINTED LABELING
`
`Mylan EX 1008, Page 1
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`Mylan EX 1008, Page 1
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`
`metlormin 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 hall-life of approx-
`imately 62 hours. In blood, the elimination half-lile 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
`pharrnacokinetics oi metlormin 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 ol 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-lite 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 phannacokinetic studies ot metlormin have been conducted in patients with hepatic
`insufficiency.
`Geriatrics
`Limited data from controlled pharmacokinetic studies of GLUCOPHAGE in healthy elderly subjects
`suggest mat total plasma clearance of mettorrnin is decreased, the hall-life is prolonged, and Cm“
`is increased, compared to healthy young subjects. From these data, it appears that the change in
`rnetformin pharmacokinetics with aging is primarily accounted for by a change in renal function
`(see Table 1). GLUCOPHAGE and GLUOOPHAGE XR (metlormin hydrochloride extended-release
`tablets) treatment should not be initiated in patients 2 80 years of age unless measurement of cre-
`atinine clearance demonstrates that renal function is not reduced. (See WARNINGS and DOSAGE
`AND ADMINISTRATION.)
`Table 1. Select Mean (:s.o.) Metfonnin Pherrnacoklnetlc Parameters Following
`Single or Multlple Oral Doses of GLUCOPHAGE
`Subject Groups: GLUCOPHAGE
`dose‘ (number at‘ subjects)
`Healthy, nondiebetlc adults:
`500 mg single dose (24)
`850 mg single dose 04)‘!
`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 doses° (9)
`Elderly’, healthy nondiebetic adults:
`850 mg single dose (12)
`Renal-impaired adults:
`850 mg single dose
`Mild (CLc,9 61-90 mUmin) (5)
`Moderate (CL), 31-so ml/min) (4)
`Severe (CLC, 10-30 mL/min) (6)
`
`1.00 (:03:-1)
`1.50 (10.33)
`2.01 (10.42)
`
`2.75 (10.51)
`2.64 (:o.a2)
`1.79 (£1.94)
`
`sou (:1a2)
`552 (1139)
`542 (2173)
`
`1.45 (20.5)
`1 .90 (e062)
`
`3.32 (11.03)
`2.01 (:1.22)
`
`491 (1133)
`550 (1100)
`
`130 (:90)
`
`Rx only
`
`GLUCOPHAGE®
`(metforrnin hydrochloride tablets)
`
`GLUCOPHAGE® XR
`
`(metformin hydrochloride extended-release tablets)
`DESCRIPTION
`GLUCOPHAGE‘ (metlormin hydrochloride tablets) and GLUCOPHAGE' XR (metlormin 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:
`
`Metformin hydrochloride is a white to off~white crystalline compound with a molecular lorrnula of
`C‘H,1N5-HCI and a molecular weight of 165.63. Metforrnin hydrochloride is freely soluble in water
`and is practically insoluble in acetone, ether, and chloroform. The pKa of metlormin is 12.4. The pH
`of a 1% aqueous solution of metformin hydrochloride is 6.68.
`GLUCOPHAGE tablets contain 500 mg, 850 mg, or 1lX)0 mg of metformin hydrochloride. Each
`tablet contains the inactive ingredients povidone and magnesium stearate. In addition, the coating
`for the 500-rng and 850-mg tablets contains hydroxypropyl methylcellulose (hypromellose) and the
`coating for the 1000-mg contains hydroxypropyl melhylcellulose and polyethylene gycol.
`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 magneeiurn stearate.
`wstem Components and Performance
`GLUCOPHAGE XR tablets comprise a dual hydrophilic polymer matrix system. Metformin hydrochlo-
`ride is combined with a dmg relewe 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 swel. Drug is
`nloasedslomyhunthedosagefambyaprocessofdiflusionttwouglthegelmatrixthatisessen-
`tially hdependent 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 ol the tablet may occasionally
`remain intact dining GI transit and will be elirrinated in the feces as a soft, hydrated mass.
`CLINICAL PNARMACOLOGY
`Mechanism of Action
`Mettorrnin 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 antihypergycsmic agents. Metlormin decreases
`hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sen-
`sitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureae, metlormin
`cloee 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-
`fonnin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plas-
`ma insulin response may actually decrease.
`Pharrnacokinetics
`Absorption and Bloaveilabillty
`The absolute bioavailability of a GLUCOPHAGE 500-mg tablet given under fasting conditions is
`approximately 50-00%. 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 (Cmx), a 2596 lower area under the plasma concentration versus time curve
`(AUC). and a 35 minute prolongation of lime to peak plasma concentration (Tmu) following adminis-
`tration ol a single 850-mg tablet of rnetformin with food, compared to the same tablet strength admin-
`istered testing. The clinical relevance of these decreases is unknown.
`Following a single oral dose of GLUCOPHAGE XR, Cm“ is achieved with a median value of 7 hours
`and a range ol 4 hours to 8 hours. Peek 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 Cm" are less than dose proportional for GLUCOPHAGE XR within the
`range 01500 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, 1500, and 2000 mg once-daily doses, respectively. The extent of
`metformin absorption (as measured by AUC) from GLUCOPHAGE XFI at a ZCDO mg once-daily dose
`is similar to the same total daily dose administered as GLUCOPHAGE tablets 1000 mg twice daily.
`After repeated administration at GLUCOPHAGE XR, metlormin did not accunulate in plasma.
`Within-subject variability in Cm“ and AUC ol metlormin from GLUCOPHAGE XR is comparable to
`that with GLUCOPHAGE.
`Although the extent of metlormin absorption (as measured by AUG‘) from the GLUCOPHAGE XFI
`tablet increased by approximately 50% when given with food, there was no effect of food on 0,“,
`and Tm“ of metlormin. Both high and low tat meals had the same effect on the phannacokinetice
`of GLUCOPHAGE XR.
`Distribution
`The apparent volume ol distribution (V/F) of metlormin following single oral doses oi
`GLUCOPHAGE 850 mg averaged 6542358 L. Mettormin is negligibly bound to plasma proteins,
`in contrast to sulforvylureas, which are more than 90% protein bound. Metlormin 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 pg/ml. During controlled clinical trials of GLUCOPHAGE, maximum met-
`lormin plasma levels did not exceed 5 pg/mL, even at maximum doses.
`Metabolism and Elimination
`Intravenous single-dose studies in normal subjects demonstrate that metlormin 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
`
`2.45 (10.70)
`
`2.71 (21.05)
`
`412 (:93)
`
`1.86 (:o.52)
`4.12 (:1 .33)
`3.93 ($0.92)
`
`3.20 (10.45)
`3.75 (:o.50)
`4.01 (:1 .10)
`
`334 (1122)
`me (:57)
`
`‘ All doses given lasting except the first 18 doses of the multiple dose studies
`Peak plasma concentration
`‘3 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
`I Elderly subjects, mean age 71 years (range 65-81 years)
`9 CL,’ = creatinine clearance normalized to body surlace area of 1.73 m2
`Pediatrics
`No pharmacokinetic data from studies of pediatric patients are cunently available.
`Gender
`Mettonnin pharrnacokinetic 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 (metlormin hydrochloride tablets) was comparable in males and females.
`Race
`No studies of metfonnin phamiacokinetic parameters according to race have been performed. In
`controlled clinical studies of GLUCOPHAGE in patients with type 2 diabetes, the antihyperglycemic
`ellect was comparable in whites (n=249), blacks (n=51)_ and Hispanics (n=24).
`CLINICAL STUDIES
`GLUCOPHAGE
`In a double-blind, placebocontrolled, multicenter U.S. clinical trial involving obese patients with
`type 2 diabetes whose hyperyycemia 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 Aw (HbA,J 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,
`HbA and Body Weight, at Final Visit (29-week study)
`GLUCOPHAGE
`Placebo
`(ft = 145)
`(n = 141)
`
`p-Value
`
`FPG (mg/dL)
`Baseline
`Change at FINAL VISIT
`Hemoglobin A,‘ (‘V-)
`Baseline
`Change at FINAL VISIT
`Body Weight (lbs)
`Baseline
`
`Change at FINAL VISIT
`
`‘All patients on diet therapy at Baseline
`
`"Not statistically significant
`
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`A 29-week, double-blind, placebo-controlled study ol GLUCOPHAGE and glyburide, alone and in
`combination, was conducted in obese patients with type 2 diabetes who had tailed to achieve
`adequate glycemic control while on maximum doses 01 glyburide (baseline FPG of approximately
`250 mg/dL) (see Table 3). Patients randomized to continue on glyburide experienced worsening of
`gycemic control, with mean increases in FPG, PPG, and HbA,c 01 14 mg/dL. 3 mgldL and 0.2%,
`respectively. In contrast, those randomized to GLUCOPHAGE (up to 2500 mg/day) experienced a
`slight improvement, with mean reductions in FPG, FPG, and HbA,c or 1 rng1dL, s mg/dL and 0.4%,
`respectively. The combimtion ol GLUCOPHAGE and glyburida was effective in reducing FPG, PPG,
`and HbA,c levels by 63 mg/dL, 65 mg/dL and 1.7%, respectively. Compared to resuts ol glyburide
`treatment alone, the net diflerences with combination treatment were -77 mg/dL, -68 mg/dL and
`-1.9%, respectively (see Table 3).
`Table 3. Combined GLUCOPHAGE/Glyburlde (Comb) vs Glyburide (Gtyb) or
`GLUCOPHAGE (GLU) Monotherepy: Summary of Mean Changes from BassIne'
`in Fasting Plasma Glucose. HbA and Body Weight, at Final Visit (29-week study)
`p-values
`GLU vs
`Comb
`
`Comb
`(n = 213)
`
`Glyb
`(n = 209)
`
`GLU
`(n = 210)
`
`Glyb vs
`Comb
`
`GLU vs
`Glyb
`
`(HbA1 : 7.15 2 0.61 versus 6.97 2 0.62 for GLUCOPHAGE plus insulin and placebo plus insulin,
`respectively) with 19% less insulin versus baseline (reduction 01 23.66 x 30.22 versus an increase
`ol 0.43 : 25.2!) units for GLUCOPHAGE plus insulin and placebo plus insulin, p<0.01). In addition,
`this study demonstrated that the combination of GLUCOPHAGE (mettormin hydrochloride tablets)
`plus insulin resulted in reduction in body weight of 3.11 2 4.30 lbs, compared to an increase ot 1.30
`2 6.08 lbs for placebo plus insulin, p=0.01.
`GLUCOPHAGE XR
`A 24-week, double-blind, placebo-controlled study ol GLUCOPHAGE XR, taken once daily with the
`evening meal, was conducted in patients with type 2 diabetes who had tailed 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 HbA,c ol 8.0% and a mean baseline FPG oi 176 mg/dL. Alter 12 weeks treat-
`ment, mean HbA,¢ 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 l>tbA,c ot 0.6% and a
`decrease in mean FPG ol 23 mg/dL in patients treated with GLUCOPHAGE XR 11200 mg once daily.
`Subsequently, the treatment dose was increased to 1500 mg once daily if HbA1c was 27.0% but
`(8.0% (patients with HbA,c 23.0% were discontinued lrom the study). At the final visit (24~week),
`mean I-lbA,c had increased 0.2% from baseline in placebo patients and decreased 0.6% with
`GLUCOPHAGE XFI (metlorrnin hydrochloride extended—release tablets).
`A 18-week. doubltbllnd, placebocontrolled, 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 lailed to achieve glycemic control with diet and exercise (HbA1c 7.0-11%, FPG
`126-280 mg/dL). Changes in glycemic control and body weight are shown in Table 8.
`
`Table 8. Summary of Mean Changes from Baseline’ in HbA,=,
`Fasting Plasma Glucose, and Body Weight at Final Visit (16-week study)
`GLUCOPHAGE XR
`1000 mg
`1500 mg
`2000 mg
`Once
`Once
`Once
`Dally
`Daily
`Daily
`
`1000 mg
`Twice
`Dally
`
`p-value‘
`
`Hemoglobin A1: (98)
`Baseline
`Change at FINAL VISIT
`p-value‘
`FPG (mg/dL)
`Baseline
`Change at FINAL VISIT
`p-value“
`Body Weight (lbs)
`Baseline
`Change at FINAL VISIT
`
`.
`
`All patients on diet therapy at Baseline
`" All comparisons versus Placebo
`" Not statistically significant
`
`in gycemic control was seen at all dose levels 01
`improvement
`Compared with placebo,
`GLUCOPHAGE XR and treatment was not associated with any significant change in weight
`(see DOSAGE AND ADMINISTRATION tor dosing recommendations for GLUCOPHAGE and
`GLUCOPHAGE )(R).
`A 24-week, double-blind, randomized study of GLUCOPHAGE XFl, taken once daily with the
`evening meal, and GLUCOPHAGE, taken twice daily (with breakfast and evening meal), was 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 ol glycemic control prior to study entry. Patients qualified tor the
`study it HbA,c was 58.5% and FPG was Qt!) 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
`?SE. 3
`GLUCOPHAGE
`500 mg ‘twice Dally
`T :4
`
`(n=74) (-0.2. 2.4)
`
`(96)
`
`Hemoglobin <
`Baseline
`Change at 12 Weeks
`(95% Cl)
`Change at FINAL VISIT
`(95% Cl)
`FPG (mgldl)
`Baseline
`Che e at 12 Weeks
`5% cl)
`Change at FINAL VISIT
`(95% Cl)
`300! Weitlhl 0!”)
`Baseline
`Change at 12 Weeks
`(95% Cl)
`Change at FINAL VISIT
`(95% Cl)
`
`(-0.03, 0.31)
`0.14-
`(004, 0.31)
`
`127.2
`12.9
`6.5, 19.4)
`
`(7.0, 21.0)
`(n=7t)
`
`GLUCOPHAGE X8
`1000 mg Once Dally 1500 mg Once Daily
`ln=72l
`("=53
`6.99
`7.02
`0.04
`(-0.03, 0.15)
`0.13
`(-0.02, 0.28)
`l'|=7°l
`131.4
`3.7
`(-0.4, 7.0)
`7.6
`(1.0, 14.2)
`01:71)
`192.7
`0.7
`(-0.4, 1.8)
`0.9
`(-0.4. 2.0
`
`(0.10, 0.36)
`0.27
`- .1 1 , 0.43)
`n=72)
`.-.
`
`(4.4, 14.6)
`
`(4.4, 18.5)
`
`.41
`
`.11
`
`Change at FINAL VISIT
`at FINAL VISI'T
`
`Fasting Plasma
`Glucose (mg/dL)
`Baseline
`Change at FINAL VISIT
`Hemoglobin A1‘ (93)
`Baseline
`Change at FINAL VISIT
`Body Weight (lbs)
`Baseline
`
`"Not statistically significant
`‘AI patients on glyburide, 20 mglday, at Baseline
`The magnitude 01 the decline in lasting blood glucose concentration lollowing the institution
`of GLUCOPHAGE (metlormin hydrochloride tablets) therapy was proportional to the level oi
`fasting hypergycemia. Patients with type 2 diabetes with higher tasting gucoee concentrations
`experienced greater declines in plasma glucose and glycoeylated hemoglobin.
`In clinical studies, GLUCOPHAGE, alone or in combination with a sulonylurea, lowered mean fast-
`ing serum triglycerides, total cholesterol, and LDL cholesterol levels and had no adverse ellects on
`other lipid levels (see Table 4).
`Table 4. Summary o1 Mean Percent Change from Baseline
`of Malor Serum Lipid Variables at Final Visit (29-week studies)
`Combined GLUCOPHAGE/Glyburide
`vs Monotherapy
`GLUCOPHAGE
`Glyburlde
`(n = 213)
`
`GLUCOPHAGE Placebo
`(n = 141)
`(rs = 145)
`Total Cholesterol (mg/dl.)
`Baseline
`Mean 96 change
`at FINAL VISIT
`
`LUCOPHAGE
`(n = 210)
`
`GLUCOPHAGE vs Placebo
`
`Baseline
`Mean % change
`at FINAL VlSl'I'
`
`Baseline
`Mean % change
`at FINAL VISIT
`
`Baseline
`Mean % change
`
`In contrast to sultonylureas, body weigll 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 pllu 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 HbA,c ol 2.10%, compared to a 1.56% reduction in HbA,c achieved
`by insulin plus placebo. The improvement in glycemic control was achieved at the line! study visit
`with 16% less insulin, 93.0 U/day vs 110.8 U/day, GLUCOPHAGE plus insulin versus insulin plus
`placebo, respectively. p=0.04.
`Table 5. Combined GLUCOPHAGE/Insulin vs Placebollnsulln
`Summary of Mean Changes lrorn Baseline in HbA and Daily Insulin Dose
`Mean 2 SE""'"°"°'
`
`n=23
`
`n=28
`
`Hemoglobin A“ (94)
`
`
`
`Change at FINAL VISIT
`Insulin Dose (U/day)
`Baseline
`Change at FINAL vlsrr
`
`- 2.10
`
`94.64
`15.93
`
`. 10.00 2 7.775
`
`5 Statistically significant using analysis at covariance with baseline as covariate (p=0.04)
`Not significant using analysis at variance (values shown in table)
`b Statistically significant for insulin (p=0.04)
`A second doubIe~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 HbA,c of 7.46 2 0.97%, the addition of GLUCOPHAGE maintained similar glycemic control
`
`' All patients on GLUCOPHAGE 500 mg twice daily at Baseline
`3 n=68
`in the
`there was an increase in mean HbA,c in all groups;
`treatment,
`After 12 weeks of
`GLUCOPHAGE XR 1000 mg group, the increase lrom baseline 010.23% was statistically signifi-
`cant (see DOSAGE AND ADMINISTRAHON).
`
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`Changes in lipid parameters in the previously described placebo-controlled dose-response study
`of GLUCOPHAGE XR are shown in Table 8.
`
`GLUCOPHAGE and GLUCOPHAGE XR should be temporarily discontinued in patients undergoing
`radiologic studies involving intravasculer 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 met-
`forrnin 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 at pathoplrysiologic conditions, including diabetes mellltue, and
`whenever there is significant tissue hypoperfusion and hypcxemia. Lactic acidosis ls char-
`acterized by elevated blood lactate levels (>5 mmoIlL), decreased blood pH, electrolyte
`dsturbances with an increased anion gap, and an Increased lactate/pyruvate ratio. When
`metformin is implicated as the cause of lactic acidosis, metformln plasma levels >5 pg/ml.
`are generally found.
`The reported incidence of lactic acidosis in patients receiving metforrnln hydrochloride is
`very low (approximately 0.03 casesltooo patient-years, with approximately 0.015 fatal
`cseesltooo patient-years). Reported cases have occurred primarily in diabetic patients
`with significant renal Insufficiency, incluclng both intrinsic renal disease and renal hypo-
`perfuslon, often in the setting of multiple concomitant medical/surgical problems and muf-
`tipls concomitant rnedlcatlons. Patients with congestive heart failure requiring pharmaco-
`Iogic management, In particular those with unstable or acute congestive heart failure who
`are at risk of hypoperfuslon and hypoxemla, are at increased risk of lactic acidosis. The
`risk of lactic acidosis increases with the degree of renal dysfunction and the patiant's age.
`The risk of lactic acidosis may, therefore, be signillcarrtfy decreased by regular monitoring
`of renal function In patients taking GLUCOPHAGE or GLUCOPI-IAGE XR and by use of the
`minimum effective dose of CLUCOPI-IAGE or GLUCOPNAGE XR. In particular, treatment of
`the elderly should be accompanied by carahl monitoring of renal function. GLUCOPI-IAGE
`or GLUCOPHAGE )6! treatment should not be inltldted in patients 2 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 hypoxemla, 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
`htalte, either acute or chronic, when taking GLUCOPHAGE or GLUCOPHAGE XR, since
`alcohol potentlatee the effects of metformln hydrochloride on lachta metabolism. In addi-
`tlon, GLUCOPIIAGE and GLUCOPHAGE XII should be temporarily discontinued prior
`to any lntravascutar rediocontrast 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, rnyalgles. respiratory distress, Increasing sornnolence, and
`nonspecific abdominal distress. There may be associated hypothennh, hypoteneion, and
`resistant bradyarrhythmias with more marked acidosis. The patient and the petlant'a
`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 XI-‘l sholld be withdrawn until the situation is
`clarified. Serum electrolytes, Itetones, 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 dmg 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 rnmol/L in patients felting 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-
`lng evidence of ltetoacidosle (ketonuria and itetonemia).
`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 metfonnln hydrochloride is dlalyzable (with a clearance of up to 170 mUmin under
`good hemodynamic conditions), prompt hemodlalysls is recommended to oorred the sol-
`doaia and remove the accumulated metformin. Such management Mtaen results in prompt
`reversal of symptoms and recovery. (See also CONTRAINDICATIONS and PRECAUTIONS.)
`
`PRECAUTIONS
`General
`Monitoring of renal function — Metforrnin is known to be substantially excreted by the kidney,
`and the risk of metformin accunulation and lactic acidosis increases with the degee of impairment
`of renal function. Thus, patients with serun creatinine levels above the upper limit of normal for
`their age should not receive GLUCOPHAGE (metforrnin hydrochloride tablets) or GLUCOPHAGE
`XR (metformln hydrochloride extended-release tablets).
`In patients with advanced age,
`GLUCOPHAGE and GLUCOPHAGE XR should be carefully titrated to establish the minlrnum dose
`for adequate gfycomic 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-
`erally, GLUCOPHAGE and GLUCOPHAGE )0? should not be titrated to the maximum dose (see
`WARNINGS and DOSAGE AND ADMINISTRATION).
`Before initiation of GLUCOPI-IAGE or GLUCOPHAGE XH therapy and at least annually thereafter,
`renal function should be assessed and verified as normal. In patients in whom development of renal
`dysfunction is anticipated, renal function should be assessed more frequently and GLUCOPHAGE
`or GLUCOPHAGE XR discontinued if evidence of renal irnpainnent is present.
`Use of concomitant rnadiudons that may affect renal hrncfion or metfonnln disposition —
`Concomitant medication(s) that may affect renal function or resut in sigiilicant hemodynernic change
`or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal
`ttbdar secretion (see PRECAUTIONS: Drug Interactions], should be used with caution.
`Radiologic studies involving die use of lntravascular iodlnafad contrast materials (for exam-
`ple, intravenous urograrn, htravenous cholangiography, angiography, and computed tomog-
`raphy (CT) scans wfbtr intrevascular contrast materials) — lntravascular contrast studies with
`iodinated materials can lead to acute alteration of renal function and have been associated with
`lactic acidosis in patients receiving metformin (see CONTRAINDICATIONS). Therefore, in patients
`in whom any such study is planned, GLUCOPHAGE or GLUCOPHAGE XFI should be temporarily
`discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the
`procedure and reinstituted only after renal function has been re-evaluated and found to be normal.
`Hypoxia: states — Cardiovascular collapse (shock) from whatever cause, acute congestive heart fail-
`ure, acute myocardial infarction and other conditions characterized by hypoxernia have been associ-
`ated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients
`
`Mylan EX 1008, Page 4
`
`Table 8. Summary of Mean Percent Changes from Baseline‘ in
`Malor Lipid Variables at Final Visit (16-week study)
`GLUCOPHAGE XR
`500mg 1000mg 1500mg 2000mg 1000mg
`Once
`Once
`Once
`Once
`Tirrlce
`Daily
`Daily
`Daily
`Daily
`Daily
`llt=120)
`(n=‘l13)
`(n=110)
`(n=l26)
`214.6
`204.4
`0.7%
`-1.6%
`
`Placebo
`
`-3.3%
`FINAL VISIT
`Change at FINAL VISIT
`
`Total Cholesterol (mgldl)
`Baseline
`Mean '36 change at
`FINAL VISIT
`Tohl Triglycerides (mgIdL) (n=12D)
`Baseline
`Mean 96 change at
`FINAL VISIT
`LDL-Cholesterol (mg/dL)
`Baseline
`Mean % change at
`FINAL VISIT
`HDL—Cholaaterol(mgldI.)
`Baseline
`Mean % change at
`FINAL VISIT
`
`(n=119)
`
`(n=120)
`
`ln=126I
`194.2
`14.9%
`
`(rt=‘l2Q
`125.8
`
`(n=l13)
`
`(n=110)
`
`(rr=113)
`
`(n=108)
`
`‘ All patients on diet therapy at Baseline
`Changes in lipid parameters in the previously described study of GLUCOPHAGE and
`GLUCOPHAGE XFI are shown in Table 9.
`
`Table 0. Summary of Mean Percent Changes from Baseline‘ in
`Major Lipid Variables at Final Visit (24-week study)
`GLUCOPHAGE XR
`SCI) mg Once Dally
`
`Total Cholesterol (mg/dl.)
`Baseline
`Mean % change at
`FINAL VISIT
`Total Triglycerides (mg/dL)
`Baseline
`Mean 96 change at
`FINAL VISIT
`LDL-Cholesterol (mg/dl.)
`Baseline
`Mean 96 change at
`FINAL VISIT
`HDL-Cholesterol (mg/dL)
`Baseline
`Mean 96 change at
`
`' 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 mgIdl.), treatment with GLUCOPHAGE (up to 2000 mg/day) for up to
`16 weeks (mean duration of treatment 11 weeks) resulted in e significant mean net reduction in FPG
`of 64.3 mg/dL compared w'rth placebo (see Table ll).
`
`Table 10. GLUCOPHAGE vs Placebo Pediatrics’)
`Summary of Mean Changes from Baseline’ in
`Plasma Glucose and Body Weight at Flrul Visit
`
`FPG (mg/dL)
`Baseline
`
`°-L°°°'"*°E
`ln=37l
`162.4
`-42.9
`
`Body Weight (lbs)
`Baseline
`Change at FINAL VISIT
`
`v
`
`(M35)
`192.3
`21.4
`ln=38)
`189.0
`-2.0
`
`" 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 (matlormin hydrochloride tablets) and GLUCOPHAGE XR (metformln hydrochloride
`extended~rslease tablets). as monotherapy, are indicated as an adjunct to diet and exercise to
`improve gycernic control in patients with type 2 diabetes. GLUCOPHAGE is indicated in patients
`10 years of age and older, and GLUCOPHAGE XR is indicated in patients 17 years of age and older.
`GLUCOPHAGE or GLUCOPHAGE XR may be used concomitantly with a sullonylurea or insulin to
`improve glycemic 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 phannacologic treatment.
`3. Known hypersensitivity to metlormin hydrochloride.
`4. Acute or chronic metabolic acidosis, including diabetic ketoacidosis. with or without come.
`Diabetic ketoacidosis should be treated with insufin.
`
`Mylan EX 1008, Page 4
`
`

`
`
`
`on GLUCOPHAGE or GLUCOPHAGE XR therapy. the dmg should be promptly discontinued.
`Surgical procedures — GLUCOPHAGE or GLUCOPHAGE XR therapy shotld be temporarily sus-
`pended for any surgical procedure (except minor procedures not associated with restricted intake
`of food and fluids) and should not be restarted until the patient‘s oral intake has resuned and renal
`function has been evaluated as normal.
`Alcohol intake — Alcohol is known to potentiate the affect of metformin on lactate metabolism.
`Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while
`receiving GLUCOPHAGE or GLUCOPHAGE XR.
`hnpaired hepatic function - Since impaired hepatic function has been associated with some
`cases of lactic acidosis, GLUCOPHAGE and GLUCOPHAGE XR should generally be avoided in
`patients with clinical or laboratory evidence of hepatic disease.
`Vitamin 5,, levels —— In controlled clinical
`trials of GLUCOPHAGE of 29 weeks duration. a
`decrease to subnonnal levels of previously normal serum \/Itamin 3,2 levels, without clinical man-
`ifestations. was obse