CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`NDA 21-574
`
`Approved Labeling
`
`

`

`NDA 21-574
`
`Page 3
`
`FORTAMETTM (metformin hydrochloride) Extended-Release Tablets
`
`RX only
`
`DESCRIPTION
`
`FORTAMETTM (metformin hydrochloride) Extended—
`Release Tablets contain an oral antihyperglycernic drug
`used in the management of type 2 diabetes. Metformin
`hydrochloride (N, N-dimethylimidodicarbonimidic diamide
`hydrochloride) is a member of the biguanide class of oral
`antihyperglycemics and is not chemically or
`pharmacologically related to any other class of oral
`antihyperglycemic agents. The empirical formula of
`metformin hydrochloride is C4H1 [NS-HCI and its
`molecular weight is 165.63; Its structural formula is:
`
`H30
`
`H3C
`
`N-C-NH-C—NHZ' HCI
`II
`II
`NH
`NH
`
`metformin hydrochloride is a white to off-white crystalline
`powder that 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.
`
`FORTAMETTM Extended—Release Tablets are designed for '
`once—a—day oral administration and deliver 500 mg or
`1000 mg of metformin hydrochloride. In addition to the
`active ingredient metforrnin hydrochloride, each tablet
`contains the following inactive ingredients: candellila wax,
`cellulose acetate, hypromellose, magnesium stearate,
`polyethylene glycols (PEG 400, PEG 8000), polysorbate
`80, povidone, sodium lauryl sulfate, synthetic black iron
`oxides, titanium dioxide, and triacetin.
`
`

`

`NDA 21-574
`
`Page 4
`
`SYSTEM COMPONENTS AND PERFORMANCE
`FORTAMETTM was developed as an extended-release
`formulation of metformin hydrochloride and designed for
`once-a—day oral administration using the patented single—
`composition osmotic technology (SCOTm). The tablet is
`similar in appearance to other film-coated oral
`administered tablets but it consists of an osmotically active
`core formulation that is surrounded by a semipermeable
`membrane. Two laser drilled exit ports exist in the
`membrane, one on either side of the tablet. The core
`
`formulation is composed primarily of drug with Small
`concentrations of excipients. The semipermeable
`membrane is permeable to water but not to higher
`molecular weight components of biological fluids. Upon
`ingestion, water is taken up through the membrane, which
`in turn dissolves the drug and excipients in the core
`formulation. The dissolved drug and excipients exit
`through the laser drilled ports in the membrane. The rate
`of drug delivery is constant and dependent upon the
`maintenance of a constant osmotic gradient across the
`membrane. This situation exists so long as there is
`undissolved drug present in the core tablet. Following the
`dissolution of the core materials, the rate of drug delivery
`slowly decreases until the osmotic gradient across the
`' membrane falls to zero at which time delivery ceases. The
`membrane coating remains intact during the transit of the
`dosage form through the gastrointestinal tract and is
`excreted in the feces.
`
`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
`pharrnacologic 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 plasma insulin levels and day-long
`plasma insulin response may actually decrease.
`
`

`

`NDA 21-574
`
`Page 5
`
`PHARMACOKINETICS AND DRUG METABOLISM
`
`Absorption and Bioavailability
`The appearance of metformin in plasma from a
`FORTAMETTM Extended—Release Tablet is slower and
`
`more prolonged compared to immediate-release metformin.
`
`In a multiple-dose crossover study, 23 patients with type 2»
`diabetes mellitus were administered either FORTAMETTM
`
`2000 mg once a day (after dinner) or immediate-release
`(IR) metformin hydrochloride 1000 mg twice a day (after
`breakfast and after dinner). After 4 weeks of treatment,
`steady-state pharrnacokinetic parameters, area under the
`concentration-time curve (AUC), time to peak plasma
`concentration (Tmax), and maximum concentration
`(Cmax) were evaluated. Results are presented in Table 1.
`
`Table 1
`
`FORTAMETTM vs. Immediate—Release Metformin
`
`Steady-State Pharmacokinetic Parameters at 4 Weeks
`
`Pharmacokinetic Parameters
`FORTAMET m
`Immediate—Release Metformin
`(mean i SD)
`2000 mg
`2000 mg
`
`
`administered q.d. after dinner)
`(1000 mg b.i.d.)
`
`
`
`3 (1—8)
`
`
`
`AUC 0.14 h, (ng-hr/mL) 27,371 i 5,781 26,811 :t 7055
`
`6 (3—10)
`
`
`
`2849 i 797Cmax (ng/mL) 1820 :r 370
`
`
`
`In four single—dose studies and one multiple-dose study, the
`bioavailability of FORTAMETTM 2000 mg given once
`daily, in the evening, under fed conditions [as measured by
`the area under the plasma concentration versus time curve
`(AUC)] was similar to the same total daily dose
`administered as immediate—release metformin 1000 mg
`given twice daily. The geometric mean ratios
`(FORTAMETTM/ immediate—release metformin) of
`AUCO,24hr, AUCO_72hr, and AUCO.inf_ for these five studies
`
`ranged from 0.96 to 1.08.
`
`

`

`NDA 21-574
`
`Page 6
`
`In a single-dose, four—period replicate crossover design
`study, comparing two 500 mg FORTAMETm tablets to one
`1000 mg FORTAMETTM tablet administered in the evening
`with food to 29 healthy male subjects, two 500 mg
`FORTAMETTM tablets were found to be equivalent to one
`1000 mg FORTAMETTM tablet.
`
`In a study carried out with FORTAMETTM, there was a
`dose-associated increase in metformin exposure over
`24 hours following oral administration of 1000, 1500,
`2000, and 2500 mg.
`
`In three studies with FORTAMETTM using different
`treatment regimens (2000 mg after dinner; 1000 mg after
`breakfast and after dimer; and 2500 mg after dinner), the
`pharmacokinetics of metformin as measured by AUC
`appeared linear following multiple—dose administration.
`
`The extent of metformin absorption (as measured by AUC)
`from FORTAMETTM increased by approximately 60%
`when given with food. When FORTAMETTM was
`administered with food, Cmax was increased by
`approximately 30% and Tmax was more prolonged
`compared with the fasting state (6.1 versus 4.0 hours).
`
`Distribution
`
`Distribution studies with FORTAMETTM have not been
`
`conducted. However, the apparent volume of distribution
`.(V/F) of metformin following single oral doses of
`immediate-release metformin 850 mg averaged 654 i
`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 immediate—release metformin,
`steady state plasma concentrations of metformin are
`reached within 24—48 hours and are generally <1 ug/mL.
`During controlled clinical trials of immediate—release
`metformin, maximum metformin plasma levels did not
`exceed 5 ug/mL, even at maximum doses.
`
`

`

`NDA 21—574
`
`Page 7
`
`Metabolism and Excretion
`
`Metabolism studies with FORTAMETT” have not been
`conducted.
`
`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.
`
`In healthy nondiabetic adults (N=18) receiving 2500 mg
`q.d. FORTAMETTM, the percent of the metformin dose
`excreted in urine over 24 hours was 40.9% and the renal
`
`clearance was 542 i 310 mL/min. After repeated
`administration of FORTAMETN, there is little or no
`accumulation of metformin in plasma, with most of the
`drug being eliminated via renal excretion over a 24-hour
`dosing interval. The ty, was 5.4 hours for FORTAMETTM
`
`Renal clearance of metformin (Table 2) 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
`eliminationlhalf—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.
`
`

`

`NDA 21—574
`
`Page 8
`
`Special Populations
`
`Geriatrics
`
`Limited data from controlled pharmacokinetic studies Of
`immediate-release metformin 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 (Table 2). FORTAMETTM treatment should not be
`initiated in patients 2 80 years of age unless measurement
`of creatinine clearance demonstrates that renal function is
`
`not reduced. (See WARNINGS, PRECAUTIONS and
`DOSAGE AND ADMINISTRATION.)
`
`Pediatrics
`
`No pharmacokinetic data from studies of pediatric patients
`are currently available. (See PRECAUTIONS.)
`
`Gender
`
`Five studies indicated that with FORTAMETW treatment,
`the pharmacokinetic results for males and females were
`comparable.
`
`

`

`NDA 21-574
`
`Page 9
`
`Table 2
`
`Select Mean ($SD) Metformin Pharmacokinetic Parameters Following Single or
`Multiple Oral Doses of Immediate-Release Metformin
`
`Subject Groups: Immediate-Release Metformin dose‘I
`(number of subjects)
`Healthy, nondiabetic adults:
`
`C...”b
`(Hg/mL)
`
`500 mg single dose (24)
`
`850 mg single dose (74)d
`
`850 mg three times daily for 19 closese (9)
`Adults with type 2 diabetes:
`
`850 mg single dose (23)
`
`'
`
`1.03 ($0.33)
`
`2.75 ($0.81)
`
`1.60 ($0.38)
`
`2.64 ($0.82)
`
`2.01 ($0.42)
`
`1.79 ($0.94)
`
`3.32 ($1.08)
`1.48 ($0.5)
`
`1.90 ($0.62)
`2.01 ($1.22)
`
`850 mg three times daily for 19 closese (9)
`Elderly', healthy nondiabetic adults:
`
`850 mg single dose (12)
`2.45 ($0.70)
`Renal-impaired adults:
`850 mg single dose
`
`Renal
`Clearance
`(mL/min)
`
`600 ($132)
`
`552 ($139)
`
`642 ($173)
`
`491 ($138)
`
`550 ($160)
`
`3 CLcr = creatinine clearance normalized to body surface area of 1.73 m2
`
`2.71 ($1.05)
`
`412 ($98)
`
`Mild (CLC,g 61-90 mL/min) (5)
`Moderate (CLU31-60 mL/min) (4)
`
`Severe (CLcr 10-30 mL/min) (6)
`
`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 ($90)
`
`a All doses given fasting except the first 18 doses of the multiple dose studies
`I’.I’eak 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
`rElderly subjects, mean age 71 years (range 65-81 years)
`
`'
`
`
`
`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 (Table 2; also see WARNINGS).
`
`Hepatic Insufficiency
`
`No pharmacokinetic studies of metformin have been
`conducted in patients with hepatic insufficiency.
`
`

`

`NDA 21-574
`
`Page 10
`
`Race
`
`No studies of metforrnin pharmacokinetic parameters
`according to race have been performed. In controlled
`clinical studies of immediate—release metformin in patients
`with type 2 diabetes, the antihyperglycemic effect was
`comparable in whites (F249), blacks (n=51), and
`Hispanics (n=24).
`
`Clinical Studies
`
`- In a double-blind, randomized, active-controlled,
`multicenter U.S. clinical study, which compared
`FORTAMETTM q.d. to immediate-release metformin b.i.d.,
`680 patients with type 2 diabetes who had been taking
`metforrnin-containing medication at study entry were
`randomly assigned in equal numbers to double-blind
`treatment with either FORTAMETTM or immediate-release
`
`metformin. Doses were adjusted during the first six weeks
`of treatment with study medication based on patients’ FPG
`levels and were then held constant over a period of 20
`weeks. The primary efficacy endpoint was the change in
`HbAlc from baseline to endpoint. The primary objective
`was to demonstrate the clinical non-inferiority of
`FORTAMETTM compared to immediate—release metformin
`on the primary endpoint.
`
`FORTAMETTM and metformin patients had mean HbAlc
`changes from baseline to endpoint equal to +0.40 and
`+0.14, respectively (Table 3). The least-square (LS) mean
`treatment difference was 0.25 (95% CI = 0.14, 0.37)
`demonstrating that FORTAMETTM was clinically similar to
`metforrnin according to the pre—defined criterion to
`establish efficacy.
`
`

`

`NDA 21-574
`
`Page 1 1
`
`N B
`
` Table 3
`
`
`
`FORTAMETm vs. Immediate-Release Metformin
`Switch Study: Summary of Mean Changes'1n HbAlc, Fasting Plasma Glucose, Body
`
`
`
`
`Weiht, Bod Mass Index, and Plasma Insulin
`Treatment difference
`Immediate-Release
`FORTAMET’”
`
`
`
`
`Metformin
`for change from baseline
`
`
`
`(FORTAMETN minus
`Immediate-Release
`Metformin)
`LS mean
`
`
`
`(2-sided 95% Cl a)
` HbAlc (%)
`
`327
`332
`0.25
`
`
`7.04 i 0.88
`7.07 i 0.76
`
`aseline (mean i SD)
`
`(0.14, 0.37) b
`
`0.40 i 0.75
`0.14 i 0.75
`Change from baseline (mean iSD)
`
`
`
` Fasting Plasma Glucose (mg/dL)
`N
`329
`333
`6.43
`
`
`
`Baseline (mean i SD)
`Change from baseline (mean iSD)
`
`
`
`
`Plasma Insulin (pu/mL)
`
`
`N
`
`
`17.3 i 10.5
`17.9 i'15.1
`Baseline (mean 1‘ SD)
`Change from baseline (mean iSD)
`-3.6 i 13.8
`-3.2 i 8.6
`
`
`
`Body Weight (kg)
`N
`
`146.8 i 32.1
`
`10.0 i 40.8
`
`145.6 i 29.5
`
`4.2 i 35.9
`
`304
`
`316
`
`(0.57, 12.29)
`
`0.02
`
`(—1.47, 1.50)
`
`.
`
`313
`
`320
`
`0.30
`
`Baseline (mean i SD)
`
`94.1 i 17.8
`
`93.3 i 17.4
`
`(-0.22. 0.81)
`
`Change from baseline (mean iSD)
`0.3 i 2.9
`0.0 i 3.7
`
`
`Body Mass Index (kg/m2)
`N
`
`Baseline (mean i SD)
`
`.
`
`313
`
`31.1 i 4.7
`
`320
`
`31.4 i 4.5
`
`0.08
`
`(—0.1 1, 0.26)
`
`0.0 i 1.3
`0.1 i 1.1
`Change from baseline (mean iSD)
`
`
`I
`
`»
`a CI = Confidence Interval
`b FORTAMET was clinically similar to immediate—release metformin based on the pre—defined
`criterion to establish efficacy. While demonstrating clinical similarity, the response to FORTAMET
`compared to immediate—release metformin was also shown to be statistically smaller as seen by the
`95% CI for the treatment difference which did not include zero.
`
`Footnote Patients were taking metformin——containing medications at baseline that were prescribed by
`their personal physician.
`
`

`

`NDA 21-574
`
`Page 12
`
`The mean changes for FPG (Table 3) and plasma insulin
`(Table 3) were small for both FORTAMETTM and
`immediate—release metformin, and were not clinically
`meaningful. Seventy-six (22%) and 49 (14%) of the
`FORTAMETTM and immediate-release patients,
`respectively, discontinued prematurely from the trial.
`Eighteen (5%) patients on FORTAMETTM" withdrew
`because of a stated lack of efficacy, as compared with 8
`patients (2%) on immediate-release metformin (p=0.047).
`
`Results from this study also indicated that neither
`FORTAMET1M nor immediate—release metformin were
`
`associated with weight gain or increases in body mass
`index.
`
`A 24-week, double blind, placebo-controlled study of
`immediate-release metformin plus insulin, versus insulin
`plus placebo, was conducted in patients with type 2
`diabetes who failed to achieve adequate glycemic control
`on insulin alone (Table 4). Patients randomized to receive
`immediate—release metformin plus insulin achieved a
`reduction in HbAlc 0f2. 10%, compared to a 1.56%
`reduction in HbAlc 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 versus
`110.6 U/day, immediate-release metformin plus insulin
`versus insulin plus placebo, respectively, p=0.04.
`
`

`

`NDA 21-574
`
`Page 13
`
`
`Table 4
`
`Combined Immediate-Release Metformin/Insulin vs. Placebo/Insulin: Summary of
`Mean Changes from Baseline in HbAlc and Daily'Insulin Dose
`
`Immediate-Release
`Metformin llnsulin
`(in = 26)
`
`Treatment difference
`Mean i SE
`
`Placebo/Insulin
`(n —— 28)
`
`
`
`
`Baseline
`8.95
`9.32
`
`Change at FINAL VISIT
`—2.10
`-I.56
`.
`-0.54 i 0.43a
`Insulin Dose (U/day)
`Baseline
`
`HbAlc (%)
`
`93.12
`
`94.64
`
`
`
`-l6.08 i 7.77b
`15.93
`-0.15
`Change at FINAL VISIT
`
`“ Statistically significant using analysis of covariance with baseline as covariate (p=0.04)
`Not significant using analysis of variance (values shown in table)
`h 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 HbAlc of 7.46 i 0.97%, the addition
`of immediate—release metformin maintained similar
`
`glycemic control (HbAlC 7.15 i 0.61 versus
`6.97 i 0.62 for immediate-release metformin plus insulin
`and placebo plus insulin, respectively) with 19% less
`_ insulin versus baseline (reduction of 23.68 1- 30.22 versus
`an increase of 0.43 i 25.20 units for immediate-release
`
`metformin plus insulin and placebo plus insulin, p<0.01).
`In addition, this study demonstrated that the combination of
`immediate-release metformin plus insulin resulted in I
`reduction in body weight of 3.11 i 4.30 lbs, compared to
`an increase of 1.30 i 6.08 lbs for placebo plus insulin,
`p=0.01.
`
`Pediatric Clinical Studies
`
`No pediatric clinical studies have been conducted with
`FORTAMETTM.
`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
`immediate—release metformin (up to 2000 mg/day) for up
`to 16 weeks (mean duration of treatment 1 1 weeks)
`resulted in a significant mean net reduction in FPG of
`64.3 mg/dL'compared with placebo (Table 5).
`
`

`

`NDA 21-574 '
`
`Page 14
`
`
`Table 5
`
`Immediate-Release Metformin vs. Placebo (Pediatricsa):
`Summary of Mean Changes from Baseline* in Plasma Glucose and
`Bod Wei ht at Final Visit
`Immediate-Release
`Metformin
`
`
`FPG (mg/dL)
`Baseline
`
`Change at FINAL VISIT
`
`'
`
`(n = 37)
`162.4
`
`—42.9
`
`
`
`(n = 39)
`Body Weight (lbs)
`205.3
`Baseline '
`—3.3
`Change at FINAL VISIT
`
`a Pediatric patients mean age l3.8 years (range 10-16 years)
`* All patients on diet therapy at Baseline
`** Not statistically significant
`
`INDICATIONS AND USAGE
`
`FORTAMET” (metformin hydrochloride) Extended—
`Release Tablets, used as a once per day monotherapy, are
`indiCated as an adjunct to diet and exercise to lower blood
`glucose. FORTAMETTM can be used concomitantly with a
`TM
`sulfonylurea or insulin to improve glycemic control in
`adults. FORTAMET is indicated in patients 17 years of
`age and older as either monotherapy or in combination
`therapy.
`
`CONTRAINDICATIONS
`
`FORTAMETTM is contraindicated in patients with:
`1. Renal disease or renal dysfunction (e.g., as suggested by
`serum creatinine levels 21.5 mg/dL [males], 21.4 mg/dL
`[females] or abnormal creatinine clearance) which may
`also result from conditions such as cardiovascular collapse
`(shock), acute myocardial infarction, and septicemia (see
`WARNINGS and PRECAUTIONS).
`2. Congestive heart failure requiring pharrnacologic
`treatment.
`
`3. Known hypersensitivity to metformin.
`4. Acute or chronic metabolic acidosis, including diabetic
`ketoacidosis, with or without coma. Diabetic ketoacidosis
`should be treated with insulin.
`
`

`

`NDA 21-574
`
`Page 15
`
`FORTAMETTM should be temporarily discontinued in
`patients undergoing radiologic studies involving
`intravascular administration of iodinated contrast materials,
`because use of such products may result in acute alteration
`of renal function. (See also PRECAUTIONS.)
`
`WARNINGS
`
` Lactic Acidosis:
`
`Lactic acidosis is a rare, but serious, metabolic
`complication that can occur due to metformin
`accumulation during treatment with FORTAMETm
`(metformin hydrochloride) Extended-Release Tablets;
`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 ug/mL are generally found.
`
`The reported incidence of lactic acidosis in patients
`receiving metformin hydrochloride is very low
`(approximately 0.03 cases/1000 patient-years, with
`approximately 0.015 fatal cases/1000 patient—years).
`Reported cases have occurred primarily in diabetic
`patients with significant renal insufficiency, including
`both intrinsic renal disease and renal hypoperfusion,
`often in the setting of multiple concomitant
`medical/surgical problems and multiple concomitant
`medications. 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
`FORTAMETTM (metformin hydrochloride) Extended-
`Release Tablets and by use of the minimum effective
`
`

`

`NDA 21-574
`
`Page 16
`
`dose of FORTAMETm. In particular, treatment of the
`
`elderly should be accompanied by careful monitoring of
`renal function. FORTAMETT“ treatment should not be
`
`initiated in patients 280 years of age unless
`measurement of creatinine clearance demonstrates that
`
`renal function is not redaced, as these patients are more
`susceptible to developing lactic acidosis. In addition,
`FORTAMETTM 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, FORTAMETTM 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
`FORTAMETTM, since alcohol potentiates the effects of
`metformin hydrochloride on lactate metabolism. In
`addition, FORTAMETTM should be temporarily
`discontinued prior to any intravascular radiocontrast
`study and for any surgical procedure (see also
`PRECAUTIONS).
`
`The onset of lactic acidosis often is subtle, and
`accompanied only by nonspecific symptoms such as
`malaise, myalgias, respiratory distress, increasing
`somnolence, and nonspecific abdominal distress. There
`may be associated hypothermia, hypotension, and
`resistant bradyarrhythmias with more marked acidosis.
`The patient and the patient’s physician must be aware
`of the possible importance of such symptoms and the
`patient should be instructed to notify the physician
`immediately if they occur (see also PRECAUTIONS).
`FORTAMETTM should be withdrawn until the situation
`
`is clarified. Serum electrolytes, ketones, blood glucose
`and, if indicated, blood pH, lactate levels, and even
`blood metformin levels may be useful. Once a patient is
`stabilized on any dose level of FORTAMETTM,
`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.
`
`’
`
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`

`NDA 21-574
`
`Page 17
`
`Levels of fasting venous plasma lactate above the upper
`limit of normal but less than 5 mmol/L in patients
`taking FORTAMETm do not necessarily indicate
`impending lactic acidosis and may be explainable by
`other mechanisms, such as poorly controlled diabetes or
`obesity, vigorous physical activity, or technical
`problems in sample handling. (See also
`PRECAUTIONS.)
`
`Lactic acidosis should be suspected in any diabetic
`patient with metabolic acidosis lacking evidence of
`ketoacidosis (ketonuria and ketonemia).
`
`Lactic acidosis is a medical emergency that must be
`treated in a hospital setting. In a patient with lactic
`acidosis who is taking FORTAMET”, the drug should
`be discontinued immediately and general supportive
`measures promptly instituted. Because metformin
`hydrochloride is dialyzable (with a clearance of up to
`170 mL/min under good hemodynamic conditions),
`prompt hemodialysis is recommended to correct the
`acidosis and remove the accumulated metformin. Such
`
`PRECAUTIONS.)
`
`management often results in prompt reversal of
`symptoms and recovery.
`(See also CONTRAINDICATIONS and
`
`'
`
`PRECAUTIONS
`
`General
`
`Monitoring of renalfunction — Metforrnin 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 FORTAMETTM. In
`patients with advanced age, FORTAMETTM should be
`carefully titrated to establish the minimum dose for
`adequate glycemic effect, because aging is associated with
`reduced renal function.
`In elderly patients, particularly
`TM
`- those 280 years of age,’ renal function should be monitored
`
`regularly and, generally, FORTAMET should not be
`titrated to the maximum dose (see WARNINGS and
`DOSAGE AND ADMINISTRATION).
`'
`
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`

`NDA 21-574
`
`Page 18
`
`Before initiation of FORTAMETTM therapy and at least
`annually thereafter, renal fimction should be assessed and
`verified as normal. In patients in whom development of
`renal dysfiinction is anticipated, renal function should be
`assessed more frequently and FORTAMETTM discontinued
`if evidence of renal impairment is present.
`
`Use ofconcomitant medications that may affect renal
`function or metformin disposition — Concomitant
`medication(s) that may affect renal filnction or result in
`significant hemodynamic change or may interfere with the
`disposition of metforrnin, such as cationic drugs that are
`eliminated by renal tubular secretion (see
`PRECAUTIONS: Drug Interactions), should be used
`with caution.
`
`Radiologic studies involving the use ofintravascular
`iodinated contrast materials (for example, intravenous
`urogram, intravenous cholangiography, angiography,
`and computed tomography (CT) scans with intravascular
`contrast materials) — Intravascular contrast studies with
`iodinated materials can lead to acute alteration of renal
`function and have been associated with lactic acidosis in
`
`patients receiving metfonnin (see
`CONTRAINDICATIONS). Therefore, in patients in
`whom any such study is- planned, FORTAMETTM 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.
`
`Hypoxic states — Cardiovascular collapse (shock) from
`whatever cause, acute congestive heart failure, acute
`myocardial infarction and other conditions characterized by
`hypoxemia have been associated with lactic acidosis and
`may also cause prerenal azotemia. When such events
`occur in patients on FORTAMETTM therapy, the drug
`should be promptly discontinued.
`
`

`

`NDA 21—574
`
`Page 19
`
`Surgical procedures — FORTAMETTM therapy should be
`temporarily suspended 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 resumed and renal function has
`been evaluated as normal.
`
`Alcohol intake — AlcohOl is known to potentiate the effect
`of metforrnin on lactate metabolism. Patients, therefore,
`should be warned against excessive alcohol intake, acute or
`chronic, while receiving FORTAMETTM.
`
`Impaired hepaticfunction — Since impaired hepatic
`. function has been associated with some cases of lactic
`acidosis, FORTAMETTM should generally be avoided in
`patients with clinical or laboratory evidence of hepatic
`disease.
`
`Vitamin BIZ levels — In controlled clinical trials of
`
`immediate—release m‘etformin of 29 weeks duration, a
`decrease to subnorrnal levels of previously normal serum
`Vitamin B12 levels, without clinical manifestations, was
`observed in approximately 7% of patients. Such decrease,
`possibly due to interference with Blz absorption from the
`Blg-intrinsic factor complex, is, however, very rarely
`associated with anemia and appears to be rapidly reversible
`with discontinuation of immediate—release metformin or
`
`Vitamin B12 supplementation. Measurement of
`hematologic parameters on an annual basis is advised in
`patients on FORTAMETTM and any apparent abnormalities
`should be appropriately investigated and managed (see
`PRECAUTIONS: Laboratory Tests). Certain
`individuals (those with inadequate Vitamin B12 or calcium
`intake or absorption) appear to be predisposed to
`developing subnormal Vitamin B12 levels.
`In these
`patients, routine serum Vitamin B12 measurements at two-
`to three—year intervals may be useful.
`
`

`

`NDA 21-5 74
`
`Page 20
`
`Change in clinical status ofpatients with previously
`controlled type 2 diabetes — A patient with type 2 diabetes
`previously well controlled on FORTAMETTM who develops
`laboratory abnormalities or clinical illness (especially
`vague and poorly defined illness) should be evaluated
`promptly for evidence of ketoacidosis or lactic acidosis.
`Evaluation should include serum electrolytes and ketones,
`blood glucose and, if indicated, blood pH, lactate, pyruvate,
`and metformin levels. If acidosis of either form occurs,
`FORTAMETTM must be stopped immediately and other
`appropriate corrective measures initiated (see also
`WARNINGS).
`
`Hypoglycemia — Hypoglycemia does not occur in patients
`receiving FORTAMETTM alone under usual circumstances
`of use, but could occur when caloric intake is deficient,
`when strenuous exercise is not compensated by caloric
`supplementation, or during concomitant use with other
`glucose-lowering agents (such as sulfonylureas and insulin)
`or ethanol. Elderly, debilitated, or malnourished patients,
`and those with adrenal or pituitary insufficiency or alcohol
`intoxication are particularly susceptible to hypoglycemic
`effects. Hypoglycemia may be difficult to recognize in the
`elderly, and in people who are taking beta—adrenergic
`blocking drugs.
`
`Loss ofcontrol ofblood glucose — When a patient
`stabilized on any diabetic regimen is exposed to stress such
`as fever, trauma, infection , or surgery, a temporary loss of
`glycemic control may occur. At such times, it may be
`necessary to withhold FORTAMETTM and temporarily
`administer insulin. FORTAMETTM may be reinstituted after
`the acute episode is resolved.
`
`The effectiveness of oral antidiabetic drugs in lowering
`blood glucose to a targeted level decreases in many patients
`over a period of time. This phenomenon, which may be
`I due to progression of the underlying disease or to
`diminished responsiveness to the drug, is known as
`secondary failure, to distinguish it from primary failure in
`which the drug is ineffective during initial therapy. Should
`secondary failure occur with FORTAMETTM or
`sulfonylurea monotherapy, combined therapy with
`FORTAMETTM and sulfonylurea may result in a response.
`Should secondary failure occur with combined
`FORTAMETm/sulfonylurea therapy, it may be necessary to
`consider therapeutic alternatives including initiation of
`insulin therapy.
`
`

`

`NDA 21-574
`
`Page 21
`
`. Information for Patients
`Patients should be informed of the potential risks and
`benefits of FORTAMETTM and of alternative modes of
`therapy. They should also be informed about the
`importance of adherence to dietary instructions, of a
`regular exercise program, and of regular testing of blood
`glucose, glycosylated hemoglobin, renal function, and
`hematologic parameters.
`
`The risks of lactic acidosis, its symptoms, and conditions
`that predispose to its development, as noted in the
`WARNINGS and PRECAUTIONS sections, should be
`explained to patients. Patients should be advised to
`discontinue FORTAMETTM immediately and to promptly
`notify their health practitioner if unexplained
`hyperventilation, myalgia, malaise, unusual somnolence, or
`other nonspecific symptoms occur. Once a patient is
`stabilized on any dose level of FORTAMETTM,
`gastrointestinal symptoms, which are common during
`initiation of metforrnin therapy, are unlikely to be drug
`related. Later occurrence of gastrointestinal symptoms
`could be due to lactic acidosis or other serious disease.
`
`Patients should be counseled against excessive alcohol
`intake, either acute or chronic, while receiving
`FORTAMET