NDA 21-574/S-010
`Page 3
`
`
`
`FORTAMET® (metformin hydrochloride) Extended-Release Tablets
`
`
`
`DESCRIPTION
`FORTAMET® (metformin hydrochloride) Extended-Release Tablets contain an oral
`
`
`antihyperglycemic 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 C4H11N5•HCl and its
`
`
`
`molecular weight is 165.63. Its structural formula is:
`
`
`
`
` 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.
`
`FORTAMET® 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 metformin
`
`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.
`
`FORTAMET® meets USP Dissolution Test 5.
`
`
`SYSTEM COMPONENTS AND PERFORMANCE
`FORTAMET®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
`
`(SCOT™). 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.
`
`
`

`

`NDA 21-574/S-010
`Page 4
`
`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 plasma insulin levels and day-long plasma insulin
`
`response may actually decrease.
`
`
`PHARMACOKINETICS AND DRUG METABOLISM
`
`
`Absorption and Bioavailability
`The appearance of metformin in plasma from a FORTAMET® 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
`
`
` FORTAMET® 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 pharmacokinetic
`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 FORTAMET®vs. Immediate-Release Metformin Steady-State Pharmacokinetic Parameters at 4
`
`
`Weeks
`
`
`
`
`
` FORTAMET®
`
` 2000 mg
` (administered q.d.after
`
` dinner)
`26,811 ± 7055
`6 (3-10)
`2849 ± 797
`
`Immediate-Release
`
` Metformin
`
` 2000 mg
` (1000 mg b.i.d.)
`
`
`27,371 ± 5,781
`3 (1-8)
`1820 ± 370
`
` Pharmacokinetic
`
` Parameters (mean
`
`±SD)
`
`AUC 0-24 hr (ng•hr/mL)
`
` Tmax (hr)
`Cmax (ng/mL)
`
`
`In four single-dose studies and one multiple-dose study, the bioavailability of FORTAMET® 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
`(FORTAMET®/ immediate-release metformin) of AUC0-24hr, AUC0-72hr, and AUC0-inf. for these five
`studies ranged from 0.96 to 1.08.
` In a single-dose, four-period replicate crossover design study, comparing two 500 mg FORTAMET® tablets to
`
`
` one 1000 mg FORTAMET®tablet administered in the evening with food to 29 healthy male subjects, two 500
`mg FORTAMET® tablets were found to be equivalent to one 1000 mg FORTAMET® tablet.
`
`

`

`NDA 21-574/S-010
`Page 5
`
`In a study carried out with FORTAMET®, 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 FORTAMET® using different treatment regimens (2000 mg after dinner; 1000 mg
`
` after breakfast and after dinner; 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 FORTAMET® increased by
`
`
`approximately 60% when given with food. When FORTAMET® 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 FORTAMET® 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 ± 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 µg/mL. During controlled clinical trials of
`
`immediate-release metformin, maximum metformin plasma levels did not exceed 5 µg/mL, even at maximum
`
`
`doses.
`
`Metabolism and Excretion
`Metabolism studies with FORTAMET® 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. FORTAMET®, the percent of the metformin
`
` dose excreted in urine over 24 hours was 40.9% and the renal clearance was 542 ± 310 mL/min. After repeated
`administration of FORTAMET®, 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 t1/2 was 5.4 hours for
`FORTAMET®.
`
`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 elimination half-life of approximately 6.2 hours. In blood, the elimination
`
`
`half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of
`distribution.
`
`Special Populations
`
`
`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). FORTAMET® 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, PRECAUTIONS and DOSAGE AND ADMINISTRATION).
`
`
`
`

`

`NDA 21-574/S-010
`Page 6
`
`Pediatrics
`No pharmacokinetic data from studies of pediatric patients are currently available (see PRECAUTIONS).
`
`
`Gender
`Five studies indicated that with FORTAMET® treatment, the pharmacokinetic results for males and
`
`females were comparable.
`
`
`
`
`
`
`
` 1.48 (±0.5)
` 3.32 (±1.08)
` 491 (±138)
`
` 1.90 (±0.62)
`
`
` 550 (±160)
` 2.01 (±1.22)
`
` 2.45 (±0.70)
`
`
`
`
` 2.71 (±1.05)
`
`
` 412 (±98)
`
`
`
`Table 2
`Select Mean (±SD) Metformin Pharmacokinetic Parameters Following Single or
`
`
`
`
`Multiple Oral Doses of Immediate-Release Metformin
`
`Subject Groups: Immediate-Release
` Cmaxb
` Renal
`
`
`
` Tmaxc
`
`
` Metformin dosea (number of subjects)
`
`
`
`(hrs)
`(µg/mL)
` Clearance
`
`
` (mL/min)
`
`Healthy, nondiabetic adults:
`
` 1.03 (±0.33)
` 600 (±132)
`500 mg single dose (24)
` 2.75 (±0.81)
`
`
`
`
`850 mg single dose (74)d
`
`
` 552 (±139)
`
`
` 2.64 (±0.82)
` 1.60 (±0.38)
` 850 mg three times daily for 19 dosese (9)
`
` 2.01 (±0.42)
`
` 1.79 (±0.94)
`
` 642 (±173)
`
`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
`
`
`Mild (CLcrg 61-90 mL/min) (5)
`
`
` 384 (±122)
`
` 3.20 (±0.45)
`
` 1.86 (±0.52)
`Moderate (CLcr 31-60 mL/min) (4)
`
` 3.75 (±0.50)
`
` 108 (±57)
`
` 4.12 (±1.83)
`
`
` Severe (CLcr 10-30 mL/min) (6)
`
` 130 (±90)
`
`
` 4.01 (±1.10)
` 3.93 (±0.92)
`a All doses given fasting except the first 18 doses of the multiple dose studies
`b Peak plasma concentration
`c Time to peak plasma concentration
`d Combined results (average means) of five studies: mean age 32 years (range 23-59 years)
`e Kinetic study done following dose 19, given fasting
`f Elderly subjects, mean age 71 years (range 65-81 years)
` g CLcr = creatinine clearance normalized to body surface area of 1.73 m2
`
`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.
`
`
`Race
`No studies of metformin 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 (n=249), blacks (n=51), and Hispanics (n=24).
`
`Clinical Studies
`In a double-blind, randomized, active-controlled, multicenter U.S. clinical study, which compared
`
`FORTAMET® q.d. to immediate-release metformin b.i.d., 680 patients with type 2 diabetes who
`
`
`
` had been taking metformin-containing medication at study entry were randomly assigned in equal
`numbers to double-blind treatment with either FORTAMET® or immediate-release metformin.
`
`

`

`NDA 21-574/S-010
`Page 7
`
` 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 HbA1c from baseline to endpoint. The primary objective was to demonstrate the clinical
`non-inferiority of FORTAMET® compared to immediate-release metformin on the primary
`
`endpoint.
`FORTAMET® and metformin patients had mean HbA1c 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 FORTAMET® was clinically similar to metformin
`
`
`
`according to the pre-defined criterion to establish efficacy.
`
`
`Table 3
`FORTAMET®vs. Immediate-Release Metformin Switch Study:
`
`Summary of Mean Changes in HbA1c, Fasting Plasma Glucose, Body Weight, Body Mass Index, and Plasma Insulin
`
`
`
`Treatment difference for
`
`FORTAMET®
`Immediate-
`
`change from baseline
`Release
`
`(FORTAMET® minus
`Metformin
`
`
`Immediate-Release
`
`
`Metformin)
`LS mean
`(2 sided 95% CIa)
`
`
`
`0.25
`
`(0.14,0.37)b
`
`
`
`6.43
`
`(0.57, 12.29)
`
`
`0.02
`
`(-1.47, 1.50)
`
`
`
`0.30
`
`(-0.22, 0.81)
`
`
`
`
`327
`7.04 ± 0.88
`
`0.40 ± 0.75
`
`329
`146.8 ± 32.1
`10.0 ± 40.8
`
`
`304
`17.9 ± 15.1
`
`-3.6 ± 13.8
`
`
`313
`94.1 ± 17.8
`
`0.3 ± 2.9
`
`
`
`HbA1c (%)
`N
`Baseline (mean ± SD)
`
`Change from baseline (mean ± SD)
`
`Fasting Plasma Glucose (mg/dL)
`N
`Baseline (mean ± SD)
`
`Change from baseline (mean ± SD)
`
`Plasma Insulin (µu/mL)
`
`N
`Baseline (mean ± SD)
`
`Change from baseline (mean ± SD)
`
`
`Body Weight (kg)
`
`
`N
`Baseline (mean ± SD)
`
`Change from baseline (mean ± SD)
`
`
`
`
`332
`7.07 ± 0.76
`0.14 ± 0.75
`
`333
`145.6 ± 29.5
`4.2 ± 35.9
`
`
`316
`17.3 ± 10.5
`
`-3.2 ± 8.6
`
`320
`93.3 ± 17.4
`
`0.0 ± 3.7
`
`
`
`320
`31.4 ± 4.5
`0.0 ± 1.3
`
`
`
`Body Mass Index (kg/m2)
`N
`Baseline (mean ± SD)
`
`Change from baseline (mean ± SD)
`
`
`
`
`313
`31.1 ± 4.7
`0.1 ± 1.1
`
`
`
`0.08
`
`(-0.11, 0.26)
`
`
`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.
`
`The mean changes for FPG (Table 3) and plasma insulin (Table 3) were small for both FORTAMET®
`
`and immediate-release metformin, and were not clinically meaningful. Seventy-six (22%) and 49
`
` (14%) of the FORTAMET® and immediate-release patients, respectively, discontinued prematurely
`
`
`from the trial. Eighteen (5%) patients on FORTAMET® 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 FORTAMET® 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).
`
`
`
`

`

`NDA 21-574/S-010
`Page 8
`
`Patients randomized to receive immediate-release metformin 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 versus 110.6 U/day, immediate-release metformin plus insulin versus insulin plus placebo,
`respectively, p=0.04.
`
`
`
`
`-0.54 ± 0.43a
`
`
`
` Table 4
`
`Combined Immediate-Release Metformin /Insulin vs. Placebo/Insulin:
`Summary of Mean Changes from Baseline in HbA1c and Daily Insulin Dose
`
`
`
` Treatment difference
`
`
`
` Placebo/Insulin
` Immediate-Release
` Mean ± SE
`
`
`
` (n = 28)
` Metformin /Insulin
`
`
`
` (n = 26)
`HbA1c (%)
` Baseline
` 8.95
` 9.32
`
`
`
` Change at FINAL VISIT
` -2.10
` -1.56
`
`
`
`
`Insulin Dose (U/day)
` 93.12
` 94.64
` Baseline
`
`
`
`
` -16.08 ± 7.77b
` -0.15
` Change at FINAL VISIT
` 15.93
`
`
`
`
`
`
`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 immediate-release metformin maintained similar glycemic
`
`control (HbA1c 7.15 ± 0.61 versus 6.97 ± 0.62 for immediate-release metformin 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 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 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.
`
`
`Pediatric Clinical Studies
`
`No pediatric clinical studies have been conducted with FORTAMET®. 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 11 weeks) resulted in a significant mean net reduction in FPG of 64.3 mg/dL
`compared with placebo (Table 5).
`
`
`
`
`Table 5 Immediate-Release Metformin vs. Placebo (Pediatricsa):
`
`
`Summary of Mean Changes from Baseline* in Plasma Glucose
`
`
`and Body Weight at Final Visit
`
`Placebo
`Immediate-Release
`
`Metformin
`(n = 37)
`
`162.4
`-42.9
`(n = 39)
`205.3
`-3.3
`
`(n = 36)
`
`192.3
`21.4
`(n = 38)
`189.0
`-2.0
`
`p-Value
`
`
`
`<0.001
`
`
`NS**
`
`FPG (mg/dL)
`
`Baseline
`
`
`Change at FINAL VISIT
`Body Weight (lbs)
`
`Baseline
`
`
`Change at FINAL VISIT
`
`

`

`
`
`NDA 21-574/S-010
`Page 9
`
`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
`
` FORTAMET® is indicated as an adjunct to diet and exercise to improve glycemic control in adults
`with type 2 diabetes mellitus.
`
`CONTRAINDICATIONS
`FORTAMET® is 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.
`
` 3. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic
`
`ketoacidosis should be treated with insulin.
`
`
` FORTAMET® 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 FORTAMET®(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 µg/mL are
`generally found.
`
`
`The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very
`low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000
`patient-years). Reported cases have occurred primarily in diabetic patients with significant
`renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the
`
` setting of multiple concomitant medical/ surgical problems and multiple concomitant
`
`
` medications. 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
`
`FORTAMET® (metformin hydrochloride) Extended-Release Tablets and by use of the
`minimum effective dose of FORTAMET®.
`
`

`

`NDA 21-574/S-010
`Page 10
`
`In particular, treatment of the elderly should be accompanied by careful monitoring of renal
`
`
`function. FORTAMET® treatment should not be initiated in patients ≥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, FORTAMET® 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,
`
`FORTAMET®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 FORTAMET®, since alcohol potentiates the effects of metformin
`
`hydrochloride on lactate metabolism. In addition, FORTAMET® 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). FORTAMET® 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 FORTAMET®, gastrointestinal symptoms, which are
`
`common during initiation of therapy, are unlikely to be drug related. Later occurrence of
`
`gastrointestinal symptoms could be due to lactic acidosis or other serious disease.
`
`
`Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L
`
`in patients taking FORTAMET® 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 management often results in prompt reversal of symptoms and recovery (see also
`CONTRAINDICATIONS and PRECAUTIONS).
`
`
`PRECAUTIONS
`
`General
`
`Monitoring of renal function – Metformin is known to be substantially excreted by the kidney, and
`
`the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal
`function.
`
`

`

`NDA 21-574/S-010
`Page 11
`
`Thus, patients with serum creatinine levels above the upper limit of normal for their age should not
`receive FORTAMET®. In patients with advanced age, FORTAMET® 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 those ≥80 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).
`
`
` Before initiation of FORTAMET® 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 FORTAMET® discontinued if evidence of
`
`renal impairment is present.
`
`Macrovascular Outcomes –
`There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction
`
`with FORTAMET® or any other anti-diabetic drug.
`
`
`Use of concomitant medications that may affect renal function or metformin disposition –
`
`
`Concomitant medication(s) that may affect renal function or result in significant hemodynamic change
`
`
`or may interfere with the disposition of metformin, 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 of intravascular 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 metformin (see CONTRAINDICATIONS). Therefore, in patients in whom any such study
`
`is planned, FORTAMET® 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
`
`
`FORTAMET® therapy, the drug should be promptly discontinued.
`
`Surgical procedures – FORTAMET® 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 metformin on lactate metabolism.
`Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while
`receiving FORTAMET®.
`
`Impaired hepatic function – Since impaired hepatic function has been associated with some cases of
`
`lactic acidosis, FORTAMET® should generally be avoided in patients with clinical or laboratory
`
`
`evidence of hepatic disease.
`
`
`

`

`NDA 21-574/S-010
`Page 12
`
`Vitamin B12 levels – In controlled clinical trials of immediate-release metformin of 29 weeks duration,
`a decrease to subnormal 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 B12 absorption from the B12-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 FORTAMET® 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.
`
`Change in clinical status of patients with previously controlled type 2 diabetes – A patient with type
`
`2 diabetes previously well controlled on FORTAMET® 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, FORTAMET® must be stopped immediately and other appropriate corrective measures
`initiated (see also WARNINGS).
`
` Hypoglycemia – Hypoglycemia does not occur in patients receiving FORTAMET® 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 mal