FORTAMET (metformin Hydrochloride) Extended-Release Tablets Rx Only .

been taking metformin-containing medication at study entry were randomly assigned in equal numbers todouble-blind treatment with either FORTAMET or immediate-release metformin. Doses wereadjusted during the first six weeks of treatment with study medication based on patients’ FPG levelsand were then held constant over a period of 20 weeks. The primary efficacy endpoint was the changein HbA1c from baseline to endpoint. The primary objective was to demonstrate the clinical noninferiority 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 accordingto the pre-defined criterion to establish efficacy.Table 3FORTAMET vs. Immediate-ReleaseMetformin Switch Study: Summary of Mean Changes in HbA1c,Fasting Plasma Glucose, Body Weight, Body Mass Index,and Plasma InsulinFORTAMET Immediate- Treatment difference forchange fromReleasebaselineMetformin(FORTAMET minusImmediate-ReleaseMetformin)LS mean(2 sided 95% Cla)HbA1c (%)NBaseline (mean SD)Change from baseline (mean SD)Fasting Plasma Glucose (mg/dL)NBaseline (mean SD)Change from baseline (mean SD)Plasma Insulin (µu/mL)NBaseline (mean SD)Change from baseline (mean SD)Body Weight (kg)NBaseline (mean SD)Change from baseline (mean SD)Body Mass Index (kg/m2)NBaseline (mean SD)Change from baseline (mean SD)3277.04 0.880.40 0.753327.07 0.760.14 0.750.25(0.14, 0.37)b329146.8 32.110.0 40.8333145.6 29.54.2 35.96.43(0.57, 12.29)30417.9 15.1-3.6 13.831617.3 10.5-3.2 8.60.02(-1.47, 1.50)31394.1 17.80.3 2.932093.3 17.40.0 3.70.30(-0.22, 0.81)31331.1 4.70.1 1.132031.4 4.50.0 1.30.08(-0.11, 0.26)a CI Confidence Intervalb FORTAMET was clinically similar to immediate-release metformin based on the pre-definedcriterion to establish efficacy. While demonstrating clinical similarity, the response toFORTAMET compared to immediate-release metformin was also shown to be statistically smallerReference ID: 4079184

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 bytheir personal physician.The mean changes for FPG (Table 3) and plasma insulin (Table 3) were small for bothFORTAMET and immediate-release metformin, and were not clinically meaningful. Seventy-six(22%) and 49 (14%) of the FORTAMET and immediate-release patients, respectively, discontinuedprematurely from the trial. Eighteen (5%) patients on FORTAMET withdrew because of a statedlack 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 metforminwere 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 achieveadequate glycemic control on insulin alone (Table 4). Patients randomized to receive immediaterelease metformin plus insulin achieved a reduction in HbA1c of 2.10%, compared to a 1.56% reductionin HbA1c achieved by insulin plus placebo. The improvement in glycemic control was achieved atthe final study visit with 16% less insulin, 93.0 U/day versus 110.6 U/day, immediate-releasemetformin plus insulin versus insulin plus placebo, respectively, p 0.04.Table 4Combined Immediate-Release Metformin/Insulin vs.Placebo/Insulin: Summary of Mean Changes from Baselinein HbA1c and Daily Insulin DoseImmediate-ReleasePlacebo/Insulin Treatment differenceMetformin/Insulin(n 28)Mean SE(n 26)HbA1c (%)BaselineChange at FINAL VISITInsulin Dose (U/day)BaselineChange at FINAL VISIT8.95-2.109.32-1.56-0.54 0.43a93.12-0.1594.6415.93-16.08 7.77ba 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 averageHbA1c of 7.46 0.97%, the addition of immediate-release metformin maintained similar glycemiccontrol (HbA1c 7.15 0.61 versus 6.97 0.62 for immediate-release metformin plus insulin andplacebo plus insulin, respectively) with 19% less insulin versus baseline (reduction of 23.68 30.22versus an increase of 0.43 25.20 units for immediate-release metformin plus insulin and placebo plusinsulin, p 0.01). In addition, this study demonstrated that the combination of immediate-releasemetformin plus insulin resulted in reduction in body weight of 3.11 4.30 lbs, compared to anincrease of 1.30 6.08 lbs for placebo plus insulin, p 0.01.Reference ID: 4079184

Pediatric Clinical StudiesNo pediatric clinical studies have been conducted with FORTAMET . In a double-blind, placebocontrolled study in pediatric patients aged 10 to 16 years with type 2 diabetes (mean FPG 182.2mg/dL), treatment with immediate-release metformin (up to 2000 mg/day) for up to 16 weeks (meanduration of treatment 11 weeks) resulted in a significant mean net reduction in FPG of 64.3 mg/dLcompared with placebo (Table 5).Table 5Immediate-Release Metformin vs. Placebo (Pediatricsa):Summary of Mean Changes from Baseline*in Plasma Glucose and Body Weight at Final VisitImmediate-ReleasePlaceboMetforminFPG (mg/dL)(n 37)(n 36)Baseline162.4192.3Change at FINAL VISIT-42.921.4Body Weight (lbs)(n 39)(n 38)Baseline205.3189.0Change at FINAL VISIT-3.3-2.0p-Value 0.001NS**a Pediatric patients mean age 13.8 years (range 10 to 16 years)* All patients on diet therapy at Baseline** Not statistically significantINDICATIONS AND USAGEFORTAMET is indicated as an adjunct to diet and exercise to improve glycemic control in adultswith type 2 diabetes mellitus.CONTRAINDICATIONSFORTAMET is contraindicated in patients with:1. Severe renal impairment (eGFR below 30 mL/min/1.73 m2) (see WARNINGS andPRECAUTIONS).2. Known hypersensitivity to metformin.3. Acute or chr oni c me t a bol ic a ci dosi s , including diabetic ketoacidosis, with or withoutcoma. Diabetic ketoacidosis should be treated with insulin.WARNING: LACTIC ACIDOSISPost-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia,hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis isoften subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratorydistress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterizedby elevated blood lactate levels ( 5 mmol/Liter), anion gap acidosis (without evidence of ketonuriaor ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally 5mcg/mL [see Precautions].Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use ofcertain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater,having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acutecongestive heart failure), excessive alcohol intake, and hepatic impairment.Reference ID: 4079184

Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high riskgroups are provided [see Dosage and Administration, Contraindications, and Precautions].If metformin-associated lactic acidosis is suspected, immediately discontinue FORTAMET andinstitute general supportive measures in a hospital setting. Prompt hemodialysis is recommended[see Precautions)].PRECAUTIONSGeneralLactic Acidosis—There have been post-marketing cases of metformin-associated lactic acidosis, includingfatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such asmalaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypotensionand resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosiswas characterized by elevated blood lactate concentrations ( 5 mmol/L), anion gap acidosis (withoutevidence of ketonuria or ketonemia), and an increases lactate:pyruvate ratio; metformin plasma levelswere generally 5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levelswhich may increase the risk of lactic acidosis, especially in patients at risk.If metformin-associated lactic acidosis is suspected, general supportive measures should be institutedpromptly in a hospital setting, along with immediate discontinuation of FORTAMET. In FORTAMETtreated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis isrecommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride isdialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis hasoften resulted in reversal of symptoms and recovery.Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur,instruct them to discontinue FORTAMET and report these symptoms to their healthcare provider.For each of the known and possible risk factors for metformin-associated lactic acidosis,recommendations to reduce the risk of and manage metformin-associated lactic acidosis are providedbelow: Renal Impairment—The postmarketing metformin-associated lactic acidosis cases primarilyoccurred in patients with significant renal impairment. The risk of metformin accumulation andmetformin-associated lactic acidosis increases with the severity of renal impairment becausemetformin is substantially excreted by the kidney. Clinical recommendations based upon thepatient’s renal function include (see Dosage and Administration and Clinical Pharmacology):Reference ID: 4079184oBefore initiating FORTAMET, obtain an estimated glomerular filtration rate (eGFR)oFORTAMET is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2(see Contraindications).oInitiation of FORTAMET is not recommended in patients with eGFR between 30 45mL/min/1.73 m2.oObtain an eGFR at least annually in all patient taking FORTAMET. In patients at risk forthe development of renal impairment (e.g., the elderly), renal function should be assessedmore frequently.

oIn patients taking FORTAMET whose eGFR falls below 45 mL/min/1.73 m2, assess thebenefit and risk of continuing therapy. Drug interactions—The concomitant use of FORTAMET with specific drugs may increase therisk of metformin-associated lactic acidosis: those that impair renal function, result in significanthemodynamic change, interfere with acid-base balance, or increase metformin accumulation.Consider more frequent monitoring of patients. Age 65 or Greater—The risk of metformin-associated lactic acidosis increases with the patient’sage because elderly patients have a greater likelihood of having hepatic, renal, or cardiacimpairment than younger patients. Assess renal function more frequently in elderly patients. Radiologic studies with contrast—Administration of intravascular iodinated contrast agents inmetformin-treated patients has led to an acute decrease in renal function and the occurrence oflactic acidosis. Stop FORTAMET at the time of, or prior to, an iodinated contrast imagingprocedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with ahistory of hepatic impairment, alcoholism or heart failure, or in patients who will be administeredintra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, andrestart FORTAMET if renal function is stable. Surgery and other procedures—Withholding of food and fluids during surgical or otherprocedures may increase the risk for volume depletion, hypotension, and renal impairment.FORTAMET should be temporarily discontinued while patients have restricted food and fluidintake. Hypoxic states—Several of the postmarketing cases of metformin-associated lactic acidosisoccurred in the setting of acute congestive heart failure (particularly when accompanied byhypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction,sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosisand may cause prerenal azotemia. When such an event occurs, discontinue FORTAMET. Excessive Alcohol intake—Alcohol is known to potentiate the effect of metformin on lactatemetabolism. Patients, therefore, should be warned against excessive alcohol intake, acute orchronic, while receiving FORTAMET. Hepatic impairment—Patients with hepatic impairment have developed cases of metformin associated lactic acidosis. This may be due to impaired lactate clearance resulting in higherlactate blood levels. Therefore, avoid use of FORTAMET in patients with clinical or laboratoryevidence of hepatic disease.Vitamin B12 levels – In controlled clinical trials of immediate-release metformin of 29 weeksduration, a decrease to subnormal levels of previously normal serum Vitamin B12 levels, withoutclinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly dueto interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarelyassociated with anemia and appears to be rapidly reversible with discontinuation of immediate-releasemetformin or Vitamin B12 supplementation. Measurement of hematologic parameters on an annualbasis is advised in patients on FORTAMET and any apparent abnormalities should be appropriatelyinvestigated and managed (see PRECAUTIONS: Laboratory Tests). Certain individuals (thosewith inadequate Vitamin B12 or calcium intake or absorption) appear to be predisposed to developingsubnormal Vitamin B12 levels. In these patients, routine serum Vitamin B12 measurements at two- toReference ID: 4079184

three-year intervals may be useful.Hypoglycemia – Hypoglycemia does not occur in patients receiving FORTAMET alone underusual circumstances of use, but could occur when caloric intake is deficient, when strenuous exerciseis not compensated by caloric supplementation, or during concomitant use with other glucose-loweringagents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients,and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptibleto hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in peoplewho are taking beta-adrenergic blocking drugs.Macrovascular Outcomes –There have been no clinical studies establishing conclusive evidence ofmacrovascular risk reduction with FORTAMET or any other anti-diabetic drug.Information for PatientsPatients should be informed of the potential risks and benefits of FORTAMET and of alternativemodes of therapy. They should also be informed about the importance of adherence to dietaryinstructions, of a regular exercise program, and of regular testing of blood glucose, glycosylatedhemoglobin, renal function, and hematologic parameters.The risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as notedin the WARNINGS and PRECAUTIONS sections, should be explained to patients. Patients should beadvised to discontinue FORTAMET immediately and to promptly notify their health practitioner ifunexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptomsoccur. Once a patient is stabilized on any dose level of FORTAMET , gastrointestinal symptoms,which are common during initiation of metformin therapy, are unlikely to be drug related. Lateroccurrence 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 receivingFORTAMET .FORTAMET alone does not usually cause hypoglycemia, although it may occur whenFORTAMET is used in conjunction with oral sulfonylureas and insulin. When initiatingcombination therapy, the risks of hypoglycemia, its symptoms and treatment, and conditions thatpredispose to its development should be explained to patients and responsible family members (seePatient Information Printed Below).Patients should be informed that FORTAMET must be swallowed whole and not chewed, cut, orcrushed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft massthat may resemble the original tablet (see Patient Information).Laboratory TestsResponse to all diabetic therapies should be monitored by periodic measurements of fasting bloodglucose and glycosylated hemoglobin levels, with a goal of decreasing these levels toward the normalrange. During initial dose titration, fasting glucose can be used to determine the therapeutic response.Thereafter, both glucose and glycosylated hemoglobin should be monitored. Measurements ofglycosylated hemoglobin may be especially useful for evaluating long-term control (see alsoDOSAGE AND ADMINISTRATION).Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and redblood cell indices) and renal function (serum creatinine) should be performed, at least on an annualbasis. While megaloblastic anemia has rarely been seen with immediate-release metformin therapy,Reference ID: 4079184

if this is suspected, Vitamin B12 deficiency should be excluded.Instruct patients to inform their doctor that they are taking FORTAMET prior to any surgical orradiological procedure, as temporary discontinuation of FORTAMET may be required until renalfunction has been confirmed to be normal (see Precautions).Drug Interactions (Clinical Evaluation of Drug Interactions Conducted with Immediate-ReleaseMetformin)Glyburide – In a single-dose interaction study in type 2 diabetes patients, coadministration ofmetformin and glyburide did not result in any changes in either metformin pharmacokinetics orpharmacodynamics. Decreases in glyburide AUC and Cmax were observed, but were highly variable.The single-dose nature of this study and the lack of correlation between glyburide blood levels andpharmacodynamic effects, makes the clinical significance of this interaction uncertain (see DOSAGEAND ADMINISTRATION: Concomitant FORTAMET and Oral Sulfonylurea Therapy in AdultPatients).Furosemide – A single-dose, metformin-furosemide drug interac

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.