HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. How Supplied. ONGLYZA(R) (saxagliptin) tablets have markingson both sides and are available in the strengths and packages listed in Table 12.Table 12: ONGLYZA Tablet PresentationsTablet StrengthFilm-Coated TabletColor/ShapeTablet MarkingsPackage SizeNDC Code5 mgpinkbiconvex,round5 on one sideand 4215 on the reverse, in blue inkBottles of 3054868-6309-0. Storage and Handling. Store at 20-25C (68-77F); excursionspermitted to 15-30C (59-86F) [see USP Controlled Room Temperature].

OVERDOSAGE SECTION.

10 OVERDOSAGE. In controlled clinical trial, once-daily,orally-administered ONGLYZA in healthy subjects at doses up to 400 mg dailyfor weeks (80 times the MRHD) had no dose-related clinical adverse reactionsand no clinically meaningful effect on QTc interval or heart rate.Inthe event of an overdose, appropriate supportive treatment should be initiatedas dictated by the patients clinical status. Saxagliptin and its active metaboliteare removed by hemodialysis (23% of dose over hours).

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

---------------------------------------------REPRESENTATIVE PACKAGINGSee How Supplied section for complete list of available packages of ONGLYZA.30 Tablets ONGLYZA(R) (saxagliptin) tablets5 mgDISPENSE WITH MEDICATION GUIDERx only Onglyza mg Bottle Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness of ONGLYZAin pediatric patients have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. In patients with type diabetes mellitus,administration of ONGLYZA inhibits DPP4 enzyme activity for 24-hour period.After an oral glucose load or meal, this DPP4 inhibition resulted in 2-to 3-fold increase in circulating levels of active GLP-1 and GIP, decreasedglucagon concentrations, and increased glucose-dependent insulin secretionfrom pancreatic beta cells. The rise in insulin and decrease in glucagon wereassociated with lower fasting glucose concentrations and reduced glucose excursionfollowing an oral glucose load or meal.. Cardiac Electrophysiology. In randomized, double-blind, placebo-controlled,4-way crossover, active comparator study using moxifloxacin in 40 healthysubjects, ONGLYZA was not associated with clinically meaningful prolongationof the QTc interval or heart rate at daily doses up to 40 mg (8 times theMRHD).

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of saxagliptinand its active metabolite, 5-hydroxy saxagliptin were similar in healthy subjectsand in patients with type diabetes mellitus. The Cmax andAUC values of saxagliptin and its active metabolite increased proportionallyin the 2.5 to 400 mg dose range. Following 5 mg single oral dose of saxagliptinto healthy subjects, the mean plasma AUC values for saxagliptin and its activemetabolite were 78 ngoh/mL and 214 ngoh/mL, respectively. The correspondingplasma Cmax values were 24 ng/mL and 47 ng/mL, respectively.The average variability (%CV) for AUC and Cmax forboth saxagliptin and its active metabolite was less than 25%.Noappreciable accumulation of either saxagliptin or its active metabolite wasobserved with repeated once-daily dosing at any dose level. No dose- and time-dependencewere observed in the clearance of saxagliptin and its active metabolite over14 days of once-daily dosing with saxagliptin at doses ranging from 2.5 to400 mg.. Absorption. The median time to maximum concentration(Tmax) following the mg once daily dose was hoursfor saxagliptin and hours for its active metabolite. Administration witha high-fat meal resulted in an increase in Tmax ofsaxagliptin by approximately 20 minutes as compared to fasted conditions.There was 27% increase in the AUC of saxagliptin when given with mealas compared to fasted conditions. ONGLYZA may be administered with or withoutfood.. Distribution. The in vitro proteinbinding of saxagliptin and its active metabolite in human serum is negligible.Therefore, changes in blood protein levels in various disease states (e.g.,renal or hepatic impairment) are not expected to alter the disposition ofsaxagliptin.. Metabolism. The metabolism of saxagliptin isprimarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major metaboliteof saxagliptin is also DPP4 inhibitor, which is one-half as potent as saxagliptin.Therefore, strong CYP3A4/5 inhibitors and inducers will alter the pharmacokineticsof saxagliptin and its active metabolite. [See DrugInteractions (7).]. Excretion. Saxagliptin is eliminated by bothrenal and hepatic pathways. Following single 50 mg dose of 14C-saxagliptin,24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, itsactive metabolite, and total radioactivity, respectively. The average renalclearance of saxagliptin (~230 mL/min) was greater than the average estimatedglomerular filtration rate (~120 mL/min), suggesting some active renal excretion.A total of 22% of the administered radioactivity was recovered in feces representingthe fraction of the saxagliptin dose excreted in bile and/or unabsorbed drugfrom the gastrointestinal tract. Following single oral dose of ONGLYZA 5mg to healthy subjects, the mean plasma terminal half-life (t1/2)for saxagliptin and its active metabolite was 2.5 and 3.1 hours, respectively.. Specific Populations. Renal Impairment. single-dose, open-label study wasconducted to evaluate the pharmacokinetics of saxagliptin (10 mg dose) insubjects with varying degrees of chronic renal impairment (N=8 per group)compared to subjects with normal renal function. The study included patientswith renal impairment classified on the basis of creatinine clearance as mild(>50 to <=80 mL/min), moderate (30 to <=50 mL/min), and severe (<30 mL/min),as well as patients with end-stage renal disease on hemodialysis. Creatinineclearance was estimated from serum creatinine based on the Cockcroft-Gaultformula:CrCl [140 age (years)] weight (kg) 0.85 for female patients [72 serum creatinine (mg/dL)] The degree of renal impairment did not affect the Cmax ofsaxagliptin or its active metabolite. In subjects with mild renal impairment,the AUC values of saxagliptin and its active metabolite were 20% and 70%higher, respectively, than AUC values in subjects with normal renal function.Because increases of this magnitude are not considered to be clinically relevant,dosage adjustment in patients with mild renal impairment is not recommended.In subjects with moderate or severe renal impairment, the AUC values of saxagliptinand its active metabolite were up to 2.1- and 4.5-fold higher, respectively,than AUC values in subjects with normal renal function. To achieve plasmaexposures of saxagliptin and its active metabolite similar to those in patientswith normal renal function, the recommended dose is 2.5 mg once daily in patientswith moderate and severe renal impairment, as well as in patients with end-stagerenal disease requiring hemodialysis. Saxagliptin is removed by hemodialysis.. Hepatic Impairment. In subjects with hepatic impairment(Child-Pugh classes A, B, and C), mean Cmax and AUCof saxagliptin were up to 8% and 77% higher, respectively, compared to healthymatched controls following administration of single 10 mg dose of saxagliptin.The corresponding Cmax and AUC of the active metabolitewere up to 59% and 33% lower, respectively, compared to healthy matched controls.These differences are not considered to be clinically meaningful. No dosageadjustment is recommended for patients with hepatic impairment. Body Mass Index. No dosage adjustment is recommendedbased on body mass index (BMI) which was not identified as significant covariateon the apparent clearance of saxagliptin or its active metabolite in the populationpharmacokinetic analysis.. Gender. Nodosage adjustment is recommended based on gender. There were no differencesobserved in saxagliptin pharmacokinetics between males and females. Comparedto males, females had approximately 25% higher exposure values for the activemetabolite than males, but this difference is unlikely to be of clinical relevance.Gender was not identified as significant covariate on the apparent clearanceof saxagliptin and its active metabolite in the population pharmacokineticanalysis.. Geriatric. No dosage adjustment is recommendedbased on age alone. Elderly subjects (65-80 years) had 23% and 59% highergeometric mean Cmax and geometric mean AUC values,respectively, for saxagliptin than young subjects (18-40 years). Differencesin active metabolite pharmacokinetics between elderly and young subjects generallyreflected the differences observed in saxagliptin pharmacokinetics. The differencebetween the pharmacokinetics of saxagliptin and the active metabolite in youngand elderly subjects is likely due to multiple factors including decliningrenal function and metabolic capacity with increasing age. Age was not identifiedas significant covariate on the apparent clearance of saxagliptin and itsactive metabolite in the population pharmacokinetic analysis.. Pediatric. Studies characterizing the pharmacokineticsof saxagliptin in pediatric patients have not been performed.. Race and Ethnicity. No dosage adjustment is recommendedbased on race. The population pharmacokinetic analysis compared the pharmacokineticsof saxagliptin and its active metabolite in 309 Caucasian subjects with 105non-Caucasian subjects (consisting of six racial groups). No significant differencein the pharmacokinetics of saxagliptin and its active metabolite were detectedbetween these two populations.. Drug-Drug Interactions. In Vitro Assessment of Drug Interactions. The metabolism of saxagliptin is primarilymediated by CYP3A4/5.In in vitro studies,saxagliptin and its active metabolite did not inhibit CYP1A2, 2A6, 2B6, 2C9,2C19, 2D6, 2E1, or 3A4, or induce CYP1A2, 2B6, 2C9, or 3A4. Therefore, saxagliptinis not expected to alter the metabolic clearance of coadministered drugs thatare metabolized by these enzymes. Saxagliptin is P-glycoprotein (P-gp) substratebut is not significant inhibitor or inducer of P-gp.. In Vivo Assessment of Drug Interactions. Table 3: Effect of Coadministered Drugs on Systemic Exposures of Saxagliptin and its Active Metabolite, 5-hydroxy SaxagliptinCoadministered DrugDose ofCoadministered DrugDosing ofSaxagliptinGeometric Mean Ratio(ratio with/without coadministered drug)No Effect 1.00 AUC+ Cmax Single dose unless otherwise noted+ AUC AUC(INF) for drugs given as single dose and AUC AUC(TAU) for drugs given in multiple doses Results exclude one subject The plasma dipeptidyl peptidase-4 (DPP4) activity inhibition over 24-hour dose interval was not affected by rifampin.ND=not determined; QD=once daily; q6h=every hours; q12h=every 12 hours; BID=twice daily; LA=long actingNo dosing adjustments required for the following:Metformin1000 mg100 mgsaxagliptin5-hydroxy saxagliptin0.980.990.790.88Glyburide5 mg10 mgsaxagliptin5-hydroxy saxagliptin0.98ND1.08NDPioglitazone 45 mg QD for 10 days10 mg QD for dayssaxagliptin5-hydroxy saxagliptin1.11ND1.11NDDigoxin0.25 mg q6h first day followed by q12h second day followed by QD for5 days10 mg QD for dayssaxagliptin5-hydroxy saxagliptin1.051.060.991.02Simvastatin40 mg QD for days10 mg QD for dayssaxagliptin5-hydroxy saxagliptin1.121.021.211.08Diltiazem360 mg LA QD for days10 mgsaxagliptin5-hydroxy saxagliptin2.090.661.630.57Rifampin 600 mg QD for days5 mgsaxagliptin5-hydroxy saxagliptin0.241.030.471.39Omeprazole40 mg QD for days10 mgsaxagliptin5-hydroxy saxagliptin1.13ND0.98NDAluminum hydroxide magnesium hydroxide simethiconealuminum hydroxide:2400 mgmagnesium hydroxide:2400 mgsimethicone: 240 mg10 mgsaxagliptin5-hydroxy saxagliptin0.97ND0.74NDFamotidine40 mg10 mgsaxagliptin5-hydroxy saxagliptin1.03ND1.14NDLimit ONGLYZA dose to 2.5 mg once daily when coadministered with strong CYP3A4/5 inhibitors:Ketoconazole200 mg BID for days100 mgsaxagliptin5-hydroxy saxagliptin2.450.121.620.05Ketoconazole200 mg BID for days20 mgsaxagliptin5-hydroxy saxagliptin3.67ND2.44NDTable 4: Effect of Saxagliptin on Systemic Exposures of Coadministered DrugsCoadministered DrugDose ofCoadministered DrugDosing ofSaxagliptinGeometric Mean Ratio(ratio with/without saxagliptin)No Effect 1.00 AUC+ Cmax Single dose unless otherwise noted+ AUC AUC(INF) for drugs given as single dose and AUC AUC(TAU) for drugs given in multiple doses Results include all subjectsND=not determined; QD=once daily; q6h=every hours; q12h=every 12 hours; BID=twice daily; LA=long actingNo dosing adjustments required for the following:Metformin1000 mg100 mgmetformin1.201.09Glyburide5 mg10 mgglyburide1.061.16Pioglitazone 45 mg QD for 10 days10 mg QD for dayspioglitazonehydroxy-pioglitazone1.08ND1.14NDDigoxin0.25 mg q6h first day followed by q12h second day followed by QD for5 days10 mg QD for daysdigoxin1.061.09Simvastatin40 mg QD for days10 mg QD for dayssimvastatinsimvastatin acid1.041.160.881.00Diltiazem360 mg LA QD for days10 mgdiltiazem1.101.16Ketoconazole200 mg BID for days100 mgketoconazole0.870.84Ethinyl estradiol and Norgestimateethinyl estradiol 0.035 mg and norgestimate 0.250 mg for 21 days5 mg QD for 21 daysethinyl estradiolnorelgestrominnorgestrel1.071.101.13 0.981.091.17.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Adverse reactions reported in >=5% of patients treated with ONGLYZAand more commonly than in patients treated with placebo are: upper respiratorytract infection, urinary tract infection, and headache. (6.1) Peripheral edema was reported more commonly in patients treatedwith the combination of ONGLYZA and thiazolidinedione (TZD) than in patientstreated with the combination of placebo and TZD. (6.1) In the add-on to sulfonylurea and add-on to insulin trials, confirmed hypoglycemia was reported more commonly in patients treated with ONGLYZA compared to placebo. (6.1) Hypersensitivity-related events (e.g., urticaria, facial edema)were reported more commonly in patients treated with ONGLYZA than in patientstreated with placebo. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch Adverse reactions reported in >=5% of patients treated with ONGLYZAand more commonly than in patients treated with placebo are: upper respiratorytract infection, urinary tract infection, and headache. (6.1) Peripheral edema was reported more commonly in patients treatedwith the combination of ONGLYZA and thiazolidinedione (TZD) than in patientstreated with the combination of placebo and TZD. (6.1) In the add-on to sulfonylurea and add-on to insulin trials, confirmed hypoglycemia was reported more commonly in patients treated with ONGLYZA compared to placebo. (6.1) Hypersensitivity-related events (e.g., urticaria, facial edema)were reported more commonly in patients treated with ONGLYZA than in patientstreated with placebo. (6.1) 6.1 Clinical Trials Experience. Because clinical trials are conductedunder widely varying conditions, adverse reaction rates observed in the clinicaltrials of drug cannot be directly compared to rates in the clinical trialsof another drug and may not reflect the rates observed in practice.. Monotherapy and Add-On Combination Therapy. In two placebo-controlled monotherapytrials of 24-weeks duration, patients were treated with ONGLYZA 2.5 mg daily,ONGLYZA mg daily, and placebo. Three 24-week, placebo-controlled, add-oncombination therapy trials were also conducted: one with metformin, one with athiazolidinedione (pioglitazone or rosiglitazone), and one with glyburide.In these three trials, patients were randomized to add-on therapy with ONGLYZA2.5 mg daily, ONGLYZA mg daily, or placebo. saxagliptin 10 mg treatmentarm was included in one of the monotherapy trials and in the add-on combinationtrial with metformin.In prespecified pooled analysisof the 24-week data (regardless of glycemic rescue) from the two monotherapytrials, the add-on to metformin trial, the add-on to thiazolidinedione (TZD)trial, and the add-on to glyburide trial, the overall incidence of adverseevents in patients treated with ONGLYZA 2.5 mg and ONGLYZA mg was similarto placebo (72.0% and 72.2% versus 70.6%, respectively). Discontinuation oftherapy due to adverse events occurred in 2.2%, 3.3%, and 1.8% of patientsreceiving ONGLYZA 2.5 mg, ONGLYZA mg, and placebo, respectively. The mostcommon adverse events (reported in at least patients treated with ONGLYZA2.5 mg or at least patients treated with ONGLYZA mg) associated with prematurediscontinuation of therapy included lymphopenia (0.1% and 0.5% versus 0%,respectively), rash (0.2% and 0.3% versus 0.3%), blood creatinine increased(0.3% and 0% versus 0%), and blood creatine phosphokinase increased (0.1%and 0.2% versus 0%). The adverse reactions in this pooled analysis reported(regardless of investigator assessment of causality) in >=5% of patients treatedwith ONGLYZA mg, and more commonly than in patients treated with placeboare shown in Table 1.Table 1: Adverse Reactions (Regardless of Investigator Assessmentof Causality) in Placebo-Controlled Trials Reported in >=5% of Patients Treatedwith ONGLYZA mg and More Commonly than in Patients Treated with Placebo Number (%)of Patients ONGLYZA5 mgN=882PlaceboN=799 The 5placebo-controlled trials include two monotherapy trials and one add-on combinationtherapy trial with each of the following: metformin, thiazolidinedione, orglyburide. Table shows 24-week data regardless of glycemic rescue.Upper respiratory tract infection68 (7.7)61 (7.6)Urinary tract infection60 (6.8)49 (6.1)Headache57 (6.5)47 (5.9)In patients treated with ONGLYZA 2.5 mg, headache (6.5%)was the only adverse reaction reported at rate >=5% and more commonly thanin patients treated with placebo.In this pooled analysis,adverse reactions that were reported in >=2% of patients treated with ONGLYZA2.5 mg or ONGLYZA mg and >=1% more frequently compared to placebo included:sinusitis (2.9% and 2.6% versus 1.6%, respectively), abdominal pain (2.4%and 1.7% versus 0.5%), gastroenteritis (1.9% and 2.3% versus 0.9%), and vomiting(2.2% and 2.3% versus 1.3%).In the add-on to TZD trial,the incidence of peripheral edema was higher for ONGLYZA mg versus placebo(8.1% and 4.3%, respectively). The incidence of peripheral edema for ONGLYZA2.5 mg was 3.1%. None of the reported adverse reactions of peripheral edemaresulted in study drug discontinuation. Rates of peripheral edema for ONGLYZA2.5 mg and ONGLYZA mg versus placebo were 3.6% and 2% versus 3% given asmonotherapy, 2.1% and 2.1% versus 2.2% given as add-on therapy to metformin,and 2.4% and 1.2% versus 2.2% given as add-on therapy to glyburide.Theincidence rate of fractures was 1.0 and 0.6 per 100 patient-years, respectively,for ONGLYZA (pooled analysis of 2.5 mg, mg, and 10 mg) and placebo. Theincidence rate of fracture events in patients who received ONGLYZA did notincrease over time. Causality has not been established and nonclinical studieshave not demonstrated adverse effects of saxagliptin on bone.Anevent of thrombocytopenia, consistent with diagnosis of idiopathic thrombocytopenicpurpura, was observed in the clinical program. The relationship of this eventto ONGLYZA is not known.. Use in Renal Impairment. ONGLYZA 2.5 mg was compared to placebo in 12-week trial in 170 patients with type diabetes and moderate or severe renal impairment or end-stage renal disease (ESRD). The incidence of adverse events, including serious adverse events and discontinuations due to adverse events, was similar between ONGLYZA and placebo.. Use in Combination with Insulin. In the add-on to insulin trial [see Clinical Studies (14.2)], the incidence of adverse events, including serious adverse events and discontinuations due to adverse events, was similar between ONGLYZA and placebo, except for confirmed hypoglycemia (see Hypoglycemia subsection).. Adverse Reactions Associated with ONGLYZA Coadministered with Metformin in Treatment-Naive Patients with Type Diabetes. Table shows the adverse reactionsreported (regardless of investigator assessment of causality) in >=5% of patientsparticipating in an additional 24-week, active-controlled trial of coadministeredONGLYZA and metformin in treatment-naive patients.Table 2: Initial Therapy with Combination of ONGLYZA and Metforminin Treatment-Naive Patients: Adverse Reactions Reported (Regardless of InvestigatorAssessment of Causality) in >=5% of Patients Treated with Combination Therapyof ONGLYZA mg Plus Metformin (and More Commonly than in Patients Treatedwith Metformin Alone) Number(%) of Patients ONGLYZA5 mg MetforminN=320MetforminN=328 Metforminwas initiated at starting dose of 500 mg daily and titrated up to maximumof 2000 mg daily.Headache24 (7.5)17 (5.2)Nasopharyngitis22 (6.9)13 (4.0). Hypoglycemia. Adverse reactions of hypoglycemia werebased on all reports of hypoglycemia. concurrent glucose measurement wasnot required or was normal in some patients. Therefore, it is not possible to conclusively determine that all these reports reflect true hypoglycemia.In the add-on to glyburide study, the overall incidence of reportedhypoglycemia was higher for ONGLYZA 2.5 mg and ONGLYZA mg (13.3% and 14.6%)versus placebo (10.1%). The incidence of confirmed hypoglycemia in this study,defined as symptoms of hypoglycemia accompanied by fingerstick glucose valueof <=50 mg/dL, was 2.4% and 0.8% for ONGLYZA 2.5 mg and ONGLYZA mg and 0.7%for placebo [see Warnings and Precautions (5.2)]. The incidence of reported hypoglycemia for ONGLYZA 2.5 mg andONGLYZA mg versus placebo given as monotherapy was 4.0% and 5.6% versus4.1%, respectively, 7.8% and 5.8% versus 5% given as add-on therapy to metformin,and 4.1% and 2.7% versus 3.8% given as add-on therapy to TZD. The incidenceof reported hypoglycemia was 3.4% in treatment-naive patients given ONGLYZA5 mg plus metformin and 4.0% in patients given metformin alone.In the active-controlled trial comparing add-on therapy with ONGLYZA mg to glipizide in patients inadequately controlled on metformin alone, the incidence of reported hypoglycemia was 3% (19 events in 13 patients) with ONGLYZA mg versus 36.3% (750 events in 156 patients) with glipizide. Confirmed symptomatic hypoglycemia (accompanying fingerstick blood glucose <=50 mg/dL) was reported in none of the ONGLYZA-treated patients and in 35 glipizide-treated patients (8.1%) (p<0.0001).During 12 weeks of treatment in patients with moderate or severe renal impairment or ESRD, the overall incidence of reported hypoglycemia was 20% among patients treated with ONGLYZA 2.5 mg and 22% among patients treated with placebo. Four ONGLYZA-treated patients (4.7%) and three placebo-treated patients (3.5%) reported at least one episode of confirmed symptomatic hypoglycemia (accompanying fingerstick glucose <=50 mg/dL).In the add-on to insulin trial, the overall incidence of reported hypoglycemia was 18.4% for ONGLYZA mg and 19.9% for placebo. However, the incidence of confirmed symptomatic hypoglycemia (accompanying fingerstick blood glucose <=50 mg/dL) was higher with ONGLYZA mg (5.3%) versus placebo (3.3%) [see Warnings and Precautions (5.2)].. Hypersensitivity Reactions. Hypersensitivity-related events, suchas urticaria and facial edema in the 5-study pooled analysis up to Week 24were reported in 1.5%, 1.5%, and 0.4% of patients who received ONGLYZA 2.5mg, ONGLYZA mg, and placebo, respectively. None of these events in patientswho received ONGLYZA required hospitalization or were reported as life-threateningby the investigators. One saxagliptin-treated patient in this pooled analysisdiscontinued due to generalized urticaria and facial edema.. Infections. In the unblinded, controlled, clinical trial database for saxagliptin to date, there have been (0.12%) reports of tuberculosis among the 4959 saxagliptin-treated patients (1.1 per 1000 patient-years) compared to no reports of tuberculosis among the 2868 comparator-treated patients. Two of these six cases were confirmed with laboratory testing. The remaining cases had limited information or had presumptive diagnoses of tuberculosis. None of the six cases occurred in the United States or in Western Europe. One case occurred in Canada in patient originally from Indonesia who had recently visited Indonesia. The duration of treatment with saxagliptin until report of tuberculosis ranged from 144 to 929 days. Post-treatment lymphocyte counts were consistently within the reference range for four cases. One patient had lymphopenia prior to initiation of saxagliptin that remained stable throughout saxagliptin treatment. The final patient had an isolated lymphocyte count below normal approximately four months prior to the report of tuberculosis. There have been no spontaneous reports of tuberculosis associated with saxagliptin use. Causality has not been estimated and there are too few cases to date to determine whether tuberculosis is related to saxagliptin use.There has been one case of potential opportunistic infection in the unblinded, controlled clinical trial database to date in saxagliptin-treated patient who developed suspected foodborne fatal salmonella sepsis after approximately 600 days of saxagliptin therapy. There have been no spontaneous reports of opportunistic infections associated with saxagliptin use.. Vital Signs. No clinically meaningful changes in vitalsigns have been observed in patients treated with ONGLYZA.. Laboratory Tests. Absolute Lymphocyte Counts. There was dose-related mean decreasein absolute lymphocyte count observed with ONGLYZA. From baseline mean absolutelymphocyte count of approximately 2200 cells/microL, mean decreases of approximately100 and 120 cells/microL with ONGLYZA mg and 10 mg, respectively, relativeto placebo were observed at 24 weeks in pooled analysis of five placebo-controlledclinical studies. Similar effects were observed when ONGLYZA mg was givenin initial combination with metformin compared to metformin alone. There wasno difference observed for ONGLYZA 2.5 mg relative to placebo. The proportionof patients who were reported to have lymphocyte count <=750 cells/microLwas 0.5%, 1.5%, 1.4%, and 0.4% in the saxagliptin 2.5 mg, mg, 10 mg, andplacebo groups, respectively. In most patients, recurrence was not observedwith repeated exposure to ONGLYZA although some patients had recurrent decreasesupon rechallenge that led to discontinuation of ONGLYZA. The decreases inlymphocyte count were not associated with clinically relevant adverse reactions.Theclinical significance of this decrease in lymphocyte count relative to placebois not known. When clinically indicated, such as in settings of unusual orprolonged infection, lymphocyte count should be measured. The effect of ONGLYZAon lymphocyte counts in patients with lymphocyte abnormalities (e.g., humanimmunodeficiency virus) is unknown.. Platelets. ONGLYZA did not demonstrate clinicallymeaningful or consistent effect on platelet count in the six, double-blind,controlled clinical safety and efficacy trials.. 6.2 Postmarketing Experience. Additional adverse reactions have been identified during postapproval use of ONGLYZA. Because these reactions are reported voluntarily from population of uncertain size, it is generally not possible to reliably estimate their frequency or establish causal relationship to drug exposure.Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions. [See Contraindications (4) and Warnings and Precautions (5.3).]Acute pancreatitis. [See Indications and Usage (1.2) and Warnings and Precautions (5.1).]. Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions. [See Contraindications (4) and Warnings and Precautions (5.3).]. Acute pancreatitis. [See Indications and Usage (1.2) and Warnings and Precautions (5.1).].

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology. Saxagliptin produced adverse skinchanges in the extremities of cynomolgus monkeys (scabs and/or ulcerationof tail, digits, scrotum, and/or nose). Skin lesions were reversible at >=20times the MRHD but in some cases were irreversible and necrotizing at higherexposures. Adverse skin changes were not observed at exposures similar to(1 to times) the MRHD of mg. Clinical correlates to skin lesions in monkeyshave not been observed in human clinical trials of saxagliptin.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Saxagliptin did not induce tumorsin either mice (50, 250, and 600 mg/kg) or rats (25, 75, 150, and 300 mg/kg)at the highest doses evaluated. The highest doses evaluated in mice were equivalentto approximately 870 (males) and 1165 (females) times the human exposure atthe MRHD of mg/day. In rats, exposures were approximately 355 (males) and2217 (females) times the MRHD.Saxagliptin was not mutagenicor clastogenic with or without metabolic activation in an in vitro Amesbacterial assay, an in vitro cytogenetics assay in primaryhuman lymphocytes, an in vivo oral micronucleus assay inrats, an in vivo oral DNA repair study in rats, and an oral invivo/in vitro cytogenetics study in rat peripheralblood lymphocytes. The active metabolite was not mutagenic in an invitro Ames bacterial assay.In rat fertilitystudy, males were treated with oral gavage doses for weeks prior to mating,during mating, and up to scheduled termination (approximately weeks total)and females were treated with oral gavage doses for weeks prior to matingthrough gestation day 7. No adverse effects on fertility were observed atexposures of approximately 603 (males) and 776 (females) times the MRHD. Higherdoses that elicited maternal toxicity also increased fetal resorptions (approximately2069 and 6138 times the MRHD). Additional effects on estrous cycling, fertility,ovulation, and implantation were observed at approximately 6138 times theMRHD.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Increased concentrations of the incretinhormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropicpolypeptide (GIP) are released into the bloodstream from the small intestinein response to meals. These hormones cause insulin release from the pancreaticbeta cells in glucose-dependent manner but are inactivated by the DPP4 enzyme within minutes. GLP-1 also lowers glucagon secretionfrom pancreatic alpha cells, reducing hepatic glucose production. In patientswith type diabetes, concentrations of GLP-1 are reduced but the insulinresponse to GLP-1 is preserved. Saxagliptin is competitive DPP4 inhibitorthat slows the inactivation of the incretin hormones, thereby increasing theirbloodstream concentrations and reducing fasting and postprandial glucose concentrationsin glucose-dependent manner in patients with type diabetes mellitus.. 12.2 Pharmacodynamics. In patients with type diabetes mellitus,administration of ONGLYZA inhibits DPP4 enzyme activity for 24-hour period.After an oral glucose load or meal, this DPP4 inhibition resulted in 2-to 3-fold increase in circulating levels of active GLP-1 and GIP, decreasedglucagon concentrations, and increased glucose-dependent insulin secretionfrom pancreatic beta cells. The rise in insulin and decrease in glucagon wereassociated with lower fasting glucose concentrations and reduced glucose excursionfollowing an oral glucose load or meal.. Cardiac Electrophysiology. In randomized, double-blind, placebo-controlled,4-way crossover, active comparator study using moxifloxacin in 40 healthysubjects, ONGLYZA was not associated with clinically meaningful prolongationof the QTc interval or heart rate at daily doses up to 40 mg (8 times theMRHD).. 12.3 Pharmacokinetics. The pharmacokinetics of saxagliptinand its active metabolite, 5-hydroxy saxagliptin were similar in healthy subjectsand in patients with type diabetes mellitus. The Cmax andAUC values of saxagliptin and its active metabolite increased proportionallyin the 2.5 to 400 mg dose range. Following 5 mg single oral dose of saxagliptinto healthy subjects, the mean plasma AUC values for saxagliptin and its activemetabolite were 78 ngoh/mL and 214 ngoh/mL, respectively. The correspondingplasma Cmax values were 24 ng/mL and 47 ng/mL, respectively.The average variability (%CV) for AUC and Cmax forboth saxagliptin and its active metabolite was less than 25%.Noappreciable accumulation of either saxagliptin or its active metabolite wasobserved with repeated once-daily dosing at any dose level. No dose- and time-dependencewere observed in the clearance of saxagliptin and its active metabolite over14 days of once-daily dosing with saxagliptin at doses ranging from 2.5 to400 mg.. Absorption. The median time to maximum concentration(Tmax) following the mg once daily dose was hoursfor saxagliptin and hours for its active metabolite. Administration witha high-fat meal resulted in an increase in Tmax ofsaxagliptin by approximately 20 minutes as compared to fasted conditions.There was 27% increase in the AUC of saxagliptin when given with mealas compared to fasted conditions. ONGLYZA may be administered with or withoutfood.. Distribution. The in vitro proteinbinding of saxagliptin and its active metabolite in human serum is negligible.Therefore, changes in blood protein levels in various disease states (e.g.,renal or hepatic impairment) are not expected to alter the disposition ofsaxagliptin.. Metabolism. The metabolism of saxagliptin isprimarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major metaboliteof saxagliptin is also DPP4 inhibitor, which is one-half as potent as saxagliptin.Therefore, strong CYP3A4/5 inhibitors and inducers will alter the pharmacokineticsof saxagliptin and its active metabolite. [See DrugInteractions (7).]. Excretion. Saxagliptin is eliminated by bothrenal and hepatic pathways. Following single 50 mg dose of 14C-saxagliptin,24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, itsactive metabolite, and total radioactivity, respectively. The average renalclearance of saxagliptin (~230 mL/min) was greater than the average estimatedglomerular filtration rate (~120 mL/min), suggesting some active renal excretion.A total of 22% of the administered radioactivity was recovered in feces representingthe fraction of the saxagliptin dose excreted in bile and/or unabsorbed drugfrom the gastrointestinal tract. Following single oral dose of ONGLYZA 5mg to healthy subjects, the mean plasma terminal half-life (t1/2)for saxagliptin and its active metabolite was 2.5 and 3.1 hours, respectively.. Specific Populations. Renal Impairment. single-dose, open-label study wasconducted to evaluate the pharmacokinetics of saxagliptin (10 mg dose) insubjects with varying degrees of chronic renal impairment (N=8 per group)compared to subjects with normal renal function. The study included patientswith renal impairment classified on the basis of creatinine clearance as mild(>50 to <=80 mL/min), moderate (30 to <=50 mL/min), and severe (<30 mL/min),as well as patients with end-stage renal disease on hemodialysis. Creatinineclearance was estimated from serum creatinine based on the Cockcroft-Gaultformula:CrCl [140 age (years)] weight (kg) 0.85 for female patients [72 serum creatinine (mg/dL)] The degree of renal impairment did not affect the Cmax ofsaxagliptin or its active metabolite. In subjects with mild renal impairment,the AUC values of saxagliptin and its active metabolite were 20% and 70%higher, respectively, than AUC values in subjects with normal renal function.Because increases of this magnitude are not considered to be clinically relevant,dosage adjustment in patients with mild renal impairment is not recommended.In subjects with moderate or severe renal impairment, the AUC values of saxagliptinand its active metabolite were up to 2.1- and 4.5-fold higher, respectively,than AUC values in subjects with normal renal function. To achieve plasmaexposures of saxagliptin and its active metabolite similar to those in patientswith normal renal function, the recommended dose is 2.5 mg once daily in patientswith moderate and severe renal impairment, as well as in patients with end-stagerenal disease requiring hemodialysis. Saxagliptin is removed by hemodialysis.. Hepatic Impairment. In subjects with hepatic impairment(Child-Pugh classes A, B, and C), mean Cmax and AUCof saxagliptin were up to 8% and 77% higher, respectively, compared to healthymatched controls following administration of single 10 mg dose of saxagliptin.The corresponding Cmax and AUC of the active metabolitewere up to 59% and 33% lower, respectively, compared to healthy matched controls.These differences are not considered to be clinically meaningful. No dosageadjustment is recommended for patients with hepatic impairment. Body Mass Index. No dosage adjustment is recommendedbased on body mass index (BMI) which was not identified as significant covariateon the apparent clearance of saxagliptin or its active metabolite in the populationpharmacokinetic analysis.. Gender. Nodosage adjustment is recommended based on gender. There were no differencesobserved in saxagliptin pharmacokinetics between males and females. Comparedto males, females had approximately 25% higher exposure values for the activemetabolite than males, but this difference is unlikely to be of clinical relevance.Gender was not identified as significant covariate on the apparent clearanceof saxagliptin and its active metabolite in the population pharmacokineticanalysis.. Geriatric. No dosage adjustment is recommendedbased on age alone. Elderly subjects (65-80 years) had 23% and 59% highergeometric mean Cmax and geometric mean AUC values,respectively, for saxagliptin than young subjects (18-40 years). Differencesin active metabolite pharmacokinetics between elderly and young subjects generallyreflected the differences observed in saxagliptin pharmacokinetics. The differencebetween the pharmacokinetics of saxagliptin and the active metabolite in youngand elderly subjects is likely due to multiple factors including decliningrenal function and metabolic capacity with increasing age. Age was not identifiedas significant covariate on the apparent clearance of saxagliptin and itsactive metabolite in the population pharmacokinetic analysis.. Pediatric. Studies characterizing the pharmacokineticsof saxagliptin in pediatric patients have not been performed.. Race and Ethnicity. No dosage adjustment is recommendedbased on race. The population pharmacokinetic analysis compared the pharmacokineticsof saxagliptin and its active metabolite in 309 Caucasian subjects with 105non-Caucasian subjects (consisting of six racial groups). No significant differencein the pharmacokinetics of saxagliptin and its active metabolite were detectedbetween these two populations.. Drug-Drug Interactions. In Vitro Assessment of Drug Interactions. The metabolism of saxagliptin is primarilymediated by CYP3A4/5.In in vitro studies,saxagliptin and its active metabolite did not inhibit CYP1A2, 2A6, 2B6, 2C9,2C19, 2D6, 2E1, or 3A4, or induce CYP1A2, 2B6, 2C9, or 3A4. Therefore, saxagliptinis not expected to alter the metabolic clearance of coadministered drugs thatare metabolized by these enzymes. Saxagliptin is P-glycoprotein (P-gp) substratebut is not significant inhibitor or inducer of P-gp.. In Vivo Assessment of Drug Interactions. Table 3: Effect of Coadministered Drugs on Systemic Exposures of Saxagliptin and its Active Metabolite, 5-hydroxy SaxagliptinCoadministered DrugDose ofCoadministered DrugDosing ofSaxagliptinGeometric Mean Ratio(ratio with/without coadministered drug)No Effect 1.00 AUC+ Cmax Single dose unless otherwise noted+ AUC AUC(INF) for drugs given as single dose and AUC AUC(TAU) for drugs given in multiple doses Results exclude one subject The plasma dipeptidyl peptidase-4 (DPP4) activity inhibition over 24-hour dose interval was not affected by rifampin.ND=not determined; QD=once daily; q6h=every hours; q12h=every 12 hours; BID=twice daily; LA=long actingNo dosing adjustments required for the following:Metformin1000 mg100 mgsaxagliptin5-hydroxy saxagliptin0.980.990.790.88Glyburide5 mg10 mgsaxagliptin5-hydroxy saxagliptin0.98ND1.08NDPioglitazone 45 mg QD for 10 days10 mg QD for dayssaxagliptin5-hydroxy saxagliptin1.11ND1.11NDDigoxin0.25 mg q6h first day followed by q12h second day followed by QD for5 days10 mg QD for dayssaxagliptin5-hydroxy saxagliptin1.051.060.991.02Simvastatin40 mg QD for days10 mg QD for dayssaxagliptin5-hydroxy saxagliptin1.121.021.211.08Diltiazem360 mg LA QD for days10 mgsaxagliptin5-hydroxy saxagliptin2.090.661.630.57Rifampin 600 mg QD for days5 mgsaxagliptin5-hydroxy saxagliptin0.241.030.471.39Omeprazole40 mg QD for days10 mgsaxagliptin5-hydroxy saxagliptin1.13ND0.98NDAluminum hydroxide magnesium hydroxide simethiconealuminum hydroxide:2400 mgmagnesium hydroxide:2400 mgsimethicone: 240 mg10 mgsaxagliptin5-hydroxy saxagliptin0.97ND0.74NDFamotidine40 mg10 mgsaxagliptin5-hydroxy saxagliptin1.03ND1.14NDLimit ONGLYZA dose to 2.5 mg once daily when coadministered with strong CYP3A4/5 inhibitors:Ketoconazole200 mg BID for days100 mgsaxagliptin5-hydroxy saxagliptin2.450.121.620.05Ketoconazole200 mg BID for days20 mgsaxagliptin5-hydroxy saxagliptin3.67ND2.44NDTable 4: Effect of Saxagliptin on Systemic Exposures of Coadministered DrugsCoadministered DrugDose ofCoadministered DrugDosing ofSaxagliptinGeometric Mean Ratio(ratio with/without saxagliptin)No Effect 1.00 AUC+ Cmax Single dose unless otherwise noted+ AUC AUC(INF) for drugs given as single dose and AUC AUC(TAU) for drugs given in multiple doses Results include all subjectsND=not determined; QD=once daily; q6h=every hours; q12h=every 12 hours; BID=twice daily; LA=long actingNo dosing adjustments required for the following:Metformin1000 mg100 mgmetformin1.201.09Glyburide5 mg10 mgglyburide1.061.16Pioglitazone 45 mg QD for 10 days10 mg QD for dayspioglitazonehydroxy-pioglitazone1.08ND1.14NDDigoxin0.25 mg q6h first day followed by q12h second day followed by QD for5 days10 mg QD for daysdigoxin1.061.09Simvastatin40 mg QD for days10 mg QD for dayssimvastatinsimvastatin acid1.041.160.881.00Diltiazem360 mg LA QD for days10 mgdiltiazem1.101.16Ketoconazole200 mg BID for days100 mgketoconazole0.870.84Ethinyl estradiol and Norgestimateethinyl estradiol 0.035 mg and norgestimate 0.250 mg for 21 days5 mg QD for 21 daysethinyl estradiolnorelgestrominnorgestrel1.071.101.13 0.981.091.17.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. ONGLYZA has been studied as monotherapyand in combination with metformin, glyburide, and thiazolidinedione (pioglitazoneand rosiglitazone) therapy.A total of 4148 patients with type diabetesmellitus were randomized in six, double-blind, controlled clinical trialsconducted to evaluate the safety and glycemic efficacy of ONGLYZA. totalof 3021 patients in these trials were treated with ONGLYZA. In these trials,the mean age was 54 years, and 71% of patients were Caucasian, 16% were Asian,4% were black, and 9% were of other racial groups. An additional 423 patients,including 315 who received ONGLYZA, participated in placebo-controlled,dose-ranging study of to 12 weeks in duration.Inthese six, double-blind trials, ONGLYZA was evaluated at doses of 2.5 mg and5 mg once daily. Three of these trials also evaluated saxagliptin dose of10 mg daily. The 10 mg daily dose of saxagliptin did not provide greater efficacythan the mg daily dose. Treatment with ONGLYZA at all doses produced clinicallyrelevant and statistically significant improvements in hemoglobin A1c (A1C),fasting plasma glucose (FPG), and 2-hour postprandial glucose (PPG) followinga standard oral glucose tolerance test (OGTT), compared to control. Reductionsin A1C were seen across subgroups including gender, age, race, and baselineBMI.ONGLYZA was not associated with significant changesfrom baseline in body weight or fasting serum lipids compared to placebo.ONGLYZA has also been evaluated in three additional trials in patients with type diabetes: an active-controlled trial comparing add-on therapy with ONGLYZA to glipizide in 858 patients inadequately controlled on metformin alone, trial comparing ONGLYZA to placebo in 455 patients inadequately controlled on insulin alone or on insulin in combination with metformin, and trial comparing ONGLYZA to placebo in 170 patients with type diabetes and moderate or severe renal impairment or ESRD.. 14.1 Monotherapy. total of 766 patients with type2 diabetes inadequately controlled on diet and exercise (A1C >=7% to <=10%)participated in two 24-week, double-blind, placebo-controlled trials evaluatingthe efficacy and safety of ONGLYZA monotherapy.In thefirst trial, following 2-week single-blind diet, exercise, and placebo lead-inperiod, 401 patients were randomized to 2.5 mg, mg, or 10 mg of ONGLYZAor placebo. Patients who failed to meet specific glycemic goals during thestudy were treated with metformin rescue therapy, added on to placebo or ONGLYZA.Efficacy was evaluated at the last measurement prior to rescue therapy forpatients needing rescue. Dose titration of ONGLYZA was not permitted. Treatmentwith ONGLYZA 2.5 mg and mg daily provided significant improvements in A1C,FPG, and PPG compared to placebo (Table 5). The percentage of patients whodiscontinued for lack of glycemic control or who were rescued for meetingprespecified glycemic criteria was 16% in the ONGLYZA 2.5 mg treatment group,20% in the ONGLYZA mg treatment group, and 26% in the placebo group.. Table 5: Glycemic Parameters at Week 24 in Placebo-Controlled Studyof ONGLYZA Monotherapy in Patients with Type DiabetesEfficacyParameterONGLYZA2.5mgN=102ONGLYZA5mgN=106Placebo N=95 Intent-to-treat populationusing last observation on study or last observation prior to metformin rescuetherapy for patients needing rescue.+ Leastsquares mean adjusted for baseline value. p-value<0.0001 compared to placebo p-value<0.05 compared to placebo Significancewas not tested for the 2-hour PPG for the 2.5 mg dose of ONGLYZA.Hemoglobin A1C (%)N=100N=103N=92 Baseline (mean)7.98.07.9 Change frombaseline (adjusted mean+)-0.4-0.5+0.2 Differencefrom placebo (adjusted mean+)-0.6 -0.6 95%Confidence Interval(-0.9, -0.3)(-0.9, -0.4) Percentof patients achieving A1C <7%35% (35/100)38% (39/103)24% (22/92)Fasting Plasma Glucose (mg/dL)N=101N=105N=92 Baseline (mean)178171172 Change frombaseline (adjusted mean+)-15-9+6 Differencefrom placebo (adjusted mean+)-21 -15 95%Confidence Interval(-31, -10)(-25, -4) 2-hour Postprandial Glucose (mg/dL)N=78N=84N=71 Baseline (mean)279278283 Change frombaseline (adjusted mean+)-45-43-6 Differencefrom placebo (adjusted mean+)-39 -37 95%Confidence Interval(-61, -16)(-59, -15) A second 24-week monotherapy trialwas conducted to assess range of dosing regimens for ONGLYZA. Treatment-naivepatients with inadequately controlled diabetes (A1C >=7% to <=10%) underwenta 2-week, single-blind diet, exercise, and placebo lead-in period. totalof 365 patients were randomized to 2.5 mg every morning, mg every morning,2.5 mg with possible titration to mg every morning, or mg every eveningof ONGLYZA, or placebo. Patients who failed to meet specific glycemic goalsduring the study were treated with metformin rescue therapy added on to placeboor ONGLYZA; the number of patients randomized per treatment group ranged from71 to 74.Treatment with either ONGLYZA mg every morningor mg every evening provided significant improvements in A1C versus placebo(mean placebo-corrected reductions of -0.4% and -0.3%, respectively). Treatmentwith ONGLYZA 2.5 mg every morning also provided significant improvement inA1C versus placebo (mean placebo-corrected reduction of -0.4%).. 14.2 Combination Therapy. Add-On Combination Therapy with Metformin. total of 743 patients with type diabetesparticipated in this 24-week, randomized, double-blind, placebo-controlledtrial to evaluate the efficacy and safety of ONGLYZA in combination with metforminin patients with inadequate glycemic control (A1C >=7% and <=10%) on metforminalone. To qualify for enrollment, patients were required to be on stabledose of metformin (1500-2550 mg daily) for at least weeks.Patientswho met eligibility criteria were enrolled in single-blind, 2-week, dietaryand exercise placebo lead-in period during which patients received metforminat their pre-study dose, up to 2500 mg daily.Following the lead-in period, eligible patients were randomized to 2.5 mg,5 mg, or 10 mg of ONGLYZA or placebo in addition to their current dose ofopen-label metformin. Patients who failed to meet specific glycemic goalsduring the study were treated with pioglitazone rescue therapy, added on toexisting study medications. Dose titrations of ONGLYZA and metformin werenot permitted.ONGLYZA 2.5 mg and mg add-on to metforminprovided significant improvements in A1C, FPG, and PPG compared with placeboadd-on to metformin (Table 6). Mean changes from baseline for A1C over timeand at endpoint are shown in Figure 1. The proportion of patients who discontinuedfor lack of glycemic control or who were rescued for meeting prespecifiedglycemic criteria was 15% in the ONGLYZA 2.5 mg add-on to metformin group,13% in the ONGLYZA mg add-on to metformin group, and 27% in the placeboadd-on to metformin group.Table 6: Glycemic Parameters at Week 24 in Placebo-Controlled Studyof ONGLYZA as Add-On Combination Therapy with MetforminEfficacyParameterONGLYZA2.5 mg+MetforminN=192ONGLYZA5 mg+MetforminN=191Placebo+MetforminN=179 Intent-to-treat populationusing last observation on study or last observation prior to pioglitazonerescue therapy for patients needing rescue.+ Leastsquares mean adjusted for baseline value. p-value<0.0001 compared to placebo metformin p-value<0.05 compared to placebo metforminHemoglobin A1C (%)N=186N=186N=175 Baseline (mean)8.18.18.1 Change frombaseline (adjusted mean+)-0.6-0.7+0.1 Differencefrom placebo (adjusted mean+)-0.7 -0.8 95%Confidence Interval(-0.9, -0.5)(-1.0, -0.6) Percentof patients achieving A1C <7%37% (69/186)44% (81/186)17% (29/175)Fasting Plasma Glucose (mg/dL)N=188N=187N=176 Baseline (mean)174179175 Change frombaseline (adjusted mean+)-14-22+1 Differencefrom placebo (adjusted mean+)-16 -23 95%Confidence Interval(-23, -9)(-30, -16) 2-hour Postprandial Glucose (mg/dL)N=155N=155N=135 Baseline (mean)294296295 Change frombaseline (adjusted mean+)-62-58-18 Differencefrom placebo (adjusted mean+)-44 -40 95%Confidence Interval(-60, -27)(-56, -24) Figure 1: Mean Change from Baseline in A1C in Placebo-ControlledTrial of ONGLYZA as Add-On Combination Therapy with Metformin Includes patients with baselineand week 24 value.Week 24 (LOCF) includes intent-to-treat populationusing last observation on study prior to pioglitazone rescue therapy forpatients needing rescue. Mean change from baseline is adjusted for baselinevalue.. Figure 1. Add-On Combination Therapy with Thiazolidinedione. total of 565 patients with type2 diabetes participated in this 24-week, randomized, double-blind, placebo-controlledtrial to evaluate the efficacy and safety of ONGLYZA in combination with athiazolidinedione (TZD) in patients with inadequate glycemic control (A1C>=7% to <=10.5%) on TZD alone. To qualify for enrollment, patients were requiredto be on stable dose of pioglitazone (30-45 mg once daily) or rosiglitazone(4 mg once daily or mg either once daily or in two divided doses of mg)for at least 12 weeks.Patients who met eligibilitycriteria were enrolled in single-blind, 2-week, dietary and exercise placebolead-in period during which patients received TZD at their pre-study dose. Following the lead-in period, eligible patientswere randomized to 2.5 mg or mg of ONGLYZA or placebo inaddition to their current dose of TZD. Patients who failed to meet specificglycemic goals during the study were treated with metformin rescue, addedon to existing study medications. Dose titration of ONGLYZA or TZD was notpermitted during the study. change in TZD regimen from rosiglitazone topioglitazone at specified, equivalent therapeutic doses was permitted at theinvestigators discretion if believed to be medically appropriate.ONGLYZA2.5 mg and mg add-on to TZD provided significant improvements in A1C, FPG,and PPG compared with placebo add-on to TZD (Table 7). The proportion of patientswho discontinued for lack of glycemic control or who were rescued for meetingprespecified glycemic criteria was 10% in the ONGLYZA 2.5 mg add-on to TZDgroup, 6% for the ONGLYZA mg add-on to TZD group, and 10% in the placeboadd-on to TZD group.Table 7: Glycemic Parameters at Week 24 in Placebo-Controlled Studyof ONGLYZA as Add-On Combination Therapy with ThiazolidinedioneEfficacyParameterONGLYZA2.5 mg+TZDN=195ONGLYZA5 mg+TZDN=186Placebo+TZDN=184 Intent-to-treat populationusing last observation on study or last observation prior to metformin rescuetherapy for patients needing rescue.+ Leastsquares mean adjusted for baseline value. p-value<0.0001 compared to placebo TZD p-value<0.05 compared to placebo TZDHemoglobin A1C (%)N=192N=183N=180 Baseline (mean)8.38.48.2 Change frombaseline (adjusted mean+)-0.7-0.9-0.3 Differencefrom placebo (adjusted mean+)-0.4 -0.6 95%Confidence Interval(-0.6, -0.2)(-0.8, -0.4) Percentof patients achieving A1C <7%42% (81/192)42% (77/184)26% (46/180)Fasting Plasma Glucose (mg/dL)N=193N=185N=181 Baseline (mean)163160162 Change frombaseline (adjusted mean+)-14-17-3 Differencefrom placebo (adjusted mean+)-12 -15 95%Confidence Interval(-20, -3)(-23, -6) 2-hour Postprandial Glucose (mg/dL)N=156N=134N=127 Baseline (mean)296303291 Change frombaseline (adjusted mean+)-55-65-15 Differencefrom placebo (adjusted mean+)-40 -50 95%Confidence Interval(-56, -24)(-66, -34) Add-On Combination Therapy with Glyburide. total of 768 patients with type2 diabetes participated in this 24-week, randomized, double-blind, placebo-controlledtrial to evaluate the efficacy and safety of ONGLYZA in combination with asulfonylurea (SU) in patients with inadequate glycemic control at enrollment(A1C >=7.5% to <=10%) on submaximal dose of SU alone. To qualify for enrollment,patients were required to be on submaximal dose of SU for months or greater.In this study, ONGLYZA in combination with fixed, intermediate dose of SUwas compared to titration to higher dose of SU.Patientswho met eligibility criteria were enrolled in single-blind, 4-week, dietaryand exercise lead-in period, and placed on glyburide 7.5 mg once daily. Followingthe lead-in period, eligible patients with A1C >=7% to <=10% were randomizedto either 2.5 mg or mg of ONGLYZA add-on to 7.5 mg glyburide or to placeboplus 10 mg total daily dose of glyburide. Patients who received placebowere eligible to have glyburide up-titrated to total daily dose of 15 mg.Up-titration of glyburide was not permitted in patients who received ONGLYZA2.5 mg or mg. Glyburide could be down-titrated in any treatment group onceduring the 24-week study period due to hypoglycemia as deemed necessary bythe investigator. Approximately 92% of patients in the placebo plus glyburidegroup were up-titrated to final total daily dose of 15 mg during the first4 weeks of the study period. Patients who failed to meet specific glycemicgoals during the study were treated with metformin rescue, added on to existingstudy medication. Dose titration of ONGLYZA was not permitted during the study. Incombination with glyburide, ONGLYZA 2.5 mg and mg provided significant improvementsin A1C, FPG, and PPG compared with the placebo plus up-titrated glyburidegroup (Table 8). The proportion of patients who discontinued for lack of glycemiccontrol or who were rescued for meeting prespecified glycemic criteria was18% in the ONGLYZA 2.5 mg add-on to glyburide group, 17% in the ONGLYZA 5mg add-on to glyburide group, and 30% in the placebo plus up-titrated glyburidegroup.Table 8: Glycemic Parameters at Week 24 in Placebo-Controlled Studyof ONGLYZA as Add-On Combination Therapy with GlyburideEfficacyParameterONGLYZA2.5mg+ Glyburide7.5 mgN=248ONGLYZA5mg+ Glyburide7.5 mgN=253Placebo Up-TitratedGlyburideN=267 Intent-to-treat populationusing last observation on study or last observation prior to metformin rescuetherapy for patients needing rescue.+ Leastsquares mean adjusted for baseline value. p-value<0.0001 compared to placebo up-titrated glyburide p-value<0.05 compared to placebo up-titrated glyburideHemoglobin A1C (%)N=246N=250N=264 Baseline (mean)8.48.58.4 Change frombaseline (adjusted mean+)-0.5-0.6+0.1 Differencefrom up-titrated glyburide (adjusted mean+)-0.6 -0.7 95%Confidence Interval(-0.8, -0.5)(-0.9, -0.6) Percentof patients achieving A1C <7%22% (55/246)23% (57/250)9% (24/264)Fasting Plasma Glucose (mg/dL)N=247N=252N=265 Baseline (mean)170175174 Change frombaseline (adjusted mean+)-7-10+1 Differencefrom up-titrated glyburide (adjusted mean+)-8 -10 95%Confidence Interval(-14, -1)(-17, -4) 2-hour Postprandial Glucose (mg/dL)N=195N=202N=206 Baseline (mean)309315323 Change frombaseline (adjusted mean+)-31-34+8 Differencefrom up-titrated glyburide (adjusted mean+)-38 -42 95%Confidence Interval(-50, -27)(-53, -31) Coadministration with Metformin in Treatment-Naive Patients. total of 1306 treatment-naive patientswith type diabetes mellitus participated in this 24-week, randomized, double-blind,active-controlled trial to evaluate the efficacy and safety of ONGLYZA coadministeredwith metformin in patients with inadequate glycemic control (A1C >=8% to <=12%)on diet and exercise alone. Patients were required to be treatment-naive tobe enrolled in this study. Patients who met eligibilitycriteria were enrolled in single-blind, 1-week, dietary and exercise placebolead-in period. Patients were randomized to one of four treatment arms: ONGLYZA5 mg metformin 500 mg, saxagliptin 10 mg metformin 500 mg, saxagliptin10 mg placebo, or metformin 500 mg placebo. ONGLYZA was dosed once daily.In the treatment groups using metformin, the metformin dose was up-titratedweekly in 500 mg per day increments, as tolerated, to maximum of 2000 mgper day based on FPG. Patients who failed to meet specific glycemic goalsduring the studies were treated with pioglitazone rescue as add-on therapy. Coadministrationof ONGLYZA mg plus metformin provided significant improvements in A1C, FPG,and PPG compared with placebo plus metformin (Table 9).Table 9: Glycemic Parameters at Week 24 in Placebo-Controlled Trialof ONGLYZA Coadministration with Metformin in Treatment-Naive PatientsEfficacyParameterONGLYZA5 mg+ MetforminN=320Placebo+MetforminN=328 Intent-to-treat populationusing last observation on study or last observation prior to pioglitazonerescue therapy for patients needing rescue.+ Leastsquares mean adjusted for baseline value. p-value<0.0001 compared to placebo metformin p-value<0.05 compared to placebo metforminHemoglobin A1C (%)N=306N=313 Baseline (mean)9.49.4 Change frombaseline (adjusted mean+)-2.5-2.0 Differencefrom placebo metformin (adjusted mean+)-0.5 95%Confidence Interval(-0.7, -0.4) Percentof patients achieving A1C <7%60% (185/307)41% (129/314)Fasting Plasma Glucose (mg/dL)N=315N=320 Baseline (mean)199199 Change frombaseline (adjusted mean+)-60-47 Differencefrom placebo metformin (adjusted mean+)-13 95%Confidence Interval(-19, -6) 2-hour Postprandial Glucose (mg/dL)N=146N=141 Baseline (mean)340355 Change frombaseline (adjusted mean+)-138-97 Differencefrom placebo metformin (adjusted mean+)-41 95%Confidence Interval(-57, -25) Add-On Combination Therapy with Metformin versus Glipizide Add-On Combination Therapy with Metformin. In this 52-week, active-controlled trial, total of 858 patients with type diabetes and inadequate glycemic control (A1C >6.5% and <=10%) on metformin alone were randomized to double-blind add-on therapy with ONGLYZA or glipizide. Patients were required to be on stable dose of metformin (at least 1500 mg daily) for at least weeks prior to enrollment.Patients who met eligibility criteria were enrolled in single-blind, 2-week, dietary and exercise placebo lead-in period during which patients received metformin (1500-3000 mg based on their pre-study dose). Following the lead-in period, eligible patients were randomized to mg of ONGLYZA or mg of glipizide in addition to their current dose of open-label metformin. Patients in the glipizide plus metformin group underwent blinded titration of the glipizide dose during the first 18 weeks of the trial up to maximum glipizide dose of 20 mg per day. Titration was based on goal FPG <=110 mg/dL or the highest tolerable glipizide dose. Fifty percent (50%) of the glipizide-treated patients were titrated to the 20-mg daily dose; 21% of the glipizide-treated patients had final daily glipizide dose of mg or less. The mean final daily dose of glipizide was 15 mg.After 52 weeks of treatment, ONGLYZA and glipizide resulted in similar mean reductions from baseline in A1C when added to metformin therapy (Table 10). This conclusion may be limited to patients with baseline A1C comparable to those in the trial (91% of patients had baseline A1C <9%).From baseline mean body weight of 89 kg, there was statistically significant mean reduction of 1.1 kg in patients treated with ONGLYZA compared to mean weight gain of 1.1 kg in patients treated with glipizide (p<0.0001).Table 10: Glycemic Parameters at Week 52 in an Active-Controlled Trial of ONGLYZA versus Glipizide in Combination with MetforminEfficacy ParameterONGLYZA mg+ MetforminN=428Titrated Glipizide +MetforminN=430 Intent-to-treat population using last observation on study.+ Least squares mean adjusted for baseline value. Saxagliptin metformin is considered non-inferior to glipizide metformin because the upper limit of this confidence interval is less than the prespecified non-inferiority margin of 0.35%. Significance not tested.Hemoglobin A1C (%)N=423N=423 Baseline (mean)7.77.6 Change from baseline (adjusted mean+)-0.6-0.7 Difference from glipizide metformin (adjusted mean+)0.1 95% Confidence Interval(-0.02, 0.2) Fasting Plasma Glucose (mg/dL)N=420N=420 Baseline (mean)162161 Change from baseline (adjusted mean+)-9-16 Difference from glipizide metformin (adjusted mean+)6 95% Confidence Interval(2, 11) Add-On Combination Therapy with Insulin (with or without metformin). total of 455 patients with type diabetes participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of ONGLYZA in combination with insulin in patients with inadequate glycemic control (A1C >=7.5% and <=11%) on insulin alone (N=141) or on insulin in combination with stable dose of metformin (N=314). Patients were required to be on stable dose of insulin (>=30 units to <=150 units daily) with <=20% variation in total daily dose for >=8 weeks prior to screening. Patients entered the trial on intermediate- or long-acting (basal) insulin or premixed insulin. Patients using short-acting insulins were excluded unless the short-acting insulin was administered as part of premixed insulin.Patients who met eligibility criteria were enrolled in single-blind, four-week, dietary and exercise placebo lead-in period during which patients received insulin (and metformin if applicable) at their pretrial dose(s). Following the lead-in period, eligible patients were randomized to add-on therapy with either ONGLYZA mg or placebo. Doses of the antidiabetic therapies were to remain stable but patients were rescued and allowed to adjust the insulin regimen if specific glycemic goals were not met or if the investigator learned that the patient had self-increased the insulin dose by >20%. Data after rescue were excluded from the primary efficacy analyses.Add-on therapy with ONGLYZA mg provided significant improvements from baseline to Week 24 in A1C and PPG compared with add-on placebo (Table 11). Similar mean reductions in A1C versus placebo were observed for patients using ONGLYZA mg add-on to insulin alone and ONGLYZA mg add-on to insulin in combination with metformin (-0.4% and -0.4%, respectively). The percentage of patients who discontinued for lack of glycemic control or who were rescued was 23% in the ONGLYZA group and 32% in the placebo group.The mean daily insulin dose at baseline was 53 units in patients treated with ONGLYZA mg and 55 units in patients treated with placebo. The mean change from baseline in daily dose of insulin was units for the ONGLYZA mg group and units for the placebo group.Table 11: Glycemic Parameters at Week 24 in Placebo-Controlled Trial of ONGLYZA as Add-On Combination Therapy with InsulinEfficacyParameterONGLYZA5 mg+ Insulin(+/- Metformin)N=304Placebo+Insulin(+/- Metformin)N=151 Intent-to-treat population using last observation on study or last observation prior to insulin rescue therapy for patients needing rescue.+ Least squares mean adjusted for baseline value and metformin use at baseline. p-value<0.0001 compared to placebo insulin p-value <0.05 compared to placebo insulinHemoglobin A1C (%)N=300N=149 Baseline (mean)8.78.7 Change frombaseline (adjusted mean+)-0.7-0.3 Differencefrom placebo (adjusted mean+)-0.4 95%Confidence Interval(-0.6, -0.2) Percentof patients achieving A1C <7%17% (52/300)7% (10/149)Fasting Plasma Glucose (mg/dL)N=300N=149 Baseline (mean)173173 Change frombaseline (adjusted mean+)-10-6 Differencefrom placebo (adjusted mean+)-4 95%Confidence Interval(-13, 5) 2-hour Postprandial Glucose (mg/dL)N=262N=129 Baseline (mean)251255 Change frombaseline (adjusted mean+)-27-4 Differencefrom placebo (adjusted mean+)-23 95%Confidence Interval(-37, -9) 14.3 Renal Impairment. total of 170 patients participated in 12-week, randomized, double-blind, placebo-controlled trial conducted to evaluate the efficacy and safety of ONGLYZA 2.5 mg once daily compared with placebo in patients with type diabetes and moderate (n=90) or severe (n=41) renal impairment or ESRD (n=39). In this trial, 98% of the patients were using background antidiabetic medications (75% were using insulin and 31% were using oral antidiabetic medications, mostly sulfonylureas).After 12 weeks of treatment, ONGLYZA 2.5 mg provided significant improvement in A1C compared to placebo (Table 12). In the subgroup of patients with ESRD, ONGLYZA and placebo resulted in comparable reductions in A1C from baseline to Week 12. This finding is inconclusive because the trial was not adequately powered to show efficacy within specific subgroups of renal impairment.After 12 weeks of treatment, the mean change in FPG was -12 mg/dL with ONGLYZA 2.5 mg and -13 mg/dL with placebo. Compared to placebo, the mean change in FPG with ONGLYZA was -12 mg/dL in the subgroup of patients with moderate renal impairment, -4 mg/dL in the subgroup of patients with severe renal impairment, and +44 mg/dL in the subgroup of patients with ESRD. These findings are inconclusive because the trial was not adequately powered to show efficacy within specific subgroups of renal impairment.Table 12: A1C at Week 12 in Placebo-Controlled Trial of ONGLYZA in Patients with Renal ImpairmentEfficacy ParameterONGLYZA 2.5 mgN=85PlaceboN=85 Intent-to-treat population using last observation on study.+ Least squares mean adjusted for baseline value. p-value <0.01 compared to placeboHemoglobin A1C (%)N=81N=83 Baseline (mean)8.48.1 Change from baseline (adjusted mean+)-0.9-0.4 Difference from placebo (adjusted mean+)-0.4 95% Confidence Interval(-0.7, -0.1).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. History of serious hypersensitivity reaction to ONGLYZA, such as anaphylaxis, angioedema, or exfoliative skin conditions. [See Warnings and Precautions (5.3) and Adverse Reactions (6.2).]. History of serious hypersensitivity reaction (e.g., anaphylaxis, angioedema, exfoliative skin conditions) to ONGLYZA. (4) History of serious hypersensitivity reaction (e.g., anaphylaxis, angioedema, exfoliative skin conditions) to ONGLYZA. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Saxagliptin is an orally-active inhibitorof the DPP4 enzyme.Saxagliptin monohydrate is describedchemically as (1S,3S,5S)-2-[(2S)-2-Amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile,monohydrate or (1S,3S,5S)-2-[(2S)-2-Amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrate. The empirical formula is C18H25N3O2oH2O and the molecular weightis 333.43. The structural formula is:Saxagliptin monohydrateis white to light yellow or light brown, non-hygroscopic, crystalline powder.It is sparingly soluble in water at 24C +- 3C, slightly soluble in ethylacetate, and soluble in methanol, ethanol, isopropyl alcohol, acetonitrile,acetone, and polyethylene glycol 400 (PEG 400).Eachfilm-coated tablet of ONGLYZA for oral use contains either 2.79 mg saxagliptinhydrochloride (anhydrous) equivalent to 2.5 mg saxagliptin or 5.58 mg saxagliptinhydrochloride (anhydrous) equivalent to mg saxagliptin and the followinginactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellosesodium, and magnesium stearate. In addition, the film coating contains thefollowing inactive ingredients: polyvinyl alcohol, polyethylene glycol, titaniumdioxide, talc, and iron oxides.. Saxagliptin Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION . The recommended dose is 2.5 mg or mg once daily taken regardlessof meals. (2.1) 2.5 mg daily is recommended for patients with moderate or severerenal impairment, or end-stage renal disease (CrCl <=50 mL/min). Assess renalfunction before starting ONGLYZA and periodically thereafter. (2.2) 2.5 mg daily is recommended for patients also taking strong cytochromeP450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole). (2.3, 7.1) The recommended dose is 2.5 mg or mg once daily taken regardlessof meals. (2.1) 2.5 mg daily is recommended for patients with moderate or severerenal impairment, or end-stage renal disease (CrCl <=50 mL/min). Assess renalfunction before starting ONGLYZA and periodically thereafter. (2.2) 2.5 mg daily is recommended for patients also taking strong cytochromeP450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole). (2.3, 7.1) 2.1 Recommended Dosing. The recommended dose of ONGLYZA is2.5 mg or mg once daily taken regardless of meals.ONGLYZA tablets must not be split or cut.. 2.2 Patients with Renal Impairment. No dosage adjustment for ONGLYZAis recommended for patients with mild renal impairment (creatinine clearance[CrCl] >50 mL/min).The dose of ONGLYZA is 2.5 mg oncedaily for patients with moderate or severe renal impairment, or with end-stagerenal disease (ESRD) requiring hemodialysis (creatinine clearance [CrCl] <=50 mL/min) [see Clinical Pharmacology (12.3) and Clinical Studies (14.3)].ONGLYZA should be administered following hemodialysis. ONGLYZA has not beenstudied in patients undergoing peritoneal dialysis.Becausethe dose of ONGLYZA should be limited to 2.5 mg based upon renal function,assessment of renal function is recommended prior to initiation of ONGLYZAand periodically thereafter. Renal function can be estimated from serum creatinineusing the Cockcroft-Gault formula or Modification of Diet in Renal Diseaseformula. [See Clinical Pharmacology (12.3).]. 2.3 Strong CYP3A4/5 Inhibitors. The dose of ONGLYZA is 2.5 mg once dailywhen coadministered with strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors(e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole,nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). [See Drug Interactions (7.1) and ClinicalPharmacology (12.3).]. 2.4 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin. When ONGLYZA is used in combination with an insulin secretagogue (e.g., sulfonylurea) or with insulin, lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia. [See Warnings and Precautions (5.1).].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Tablets: mg and 2.5 mg (3) Tablets: mg and 2.5 mg (3) ONGLYZA (saxagliptin) mg tablets are pink, biconvex, round, film-coatedtablets with 5 printed on one side and 4215 printed on the reverse side,in blue ink.ONGLYZA (saxagliptin) 2.5 mg tablets are pale yellow to light yellow,biconvex, round, film-coated tablets with 2.5 printed on one side and 4214printed on the reverse side, in blue ink.. ONGLYZA (saxagliptin) mg tablets are pink, biconvex, round, film-coatedtablets with 5 printed on one side and 4215 printed on the reverse side,in blue ink.. ONGLYZA (saxagliptin) 2.5 mg tablets are pale yellow to light yellow,biconvex, round, film-coated tablets with 2.5 printed on one side and 4214printed on the reverse side, in blue ink.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Coadministration with strong CYP3A4/5 inhibitors (e.g., ketoconazole)significantly increases saxagliptin concentrations. Recommend limiting ONGLYZAdose to 2.5 mg once daily. (2.3, 7.1) Coadministration with strong CYP3A4/5 inhibitors (e.g., ketoconazole)significantly increases saxagliptin concentrations. Recommend limiting ONGLYZAdose to 2.5 mg once daily. (2.3, 7.1) 7.1 Strong Inhibitors of CYP3A4/5 Enzymes. Ketoconazole significantly increased saxagliptinexposure. Similar significant increases in plasma concentrations of saxagliptinare anticipated with other strong CYP3A4/5 inhibitors (e.g., atazanavir, clarithromycin,indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, andtelithromycin). The dose of ONGLYZA should be limited to 2.5 mg when coadministeredwith strong CYP3A4/5 inhibitor. [See Dosage andAdministration (2.3) and ClinicalPharmacology (12.3).].

GERIATRIC USE SECTION.

8.5 Geriatric Use. In the six, double-blind, controlledclinical safety and efficacy trials of ONGLYZA, 634 (15.3%) of the 4148 randomizedpatients were 65 years and over, and 59 (1.4%) patients were 75 years andover. No overall differences in safety or effectiveness were observed betweenpatients >=65 years old and the younger patients. While this clinical experiencehas not identified differences in responses between the elderly and youngerpatients, greater sensitivity of some older individuals cannot be ruled out.Saxagliptinand its active metabolite are eliminated in part by the kidney. Because elderlypatients are more likely to have decreased renal function, care should betaken in dose selection in the elderly based on renal function. [See Dosage and Administration (2.2) and Clinical Pharmacology (12.3).].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. ONGLYZA is dipeptidylpeptidase-4 (DPP4) inhibitor indicated as an adjunct to diet and exercise to improveglycemic control in adults with type diabetes mellitus in multiple clinical settings. (1.1, 14) Importantlimitations of use: Should not be used for the treatment of type diabetes mellitusor diabetic ketoacidosis. (1.2) Has not been studied in patients with history of pancreatitis. (1.2, 5.1) Should not be used for the treatment of type diabetes mellitusor diabetic ketoacidosis. (1.2) Has not been studied in patients with history of pancreatitis. (1.2, 5.1) 1.1 Monotherapy and Combination Therapy. ONGLYZA is indicated as an adjunctto diet and exercise to improve glycemic control in adults with type diabetesmellitus in multiple clinical settings. [See Clinical Studies (14).]. 1.2 Important Limitations of Use. ONGLYZA should not be used for the treatment of type diabetes mellitus or diabetic ketoacidosis, as it wouldnot be effective in these settings.ONGLYZA has not been studied in patients with history of pancreatitis. It is unknown whether patients with history of pancreatitis are at an increased risk for the development of pancreatitis while using ONGLYZA. [See Warnings and Precautions (5.1).].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. See FDA-approved Medication Guide.. 17.1 Instructions. Patients should be informed of thepotential risks and benefits of ONGLYZA and of alternative modes of therapy.Patients should also be informed about the importance of adherence to dietaryinstructions, regular physical activity, periodic blood glucose monitoringand A1C testing, recognition and management of hypoglycemia and hyperglycemia,and assessment of diabetes complications. During periods of stress such asfever, trauma, infection, or surgery, medication requirements may change andpatients should be advised to seek medical advice promptly.Patients should be informed that acute pancreatitis has been reported during postmarketing use of ONGLYZA. Before initiating ONGLYZA, patients should be questioned about other risk factors for pancreatitis, such as history of pancreatitis, alcoholism, gallstones, or hypertriglyceridemia. Patients should also be informed that persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Patients should be instructed to promptly discontinue ONGLYZA and contact their healthcare provider if persistent severe abdominal pain occurs [see Warnings and Precautions (5.1)].Patients should be informed that serious allergic (hypersensitivity) reactions, such as angioedema, anaphylaxis, and exfoliative skin conditions, have been reported during postmarketing use of ONGLYZA. If symptoms of these allergic reactions (such as rash, skin flaking or peeling, urticaria, swelling of the skin, or swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing) occur, patients must stop taking ONGLYZA and seek medical advice promptly.Patients should be informed that if they miss dose of ONGLYZA they should take the next dose as prescribed, unless otherwise instructed by their healthcare provider. Patients should be instructed not to take an extra dose the next day.Healthcare providers should instruct their patients to read the Medication Guide before starting ONGLYZA therapy and to reread it each time the prescription is renewed. Patients should be instructed to inform their healthcare provider if they develop any unusual symptom or if any existing symptom persists or worsens.Patients should be informed that ONGLYZA tablets must not be split or cut.. 17.2 Laboratory Tests. Patients should be informed thatresponse to all diabetic therapies should be monitored by periodic measurementsof blood glucose and A1C, with goal of decreasing these levels toward thenormal range. A1C is especially useful for evaluating long-term glycemic control.Patients should be informed of the potential need to adjust their dose basedon changes in renal function tests over time.

LABORATORY TESTS SECTION.

Laboratory Tests. Absolute Lymphocyte Counts. There was dose-related mean decreasein absolute lymphocyte count observed with ONGLYZA. From baseline mean absolutelymphocyte count of approximately 2200 cells/microL, mean decreases of approximately100 and 120 cells/microL with ONGLYZA mg and 10 mg, respectively, relativeto placebo were observed at 24 weeks in pooled analysis of five placebo-controlledclinical studies. Similar effects were observed when ONGLYZA mg was givenin initial combination with metformin compared to metformin alone. There wasno difference observed for ONGLYZA 2.5 mg relative to placebo. The proportionof patients who were reported to have lymphocyte count <=750 cells/microLwas 0.5%, 1.5%, 1.4%, and 0.4% in the saxagliptin 2.5 mg, mg, 10 mg, andplacebo groups, respectively. In most patients, recurrence was not observedwith repeated exposure to ONGLYZA although some patients had recurrent decreasesupon rechallenge that led to discontinuation of ONGLYZA. The decreases inlymphocyte count were not associated with clinically relevant adverse reactions.Theclinical significance of this decrease in lymphocyte count relative to placebois not known. When clinically indicated, such as in settings of unusual orprolonged infection, lymphocyte count should be measured. The effect of ONGLYZAon lymphocyte counts in patients with lymphocyte abnormalities (e.g., humanimmunodeficiency virus) is unknown.. Platelets. ONGLYZA did not demonstrate clinicallymeaningful or consistent effect on platelet count in the six, double-blind,controlled clinical safety and efficacy trials.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Increased concentrations of the incretinhormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropicpolypeptide (GIP) are released into the bloodstream from the small intestinein response to meals. These hormones cause insulin release from the pancreaticbeta cells in glucose-dependent manner but are inactivated by the DPP4 enzyme within minutes. GLP-1 also lowers glucagon secretionfrom pancreatic alpha cells, reducing hepatic glucose production. In patientswith type diabetes, concentrations of GLP-1 are reduced but the insulinresponse to GLP-1 is preserved. Saxagliptin is competitive DPP4 inhibitorthat slows the inactivation of the incretin hormones, thereby increasing theirbloodstream concentrations and reducing fasting and postprandial glucose concentrationsin glucose-dependent manner in patients with type diabetes mellitus.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Saxagliptin did not induce tumorsin either mice (50, 250, and 600 mg/kg) or rats (25, 75, 150, and 300 mg/kg)at the highest doses evaluated. The highest doses evaluated in mice were equivalentto approximately 870 (males) and 1165 (females) times the human exposure atthe MRHD of mg/day. In rats, exposures were approximately 355 (males) and2217 (females) times the MRHD.Saxagliptin was not mutagenicor clastogenic with or without metabolic activation in an in vitro Amesbacterial assay, an in vitro cytogenetics assay in primaryhuman lymphocytes, an in vivo oral micronucleus assay inrats, an in vivo oral DNA repair study in rats, and an oral invivo/in vitro cytogenetics study in rat peripheralblood lymphocytes. The active metabolite was not mutagenic in an invitro Ames bacterial assay.In rat fertilitystudy, males were treated with oral gavage doses for weeks prior to mating,during mating, and up to scheduled termination (approximately weeks total)and females were treated with oral gavage doses for weeks prior to matingthrough gestation day 7. No adverse effects on fertility were observed atexposures of approximately 603 (males) and 776 (females) times the MRHD. Higherdoses that elicited maternal toxicity also increased fetal resorptions (approximately2069 and 6138 times the MRHD). Additional effects on estrous cycling, fertility,ovulation, and implantation were observed at approximately 6138 times theMRHD.. 13.2 Animal Toxicology. Saxagliptin produced adverse skinchanges in the extremities of cynomolgus monkeys (scabs and/or ulcerationof tail, digits, scrotum, and/or nose). Skin lesions were reversible at >=20times the MRHD but in some cases were irreversible and necrotizing at higherexposures. Adverse skin changes were not observed at exposures similar to(1 to times) the MRHD of mg. Clinical correlates to skin lesions in monkeyshave not been observed in human clinical trials of saxagliptin.

NURSING MOTHERS SECTION.

8.3 Nursing Mothers. Saxagliptin is secreted in the milkof lactating rats at approximately 1:1 ratio with plasma drug concentrations.It is not known whether saxagliptin is secreted in human milk. Because manydrugs are secreted in human milk, caution should be exercised when ONGLYZAis administered to nursing woman.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Category B. There are no adequate and well-controlledstudies in pregnant women. Because animal reproduction studies are not alwayspredictive of human response, ONGLYZA, like other antidiabetic medications,should be used during pregnancy only if clearly needed.Saxagliptinwas not teratogenic at any dose tested when administered to pregnant ratsand rabbits during periods of organogenesis. Incomplete ossification of thepelvis, form of developmental delay, occurred in rats at dose of 240 mg/kg,or approximately 1503 and 66 times human exposure to saxagliptin and the activemetabolite, respectively, at the maximum recommended human dose (MRHD) of5 mg. Maternal toxicity and reduced fetal body weights were observed at 7986and 328 times the human exposure at the MRHD for saxagliptin and the activemetabolite, respectively. Minor skeletal variations in rabbits occurred ata maternally toxic dose of 200 mg/kg, or approximately 1432 and 992 timesthe MRHD.Coadministration of saxagliptin and metformin, to pregnant rats and rabbits during the period of organogenesis, was neither embryolethal nor teratogenic in either species when tested at doses yielding systemic exposures (AUC) up to 100 and 10 times the MRHD (saxagliptin mg and metformin 2000 mg), respectively, in rats; and 249 and 1.1 times the MRHDs in rabbits. In rats, minor developmental toxicity was limited to an increased incidence of wavy ribs; associated maternal toxicity was limited to weight decrements of 11% to 17% over the course of the study, and related reductions in maternal food consumption. In rabbits, coadministration was poorly tolerated in subset of mothers (12 of 30), resulting in death, moribundity, or abortion. However, among surviving mothers with evaluable litters, maternal toxicity was limited to marginal reductions in body weight over the course of gestation days 21 to 29; and associated developmental toxicity in these litters was limited to fetal body weight decrements of 7%, and low incidence of delayed ossification of the fetal hyoid.Saxagliptinadministered to female rats from gestation day to lactation day 20 resultedin decreased body weights in male and female offspring only at maternallytoxic doses (exposures >=1629 and 53 times saxagliptin and its active metaboliteat the MRHD). No functional or behavioral toxicity was observed in offspringof rats administered saxagliptin at any dose.Saxagliptincrosses the placenta into the fetus following dosing in pregnant rats.

RECENT MAJOR CHANGES SECTION.

Indications and Usage Important Limitations of Use (1.2) 11/2011Dosage and Administration Recommended Dosing (2.1) 12/2011 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin (2.4) 12/2011Contraindications (4) 11/2011Warnings and Precautions Pancreatitis (5.1) 11/2011 Use with Medications Known to Cause Hypoglycemia (5.2) 12/2011 Hypersensitivity Reactions (5.3) 11/2011.

SPL MEDGUIDE SECTION.

MEDICATION GUIDEONGLYZA (on-GLY-zah)(saxagliptin)tabletsRead this Medication Guide carefully before you start taking ONGLYZA and each time you get refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment. If you have any questions about ONGLYZA, ask your healthcare provider.What is the most important information should know about ONGLYZASerious side effects can happen to people taking ONGLYZA, including inflammation of the pancreas (pancreatitis) which may be severe and lead to death.Certain medical problems make you more likely to get pancreatitis.Before you start taking ONGLYZA:Tell your healthcare provider if you have ever hadinflammation of your pancreas (pancreatitis)stones in your gallbladder (gallstones)a history of alcoholismhigh blood triglyceride levelsIt is not known if having these medical problems will make you more likely to get pancreatitis with ONGLYZA.Stop taking ONGLYZA and contact your healthcare provider right away if you have pain in your stomach area (abdomen) that is severe and will not go away. The pain may be felt going from your abdomen through to your back. The pain may happen with or without vomiting. These may be symptoms of pancreatitis.What is ONGLYZAONGLYZAis prescription medicine used with diet and exercise to control high bloodsugar (hyperglycemia) in adults with type diabetes.ONGLYZAlowers blood sugar by helping the body increase the level of insulin aftermeals.ONGLYZA is unlikely by itself to cause your blood sugarto be lowered to dangerous level (hypoglycemia) because it does not workwell when your blood sugar is low. However, hypoglycemia may still occur with ONGLYZA. Your risk for getting hypoglycemia is higher if you take ONGLYZA with some other diabetes medicines, such as sulfonylurea or insulin.ONGLYZA is not for people with type diabetes.ONGLYZA is not for people with diabetic ketoacidosis (increased ketones in your blood or urine).If you have had pancreatitis in the past, it is not known if you have higher chance of getting pancreatitis while you take ONGLYZA.It is not known if ONGLYZA is safe and effective in children younger than 18 years old.Who should not take ONGLYZADo not take ONGLYZA if you:are allergic to any ingredients in ONGLYZA. See the end of this Medication Guide for complete list of ingredients in ONGLYZA. Symptoms of serious allergic reaction to ONGLYZA may include:swelling of your face, lips, throat, and other areas on your skindifficulty with swallowing or breathingraised, red areas on your skin (hives)skin rash, itching, flaking, or peeling If you have these symptoms, stop taking ONGLYZA and contact your healthcare provider right away.What should tell my healthcare providerbefore taking ONGLYZABefore you take ONGLYZA, tell your healthcare provider if you:have kidney problems.are pregnant or plan to become pregnant. It is not known if ONGLYZAwill harm your unborn baby. If you are pregnant, talk with your healthcareprovider about the best way to control your blood sugar while you are pregnant.are breast-feeding or plan to breast-feed. ONGLYZA may be passedin your milk to your baby. Talk with your healthcare provider about the bestway to feed your baby while you take ONGLYZA.Tell your healthcare provider about all the medicinesyou take, including prescription and nonprescription medicines, vitamins,and herbal supplements.Know the medicines you take. Keep list of your medicinesand show it to your healthcare provider and pharmacist when you get newmedicine.ONGLYZA may affect the way other medicineswork, and other medicines may affect how ONGLYZA works. Contact your healthcareprovider if you will be starting or stopping certain other types of medications,such as antibiotics, or medicines that treat fungus or HIV/AIDS, because yourdose of ONGLYZA might need to be changed.How should take ONGLYZATake ONGLYZA by mouth one time each day exactly as directed by yourhealthcare provider. Do not change your dose without talking to your healthcareprovider.ONGLYZA can be taken with or without food.Do not split or cut ONGLYZA tablets.During periods of stress on the body, such as:fevertraumainfectionsurgery Contactyour healthcare provider right away as your medication needs may change.Your healthcare provider should test your blood to measure how wellyour kidneys are working before and during your treatment with ONGLYZA. You may need lower dose of ONGLYZA if your kidneys arenot working well.Follow your healthcare providers instructions for treating bloodsugar that is too low (hypoglycemia). Talk to your healthcare provider iflow blood sugar is problem for you.If you miss dose of ONGLYZA, take it as soon as you remember.If it is almost time for your next dose, skip the missed dose. Just take thenext dose at your regular time. Do not take two doses at the same time unlessyour healthcare provider tells you to do so. Talk to your healthcare providerif you have questions about missed dose.If you take too much ONGLYZA, call your healthcare provider or PoisonControl Center at 1-800-222-1222, or go to the nearest hospital emergencyroom right away.Whatare the possible side effects of ONGLYZAONGLYZA can cause serious side effects, including:See What is the most important information should know about ONGLYZAAllergic (hypersensitivity) reactions, such as:swelling of your face, lips, throat, and other areas on your skindifficulty with swallowing or breathingraised, red areas on your skin (hives)skin rash, itching, flaking, or peeling If you have these symptoms, stop taking ONGLYZA and contact your healthcare provider right away.Commonside effects of ONGLYZA include:upper respiratory tract infectionurinary tract infectionheadacheLow blood sugar (hypoglycemia) may become worsein people who also take another medication to treat diabetes, such as sulfonylureas or insulin.Tell your healthcare provider if you take other diabetes medicines. If youhave symptoms of low blood sugar, you should check your blood sugar and treatif low, then call your healthcare provider. Symptoms of low blood sugar include:shakingsweatingrapid heartbeatchange in visionhungerheadachechange in moodSwelling or fluid retention in your hands,feet, or ankles (peripheral edema) may become worse in people who also takea thiazolidinedione to treat diabetes. If you do not know whether you arealready on this type of medication, ask your healthcare provider.Theseare not all of the possible side effects of ONGLYZA. Tell your healthcareprovider if you have any side effects that bother you or that do not go away.For more information, ask your healthcare provider.Callyour healthcare provider for medical advice about side effects. You may reportside effects to the FDA at 1-800-FDA-1088.How should store ONGLYZAStoreONGLYZA between 68F and 77F (20C and 25C).KeepONGLYZA and all medicines out of the reach of children.General information about the use ofONGLYZAMedicines are sometimesprescribed for conditions that are not mentioned in Medication Guides. Do notuse ONGLYZA for condition for which it was not prescribed. Do not give ONGLYZAto other people, even if they have the same symptoms you have. It may harmthem.This Medication Guide summarizes the most importantinformation about ONGLYZA. If you would like to know more information aboutONGLYZA, talk with your healthcare provider. You can ask your healthcare providerfor additional information about ONGLYZA that is written for healthcare professionals.For more information, go to www.ONGLYZA.com or call 1-800-ONGLYZA.What are the ingredients of ONGLYZAActiveingredient: saxagliptinInactive ingredients: lactosemonohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesiumstearate. In addition, the film coating contains the following inactive ingredients:polyvinyl alcohol, polyethylene glycol, titanium dioxide, talc, and iron oxides.What is type diabetesType2 diabetes is condition in which your body does not make enough insulin,and the insulin that your body produces does not work as well as it should.Your body can also make too much sugar. When this happens, sugar (glucose)builds up in the blood. This can lead to serious medical problems.Themain goal of treating diabetes is to lower your blood sugar so that it is as close to normal as possible.Highblood sugar can be lowered by diet and exercise, and by certain medicineswhen necessary.. inflammation of your pancreas (pancreatitis). stones in your gallbladder (gallstones). history of alcoholism. high blood triglyceride levels. ONGLYZAis prescription medicine used with diet and exercise to control high bloodsugar (hyperglycemia) in adults with type diabetes.. ONGLYZAlowers blood sugar by helping the body increase the level of insulin aftermeals.. ONGLYZA is unlikely by itself to cause your blood sugarto be lowered to dangerous level (hypoglycemia) because it does not workwell when your blood sugar is low. However, hypoglycemia may still occur with ONGLYZA. Your risk for getting hypoglycemia is higher if you take ONGLYZA with some other diabetes medicines, such as sulfonylurea or insulin.. ONGLYZA is not for people with type diabetes.. ONGLYZA is not for people with diabetic ketoacidosis (increased ketones in your blood or urine).. If you have had pancreatitis in the past, it is not known if you have higher chance of getting pancreatitis while you take ONGLYZA.. are allergic to any ingredients in ONGLYZA. See the end of this Medication Guide for complete list of ingredients in ONGLYZA.. Symptoms of serious allergic reaction to ONGLYZA may include:swelling of your face, lips, throat, and other areas on your skindifficulty with swallowing or breathingraised, red areas on your skin (hives)skin rash, itching, flaking, or peeling. swelling of your face, lips, throat, and other areas on your skin. difficulty with swallowing or breathing. raised, red areas on your skin (hives). skin rash, itching, flaking, or peeling. If you have these symptoms, stop taking ONGLYZA and contact your healthcare provider right away.. have kidney problems.. are pregnant or plan to become pregnant. It is not known if ONGLYZAwill harm your unborn baby. If you are pregnant, talk with your healthcareprovider about the best way to control your blood sugar while you are pregnant.. are breast-feeding or plan to breast-feed. ONGLYZA may be passedin your milk to your baby. Talk with your healthcare provider about the bestway to feed your baby while you take ONGLYZA.. Take ONGLYZA by mouth one time each day exactly as directed by yourhealthcare provider. Do not change your dose without talking to your healthcareprovider.. ONGLYZA can be taken with or without food.. Do not split or cut ONGLYZA tablets.. During periods of stress on the body, such as:fevertraumainfectionsurgery fever. trauma. infection. surgery. Contactyour healthcare provider right away as your medication needs may change.. Your healthcare provider should test your blood to measure how wellyour kidneys are working before and during your treatment with ONGLYZA. You may need lower dose of ONGLYZA if your kidneys arenot working well.. Follow your healthcare providers instructions for treating bloodsugar that is too low (hypoglycemia). Talk to your healthcare provider iflow blood sugar is problem for you.. If you miss dose of ONGLYZA, take it as soon as you remember.If it is almost time for your next dose, skip the missed dose. Just take thenext dose at your regular time. Do not take two doses at the same time unlessyour healthcare provider tells you to do so. Talk to your healthcare providerif you have questions about missed dose.. If you take too much ONGLYZA, call your healthcare provider or PoisonControl Center at 1-800-222-1222, or go to the nearest hospital emergencyroom right away.. See What is the most important information should know about ONGLYZA. Allergic (hypersensitivity) reactions, such as:swelling of your face, lips, throat, and other areas on your skindifficulty with swallowing or breathingraised, red areas on your skin (hives)skin rash, itching, flaking, or peeling. swelling of your face, lips, throat, and other areas on your skin. difficulty with swallowing or breathing. raised, red areas on your skin (hives). skin rash, itching, flaking, or peeling. If you have these symptoms, stop taking ONGLYZA and contact your healthcare provider right away.. upper respiratory tract infection. urinary tract infection. headache. shaking. sweating. rapid heartbeat. change in vision. hunger. headache. change in mood.

SPL UNCLASSIFIED SECTION.

1.1 Monotherapy and Combination Therapy. ONGLYZA is indicated as an adjunctto diet and exercise to improve glycemic control in adults with type diabetesmellitus in multiple clinical settings. [See Clinical Studies (14).].

STORAGE AND HANDLING SECTION.

Storage and Handling. Store at 20-25C (68-77F); excursionspermitted to 15-30C (59-86F) [see USP Controlled Room Temperature].

TERATOGENIC EFFECTS SECTION.

Pregnancy Category B. There are no adequate and well-controlledstudies in pregnant women. Because animal reproduction studies are not alwayspredictive of human response, ONGLYZA, like other antidiabetic medications,should be used during pregnancy only if clearly needed.Saxagliptinwas not teratogenic at any dose tested when administered to pregnant ratsand rabbits during periods of organogenesis. Incomplete ossification of thepelvis, form of developmental delay, occurred in rats at dose of 240 mg/kg,or approximately 1503 and 66 times human exposure to saxagliptin and the activemetabolite, respectively, at the maximum recommended human dose (MRHD) of5 mg. Maternal toxicity and reduced fetal body weights were observed at 7986and 328 times the human exposure at the MRHD for saxagliptin and the activemetabolite, respectively. Minor skeletal variations in rabbits occurred ata maternally toxic dose of 200 mg/kg, or approximately 1432 and 992 timesthe MRHD.Coadministration of saxagliptin and metformin, to pregnant rats and rabbits during the period of organogenesis, was neither embryolethal nor teratogenic in either species when tested at doses yielding systemic exposures (AUC) up to 100 and 10 times the MRHD (saxagliptin mg and metformin 2000 mg), respectively, in rats; and 249 and 1.1 times the MRHDs in rabbits. In rats, minor developmental toxicity was limited to an increased incidence of wavy ribs; associated maternal toxicity was limited to weight decrements of 11% to 17% over the course of the study, and related reductions in maternal food consumption. In rabbits, coadministration was poorly tolerated in subset of mothers (12 of 30), resulting in death, moribundity, or abortion. However, among surviving mothers with evaluable litters, maternal toxicity was limited to marginal reductions in body weight over the course of gestation days 21 to 29; and associated developmental toxicity in these litters was limited to fetal body weight decrements of 7%, and low incidence of delayed ossification of the fetal hyoid.Saxagliptinadministered to female rats from gestation day to lactation day 20 resultedin decreased body weights in male and female offspring only at maternallytoxic doses (exposures >=1629 and 53 times saxagliptin and its active metaboliteat the MRHD). No functional or behavioral toxicity was observed in offspringof rats administered saxagliptin at any dose.Saxagliptincrosses the placenta into the fetus following dosing in pregnant rats.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. No adequate and well-controlled studies in pregnant women. (8.1) Safety and effectiveness of ONGLYZA in pediatric patients belowthe age of 18 have not been established. (8.4) No adequate and well-controlled studies in pregnant women. (8.1) Safety and effectiveness of ONGLYZA in pediatric patients belowthe age of 18 have not been established. (8.4) 8.1 Pregnancy. Pregnancy Category B. There are no adequate and well-controlledstudies in pregnant women. Because animal reproduction studies are not alwayspredictive of human response, ONGLYZA, like other antidiabetic medications,should be used during pregnancy only if clearly needed.Saxagliptinwas not teratogenic at any dose tested when administered to pregnant ratsand rabbits during periods of organogenesis. Incomplete ossification of thepelvis, form of developmental delay, occurred in rats at dose of 240 mg/kg,or approximately 1503 and 66 times human exposure to saxagliptin and the activemetabolite, respectively, at the maximum recommended human dose (MRHD) of5 mg. Maternal toxicity and reduced fetal body weights were observed at 7986and 328 times the human exposure at the MRHD for saxagliptin and the activemetabolite, respectively. Minor skeletal variations in rabbits occurred ata maternally toxic dose of 200 mg/kg, or approximately 1432 and 992 timesthe MRHD.Coadministration of saxagliptin and metformin, to pregnant rats and rabbits during the period of organogenesis, was neither embryolethal nor teratogenic in either species when tested at doses yielding systemic exposures (AUC) up to 100 and 10 times the MRHD (saxagliptin mg and metformin 2000 mg), respectively, in rats; and 249 and 1.1 times the MRHDs in rabbits. In rats, minor developmental toxicity was limited to an increased incidence of wavy ribs; associated maternal toxicity was limited to weight decrements of 11% to 17% over the course of the study, and related reductions in maternal food consumption. In rabbits, coadministration was poorly tolerated in subset of mothers (12 of 30), resulting in death, moribundity, or abortion. However, among surviving mothers with evaluable litters, maternal toxicity was limited to marginal reductions in body weight over the course of gestation days 21 to 29; and associated developmental toxicity in these litters was limited to fetal body weight decrements of 7%, and low incidence of delayed ossification of the fetal hyoid.Saxagliptinadministered to female rats from gestation day to lactation day 20 resultedin decreased body weights in male and female offspring only at maternallytoxic doses (exposures >=1629 and 53 times saxagliptin and its active metaboliteat the MRHD). No functional or behavioral toxicity was observed in offspringof rats administered saxagliptin at any dose.Saxagliptincrosses the placenta into the fetus following dosing in pregnant rats.. 8.3 Nursing Mothers. Saxagliptin is secreted in the milkof lactating rats at approximately 1:1 ratio with plasma drug concentrations.It is not known whether saxagliptin is secreted in human milk. Because manydrugs are secreted in human milk, caution should be exercised when ONGLYZAis administered to nursing woman.. 8.4 Pediatric Use. Safety and effectiveness of ONGLYZAin pediatric patients have not been established.. 8.5 Geriatric Use. In the six, double-blind, controlledclinical safety and efficacy trials of ONGLYZA, 634 (15.3%) of the 4148 randomizedpatients were 65 years and over, and 59 (1.4%) patients were 75 years andover. No overall differences in safety or effectiveness were observed betweenpatients >=65 years old and the younger patients. While this clinical experiencehas not identified differences in responses between the elderly and youngerpatients, greater sensitivity of some older individuals cannot be ruled out.Saxagliptinand its active metabolite are eliminated in part by the kidney. Because elderlypatients are more likely to have decreased renal function, care should betaken in dose selection in the elderly based on renal function. [See Dosage and Administration (2.2) and Clinical Pharmacology (12.3).].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. There have been postmarketing reports of acute pancreatitis. If pancreatitis is suspected, promptly discontinue ONGLYZA. (5.1) When used with an insulin secretagogue (e.g., sulfonylurea) or insulin, lowerdose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia. (5.2) There have been postmarketing reports of serious hypersensitivity reactions in patients treated with ONGLYZA such as anaphylaxis, angioedema, and exfoliative skin conditions. In such cases, promptly discontinue ONGLYZA, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes. (5.3, 6.2) There have been no clinical studies establishing conclusive evidenceof macrovascular risk reduction with ONGLYZA or any other antidiabetic drug. (5.4) There have been postmarketing reports of acute pancreatitis. If pancreatitis is suspected, promptly discontinue ONGLYZA. (5.1) When used with an insulin secretagogue (e.g., sulfonylurea) or insulin, lowerdose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia. (5.2) There have been postmarketing reports of serious hypersensitivity reactions in patients treated with ONGLYZA such as anaphylaxis, angioedema, and exfoliative skin conditions. In such cases, promptly discontinue ONGLYZA, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes. (5.3, 6.2) There have been no clinical studies establishing conclusive evidenceof macrovascular risk reduction with ONGLYZA or any other antidiabetic drug. (5.4) 5.1 Pancreatitis. There have been postmarketing reports of acute pancreatitis in patients taking ONGLYZA. After initiation of ONGLYZA, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, ONGLYZA should promptly be discontinued and appropriate management should be initiated. It is unknown whether patients with history of pancreatitis are at increased risk for the development of pancreatitis while using ONGLYZA.. 5.2 Use with Medications Known to Cause Hypoglycemia. When ONGLYZA was used in combination with sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of confirmed hypoglycemia was increased over that of placebo used in combination with sulfonylurea or with insulin. [See Adverse Reactions (6.1).] Therefore, lower dose of the insulin secretagogue or insulin maybe required to minimize the risk of hypoglycemia when used in combination withONGLYZA. [See Dosage and Administration (2.4).]. 5.3 Hypersensitivity Reactions. There have been postmarketing reports of serious hypersensitivity reactions in patients treated with ONGLYZA. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first months after initiation of treatment with ONGLYZA, with some reports occurring after the first dose. If serious hypersensitivity reaction is suspected, discontinue ONGLYZA, assess for other potential causes for the event, and institute alternative treatment for diabetes. [See Adverse Reactions (6.2).]Use caution in patient with history of angioedema to another dipeptidyl peptidase-4 (DPP4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with ONGLYZA.. 5.4 Macrovascular Outcomes. There have been no clinical studies establishingconclusive evidence of macrovascular risk reduction with ONGLYZA or any otherantidiabetic drug.