DOSAGE FORMS AND STRENGTHS Tablets: 100 mg, 300 mg (3)

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1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights d nt include all the infrmatin needed t use safely and effectively. See full prescribing infrmatin fr. (canagliflzin) tablets, fr ral use Initial U.S. Apprval: INDICATIONS AND USAGE is a sdium-glucse c-transprter 2 (SGLT2) inhibitr indicated as an adjunct t diet and exercise t imprve glycemic cntrl in adults with type 2 diabetes mellitus (1) Limitatin f Use: Nt fr treatment f type 1 diabetes mellitus r diabetic ketacidsis (1) DOSAGE AND ADMINISTRATION The recmmended starting dse is 100 mg nce daily, taken befre the first meal f the day (2.1) Dse can be increased t 300 mg nce daily in patients tlerating 100 mg nce daily wh have an egfr f 60 ml/min/1.73 m 2 r greater and require additinal glycemic cntrl (2.1) is limited t 100 mg nce daily in patients wh have an egfr f 45 t less than 60 ml/min/1.73 m 2 (2.2) Assess renal functin befre initiating. D nt initiate if egfr is belw 45 ml/min/1.73 m 2 (2.2) Discntinue if egfr falls persistently belw 45 ml/min/1.73 m 2 (2.2) DOSAGE FORMS AND STRENGTHS Tablets: 100 mg, 300 mg (3) CONTRAINDICATIONS Histry f serius hypersensitivity reactin t (4) Severe renal impairment, ESRD, r n dialysis (4) WARNINGS AND PRECAUTIONS Hyptensin: Befre initiating, assess vlume status and crrect hypvlemia in patients with renal impairment, the elderly, in patients with lw systlic bld pressure, r if n diuretics, ACEi, r ARB. Mnitr fr signs and symptms during therapy (5.1) FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recmmended Dsage 2.2 Patients with Renal Impairment 2.3 Cncmitant Use with UDP-Glucurnsyl Transferase (UGT) Enzyme Inducers 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hyptensin 5.2 Impairment in Renal Functin 5.3 Hyperkalemia 5.4 Hypglycemia with Cncmitant Use with Insulin and Insulin Secretaggues 5.5 Genital Myctic Infectins 5.6 Hypersensitivity Reactins 5.7 Increases in Lw-Density Lipprtein (LDL-C) 5.8 Macrvascular Outcmes 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience 7 DRUG INTERACTIONS 7.1 UGT Enzyme Inducers 7.2 Digxin 7.3 Psitive Urine Glucse Test 7.4 Interference with 1,5-anhydrglucitl (1,5-AG) Assay Impairment in Renal Functin: Mnitr renal functin during therapy. Mre frequent mnitring is recmmended in patients with egfr belw 60 ml/min/1.73 m 2 (5.2) Hyperkalemia: Mnitr ptassium levels in patients with impaired renal functin and in patients predispsed t hyperkalemia (5.3) Hypglycemia: Cnsider a lwer dse f insulin r the insulin secretaggue t reduce the risk f hypglycemia when used in cmbinatin with (5.4) Genital myctic infectins: Mnitr and treat if indicated (5.5) Hypersensitivity reactins: Discntinue and mnitr until signs and symptms reslve (5.6) Increased LDL-C: Mnitr LDL-C and treat per standard f care (5.7) ADVERSE REACTIONS Mst cmmn adverse reactins assciated with (5% r greater incidence): female genital myctic infectins, urinary tract infectin, and increased urinatin (6.1) T reprt SUSPECTED ADVERSE REACTIONS, cntact Janssen Pharmaceuticals, Inc. at r FDA at FDA-1088 r DRUG INTERACTIONS UGT inducers (e.g., rifampin): Canagliflzin expsure is reduced. Cnsider increasing dse frm 100 mg t 300 mg (2.3, 7.1) Digxin: Mnitr digxin levels (7.2) USE IN SPECIFIC POPULATIONS Pregnancy: N adequate and well-cntrlled studies in pregnant wmen. Use during pregnancy nly if the ptential benefit justifies the ptential risk t the fetus (8.1) Nursing mthers: Discntinue drug r nursing (8.3) Geriatrics: Higher incidence f adverse reactins related t reduced intravascular vlume (5.1, 8.5) Renal impairment: Higher incidence f adverse reactins related t reduced intravascular vlume and renal functin (2.2, 5.2, 8.6) Hepatic impairment: Nt recmmended with severe hepatic impairment (8.7) See 17 fr PATIENT COUNSELING INFORMATION and Medicatin Guide. Revised: 03/ USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mthers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism f Actin 12.2 Pharmacdynamics 12.3 Pharmackinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcingenesis, Mutagenesis, Impairment f Fertility 13.2 Animal Txiclgy and/r Pharmaclgy 14 CLINICAL STUDIES 14.1 Mntherapy 14.2 Cmbinatin Therapy 14.3 Studies in Special Ppulatins 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sectins r subsectins mitted frm the full prescribing infrmatin are nt listed 1

2 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE (canagliflzin) is indicated as an adjunct t diet and exercise t imprve glycemic cntrl in adults with type 2 diabetes mellitus [see Clinical Studies (14)]. Limitatin f Use is nt recmmended in patients with type 1 diabetes mellitus r fr the treatment f diabetic ketacidsis. 2 DOSAGE AND ADMINISTRATION 2.1 Recmmended Dsage The recmmended starting dse f (canagliflzin) is 100 mg nce daily, taken befre the first meal f the day. In patients tlerating 100 mg nce daily wh have an egfr f 60 ml/min/1.73 m 2 r greater and require additinal glycemic cntrl, the dse can be increased t 300 mg nce daily [see Warnings and Precautins (5.2), Clinical Pharmaclgy (12.2), and Patient Cunseling Infrmatin (17)]. In patients with vlume depletin, crrecting this cnditin prir t initiatin f is recmmended [see Warnings and Precautins (5.1), Use in Specific Ppulatins (8.5 and 8.6), and Patient Cunseling Infrmatin (17)]. 2.2 Patients with Renal Impairment N dse adjustment is needed in patients with mild renal impairment (egfr f 60 ml/min/1.73 m 2 r greater). The dse f is limited t 100 mg nce daily in patients with mderate renal impairment with an egfr f 45 t less than 60 ml/min/1.73 m 2. shuld nt be initiated in patients with an egfr less than 45 ml/min/1.73 m 2. Assessment f renal functin is recmmended prir t initiatin f therapy and peridically thereafter. shuld be discntinued when egfr is persistently less than 45 ml/min/1.73 m 2 [see Warnings and Precautins (5.2) and Use in Specific Ppulatins (8.6)]. 2.3 Cncmitant Use with UDP-Glucurnsyl Transferase (UGT) Enzyme Inducers If an inducer f UGTs (e.g., rifampin, phenytin, phenbarbital, ritnavir) is c-administered with, cnsider increasing the dsage t 300 mg nce daily in patients currently tlerating 100 mg nce daily wh have an egfr f 60 ml/min/1.73 m 2 r greater and require additinal glycemic cntrl [see Drug Interactins (7.1)]. 2

3 Cnsider anther antihyperglycemic agent in patients with an egfr f 45 t less than 60 ml/min/1.73 m 2 receiving cncurrent therapy with a UGT inducer. 3 DOSAGE FORMS AND STRENGTHS 100 mg tablets are yellw, capsule-shaped, film-cated tablets with CFZ n ne side and 100 n the ther side. 300 mg tablets are white, capsule-shaped, film-cated tablets with CFZ n ne side and 300 n the ther side. 4 CONTRAINDICATIONS Histry f a serius hypersensitivity reactin t [see Warnings and Precautins (5.6)]. Severe renal impairment (egfr less than 30 ml/min/1.73 m 2 ), end stage renal disease (ESRD), r patients n dialysis [see Warnings and Precautins (5.2) and Use in Specific Ppulatins (8.6)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hyptensin causes intravascular vlume cntractin. Symptmatic hyptensin can ccur after initiating [see Adverse Reactins (6.1)] particularly in patients with impaired renal functin (egfr less than 60 ml/min/1.73 m 2 ), elderly patients, patients n either diuretics r medicatins that interfere with the renin-angitensin-aldsterne system (e.g., angitensincnverting-enzyme [ACE] inhibitrs, angitensin receptr blckers [ARBs]), r patients with lw systlic bld pressure. Befre initiating in patients with ne r mre f these characteristics, vlume status shuld be assessed and crrected. Mnitr fr signs and symptms after initiating therapy. 5.2 Impairment in Renal Functin increases serum creatinine and decreases egfr. Patients with hypvlemia may be mre susceptible t these changes. Renal functin abnrmalities can ccur after initiating [see Adverse Reactins (6.1)]. Mre frequent renal functin mnitring is recmmended in patients with an egfr belw 60 ml/min/1.73 m Hyperkalemia can lead t hyperkalemia. Patients with mderate renal impairment wh are taking medicatins that interfere with ptassium excretin, such as ptassium-sparing diuretics, r medicatins that interfere with the renin-angitensin-aldsterne system are mre likely t develp hyperkalemia [see Adverse Reactins (6.1)]. 3

4 Mnitr serum ptassium levels peridically after initiating in patients with impaired renal functin and in patients predispsed t hyperkalemia due t medicatins r ther medical cnditins. 5.4 Hypglycemia with Cncmitant Use with Insulin and Insulin Secretaggues Insulin and insulin secretaggues are knwn t cause hypglycemia. can increase the risk f hypglycemia when cmbined with insulin r an insulin secretaggue [see Adverse Reactins (6.1)]. Therefre, a lwer dse f insulin r insulin secretaggue may be required t minimize the risk f hypglycemia when used in cmbinatin with. 5.5 Genital Myctic Infectins increases the risk f genital myctic infectins. Patients with a histry f genital myctic infectins and uncircumcised males were mre likely t develp genital myctic infectins [see Adverse Reactins (6.1)]. Mnitr and treat apprpriately. 5.6 Hypersensitivity Reactins Hypersensitivity reactins (e.g., generalized urticaria), sme serius, were reprted with treatment; these reactins generally ccurred within hurs t days after initiating. If hypersensitivity reactins ccur, discntinue use f ; treat per standard f care and mnitr until signs and symptms reslve [see Cntraindicatins (4) and Adverse Reactins (6.1)]. 5.7 Increases in Lw-Density Lipprtein (LDL-C) Dse-related increases in LDL-C ccur with [see Adverse Reactins (6.1)]. Mnitr LDL-C and treat per standard f care after initiating. 5.8 Macrvascular Outcmes There have been n clinical studies establishing cnclusive evidence f macrvascular risk reductin with r any ther antidiabetic drug. 6 ADVERSE REACTIONS The fllwing imprtant adverse reactins are described belw and elsewhere in the labeling: Hyptensin [see Warnings and Precautins (5.1)] Impairment in Renal Functin [see Warnings and Precautins (5.2)] Hyperkalemia [see Warnings and Precautins (5.3)] Hypglycemia with Cncmitant Use with Insulin and Insulin Secretaggues [see Warnings and Precautins (5.4)] Genital Myctic Infectins [see Warnings and Precautins (5.5)] 4

5 Hypersensitivity Reactins [see Warnings and Precautins (5.6)] Increases in Lw-Density Lipprtein (LDL-C) [see Warnings and Precautins (5.7)] 6.1 Clinical Studies Experience Because clinical trials are cnducted under widely varying cnditins, adverse reactin rates bserved in the clinical trials f a drug cannt be directly cmpared t the rates in the clinical trials f anther drug and may nt reflect the rates bserved in clinical practice. Pl f Placeb-Cntrlled Trials The data in Table 1 is derived frm fur 26-week placeb-cntrlled trials. In ne trial was used as mntherapy and in three trials was used as add-n therapy [see Clinical Studies (14)]. These data reflect expsure f 1667 patients t and a mean duratin f expsure t f 24 weeks. Patients received 100 mg (N=833), 300 mg (N=834) r placeb (N=646) nce daily. The mean age f the ppulatin was 56 years and 2% were lder than 75 years f age. Fifty percent (50%) f the ppulatin was male and 72% were Caucasian, 12% were Asian, and 5% were Black r African American. At baseline the ppulatin had diabetes fr an average f 7.3 years, had a mean HbA1C f 8.0% and 20% had established micrvascular cmplicatins f diabetes. Baseline renal functin was nrmal r mildly impaired (mean egfr 88 ml/min/1.73 m 2 ). Table 1 shws cmmn adverse reactins assciated with the use f. These adverse reactins were nt present at baseline, ccurred mre cmmnly n than n placeb, and ccurred in at least 2% f patients treated with either 100 mg r 300 mg. Table 1: Adverse Reactins Frm Pl f Fur 26 Week Placeb-Cntrlled Studies Reprted in 2% f -Treated Patients* 100 mg N= mg N=834 Placeb Adverse Reactin N=646 Female genital myctic infectins 3.2% 10.4% 11.4% Urinary tract infectins 4.0% 5.9% 4.3% Increased urinatin 0.8% 5.3% 4.6% Male genital myctic infectins 0.6% 4.2% 3.7% Vulvvaginal pruritus 0.0% 1.6% 3.0% Thirst # 0.2% 2.8% 2.3% Cnstipatin 0.9% 1.8% 2.3% Nausea 1.5% 2.2% 2.3% 5

6 * The fur placeb-cntrlled trials included ne mntherapy trial and three add-n cmbinatin trials with metfrmin, metfrmin and sulfnylurea, r metfrmin and piglitazne. Female genital myctic infectins include the fllwing adverse reactins: Vulvvaginal candidiasis, Vulvvaginal myctic infectin, Vulvvaginitis, Vaginal infectin, Vulvitis, and Genital infectin fungal. Percentages calculated with the number f female subjects in each grup as denminatr: placeb (N=312), 100 mg (N=425), and 300 mg (N=430). Urinary tract infectins include the fllwing adverse reactins: Urinary tract infectin, Cystitis, Kidney infectin, and Ursepsis. Increased urinatin includes the fllwing adverse reactins: Plyuria, Pllakiuria, Urine utput increased, Micturitin urgency, and Ncturia. Male genital myctic infectins include the fllwing adverse reactins: Balanitis r Balanpsthitis, Balanitis candida, and Genital infectin fungal. Percentages calculated with the number f male subjects in each grup as denminatr: placeb (N=334), 100 mg (N=408), and 300 mg (N=404). # Thirst includes the fllwing adverse reactins: Thirst, Dry muth, and Plydipsia. Abdminal pain was als mre cmmnly reprted in patients taking 100 mg (1.8%), 300 mg (1.7%) than in patients taking placeb (0.8%). Pl f Placeb- and Active-Cntrlled Trials The ccurrence f adverse reactins fr canagliflzin was evaluated in a larger pl f patients participating in placeb- and active-cntrlled trials. The data cmbined eight clinical trials [see Clinical Studies (14)] and reflect expsure f 6177 patients t. The mean duratin f expsure t was 38 weeks with 1832 individuals expsed t fr greater than 50 weeks. Patients received 100 mg (N=3092), 300 mg (N=3085) r cmparatr (N=3262) nce daily. The mean age f the ppulatin was 60 years and 5% were lder than 75 years f age. Fifty-eight percent (58%) f the ppulatin was male and 73% were Caucasian, 16% were Asian, and 4% were Black r African American. At baseline, the ppulatin had diabetes fr an average f 11 years, had a mean HbA1C f 8.0% and 33% had established micrvascular cmplicatins f diabetes. Baseline renal functin was nrmal r mildly impaired (mean egfr 81 ml/min/1.73 m 2 ). The types and frequency f cmmn adverse reactins bserved in the pl f eight clinical trials were cnsistent with thse listed in Table 1. In this pl, was als assciated with the adverse reactins f fatigue (1.7% with cmparatr, 2.2% with 100 mg, and 2.0% with 300 mg) and lss f strength r energy (i.e., asthenia) (0.6% with cmparatr, 0.7% with 100 mg, and 1.1% with 300 mg). In the pl f eight clinical trials, the incidence rate f pancreatitis (acute r chrnic) was 0.9, 2.7, and 0.9 per 1000 patient-years f expsure t cmparatr, 100 mg, and 300 mg, respectively. 6

7 In the pl f eight clinical trials with a lnger mean duratin f expsure t (68 weeks), the incidence rate f bne fracture was 14.2, 18.7, and 17.6 per 1000 patient years f expsure t cmparatr, 100 mg, and 300 mg, respectively. Upper extremity fractures ccurred mre cmmnly n than cmparatr. In the pl f eight clinical trials, hypersensitivity-related adverse reactins (including erythema, rash, pruritus, urticaria, and angiedema) ccurred in 3.0%, 3.8%, and 4.2% f patients receiving cmparatr, 100 mg, and 300 mg, respectively. Five patients experienced serius adverse reactins f hypersensitivity with, which included 4 patients with urticaria and 1 patient with a diffuse rash and urticaria ccurring within hurs f expsure t. Amng these patients, 2 patients discntinued. One patient with urticaria had recurrence when was re-initiated. Phtsensitivity-related adverse reactins (including phtsensitivity reactin, plymrphic light eruptin, and sunburn) ccurred in 0.1%, 0.2%, and 0.2% f patients receiving cmparatr, 100 mg, and 300 mg, respectively. Other adverse reactins ccurring mre frequently n than n cmparatr were: Vlume Depletin-Related Adverse Reactins results in an smtic diuresis, which may lead t reductins in intravascular vlume. In clinical studies, treatment with was assciated with a dse-dependent increase in the incidence f vlume depletin-related adverse reactins (e.g., hyptensin, pstural dizziness, rthstatic hyptensin, syncpe, and dehydratin). An increased incidence was bserved in patients n the 300 mg dse. The three factrs assciated with the largest increase in vlume depletin-related adverse reactins were the use f lp diuretics, mderate renal impairment (egfr 30 t less than 60 ml/min/1.73 m 2 ), and age 75 years and lder (Table 2) [see Dsage and Administratin (2.2), Warnings and Precautins (5.1), and Use in Specific Ppulatins (8.5 and 8.6)]. Table 2: Prprtin f Patients With at Least One Vlume Depletin-Related Adverse Reactin (Pled Results frm 8 Clinical Trials) Cmparatr Grup* % 100 mg Baseline Characteristic % Overall ppulatin 1.5% 2.3% 3.4% 75 years f age and lder 2.6% 4.9% 8.7% egfr less than 60 ml/min/1.73 m 2 2.5% 4.7% 8.1% Use f lp diuretic 4.7% 3.2% 8.8% * Includes placeb and active-cmparatr grups Patients culd have mre than 1 f the listed risk factrs 300 mg % 7

8 Impairment in Renal Functin is assciated with a dse-dependent increase in serum creatinine and a cncmitant fall in estimated GFR (Table 3). Patients with mderate renal impairment at baseline had larger mean changes. Table 3: Pl f Fur Placeb- Cntrlled Trials Mderate Renal Impairment Trial Changes in Serum Creatinine and egfr Assciated with in the Pl f Fur Placeb-Cntrlled Trials and Mderate Renal Impairment Trial Placeb N= mg N= mg N=834 * Week 26 in mitt LOCF ppulatin Baseline Creatinine (mg/dl) egfr (ml/min/1.73 m 2 ) Week 6 Change Creatinine (mg/dl) egfr (ml/min/1.73 m 2 ) End f Treatment Creatinine (mg/dl) Change* egfr (ml/min/1.73 m 2 ) Placeb N= mg N= mg N=89 Baseline Creatinine (mg/dl) egfr (ml/min/1.73 m 2 ) Week 3 Change Creatinine (mg/dl) egfr (ml/min/1.73 m 2 ) End f Treatment Creatinine (mg/dl) Change* egfr (ml/min/1.73 m 2 ) In the pl f fur placeb-cntrlled trials where patients had nrmal r mildly impaired baseline renal functin, the prprtin f patients wh experienced at least ne event f significant renal functin decline, defined as an egfr belw 80 ml/min/1.73 m 2 and 30% lwer than baseline, was 2.1% with placeb, 2.0% with 100 mg, and 4.1% with 300 mg. At the end f treatment, 0.5% with placeb, 0.7% with 100 mg, and 1.4% with 300 mg had a significant renal functin decline. In a trial carried ut in patients with mderate renal impairment with a baseline egfr f 30 t less than 50 ml/min/1.73 m 2 (mean baseline egfr 39 ml/min/1.73 m 2 ) [see Clinical Studies (14.3)], the prprtin f patients wh experienced at least ne event f significant renal functin decline, defined as an egfr 30% lwer than baseline, was 6.9% with placeb, 18% with 100 mg, and 22.5% with 300 mg. At the end f treatment, 4.6% with placeb, 3.4% with 100 mg, and 2.2% with 300 mg had a significant renal functin decline. In a pled ppulatin f patients with mderate renal impairment (N=1085) with baseline egfr f 30 t less than 60 ml/min/1.73 m 2 (mean baseline egfr 48 ml/min/1.73 m 2 ), the verall 8

9 incidence f these events was lwer than in the dedicated trial but a dse-dependent increase in incident episdes f significant renal functin decline cmpared t placeb was still bserved. Use f has been assciated with an increased incidence f renal-related adverse reactins (e.g., increased bld creatinine, decreased glmerular filtratin rate, renal impairment, and acute renal failure), particularly in patients with mderate renal impairment. In the pled analysis f patients with mderate renal impairment, the incidence f renal-related adverse reactins was 3.7% with placeb, 8.9% with 100 mg, and 9.3% with 300 mg. Discntinuatins due t renal-related adverse events ccurred in 1.0% with placeb, 1.2% with 100 mg, and 1.6% with 300 mg [see Warnings and Precautins (5.2)]. Genital Myctic Infectins In the pl f fur placeb-cntrlled clinical trials, female genital myctic infectins (e.g., vulvvaginal myctic infectin, vulvvaginal candidiasis, and vulvvaginitis) ccurred in 3.2%, 10.4%, and 11.4% f females treated with placeb, 100 mg, and 300 mg, respectively. Patients with a histry f genital myctic infectins were mre likely t develp genital myctic infectins n. Female patients wh develped genital myctic infectins n were mre likely t experience recurrence and require treatment with ral r tpical antifungal agents and anti-micrbial agents. In females, discntinuatin due t genital myctic infectins ccurred in 0% and 0.7% f patients treated with placeb and, respectively [see Warnings and Precautins (5.5)]. In the pl f fur placeb-cntrlled clinical trials, male genital myctic infectins (e.g., candidal balanitis, balanpsthitis) ccurred in 0.6%, 4.2%, and 3.7% f males treated with placeb, 100 mg, and 300 mg, respectively. Male genital myctic infectins ccurred mre cmmnly in uncircumcised males and in males with a prir histry f balanitis r balanpsthitis. Male patients wh develped genital myctic infectins n were mre likely t experience recurrent infectins (22% n versus nne n placeb), and require treatment with ral r tpical antifungal agents and anti-micrbial agents than patients n cmparatrs. In males, discntinuatins due t genital myctic infectins ccurred in 0% and 0.5% f patients treated with placeb and, respectively. In the pled analysis f 8 cntrlled trials, phimsis was reprted in 0.3% f uncircumcised male patients treated with and 0.2% required circumcisin t treat the phimsis [see Warnings and Precautins (5.5)]. 9

10 Hypglycemia In all clinical trials, hypglycemia was defined as any event regardless f symptms, where bichemical hypglycemia was dcumented (any glucse value belw r equal t 70 mg/dl). Severe hypglycemia was defined as an event cnsistent with hypglycemia where the patient required the assistance f anther persn t recver, lst cnsciusness, r experienced a seizure (regardless f whether bichemical dcumentatin f a lw glucse value was btained). In individual clinical trials [see Clinical Studies (14)], episdes f hypglycemia ccurred at a higher rate when was c-administered with insulin r sulfnylureas (Table 4) [see Warnings and Precautins (5.4)]. Table 4: Incidence f Hypglycemia* in Cntrlled Clinical Studies Mntherapy (26 weeks) Placeb (N=192) 100 mg (N=195) Overall [N (%)] 5 (2.6) 7 (3.6) 6 (3.0) In Cmbinatin with Placeb mg + Metfrmin Metfrmin Metfrmin (26 weeks) (N=183) (N=368) 300 mg (N=197) 300 mg + Metfrmin (N=367) Overall [N (%)] 3 (1.6) 16 (4.3) 17 (4.6) Severe [N (%)] 0 (0) 1 (0.3) 1 (0.3) In Cmbinatin with Metfrmin (52 weeks) Glimepiride + Metfrmin (N=482) 100 mg + Metfrmin (N=483) 300 mg + Metfrmin (N=485) Overall [N (%)] 165 (34.2) 27 (5.6) 24 (4.9) Severe [N (%)] 15 (3.1) 2 (0.4) 3 (0.6) In Cmbinatin with Sulfnylurea (18 weeks) Placeb + Sulfnylurea (N=69) 100 mg + Sulfnylurea (N=74) 300 mg + Sulfnylurea (N=72) Overall [N (%)] 4 (5.8) 3 (4.1) 9 (12.5) In Cmbinatin with Metfrmin + Sulfnylurea (26 weeks) Placeb + Metfrmin + Sulfnylurea (N=156) 100 mg + Metfrmin + Sulfnylurea (N=157) 300 mg + Metfrmin + Sulfnylurea (N=156) Overall [N (%)] 24 (15.4) 43 (27.4) 47 (30.1) Severe [N (%)] 1 (0.6) 1 (0.6) 0 In Cmbinatin with Metfrmin + Sulfnylurea (52 weeks) Sitagliptin + Metfrmin + Sulfnylurea (N=378) 300 mg + Metfrmin + Sulfnylurea (N=377) Overall [N (%)] 154 (40.7) 163 (43.2) Severe [N (%)] 13 (3.4) 15 (4.0) Placeb + In Cmbinatin with Metfrmin + Piglitazne (26 weeks) Metfrmin + Piglitazne (N=115) 100 mg + Metfrmin + Piglitazne (N=113) 300 mg + Metfrmin + Piglitazne (N=114) Overall [N (%)] 3 (2.6) 3 (2.7) 6 (5.3) In Cmbinatin with Insulin (18 weeks) Placeb (N=565) 100 mg (N=566) Overall [N (%)] 208 (36.8) 279 (49.3) 285 (48.6) Severe [N (%)] 14 (2.5) 10 (1.8) 16 (2.7) 300 mg (N=587) 10

11 Table 4: Incidence f Hypglycemia* in Cntrlled Clinical Studies * Number f patients experiencing at least ne event f hypglycemia based n either bichemically dcumented episdes r severe hypglycemic events in the intent-t-treat ppulatin Severe episdes f hypglycemia were defined as thse where the patient required the assistance f anther persn t recver, lst cnsciusness, r experienced a seizure (regardless f whether bichemical dcumentatin f a lw glucse value was btained) Labratry Tests Increases in Serum Ptassium Dse-related, transient mean increases in serum ptassium were bserved early after initiatin f (i.e., within 3 weeks) in a trial f patients with mderate renal impairment [see Clinical Studies (14.3)]. In this trial, increases in serum ptassium f greater than 5.4 meq/l and 15% abve baseline ccurred in 16.1%, 12.4%, and 27.0% f patients treated with placeb, 100 mg, and 300 mg, respectively. Mre severe elevatins (i.e., equal r greater than 6.5 meq/l) ccurred in 1.1%, 2.2%, and 2.2% f patients treated with placeb, 100 mg, and 300 mg, respectively. In patients with mderate renal impairment, increases in ptassium were mre cmmnly seen in thse with elevated ptassium at baseline and in thse using medicatins that reduce ptassium excretin, such as ptassium-sparing diuretics, angitensin-cnverting-enzyme inhibitrs, and angitensinreceptr blckers [see Warnings and Precautins (5.2 and 5.3)]. Increases in Serum Magnesium Dse-related increases in serum magnesium were bserved early after initiatin f (within 6 weeks) and remained elevated thrughut treatment. In the pl f fur placebcntrlled trials, the mean percent change in serum magnesium levels was 8.1% and 9.3% with 100 mg and 300 mg, respectively, cmpared t -0.6% with placeb. In a trial f patients with mderate renal impairment [see Clinical Studies (14.3)], serum magnesium levels increased by 0.2%, 9.2%, and 14.8% with placeb, 100 mg, and 300 mg, respectively. Increases in Serum Phsphate Dse-related increases in serum phsphate levels were bserved with. In the pl f fur placeb cntrlled trials, the mean percent change in serum phsphate levels were 3.6% and 5.1% with 100 mg and 300 mg, respectively, cmpared t 1.5% with placeb. In a trial f patients with mderate renal impairment [see Clinical Studies (14.3)], the mean serum phsphate levels increased by 1.2%, 5.0%, and 9.3% with placeb, 100 mg, and 300 mg, respectively. 11

12 Increases in Lw-Density Lipprtein Chlesterl (LDL-C) and nn-high-density Lipprtein Chlesterl (nn-hdl-c) In the pl f fur placeb-cntrlled trials, dse-related increases in LDL-C with were bserved. Mean changes (percent changes) frm baseline in LDL-C relative t placeb were 4.4 mg/dl (4.5%) and 8.2 mg/dl (8.0%) with 100 mg and 300 mg, respectively. The mean baseline LDL-C levels were 104 t 110 mg/dl acrss treatment grups [see Warnings and Precautins (5.7)]. Dse-related increases in nn-hdl-c with were bserved. Mean changes (percent changes) frm baseline in nn-hdl-c relative t placeb were 2.1 mg/dl (1.5%) and 5.1 mg/dl (3.6%) with 100 mg and 300 mg, respectively. The mean baseline nn-hdl-c levels were 140 t 147 mg/dl acrss treatment grups. Increases in Hemglbin In the pl f fur placeb-cntrlled trials, mean changes (percent changes) frm baseline in hemglbin were g/dl (-1.1%) with placeb, 0.47 g/dl (3.5%) with 100 mg, and 0.51 g/dl (3.8%) with 300 mg. The mean baseline hemglbin value was apprximately 14.1 g/dl acrss treatment grups. At the end f treatment, 0.8%, 4.0%, and 2.7% f patients treated with placeb, 100 mg, and 300 mg, respectively, had hemglbin abve the upper limit f nrmal. 7 DRUG INTERACTIONS 7.1 UGT Enzyme Inducers Rifampin: C-administratin f canagliflzin with rifampin, a nnselective inducer f several UGT enzymes, including UGT1A9, UGT2B4, decreased canagliflzin area under the curve (AUC) by 51%. This decrease in expsure t canagliflzin may decrease efficacy. If an inducer f these UGTs (e.g., rifampin, phenytin, phenbarbital, ritnavir) must be c-administered with (canagliflzin), cnsider increasing the dse t 300 mg nce daily if patients are currently tlerating 100 mg nce daily, have an egfr greater than 60 ml/min/1.73 m 2, and require additinal glycemic cntrl. Cnsider ther antihyperglycemic therapy in patients with an egfr f 45 t less than 60 ml/min/1.73 m 2 receiving cncurrent therapy with a UGT inducer and require additinal glycemic cntrl [see Dsage and Administratin (2.3) and Clinical Pharmaclgy (12.3)]. 7.2 Digxin There was an increase in the AUC and mean peak drug cncentratin (C max ) f digxin (20% and 36%, respectively) when c-administered with 300 mg [see Clinical Pharmaclgy (12.3)]. Patients taking with cncmitant digxin shuld be mnitred apprpriately. 12

13 7.3 Psitive Urine Glucse Test Mnitring glycemic cntrl with urine glucse tests is nt recmmended in patients taking SGLT2 inhibitrs as SGLT2 inhibitrs increase urinary glucse excretin and will lead t psitive urine glucse tests. Use alternative methds t mnitr glycemic cntrl. 7.4 Interference with 1,5-anhydrglucitl (1,5-AG) Assay Mnitring glycemic cntrl with 1,5-AG assay is nt recmmended as measurements f 1,5-AG are unreliable in assessing glycemic cntrl in patients taking SGLT2 inhibitrs. Use alternative methds t mnitr glycemic cntrl. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratgenic Effects Pregnancy Categry C There are n adequate and well-cntrlled studies f in pregnant wmen. Based n results frm rat studies, canagliflzin may affect renal develpment and maturatin. In a juvenile rat study, increased kidney weights and renal pelvic and tubular dilatatin were evident at greater than r equal t 0.5 times clinical expsure frm a 300 mg dse [see Nnclinical Txiclgy (13.2)]. These utcmes ccurred with drug expsure during perids f animal develpment that crrespnd t the late secnd and third trimester f human develpment. During pregnancy, cnsider apprpriate alternative therapies, especially during the secnd and third trimesters. shuld be used during pregnancy nly if the ptential benefit justifies the ptential risk t the fetus. 8.3 Nursing Mthers It is nt knwn if is excreted in human milk. is secreted in the milk f lactating rats reaching levels 1.4 times higher than that in maternal plasma. Data in juvenile rats directly expsed t shwed risk t the develping kidney (renal pelvic and tubular dilatatins) during maturatin. Since human kidney maturatin ccurs in uter and during the first 2 years f life when lactatinal expsure may ccur, there may be risk t the develping human kidney. Because many drugs are excreted in human milk and because f the ptential fr serius adverse reactins in nursing infants frm, a decisin shuld be made whether t discntinue nursing r t discntinue, taking int accunt the imprtance f the drug t the mther [see Nnclinical Txiclgy (13.2)]. 13

14 8.4 Pediatric Use Safety and effectiveness f in pediatric patients under 18 years f age have nt been established. 8.5 Geriatric Use Tw thusand thirty-fur (2034) patients 65 years and lder, and 345 patients 75 years and lder were expsed t in nine clinical studies f [see Clinical Studies (14.3)]. Patients 65 years and lder had a higher incidence f adverse reactins related t reduced intravascular vlume with (such as hyptensin, pstural dizziness, rthstatic hyptensin, syncpe, and dehydratin), particularly with the 300 mg daily dse, cmpared t yunger patients; a mre prminent increase in the incidence was seen in patients wh were 75 years and lder [see Dsage and Administratin (2.1) and Adverse Reactins (6.1)]. Smaller reductins in HbA1C with relative t placeb were seen in lder (65 years and lder; -0.61% with 100 mg and -0.74% with 300 mg relative t placeb) cmpared t yunger patients (-0.72% with 100 mg and -0.87% with 300 mg relative t placeb). 8.6 Renal Impairment The efficacy and safety f were evaluated in a study that included patients with mderate renal impairment (egfr 30 t less than 50 ml/min/1.73 m 2 ) [see Clinical Studies (14.3)]. These patients had less verall glycemic efficacy and had a higher ccurrence f adverse reactins related t reduced intravascular vlume, renal-related adverse reactins, and decreases in egfr cmpared t patients with mild renal impairment r nrmal renal functin (egfr greater than r equal t 60 ml/min/1.73 m 2 ); patients treated with 300 mg were mre likely t experience increases in ptassium [see Dsage and Administratin (2.2), Warnings and Precautins (5.1, 5.2, and 5.3), and Adverse Reactins (6.1)]. The efficacy and safety f have nt been established in patients with severe renal impairment (egfr less than 30 ml/min/1.73 m 2 ), with ESRD, r receiving dialysis. is nt expected t be effective in these patient ppulatins [see Cntraindicatins (4) and Clinical Pharmaclgy (12.3)]. 8.7 Hepatic Impairment N dsage adjustment is necessary in patients with mild r mderate hepatic impairment. The use f has nt been studied in patients with severe hepatic impairment and is therefre nt recmmended [see Clinical Pharmaclgy (12.3)]. 14

15 10 OVERDOSAGE There were n reprts f verdse during the clinical develpment prgram f (canagliflzin). In the event f an verdse, cntact the Pisn Cntrl Center. It is als reasnable t emply the usual supprtive measures, e.g., remve unabsrbed material frm the gastrintestinal tract, emply clinical mnitring, and institute supprtive treatment as dictated by the patient s clinical status. Canagliflzin was negligibly remved during a 4-hur hemdialysis sessin. Canagliflzin is nt expected t be dialyzable by peritneal dialysis. 11 DESCRIPTION (canagliflzin) cntains canagliflzin, an inhibitr f sdium-glucse ctransprter 2 (SGLT2), the transprter respnsible fr reabsrbing the majrity f glucse filtered by the kidney. Canagliflzin, the active ingredient f, is chemically knwn as (1S)-1,5-anhydr-1-[3-[[5-(4-flurphenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitl hemihydrate and its mlecular frmula and weight are C 24 H 25 FO 5 S1/2 H 2 O and , respectively. The structural frmula fr canagliflzin is: Canagliflzin is practically insluble in aqueus media frm ph 1.1 t is supplied as film-cated tablets fr ral administratin, cntaining 102 and 306 mg f canagliflzin in each tablet strength, crrespnding t 100 mg and 300 mg f canagliflzin (anhydrus), respectively. Inactive ingredients f the cre tablet are crscarmellse sdium, hydrxyprpyl cellulse, lactse anhydrus, magnesium stearate, and micrcrystalline cellulse. The magnesium stearate is vegetable-surced. The tablets are finished with a cmmercially available film-cating cnsisting f the fllwing excipients: plyvinyl alchl (partially hydrlyzed), titanium dixide, macrgl/peg, talc, and irn xide yellw, E172 (100 mg tablet nly). 15

16 12 CLINICAL PHARMACOLOGY 12.1 Mechanism f Actin Sdium-glucse c-transprter 2 (SGLT2), expressed in the prximal renal tubules, is respnsible fr the majrity f the reabsrptin f filtered glucse frm the tubular lumen. Canagliflzin is an inhibitr f SGLT2. By inhibiting SGLT2, canagliflzin reduces reabsrptin f filtered glucse and lwers the renal threshld fr glucse (RT G ), and thereby increases urinary glucse excretin (UGE) Pharmacdynamics Fllwing single and multiple ral dses f canagliflzin in patients with type 2 diabetes, dsedependent decreases in the renal threshld fr glucse (RT G ) and increases in urinary glucse excretin were bserved. Frm a starting RT G value f apprximately 240 mg/dl, canagliflzin at 100 mg and 300 mg nce daily suppressed RT G thrughut the 24-hur perid. Maximal suppressin f mean RT G ver the 24-hur perid was seen with the 300 mg daily dse t apprximately 70 t 90 mg/dl in patients with type 2 diabetes in Phase 1 studies. The reductins in RT G led t increases in mean UGE f apprximately 100 g/day in subjects with type 2 diabetes treated with either 100 mg r 300 mg f canagliflzin. In patients with type 2 diabetes given 100 mg t 300 mg nce daily ver a 16-day dsing perid, reductins in RT G and increases in urinary glucse excretin were bserved ver the dsing perid. In this study, plasma glucse declined in a dse-dependent fashin within the first day f dsing. In single-dse studies in healthy and type 2 diabetic subjects, treatment with canagliflzin 300 mg befre a mixed-meal delayed intestinal glucse absrptin and reduced pstprandial glucse. Cardiac Electrphysilgy In a randmized, duble-blind, placeb-cntrlled, active-cmparatr, 4-way crssver study, 60 healthy subjects were administered a single ral dse f canagliflzin 300 mg, canagliflzin 1,200 mg (4 times the maximum recmmended dse), mxiflxacin, and placeb. N meaningful changes in QTc interval were bserved with either the recmmended dse f 300 mg r the 1,200 mg dse Pharmackinetics The pharmackinetics f canagliflzin is similar in healthy subjects and patients with type 2 diabetes. Fllwing single-dse ral administratin f 100 mg and 300 mg f, peak plasma cncentratins (median T max ) f canagliflzin ccurs within 1 t 2 hurs pst-dse. Plasma C max and AUC f canagliflzin increased in a dse-prprtinal manner frm 50 mg t 300 mg. The apparent terminal half-life (t 1/2 ) was 10.6 hurs and 13.1 hurs fr the 100 mg and 300 mg dses, respectively. Steady-state was reached after 4 t 5 days f nce-daily dsing with canagliflzin 100 mg t 300 mg. Canagliflzin des nt exhibit time-dependent 16

17 pharmackinetics and accumulated in plasma up t 36% fllwing multiple dses f 100 mg and 300 mg. Absrptin The mean abslute ral biavailability f canagliflzin is apprximately 65%. C-administratin f a high-fat meal with canagliflzin had n effect n the pharmackinetics f canagliflzin; therefre, may be taken with r withut fd. Hwever, based n the ptential t reduce pstprandial plasma glucse excursins due t delayed intestinal glucse absrptin, it is recmmended that be taken befre the first meal f the day [see Dsage and Administratin (2.1)]. Distributin The mean steady-state vlume f distributin f canagliflzin fllwing a single intravenus infusin in healthy subjects was 119 L, suggesting extensive tissue distributin. Canagliflzin is extensively bund t prteins in plasma (99%), mainly t albumin. Prtein binding is independent f canagliflzin plasma cncentratins. Plasma prtein binding is nt meaningfully altered in patients with renal r hepatic impairment. Metablism O-glucurnidatin is the majr metablic eliminatin pathway fr canagliflzin, which is mainly glucurnidated by UGT1A9 and UGT2B4 t tw inactive O-glucurnide metablites. CYP3A4-mediated (xidative) metablism f canagliflzin is minimal (apprximately 7%) in humans. Excretin Fllwing administratin f a single ral [ 14 C] canagliflzin dse t healthy subjects, 41.5%, 7.0%, and 3.2% f the administered radiactive dse was recvered in feces as canagliflzin, a hydrxylated metablite, and an O-glucurnide metablite, respectively. Enterhepatic circulatin f canagliflzin was negligible. Apprximately 33% f the administered radiactive dse was excreted in urine, mainly as O-glucurnide metablites (30.5%). Less than 1% f the dse was excreted as unchanged canagliflzin in urine. Renal clearance f canagliflzin 100 mg and 300 mg dses ranged frm 1.30 t 1.55 ml/min. Mean systemic clearance f canagliflzin was apprximately 192 ml/min in healthy subjects fllwing intravenus administratin. 17

18 Specific Ppulatins Renal Impairment A single-dse, pen-label study evaluated the pharmackinetics f canagliflzin 200 mg in subjects with varying degrees f renal impairment (classified using the MDRD-eGFR frmula) cmpared t healthy subjects. Renal impairment did nt affect the C max f canagliflzin. Cmpared t healthy subjects (N=3; egfr greater than r equal t 90 ml/min/1.73 m 2 ), plasma AUC f canagliflzin was increased by apprximately 15%, 29%, and 53% in subjects with mild (N=10), mderate (N=9), and severe (N=10) renal impairment, respectively, (egfr 60 t less than 90, 30 t less than 60 and 15 t less than 30 ml/min/1.73 m 2, respectively), but was similar fr ESRD (N=8) subjects and healthy subjects. Increases in canagliflzin AUC f this magnitude are nt cnsidered clinically relevant. The pharmacdynamic respnse t canagliflzin declines with increasing severity f renal impairment [see Cntraindicatins (4) and Warnings and Precautins (5.2)]. Canagliflzin was negligibly remved by hemdialysis. Hepatic Impairment Relative t subjects with nrmal hepatic functin, the gemetric mean ratis fr C max and AUC f canagliflzin were 107% and 110%, respectively, in subjects with Child-Pugh class A (mild hepatic impairment) and 96% and 111%, respectively, in subjects with Child-Pugh class B (mderate hepatic impairment) fllwing administratin f a single 300 mg dse f canagliflzin. These differences are nt cnsidered t be clinically meaningful. There is n clinical experience in patients with Child-Pugh class C (severe) hepatic impairment [see Use in Specific Ppulatins (8.7)]. Pharmackinetic Effects f Age, Bdy Mass Index (BMI)/Weight, Gender and Race Based n the ppulatin PK analysis with data cllected frm 1526 subjects, age, bdy mass index (BMI)/weight, gender, and race d nt have a clinically meaningful effect n the pharmackinetics f canagliflzin [see Use in Specific Ppulatins (8.5)]. Pediatric Studies characterizing the pharmackinetics f canagliflzin in pediatric patients have nt been cnducted. 18

19 Drug Interactin Studies In Vitr Assessment f Drug Interactins Canagliflzin did nt induce CYP450 enzyme expressin (3A4, 2C9, 2C19, 2B6, and 1A2) in cultured human hepatcytes. Canagliflzin did nt inhibit the CYP450 isenzymes (1A2, 2A6, 2C19, 2D6, r 2E1) and weakly inhibited CYP2B6, CYP2C8, CYP2C9, and CYP3A4 based n in vitr studies with human hepatic micrsmes. Canagliflzin is a weak inhibitr f P-gp. Canagliflzin is als a substrate f drug transprters P-glycprtein (P-gp) and MRP2. In Viv Assessment f Drug Interactins Table 5: C-Administered Drug Effect f C Administered Drugs n Systemic Expsures f Canagliflzin Dse f C-Administered Drug * Dse f Canagliflzin * See Drug Interactins (7.1) fr the clinical relevance f the fllwing: Gemetric Mean Rati (Rati With/Withut C-Administered Drug) N Effect=1.0 AUC (90% CI) C max (90% CI) Rifampin 600 mg QD fr 8 days 300 mg 0.49 (0.44; 0.54) 0.72 (0.61; 0.84) N dse adjustments f required fr the fllwing: Cyclsprine Ethinyl estradil and levnrgestrel Hydrchlrthiazide Metfrmin 400 mg 0.03 mg ethinyl estradil and 0.15 mg levnrgestrel 25 mg QD fr 35 days 2,000 mg 300 mg QD fr 8 days 200 mg QD fr 6 days 300 mg QD fr 7 days 300 mg QD fr 8 days 300 mg QD fr 17 days 1.23 (1.19; 1.27) 0.91 (0.88; 0.94) 1.12 (1.08; 1.17) 1.10 (1.05; 1.15) 1.21 (1.16; 1.25) Prbenecid 500 mg BID fr 3 days * Single dse unless therwise nted AUC inf fr drugs given as a single dse and AUC 24h fr drugs given as multiple dses QD = nce daily; BID = twice daily 1.01 (0.91; 1.11) 0.92 (0.84; 0.99) 1.15 (1.06; 1.25) 1.05 (0.96; 1.16) 1.13 (1.00; 1.28) Table 6: C-Administered Drug Effect f Canagliflzin n Systemic Expsure f C-Administered Drugs Dse f C- Administered Drug * Dse f Canagliflzin * Gemetric Mean Rati (Rati With/Withut C-Administered Drug) N Effect = 1.0 AUC (90% CI) C max (90% CI) 19

20 Table 6: C-Administered Drug Effect f Canagliflzin n Systemic Expsure f C-Administered Drugs Dse f C- Administered Drug * Dse f Canagliflzin * Gemetric Mean Rati (Rati With/Withut C-Administered Drug) N Effect = 1.0 AUC (90% CI) C max (90% CI) See Drug Interactins (7.2) fr the clinical relevance f the fllwing: Digxin 0.5 mg QD first day fllwed by 0.25 mg QD fr 6 days 300 mg QD fr 7 days digxin 1.20 (1.12; 1.28) 1.36 (1.21; 1.53) N dse adjustments f c-administered drug required fr the fllwing: Acetaminphen Ethinyl estradil and levnrgestrel Glyburide Hydrchlrthiazide Metfrmin Simvastatin Warfarin 1,000 mg 0.03 mg ethinyl estradil and 0.15 mg levnrgestrel 1.25 mg 25 mg QD fr 35 days 2,000 mg 40 mg 30 mg 300 mg BID fr 25 days 200 mg QD fr 6 days 200 mg QD fr 6 days 300 mg QD fr 7 days 300 mg QD fr 8 days 300 mg QD fr 7 days 300 mg QD fr 12 days acetaminphen ethinyl estradil levnrgestrel glyburide 3-cis-hydrxy-glyburide 4-trans-hydrxyglyburide hydrchlrthiazide metfrmin simvastatin simvastatin acid (R)-warfarin (S)-warfarin * Single dse unless therwise nted AUC inf fr drugs given as a single dse and AUC 24h fr drugs given as multiple dses INR 1.06 (0.98; 1.14) 1.07 (0.99; 1.15) 1.06 (1.00; 1.13) 1.02 (0.98; 1.07) 1.01 (0.96; 1.07) 1.03 (0.97; 1.09) 0.99 (0.95; 1.04) 1.20 (1.08; 1.34) 1.12 (0.94; 1.33) 1.18 (1.03; 1.35) 1.01 (0.96; 1.06) 1.06 (1.00; 1.12) 1.00 (0.98; 1.03) 1.00 (0.92; 1.09) 1.22 (1.10; 1.35) 1.22 (1.11; 1.35) 0.93 (0.85; 1.01) 0.99 (0.91; 1.08) 0.96 (0.88; 1.04) 0.94 (0.87; 1.01) 1.06 (0.93; 1.20) 1.09 (0.91; 1.31) 1.26 (1.10; 1.45) 1.03 (0.94; 1.13) 1.01 (0.90; 1.13) 1.05 (0.99; 1.12) AUC 0-12h QD = nce daily; BID = twice daily; INR = Internatinal Nrmalized Rati 20

21 13 NONCLINICAL TOXICOLOGY 13.1 Carcingenesis, Mutagenesis, Impairment f Fertility Carcingenesis Carcingenicity was evaluated in 2-year studies cnducted in CD1 mice and Sprague-Dawley rats. Canagliflzin did nt increase the incidence f tumrs in mice dsed at 10, 30, r 100 mg/kg (less than r equal t 14 times expsure frm a 300 mg clinical dse). Testicular Leydig cell tumrs, cnsidered secndary t increased luteinizing hrmne (LH), increased significantly in male rats at all dses tested (10, 30, and 100 mg/kg). In a 12-week clinical study, LH did nt increase in males treated with canagliflzin. Renal tubular adenma and carcinma increased significantly in male and female rats dsed at 100 mg/kg, r apprximately 12-times expsure frm a 300 mg clinical dse. Als, adrenal phechrmcytma increased significantly in males and numerically in females dsed at 100 mg/kg. Carbhydrate malabsrptin assciated with high dses f canagliflzin was cnsidered a necessary prximal event in the emergence f renal and adrenal tumrs in rats. Clinical studies have nt demnstrated carbhydrate malabsrptin in humans at canagliflzin dses f up t 2-times the recmmended clinical dse f 300 mg. Mutagenesis Canagliflzin was nt mutagenic with r withut metablic activatin in the Ames assay. Canagliflzin was mutagenic in the in vitr muse lymphma assay with but nt withut metablic activatin. Canagliflzin was nt mutagenic r clastgenic in an in viv ral micrnucleus assay in rats and an in viv ral Cmet assay in rats. Impairment f Fertility Canagliflzin had n effects n the ability f rats t mate and sire r maintain a litter up t the high dse f 100 mg/kg (apprximately 14 times and 18 times the 300 mg clinical dse in males and females, respectively), althugh there were minr alteratins in a number f reprductive parameters (decreased sperm velcity, increased number f abnrmal sperm, slightly fewer crpra lutea, fewer implantatin sites, and smaller litter sizes) at the highest dsage administered Animal Txiclgy and/r Pharmaclgy In a juvenile txicity study in which canagliflzin was dsed directly t yung rats frm pstnatal day (PND) 21 until PND 90 at dses f 4, 20, 65, r 100 mg/kg, increased kidney weights and a dse-related increase in the incidence and severity f renal pelvic and renal tubular dilatatin were reprted at all dse levels. Expsure at the lwest dse tested was greater than r equal t 0.5 times the maximum clinical dse f 300 mg. The renal pelvic dilatatins bserved in 21

22 juvenile animals did nt fully reverse within the 1-mnth recvery perid. Similar effects n the develping kidney were nt seen when canagliflzin was administered t pregnant rats r rabbits during the perid f rgangenesis r during a study in which maternal rats were dsed frm gestatin day (GD) 6 thrugh PND 21 and pups were indirectly expsed in uter and thrughut lactatin. In embry-fetal develpment studies in rats and rabbits, canagliflzin was administered fr intervals cinciding with the first trimester perid f nn-renal rgangenesis in humans. N develpmental txicities were bserved at any dse tested ther than a slight increase in the number f fetuses with reduced ssificatin at a dse that was assciated with maternal txicity and that is apprximately 19 times the human expsure t canagliflzin at the 300 mg clinical dse. 14 CLINICAL STUDIES (canagliflzin) has been studied as mntherapy, in cmbinatin with metfrmin, sulfnylurea, metfrmin and sulfnylurea, metfrmin and a thiazlidinedine (i.e., piglitazne), and in cmbinatin with insulin (with r withut ther antihyperglycemic agents). The efficacy f was cmpared t a dipeptidyl peptidase-4 (DPP-4) inhibitr (sitagliptin) and a sulfnylurea (glimepiride). was als evaluated in adults 55 t 80 years f age and patients with mderate renal impairment. In patients with type 2 diabetes, treatment with prduced clinically and statistically significant imprvements in HbA1C cmpared t placeb. Reductins in HbA1C were bserved acrss subgrups including age, gender, race, and baseline bdy mass index (BMI) Mntherapy A ttal f 584 patients with type 2 diabetes inadequately cntrlled n diet and exercise participated in a 26-week, duble-blind, placeb-cntrlled study t evaluate the efficacy and safety f. The mean age was 55 years, 44% f patients were men, and the mean baseline egfr was 87 ml/min/1.73 m 2. Patients taking ther antihyperglycemic agents (N=281) discntinued the agent and underwent an 8-week washut fllwed by a 2-week, single-blind, placeb run-in perid. Patients nt taking ral antihyperglycemic agents (N=303) entered the 2-week, single-blind, placeb run-in perid directly. After the placeb run-in perid, patients were randmized t 100 mg, 300 mg, r placeb, administered nce daily fr 26 weeks. At the end f treatment, 100 mg and 300 mg nce daily resulted in a statistically significant imprvement in HbA1C (p<0.001 fr bth dses) cmpared t placeb. 22

23 100 mg and 300 mg nce daily als resulted in a greater prprtin f patients achieving an HbA1C less than 7%, in significant reductin in fasting plasma glucse (FPG), in imprved pstprandial glucse (PPG), and in percent bdy weight reductin cmpared t placeb (see Table 7). Statistically significant (p<0.001 fr bth dses) mean changes frm baseline in systlic bld pressure relative t placeb were -3.7 mmhg and -5.4 mmhg with 100 mg and 300 mg, respectively. Table 7: Results frm 26-Week Placeb-Cntrlled Clinical Study with as Mntherapy* Placeb (N=192) 100 mg (N=195) 300 mg (N=197) Efficacy Parameter HbA1C (%) Baseline (mean) Change frm baseline (adjusted mean) Difference frm placeb (adjusted mean) (95% CI) (-1.09; -0.73) Percent f Patients Achieving HbA1C < 7% Fasting Plasma Glucse (mg/dl) Baseline (mean) Change frm baseline (adjusted mean) (-1.34; -0.99) -36 Difference frm placeb (adjusted mean) (95% CI) (-42; -29) 2-hur Pstprandial Glucse (mg/dl) Baseline (mean) Change frm baseline (adjusted mean) (-50; -37) -48 Difference frm placeb (adjusted mean) (95% CI) (-59.1; -37.0) Bdy Weight Baseline (mean) in kg % change frm baseline (adjusted mean) Difference frm placeb (adjusted mean) (95% -2.2 CI) (-2.9; -1.6) * Intent-t-treat ppulatin using last bservatin in study prir t glycemic rescue therapy Least squares mean adjusted fr baseline value and stratificatin factrs p< (-75.0; -52.9) -3.3 (-4.0; -2.6) 14.2 Cmbinatin Therapy Add-n Cmbinatin Therapy With Metfrmin A ttal f 1284 patients with type 2 diabetes inadequately cntrlled n metfrmin mntherapy (greater than r equal t 2,000 mg/day, r at least 1,500 mg/day if higher dse nt tlerated) participated in a 26-week, duble-blind, placeb- and active-cntrlled study t evaluate the efficacy and safety f in cmbinatin with metfrmin. The mean age was 55 years, 47% f patients were men, and the mean baseline egfr was 89 ml/min/1.73 m 2. Patients already n the required metfrmin dse (N=1009) were randmized after cmpleting a 2-week, single-blind, placeb run-in perid. Patients taking less than the required metfrmin dse r 23

24 patients n metfrmin in cmbinatin with anther antihyperglycemic agent (N=275) were switched t metfrmin mntherapy (at dses described abve) fr at least 8 weeks befre entering the 2-week, single-blind, placeb run-in. After the placeb run-in perid, patients were randmized t 100 mg, 300 mg, sitagliptin 100 mg, r placeb, administered nce daily as add-n therapy t metfrmin. At the end f treatment, 100 mg and 300 mg nce daily resulted in a statistically significant imprvement in HbA1C (p<0.001 fr bth dses) cmpared t placeb when added t metfrmin. 100 mg and 300 mg nce daily als resulted in a greater prprtin f patients achieving an HbA1C less than 7%, in significant reductin in fasting plasma glucse (FPG), in imprved pstprandial glucse (PPG), and in percent bdy weight reductin cmpared t placeb when added t metfrmin (see Table 8). Statistically significant (p<0.001 fr bth dses) mean changes frm baseline in systlic bld pressure relative t placeb were -5.4 mmhg and -6.6 mmhg with 100 mg and 300 mg, respectively. Table 8: Results frm 26-Week Placeb-Cntrlled Clinical Study f in Cmbinatin with Metfrmin * Placeb + Metfrmin (N=183) 100 mg + Metfrmin (N=368) 300 mg + Metfrmin (N=367) Efficacy Parameter HbA1C (%) Baseline (mean) Change frm baseline (adjusted mean) Difference frm placeb (adjusted mean) (95% CI) (-0.76; -0.48) Percent f patients achieving HbA1C < 7% Fasting Plasma Glucse (mg/dl) Baseline (mean) Change frm baseline (adjusted mean) (-0.91; -0.64) Difference frm placeb (adjusted mean) (95% CI) -30 (-36; -24) 2-hur Pstprandial Glucse (mg/dl) Baseline (mean) Change frm baseline (adjusted mean) (-46; -34) Difference frm placeb (adjusted mean) (95% CI) -38 (-49; -27) -47 (-58; -36) Bdy Weight Baseline (mean) in kg % change frm baseline (adjusted mean) Difference frm placeb (adjusted mean) (95% -2.5 CI) (-3.1; -1.9) * Intent-t-treat ppulatin using last bservatin in study prir t glycemic rescue therapy Least squares mean adjusted fr baseline value and stratificatin factrs p< (-3.5; -2.3) 24

25 Cmpared t Glimepiride, Bth as Add-n Cmbinatin With Metfrmin A ttal f 1450 patients with type 2 diabetes inadequately cntrlled n metfrmin mntherapy (greater than r equal t 2,000 mg/day, r at least 1,500 mg/day if higher dse nt tlerated) participated in a 52-week, duble-blind, active-cntrlled study t evaluate the efficacy and safety f in cmbinatin with metfrmin. The mean age was 56 years, 52% f patients were men, and the mean baseline egfr was 90 ml/min/1.73 m 2. Patients tlerating maximally required metfrmin dse (N=928) were randmized after cmpleting a 2-week, single-blind, placeb run-in perid. Other patients (N=522) were switched t metfrmin mntherapy (at dses described abve) fr at least 10 weeks, then cmpleted a 2-week single-blind run-in perid. After the 2-week run-in perid, patients were randmized t 100 mg, 300 mg, r glimepiride (titratin allwed thrughut the 52-week study t 6 r 8 mg), administered nce daily as add-n therapy t metfrmin. As shwn in Table 9 and Figure 1, at the end f treatment, 100 mg prvided similar reductins in HbA1C frm baseline cmpared t glimepiride when added t metfrmin therapy. 300 mg prvided a greater reductin frm baseline in HbA1C cmpared t glimepiride, and the relative treatment difference was -0.12% (95% CI: 0.22; 0.02). As shwn in Table 9, treatment with 100 mg and 300 mg daily prvided greater imprvements in percent bdy weight change, relative t glimepiride. Table 9: Results frm 52 Week Clinical Study Cmparing t Glimepiride in Cmbinatin with Metfrmin* 100 mg + Metfrmin (N=483) 300 mg + Metfrmin (N=485) Glimepiride (titrated) + Metfrmin (N=482) Efficacy Parameter HbA1C (%) Baseline (mean) Change frm baseline (adjusted mean) Difference frm glimepiride (adjusted mean) (95% CI) (-0.11; 0.09) (-0.22; -0.02) Percent f patients achieving HbA1C < 7% Fasting Plasma Glucse (mg/dl) Baseline (mean) Change frm baseline (adjusted mean) Difference frm glimepiride (adjusted mean) (95% CI) -6 (-10; -2) -9 (-13; -5) Bdy Weight Baseline (mean) in kg % change frm baseline (adjusted mean) Difference frm glimepiride (adjusted mean) -5.2 (95% CI) (-5.7; -4.7) -5.7 (-6.2; -5.1) 25

26 Table 9: Results frm 52 Week Clinical Study Cmparing t Glimepiride in Cmbinatin with Metfrmin* 100 mg + Metfrmin (N=483) 300 mg + Metfrmin (N=485) Glimepiride (titrated) + Metfrmin (N=482) Efficacy Parameter * Intent-t-treat ppulatin using last bservatin in study prir t glycemic rescue therapy Least squares mean adjusted fr baseline value and stratificatin factrs + metfrmin is cnsidered nn-inferir t glimepiride + metfrmin because the upper limit f this cnfidence interval is less than the pre-specified nn-inferirity margin f < 0.3%. p<0.001 Figure 1: Mean HbA1C Change at Each Time Pint (Cmpleters) and at Week 52 Using Last Observatin Carried Frward (mitt Ppulatin) Add-n Cmbinatin Therapy With Sulfnylurea A ttal f 127 patients with type 2 diabetes inadequately cntrlled n sulfnylurea mntherapy participated in an 18-week, duble-blind, placeb-cntrlled sub-study t evaluate the efficacy and safety f in cmbinatin with sulfnylurea. The mean age was 65 years, 57% f patients were men, and the mean baseline egfr was 69 ml/min/1.73 m 2. Patients treated with sulfnylurea mntherapy n a stable prtcl-specified dse (greater than r equal t 50% maximal dse) fr at least 10 weeks cmpleted a 2-week, single-blind, placeb run-in perid. After the run-in perid, patients with inadequate glycemic cntrl were randmized t 100 mg, 300 mg, r placeb, administered nce daily as add-n t sulfnylurea. As shwn in Table 10, at the end f treatment, 100 mg and 300 mg daily prvided statistically significant (p<0.001 fr bth dses) imprvements in HbA1C relative t placeb when added t sulfnylurea. 300 mg nce daily cmpared t placeb resulted in a 26

27 greater prprtin f patients achieving an HbA1C less than 7%, (33% vs 5%), greater reductins in fasting plasma glucse (-36 mg/dl vs +12 mg/dl), and greater percent bdy weight reductin (-2.0% vs -0.2%). Table 10: Results frm 18-Week Placeb Cntrlled Clinical Study f in Cmbinatin with Sulfnylurea* Placeb + Sulfnylurea (N=45) 100 mg + Sulfnylurea (N=42) 300 mg + Sulfnylurea (N=40) Efficacy Parameter HbA1C (%) Baseline (mean) Change frm baseline (adjusted mean) Difference frm placeb (adjusted mean) (95% CI) (-1.15; -0.33) * Intent-t-treat ppulatin using last bservatin in study prir t glycemic rescue therapy Least squares mean adjusted fr baseline value p< (-1.24; -0.41) Add-n Cmbinatin Therapy With Metfrmin and Sulfnylurea A ttal f 469 patients with type 2 diabetes inadequately cntrlled n the cmbinatin f metfrmin (greater than r equal t 2,000 mg/day r at least 1,500 mg/day if higher dse nt tlerated) and sulfnylurea (maximal r near-maximal effective dse) participated in a 26-week, duble-blind, placeb-cntrlled study t evaluate the efficacy and safety f in cmbinatin with metfrmin and sulfnylurea. The mean age was 57 years, 51% f patients were men, and the mean baseline egfr was 89 ml/min/1.73 m 2. Patients already n the prtclspecified dses f metfrmin and sulfnylurea (N=372) entered a 2-week, single-blind, placeb run-in perid. Other patients (N=97) were required t be n a stable prtcl-specified dse f metfrmin and sulfnylurea fr at least 8 weeks befre entering the 2-week run-in perid. Fllwing the run-in perid, patients were randmized t 100 mg, 300 mg, r placeb, administered nce daily as add-n t metfrmin and sulfnylurea. At the end f treatment, 100 mg and 300 mg nce daily resulted in a statistically significant imprvement in HbA1C (p<0.001 fr bth dses) cmpared t placeb when added t metfrmin and sulfnylurea. 100 mg and 300 mg nce daily als resulted in a greater prprtin f patients achieving an HbA1C less than 7%, in a significant reductin in fasting plasma glucse (FPG), and in percent bdy weight reductin cmpared t placeb when added t metfrmin and sulfnylurea (see Table 11). 27

28 Table 11: Results frm 26 Week Placeb-Cntrlled Clinical Study f in Cmbinatin with Metfrmin and Sulfnylurea* Placeb + Metfrmin and Sulfnylurea (N=156) 100 mg + Metfrmin and Sulfnylurea (N=157) 300 mg + Metfrmin and Sulfnylurea (N=156) Efficacy Parameter HbA1C (%) Baseline (mean) Change frm baseline (adjusted mean) Difference frm placeb (adjusted mean) (95% CI) (-0.90; -0.52) Percent f patients achieving A1C < 7% Fasting Plasma Glucse (mg/dl) Baseline (mean) Change frm baseline (adjusted mean) (-1.11; -0.73) Difference frm placeb (adjusted mean) (95% CI) -22 (-31; -13) -35 (-44; -25) Bdy Weight Baseline (mean) in kg % change frm baseline (adjusted mean) Difference frm placeb (adjusted mean) (95% -1.4 CI) (-2.1; -0.7) * Intent-t-treat ppulatin using last bservatin in study prir t glycemic rescue therapy Least squares mean adjusted fr baseline value and stratificatin factrs p< (-2.7; -1.3) Cmpared t Sitagliptin, Bth as Add-n Cmbinatin Therapy With Metfrmin and Sulfnylurea A ttal f 755 patients with type 2 diabetes inadequately cntrlled n the cmbinatin f metfrmin (greater than r equal t 2,000 mg/day r at least 1,500 mg/day if higher dse nt tlerated) and sulfnylurea (near-maximal r maximal effective dse) participated in a 52-week, duble-blind, active-cntrlled study t cmpare the efficacy and safety f 300 mg versus sitagliptin 100 mg in cmbinatin with metfrmin and sulfnylurea. The mean age was 57 years, 56% f patients were men, and the mean baseline egfr was 88 ml/min/1.73 m 2. Patients already n prtcl-specified dses f metfrmin and sulfnylurea (N=716) entered a 2-week single-blind, placeb run-in perid. Other patients (N=39) were required t be n a stable prtcl-specified dse f metfrmin and sulfnylurea fr at least 8 weeks befre entering the 2-week run-in perid. Fllwing the run-in perid, patients were randmized t 300 mg r sitagliptin 100 mg as add-n t metfrmin and sulfnylurea. As shwn in Table 12 and Figure 2, at the end f treatment, 300 mg prvided greater HbA1C reductin cmpared t sitagliptin 100 mg when added t metfrmin and sulfnylurea (p<0.05). 300 mg resulted in a mean percent change in bdy weight frm baseline f -2.5% cmpared t +0.3% with sitagliptin 100 mg. A mean change in systlic 28

29 bld pressure frm baseline f mmhg was bserved with 300 mg cmpared t mmhg with sitagliptin 100 mg. Table 12: Results frm 52 Week Clinical Study Cmparing t Sitagliptin in Cmbinatin with Metfrmin and Sulfnylurea* 300 mg + Metfrmin and Sulfnylurea (N=377) Sitagliptin 100 mg + Metfrmin and Sulfnylurea (N=378) Efficacy Parameter HbA1C (%) Baseline (mean) Change frm baseline (adjusted mean) Difference frm sitagliptin (adjusted mean) (95% CI) (-0.50; -0.25) Percent f patients achieving HbA1C < 7% Fasting Plasma Glucse (mg/dl) Baseline (mean) Change frm baseline (adjusted mean) Difference frm sitagliptin (adjusted mean) (95% CI) -24 (-30; -18) Bdy Weight Baseline (mean) in kg % change frm baseline (adjusted mean) Difference frm sitagliptin (adjusted mean) (95% CI) -2.8 (-3.3; -2.2) * Intent-t-treat ppulatin using last bservatin in study prir t glycemic rescue therapy Least squares mean adjusted fr baseline value and stratificatin factrs + metfrmin + sulfnylurea is cnsidered nn-inferir t sitagliptin + metfrmin + sulfnylurea because the upper limit f this cnfidence interval is less than the pre-specified nn-inferirity margin f < 0.3%. p<0.001 Figure 2: Mean HbA1C Change at Each Time Pint (Cmpleters) and at Week 52 Using Last Observatin Carried Frward (mitt Ppulatin) 29

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