Bexagliflozin

1 INDICATIONS AND USAGE Bexagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use Bexagliflozin is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. [see Warnings and Precautions ( 5.1 )] . Bexagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1 ) Limitation of Use: Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. ( 1 )

2 DOSAGE AND ADMINISTRATION • Recommended dose: 20 mg once daily, taken in the morning, with or without food. Do not crush or chew the tablet. ( 2.2 ) • Assess renal function before initiating bexagliflozin tablets and as clinically indicated. Correct volume depletion before initiating ( 2.1 ) • Not recommended if eGFR less than 30 mL/min/1.73 m 2 . ( 2.1 ) • Withhold bexagliflozin tablets for at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting ( 2.3 ). 2.1 Testing Prior to Initiation and During Treatment with Bexagliflozin Tablets • Assess renal function prior to initiation of bexagliflozin tablets and periodically thereafter as clinically indicated [see Warnings and Precautions ( 5.3 )] . Bexagliflozin is not recommended in patients with an eGFR less than 30 mL/min/1.73 m 2 • Assess volume status. In patients with volume depletion, correct this condition before initiating bexagliflozin tablets [see Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.5 , 8.6 )]. 2.2 Recommended Dosage • The recommended dosage of bexagliflozin tablets is 20 mg orally taken once daily in the morning, with or without food [see Clinical Pharmacology ( 12.3 )] . • Do not crush or chew the tablet. • If a dose is missed, take the missed dose as soon as possible. Do not double the next dose. 2.3 Temporary Interruption for Surgery • Withhold bexagliflozin tablets for at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting. Resume bexagliflozin tablets when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.2 )] .

6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis [see Warnings and Precautions ( 5.1 )] Lower Limb Amputation [see Warnings and Precautions ( 5.2 ) ] Volume Depletion [see Warnings and Precautions ( 5.3 )] Urosepsis and Pyelonephritis [see Warnings and Precautions ( 5.4 )] Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions ( 5.5 )] Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) [see Warnings and Precautions ( 5.6 )] Genital Mycotic Infections [see Warnings and Precautions ( 5.7 )] Most common adverse reactions (incidence > 5%) are female genital mycotic infections, urinary tract infection and increased urination ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact the bexagliflozin information line at 1-855-273-6928 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Pool of Placebo-Controlled Trials Evaluating Bexagliflozin Tablets, 20 m g The data in Table 1 are derived from three trials in adults with type 2 diabetes mellitus: two 24-week placebo-controlled trials (one as monotherapy and another as add-on to metformin therapy; Trials 1 and 2, respectively) [see Clinical Studies ( 14.2 , 14.3 )] and a 12-week, placebo-controlled, dose-ranging, monotherapy trial (only the data from the 20 mg dosage of bexagliflozin tablets per day were included in this pool). In these pooled trials, patients received placebo (N = 300) or bexagliflozin 20 mg (N = 372), once daily. The mean age of the population was 56 years and 5% of the patients were older than 75 years of age. Fifty-seven percent (57%) were male and 45% were White, 38% Asian, 15% Black and 2% other races. At baseline, the mean duration of type 2 diabetes mellitus was 7.7 years and the mean hemoglobin A1c (HbA1c) was 8.2%. Established microvascular complications of type 2 diabetes mellitus at baseline included diabetic nephropathy (0.8%), retinopathy (24%), and peripheral neuropathy (33%). Baseline renal function was eGFR ≥ 60 mL/min/1.73 m 2 in 98% of patients and eGFR 45 to < 60 mL/min/1.73 m 2 in 2% of patients (mean eGFR 92 mL/min/1.73 m 2 ). Table 1 shows common adverse reactions associated with the use of bexagliflozin tablets in these trials. These adverse reactions occurred more commonly in bexagliflozin-treated patients than placebo-treated patients, and occurred in at least 2% of bexagliflozin-treated patients. Table 1. Adverse Reactions in Adults with Type 2 Diabetes Mellitus - Monotherapy or in Combination with Metformin* Percentage of Patients Placebo N = 300 Bexagliflozin N = 372 Increased urination a 3 7 Urinary tract infection b 4 6 Female genital mycotic infections c 0 6 Thirst d 2 3 Vaginal pruritus e 0 3 Male genital mycotic infection f 1 2 Hypoglycemia 1 2 * The three placebo-controlled trials included two monotherapy trials and one add-on combination trial with metformin in adults with type 2 diabetes mellitus (Trials 1, 2, and a 12-week dose ranging trial). Adverse reactions were those that occurred more commonly in bexagliflozin-treated patients than placebo-treated patients and occurred in at least 2% of bexagliflozin-treated patients. a Includes: polyuria, pollakiuria, micturition urgency, nocturia. b Includes: dysuria, urinary tract infection, nitrite urine present, streptococcal urinary tract infection, cystitis. c Includes: vulvovaginal mycotic infection, vaginal infection, genital infection fungal, vulvovaginal candidiasis. Percentages calculated with the number of female patients in each group as denominator: placebo (N = 130), bexagliflozin tablets(N = 156). d Includes: thirst, polydipsia. e Includes: pruritus genital, vulvovaginal pruritus. Percentages calculated with the number of females in each group as denominator: placebo (N = 130), bexagliflozin tablets (N = 156). f Includes: balanoposthitis, genital infection fungal, tinea cruris. Percentages calculated with the number of males in each group as denominator: placebo (N = 170), bexagliflozin tablets (N = 216). Clinical Trial in Patients with Increased Risk for Major Adverse Cardiovascular Events Bexagliflozin tablets were evaluated in a trial that enrolled adults with type 2 diabetes mellitus who had either established (CVD) or were at increased risk for CVD (Trial 6) [see Clinical Studies ( 14.5 )] . Patients on standard of care therapy for diabetes management were randomized to receive add-on therapy with either placebo (N = 567) or bexagliflozin 20 mg once daily (N = 1,132) for a minimum duration of 52 weeks (median duration 2.4 years). The most common adverse reactions observed in this trial were generally consistent with other trials of bexagliflozin tablets in adults with type 2 diabetes mellitus (see Table 1 ) . Other Adverse Reactions Lower Limb Amputations An increased incidence of non-traumatic lower limb amputations occurred in bexagliflozin-treated patients compared to placebo-treated patients in a trial (Trial 6) that evaluated adults with type 2 diabetes mellitus who had either established CVD or were at increased risk for CVD. Patients in this trial were followed for a median duration of 2.4 years. The lower limb amputation data are shown in Table 2 . Table 2. Non-traumatic Lower Limb Amputation in Adults with Type 2 Diabetes Mellitus who had either Established Cardiovascular Disease or were at Risk for Cardiovascular Disease (Trial 6 ) Placebo N = 567 Bexagliflozin N = 1,132 Patients with an amputation, n (%) 7 (1.2%) 23 (2.0%) Total amputations 13 25 Amputation incidence rate (per 1,000 patient-years) 5.1 8.3 Hazard Ratio (95% CI) - 1.64 (0.70, 3.82) Note: Incidence is based on the number of patients with at least one amputation, and not the total number of amputation events. A patient’s follow-up is calculated from Day 1 to the first amputation event date. Some patients had more than one amputation. Volume Depletion In a trial of adults with type 2 diabetes mellitus and moderate renal impairment (Trial 5), adverse reactions related to volume depletion (e.g., dehydration, dizziness, dizziness postural, vertigo, vertigo positional, presyncope, hypotension, and orthostatic hypotension) were reported in 3.9% and 8.9% of patients treated with placebo and bexagliflozin tablets, respectively. Genital Mycotic Infections In a pool of three placebo-controlled clinical trials (12-week dose ranging trial and Trials 1 and 2), the incidence of female genital mycotic infections occurred in 0% and 5.6% of females treated with placebo and bexagliflozin tablets, respectively (see Table 1 ). In the same pool of trials, male genital mycotic infections occurred in 1.4% and 2.2% of males treated with placebo and bexagliflozin tablets, respectively (see Table 1 ). In a trial that enrolled adults with type 2 diabetes mellitus and moderate renal impairment (Trial 5), 0% and 9.2% of female patients treated with placebo and bexagliflozin tablets, respectively, had a genital mycotic infection. In a trial that enrolled adults with type 2 diabetes mellitus who had either established CVD or were at increased risk for CVD (Trial 6), 2.8% and 9.0% of patients treated with placebo and bexagliflozin tablets, respectively, had at least one event of genital mycotic infection. In the same trial, genital mycotic infections that caused drug discontinuation were reported in 0% and 1.2% of patients treated with placebo and bexagliflozin tablets, respectively. Balanoposthitis was reported in 0% and 2.9% of male patients, and phimosis was reported in 0.3% and 0.5% of male patients treated with placebo and bexagliflozin tablets, respectively. Patients treated with bexagliflozin tablets with events of phimosis typically underwent circumcision. Fractures In a trial that enrolled adults with type 2 diabetes mellitus who had either established CVD or were at increased risk for CVD (Trial 6), the incidence rates of serious fractures, including events of hip and femur fracture, were 1.4 and 5.4 events per 1,000 patient-years of follow-up in the placebo and bexagliflozin groups, respectively. The imbalance in serious fractures was observed within the first 6 months of therapy and remained through the end of the trial. Hypoglycemia The incidence of hypoglycemia by trial is shown in Table 3 . Table 3. Incidence of Overall * and Severe † Hypoglycemia in Placebo-Controlled Clinical Trials in Adults with Type 2 Diabetes Mellitus Placebo Bexagliflozin Monotherapy (24 weeks) (Trial 1) All subjects -Overall [N (%)] -Severe [N (%)] N = 69 0 (0) 0 (0) N = 138 0 (0) 0 (0) Add-on to Metformin (24 weeks) (Trial 2) All subjects -Overall [N (%)] -Severe [N (%)] N = 159 0 (0) 0 (0) N = 158 1 (0.6) 0 (0) Add-on to Standard of Care Therapy in Patients with Moderate Renal Impairment (24 weeks) (Trial 5) β All subjects -Overall [N (%)] -Severe [N (%)] Subjects on background insulin and/or sulfonylurea -Overall [N (%)] -Severe [N (%)] N = 155 0 (0) 0 (0) N = 109 0 (0) 0 (0) N = 157 2 (1.3) 1 (0.6) N = 106 2 (1.9) 1 (0.9) Add-on to Standard of Care Therapy in Patients with Increased CV Risk (Trial 6) β All subjects -Overall [N (%)] -Severe [N (%)] Subjects on background insulin and/or sulfonylurea -Overall [N (%)] -Severe [N (%)] N = 567 11 (1.9) 8 (1.4) N = 454 10 (2.2) 8 (1.8) N = 1,132 23 (2.0) 10 (0.9) N = 923 22 (2.4) 10 (1.1) * Overall hypoglycemia: plasma or capillary glucose of less than 54 mg/dL. † Severe hypoglycemia: patient required assistance, lost consciousness, or experienced a seizure (irrespective of blood glucose concentration). β No restrictions were placed on background antihyperglycemic therapy (aside from treatment with another SGLT2 inhibitor) and approximately 50% of patients used insulin and/or an insulin secretagogue at baseline. Rash and Dermatitis In the clinical program of bexagliflozin tablets, one event of rash and one event of dermatitis was confirmed to be attributable to bexagliflozin exposure by withdrawal and rechallenge. The rash and dermatitis events occurred on day 37 and day 3 of exposure to bexagliflozin, respectively. In a trial that enrolled adults with type 2 diabetes mellitus who had either established CVD or were at increased risk for CVD (Trial 6), 3.4% and 5.4% of patients experienced at least one event of rash with placebo and bexagliflozin, respectively. Sepsis Bexagliflozin was associated with an increased risk of sepsis/septic shock events, including events that may have caused or contributed to death, in a trial that enrolled adults with type 2 diabetes mellitus who had either established CVD or were at increased risk for CVD (Trial 6). Sepsis events occurred in 2 (0.4%) and 14 (1.2%) of placebo-treated patients and bexagliflozin-treated patients in the trial, respectively. Of these, 1 sepsis event among placebo-treated patients and 3 sepsis events among bexagliflozin-treated patients were related to urinary tract infections. Laboratory Abnormalities Changes in Serum Creatinine and eGFR Initiation of bexagliflozin tablets causes an increase in serum creatinine and decrease in eGFR within weeks of starting therapy that stabilizes by week 6 to 12. In a trial enrolling adults with type 2 diabetes mellitus and moderate renal impairment (Trial 5), a mean change in serum creatinine of 0.0 mg/dL and a decrease in eGFR of 0.1 mL/min/1.73 m 2 was observed in the placebo group as compared to a mean increase in serum creatinine of 0.1 mg/dL and a mean decrease in eGFR of 4.6 mL/min/1.73 m 2 with bexagliflozin tablets, within the first 6 weeks of treatment. In a trial that enrolled adults with type 2 diabetes mellitus who had either established CVD or were at increased risk for CVD (Trial 6), an initial decrease in eGFR was seen within weeks of starting therapy (eGFR changes from baseline to week 12 of 0 and -3.1 mL/min/1.73 m 2 in the placebo and bexagliflozin arms, respectively). Acute hemodynamic changes may play a role in the early renal function changes observed with bexagliflozin tablets since they are reversed after treatment discontinuation. Increases in Low-Density Lipoprotein Cholesterol (LDL-C) In a pool of two placebo-controlled clinical trials (Trials 1 and 2), mean LDL-C decreased by 3.8 mg/dL (3.7%) in patients treated with placebo (N = 195) and increased by 1.7 mg/dL (1.6%) in patients treated with bexagliflozin tablets (N = 247) at week 24. In a trial that enrolled adults with type 2 diabetes mellitus who had either established CVD or were at increased risk for CVD (Trial 6), LDL-C increased by 3 mg/dL (3.2%) and 3 mg/dL (4.1%) with placebo and bexagliflozin treatment, respectively, at Week 24. Increases in Hemoglobin and Hematocrit In a pool of two placebo-controlled trials (Trials 1 and 2), mean changes from baseline to Week 24 in hemoglobin were -0.3 g/dL (-2.1%) with placebo and 0.4 g/dL (2.9%) with bexagliflozin tablets. In the same pool, mean changes from baseline to Week 24 in hematocrit were -0.6% with placebo and 1.3% with bexagliflozin 20 mg. Fewer patients had > 2 g/dL increases in hemoglobin from baseline for placebo (0.5%) compared to bexagliflozin tablets (4.9%). Increases in hemoglobin > 3 g/dL from baseline were observed in 0% of placebo-treated patients compared to 0.7% of bexagliflozin-treated patients.

12.3 Pharmacokinetics The pharmacokinetics of bexagliflozin are similar in healthy subjects and adults with type 2 diabetes mellitus. Following dosing in the fasted state, mean C max and AUC 0-∞ were 134 ng/mL and 1,162 ng·h/mL, respectively. Bexagliflozin does not exhibit time-dependent pharmacokinetics and accumulates in plasma up to ~20% following multiple dosing. Absorption Following oral administration of bexagliflozin tablets, peak plasma concentrations of bexagliflozin were reached between 2 – 4 hours post-dose and can be delayed if taken after a meal or by medications that slow gastric emptying. Plasma C max and AUC of bexagliflozin increase in a dose-proportional manner following single doses from 3 mg (0.15 times the recommended dose) to 90 mg (4.5 times the recommended dose). Effect of Food Administration of bexagliflozin tablets after consumption of a standard high-fat, high-caloric meal increased C max and AUC by 31% and 10%, respectively, compared to dosing in the fasted state. The median T max was increased to 5 hours. The effects of food on bexagliflozin pharmacokinetics are not considered clinically relevant [see Dosage and Administration ( 2.2 )] . Distribution Bexagliflozin is approximately 93% bound to plasma protein. Neither renal nor hepatic impairment substantially alters protein binding. The apparent volume of distribution is 262 L. Elimination Metabolism Bexagliflozin is mainly metabolized by UGT1A9 and, to a lesser extent, CYP3A. In plasma the most abundant metabolite is the pharmacologically inactive 3′- O -glucuronide, which was found to constitute 32.2% of the parent compound AUC in a radiolabeled tracer study. None of the metabolites are expected to have clinically relevant pharmacological effects. Excretion The apparent oral clearance of bexagliflozin is 19.1 L/h by population pharmacokinetic modeling. The apparent terminal elimination half-life of bexagliflozin was approximately 12 hours. Following administration of an oral [ 14 C]-bexagliflozin solution to healthy subjects, 91.6% of input radioactivity was recovered, 51.1% in feces, the majority as bexagliflozin, and 40.5% in urine, largely as the 3′- O -glucuronide. The proportion of input radioactivity recovered as bexagliflozin in urine and feces was 1.5% and 28.7%, respectively Specific Populations Patients with Renal Impairment In a clinical pharmacology study in patients with type 2 diabetes mellitus and mild (eGFR 60 to 89 mL/min/1.73 m 2 ), moderate (eGFR 30 to 59 mL/min/1.73 m 2 ), and severe (eGFR less than 30 mL/min/1.73 m 2 ) renal impairment, the AUC of bexagliflozin was 7%, 34% and 54% greater than in patients with normal renal function, respectively, after administration of a single 20 mg dose of bexagliflozin. These increases in bexagliflozin AUC are not considered clinically meaningful. Consistent with the mechanism of action of bexagliflozin, the 24-hour UGE in patients with type 2 diabetes mellitus and mild, moderate, and severe renal impairment was 17%, 60%, and 83% lower than in patients with type 2 diabetes mellitus with normal renal function, respectively. Therefore, the glucose-lowering pharmacodynamic response to bexagliflozin declines with increasing severity of renal impairment [see Dosage and Administration ( 2.1 ), Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.6 ), and Clinical Studies ( 14 )] . The impact of hemodialysis on bexagliflozin exposure is not known. Patients with Hepatic Impairment In patients with moderate hepatic impairment (Child-Pugh class B), the AUC of bexagliflozin increased by 28%, and C max increased by 6.3% compared to subjects with normal hepatic function. These increases in bexagliflozin AUC and C max are not considered clinically meaningful. There is no clinical experience in patients with Child-Pugh class C (severe) hepatic impairment [see Use in Specific Populations ( 8.7 )] Effects of Age, Body Weight, Sex, and Race Based on a population pharmacokinetic analysis, age, body weight, sex and race do not have a clinically relevant effect on the pharmacokinetics of bexagliflozin. Drug Interaction Studies In vitro Assessment of Drug Interactions Based on in vitro studies, bexagliflozin is not expected to inhibit CYP450 isoenzymes (CYPs) 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4, or induce CYPs 1A2, 2C19 and 3A4 at clinically relevant plasma concentrations. Bexagliflozin is not expected to inhibit drug transporters including breast cancer resistance protein (BRCP), bile salt export pump (BSEP), organic anion transporting polypeptides (OATP1B1, OATP1B3), anion transporters (OAT1, OAT3), organic cation transporters (OCT1, OCT2), and multidrug and toxin extrusion transporters (MATE1, MATE2-K) at clinically relevant plasma concentrations. Bexagliflozin is a substrate for P-glycoprotein (P-gp) . In vivo Assessment of Drug Interactions There are no clinically meaningful changes in bexagliflozin exposure when taken with metformin, glimepiride, sitagliptin, exenatide, probenecid, or verapamil ( Figure 1 ). Bexagliflozin had no clinically relevant effect on the pharmacokinetics of metformin, glimepiride, sitagliptin, and digoxin ( Figure 2 ). Figure 1. Effect of Other Drugs on the Pharmacokinetics of Bexagliflozin Note: Rifampin dosing over 5 days, the regimen may not represent the maximal impact on bexagliflozin exposure. All others were single day dosing (once daily or twice daily). Figure 2. Effect of Bexagliflozin on the Pharmacokinetics of Other Drugs Note: Single day dosing. bexagliflozin-figure-1 bexagliflozin-figure-2