Brenzavvy Drug Information

is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use BRENZAVVY is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. . BRENZAVVY 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. Limitation of Use: Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus.

• 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 BRENZAVVY 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 BRENZAVVY 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 BRENZAVVY
• Assess renal function prior to initiation of BRENZAVVY and periodically thereafter as clinically indicated [see Warnings and Precautions ( 5.3 )] . BRENZAVVY 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 BRENZAVVY [see Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.5 , 8.6 )]. 2.2 Recommended Dosage
• The recommended dosage of BRENZAVVY 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 BRENZAVVY for at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting. Resume BRENZAVVY when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.2 )] .

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 BRENZAVVY 20 mg 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) and a 12-week, placebo-controlled, dose-ranging, monotherapy trial (only the data from the 20 mg dosage of BRENZAVVY per day were included in this pool). In these pooled trials, patients received placebo (N = 300) or BRENZAVVY 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 BRENZAVVY in these trials. These adverse reactions occurred more commonly in BRENZAVVY-treated patients than placebo-treated patients, and occurred in at least 2% of BRENZAVVY-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 BRENZAVVY 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 BRENZAVVY-treated patients than placebo-treated patients and occurred in at least 2% of BRENZAVVY-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), BRENZAVVY (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), BRENZAVVY (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), BRENZAVVY (N = 216). Clinical Trial in Patients with Increased Risk for Major Adverse Cardiovascular Events BRENZAVVY was 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) . Patients on standard of care therapy for diabetes management were randomized to receive add-on therapy with either placebo (N = 567) or BRENZAVVY 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 BRENZAVVY 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 BRENZAVVY-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 BRENZAVVY 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

Hazard Ratio (95% CI) - 1.64 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 BRENZAVVY, 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 BRENZAVVY, 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 BRENZAVVY, 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 BRENZAVVY, 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 BRENZAVVY, 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 BRENZAVVY, 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 BRENZAVVY, respectively. Patients treated with BRENZAVVY 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 BRENZAVVY 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 BRENZAVVY Monotherapy (24 weeks) (Trial 1) All subjects -Overall -Severe N = 69 0 0 N = 138 0 0 Add-on to Metformin (24 weeks) (Trial 2) All subjects -Overall -Severe N = 159 0 0 N = 158 1 0 Add-on to Standard of Care Therapy in Patients with Moderate Renal Impairment (24 weeks) (Trial 5) β All subjects -Overall -Severe Subjects on background insulin and/or sulfonylurea -Overall -Severe N = 155 0 0 N = 109 0 0 N = 157 2 1 N = 106 2 1 Add-on to Standard of Care Therapy in Patients with Increased CV Risk (Trial 6) β All subjects -Overall -Severe Subjects on background insulin and/or sulfonylurea -Overall -Severe N = 567 11 8 N = 454 10 8 N = 1,132 23 10 N = 923 22 10 * 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 BRENZAVVY, one event of rash and one event of dermatitis was confirmed to be attributable to BRENZAVVY exposure by withdrawal and rechallenge. The rash and dermatitis events occurred on day 37 and day 3 of exposure to BRENZAVVY, 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 BRENZAVVY, respectively.

Sepsis BRENZAVVY 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 BRENZAVVY-treated patients in the trial, respectively. Of these, 1 sepsis event among placebo-treated patients and 3 sepsis events among BRENZAVVY-treated patients were related to urinary tract infections. Laboratory Abnormalities Changes in Serum Creatinine and eGFR Initiation of BRENZAVVY 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 BRENZAVVY, 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 BRENZAVVY arms, respectively). Acute hemodynamic changes may play a role in the early renal function changes observed with BRENZAVVY 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 BRENZAVVY (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 BRENZAVVY 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 BRENZAVVY. In the same pool, mean changes from baseline to Week 24 in hematocrit were -0.6% with placebo and 1.3% with BRENZAVVY 20 mg. Fewer patients had > 2 g/dL increases in hemoglobin from baseline for placebo (0.5%) compared to BRENZAVVY (4.9%). Increases in hemoglobin > 3 g/dL from baseline were observed in 0% of placebo-treated patients compared to 0.7% of BRENZAVVY-treated patients.

See Table 4 for clinically significant interactions with BRENZAVVY. Table 4. Clinically Significant Interactions with BRENZAVVY UGT Enzyme Inducers Clinical Impact UGT Enzyme Inducers may significantly reduce exposure to BRENZAVVY and lead to a decreased efficacy. Intervention Consider adding another antihyperglycemic agent in patients who require additional glycemic control. Concomitant Use with Insulin and Insulin Secretagogues Clinical Impact The risk of hypoglycemia is increased when BRENZAVVY is used in combination with insulin and/or an insulin secretagogue.

Intervention A lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with BRENZAVVY. Lithium Clinical Impact Concomitant use with SGLT2 inhibitors such as BRENZAVVY may decrease serum lithium concentrations. Intervention Monitor serum lithium concentration more frequently upon BRENZAVVY initiation and discontinuation. Positive Urine Glucose Test Clinical Impact SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests.

Intervention Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control. Interference with 1,5-anhydroglucitol (1,5-AG) Assay Clinical Impact Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors.

Intervention Monitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor glycemic control.

Pregnancy Risk Summary Based on animal data showing adverse renal effects, BRENZAVVY is not recommended during the second and third trimesters of pregnancy. The available data on use of BRENZAVVY during pregnancy are insufficient to determine a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations ). In animal studies, adverse renal pelvic and tubule dilatations that were not fully reversible were observed in rats when bexagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy at exposures 11 times the 20 mg clinical dose (see Data ). The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with a peri-conceptional HbA1c > 7% and has been reported to be as high as 20% to 25% in women with a peri-conceptional HbA1c > 10%. The estimated background risk of miscarriage for the indicated population is unknown.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Hypoglycemia and hyperglycemia occur more frequently during pregnancy in patients with pre-gestational diabetes. Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications.

Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Animal Data Bexagliflozin administered to juvenile rats at 0.3, 3 or 30 mg/kg/day by oral gavage from postnatal days 21 to 90 caused a dose dependent increase in the incidence and severity of renal pelvic and tubular dilatation at ≥ 3 mg/kg (11 times the clinical dose of 20 mg based on AUC). These outcomes occurred with drug exposure during periods of renal development in rats equivalent to the late second and third trimester of human renal development and did not fully reverse following a 1-month recovery period. In embryofetal development studies in rats and rabbits, bexagliflozin was administered at 7, 40, and 200 mg/kg/day (rats) and 5, 25, and 150 mg/kg/day (rabbits) during organogenesis.

No adverse developmental effects were observed in rats at doses up to 200 mg/kg/day (551 times the clinical dose of 20 mg based on AUC). Reduced maternal body weight, embryo lethality, and fetal malformations were observed in rabbits at 150 mg/kg/day (368 times the clinical dose of 20 mg based on AUC). In a prenatal and postnatal development study, bexagliflozin was administered to maternal rats by oral gavage during organogenesis and until weaning at doses of 7, 40, or 200 mg/kg/day. Maternal mortality occurred at ≥ 40 mg/kg (79 times the clinical dose of 20 mg based on AUC), primarily following parturition. Reduced gestational body weight, increased post-implantation loss, and smaller litter size were noted at 200 mg/kg (361 times the clinical dose of 20 mg based on AUC). In the offspring, lower body weight gain and decreased survival were noted at 200 mg/kg, which occurred in the presence of significant maternal toxicity.

Pediatric Use The safety and effectiveness of BRENZAVVY have not been established in pediatric patients.

• is contraindicated in patients: With hypersensitivity to bexagliflozin or any excipient in BRENZAVVY. Anaphylaxis and angioedema have been reported with sodium-glucose co-transporter 2 (SGLT2) inhibitors.
• Hypersensitivity to bexagliflozin or any excipient in BRENZAVVY

In the event of an overdose of BRENZAVVY, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. Employ the usual supportive measures as dictated by the patient’s clinical status. Removal of bexagliflozin by hemodialysis has not been studied.