bexagliflozin

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 ] . 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. 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.
• Assess renal function before initiating bexagliflozin tablets and as clinically indicated. Correct volume depletion before initiating
• Not recommended if eGFR less than 30 mL/min/1.73 m 2 .
• Withhold bexagliflozin tablets for at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting .

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 ] . 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 , Use in Specific Populations ].

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 ] .
• 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.

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 and Clinical Pharmacology ] .

12.1 Mechanism of Action Bexagliflozin is an inhibitor of sodium-glucose co-transporter 2 (SGLT2), the transporter responsible for reabsorption of the majority of glucose from the renal glomerular filtrate in the renal proximal tubule. By inhibiting SGLT2, bexagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.

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 ] Lower Limb Amputation [see Warnings and Precautions ] Volume Depletion [see Warnings and Precautions ] Urosepsis and Pyelonephritis [see Warnings and Precautions ] Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions ] Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) [see Warnings and Precautions ] Genital Mycotic Infections [see Warnings and Precautions ] Most common adverse reactions (incidence > 5%) are female genital mycotic infections, urinary tract infection and increased urination 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 ] 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 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.

See Table 4 for clinically significant interactions with bexagliflozin tablets. Table 4. Clinically Significant Interactions with Bexagliflozin Tablets UGT Enzyme Inducers Clinical Impact UGT Enzyme Inducers may significantly reduce exposure to bexagliflozin and lead to a decreased efficacy [ see Clinical Pharmacology ]. 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 bexagliflozin tablets are 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 bexagliflozin tablets. Lithium Clinical Impact Concomitant use with SGLT2 inhibitors such as bexagliflozin tablets may decrease serum lithium concentrations. Intervention Monitor serum lithium concentration more frequently upon bexagliflozin tablets 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: Advise females of the potential risk to a fetus especially during the second and third trimesters. Bexagliflozin tablets are not recommended during the second and third trimesters of pregnancy Lactation: Not recommended when breastfeeding. Geriatric patients: Higher incidence of adverse reactions related to volume depletion. Renal Impairment: Higher incidence of adverse reactions related to reduced renal function Hepatic Impairment: Not recommended for patients with severe hepatic impairment 8.1 Pregnancy Risk Summary Based on animal data showing adverse renal effects, bexagliflozin is not recommended during the second and third trimesters of pregnancy. The available data on use of bexagliflozin tablets 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. 8.2 Lactation Risk Summary There is no information regarding the presence of bexagliflozin in human milk, the effects on the breastfed infant or the effects on milk production. Bexagliflozin is excreted in the milk of lactating rats (see Data ) . When a drug is present in animal milk, it is likely that the drug will be present in human milk. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. Because of the potential for serious adverse reactions in a breastfed infant, including the potential for bexagliflozin to affect postnatal renal development, advise patients that use of bexagliflozin tablets is not recommended while breastfeeding. Data Bexagliflozin was present in rat milk at a milk:plasma ratio of approximately 2. The concentration of bexagliflozin in animal milk does not necessarily predict the concentration of bexagliflozin in human milk. Juvenile rats directly exposed to bexagliflozin showed a risk to the developing kidney (renal pelvic and tubular dilatation) during the period of renal development in rats corresponding to the late second and third trimester of human renal development. 8.4 Pediatric Use The safety and effectiveness of bexagliflozin tablets have not been established in pediatric patients. 8.5 Geriatric Use In 9 clinical trials of bexagliflozin tablets, 1047 (40.6%) patients 65 years and older, and 212 (8.2%) patients 75 years and older were exposed to bexagliflozin tablets [see Clinical Studies ] . One of the 9 trials enrolled patients with type 2 diabetes mellitus who had either established CVD or were at increased risk for CVD (Trial 6), and had a total of 571 (50%) patients treated with bexagliflozin tablets who were 65 years and older, and 113 (10%) patients treated with bexagliflozin tablets who were 75 years and older [see Clinical Studies ] . No overall differences in the effectiveness of bexagliflozin tablets have been observed between patients 65 years of age and older and younger adult patients. Among patients aged 65 and older in this trial, volume depletion events were reported in 7.6% and 9.8% of patients in the placebo and bexagliflozin tablets groups, respectively [see Warnings and Precautions ] . 8.6 Renal Impairment Bexagliflozin is not recommended in patients with an eGFR less than 30 mL/min/1.73 m 2 due to the decline of the glucose lowering effect of bexagliflozin tablets and reduction in urine output in these patients [see Clinical Pharmacology ] . The recommended dosage for patients with an eGFR greater than or equal to 30 mL/min/1.73 m 2 is the same as the recommended dosage for patients with normal renal function [see Dosage and Administration ] . The safety and efficacy of bexagliflozin tablets in adults with type 2 diabetes mellitus and moderate renal impairment (eGFR between 30 and 60 mL/min/1.73 m 2 ) were evaluated in Trial 5 [see Clinical Studies ] . Efficacy and safety studies with bexagliflozin tablets did not enroll patients with an eGFR less than 30 mL/min/1.73 m 2 . Bexagliflozin-treated patients with renal impairment may be more likely to experience adverse reactions associated with bexagliflozin treatment, including female genital mycotic infection, increased urination, and thirst, and may be at higher risk for volume depletion and acute kidney injury [see Warnings and Precautions and Adverse Reactions ] . 8.7 Hepatic Impairment Bexagliflozin tablets have not been studied in patients with severe hepatic impairment and is not recommended for use in this patient population. The recommended dosage for patients with mild to moderate hepatic impairment is the same as the recommended dosage for patients with normal hepatic function [see Clinical Pharmacology ] .