Bexagliflozin

UGT enzyme inducers may significantly reduce exposure to bexagliflozin and lead to a decreased efficacy.

Consider adding another antihyperglycemic agent in patients who require additional glycemic control.

Bexagliflozin has not been studied in patients with severe hepatic impairment and is not recommended for use in this patient population.

Insulin and insulin secretagogues (e.g., sulfonylureas) are known to cause hypoglycemia. Bexagliflozin may increase the risk of hypoglycemia when used in combination with insulin and/or an insulin secretagogue. A lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with bexagliflozin.

Concomitant use with SGLT2 inhibitors such as bexagliflozin may decrease serum lithium concentrations.

Monitor serum lithium concentration more frequently upon bexagliflozin initiation and discontinuation.

Before initiating bexagliflozin, consider factors in the patient history that may predispose to the need for amputations, such as a history of prior amputation, peripheral vascular disease, neuropathy and diabetic foot ulcers. Counsel patients about the importance of routine preventative foot care. Monitor patients receiving bexagliflozin for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue bexagliflozin if these complications occur.

Patients who have a history of genital mycotic infections or who are uncircumcised are more likely to develop genital mycotic infections.

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 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.

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 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.

Carcinogenesis

Carcinogenesis was evaluated in 2-year studies in CD-1 mice at oral gavage doses of 15, 50, and 150 mg/kg/day and in Sprague-Dawley (SD) rats at 3, 10, and 30 mg/kg/day. In male rats, the dose was reduced to 1, 3, and 10 mg/kg/day at week 73 due to exacerbation of chronic progressive nephropathy resulting in excessive mortality. There were no drug-related neoplastic findings in mice or rats at up to the highest doses tested representing up to 156 times (mice) and 68 times (rats) the clinical dose of 20 mg based on AUC.

Mutagenesis

Bexagliflozin was not mutagenic or clastogenic with or without metabolic activation in the in vitro Ames bacterial mutagenicity assay, the in vitro CHO cell assay, an in vivo micronucleus assay in rats, and an in vivo unscheduled hepatic DNA synthesis study in rats.

Impairment of Fertility

Bexagliflozin had no effects on mating, fertility or early embryonic development in male or female rats at any dose up to the highest dose of 200 mg/kg/day, which resulted in exposures 280 times (males) and 439 times (females) the 20 mg clinical dose (based on AUC).

• Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis
• Lower Limb Amputation
• Volume Depletion
• Urosepsis and Pyelonephritis
• Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
• Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
• Genital Mycotic Infections

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 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 bexagliflozin 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 m² in 98% of patients and eGFR 45 to <60 mL/min/1.73 m² in 2% of patients (mean eGFR 92 mL/min/1.73 m²).

Table 1 shows common adverse reactions associated with the use of bexagliflozin 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*:

^* 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 (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 (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 (N=216).

Clinical Trial in Patients with Increased Risk for Major Adverse Cardiovascular Events

bexagliflozin 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 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 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):

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, 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, 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, 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, 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, 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, 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, respectively. Patients treated with bexagliflozin 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:

^* 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, 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 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 m² 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 m² with bexagliflozin, 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 m² in the placebo and bexagliflozin arms, respectively). Acute hemodynamic changes may play a role in the early renal function changes observed with bexagliflozin 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 (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. 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 (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.