BEXAGLIFLOZIN (bexagliflozin)

There are 2 contraindications. Absolute contraindication.

Contraindication List
Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
Chronic kidney disease stage 5 (failure) GFr<15 ml/min

There are 9 severe contraindications. Adequate patient monitoring is recommended for safer drug use.

Severe List
Diabetic foot infection
Diabetic peripheral neuropathy
History of diabetes-related lower-extremity amputation
Hypovolemia
Invasive surgical procedure
Kidney disease with likely reduction in glomerular filtration rate (GFr)
Necrotizing fasciitis of perineum or genital area
Peripheral vascular disease
Pregnancy

There are 1 moderate contraindications. Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.

Moderate List
Hypoglycemic disorder

There are 5 severe adverse reactions.

More Frequent	Less Frequent
Hypoglycemic disorder	None.

Rare/Very Rare
Acute kidney injury Diabetic ketoacidosis Necrotizing fasciitis of perineum or genital area Urosepsis

There are 9 less severe adverse reactions.

More Frequent	Less Frequent
Hypovolemia Polyuria Urinary tract infection Vulvovaginal candidiasis	Candidal balanitis Polydipsia Vulvovaginal pruritus

Rare/Very Rare
Dizziness Skin rash

There is insufficient evidence with bexagliflozin in pregnant women to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Based on animal data showing adverse renal effects, bexagliflozin is not recommended during the second and third trimesters of pregnancy. In animal studies, adverse renal pelvic and tubule dilatations that were not fully reversible were observed in rats when bexagliflozin was administrated 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 dosage.

Bexagliflozin administered to juvenile rats at 0.3, 3, or 30 mg/kg per 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 human dosage 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 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 per day. Maternal mortality occurred at >=40 mg/kg (79 times the human dosage 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 human dosage 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. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy. 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.

There are no data on the presence of bexagliflozin in human milk, the effects on the breast-fed child, or the effects on milk production. Bexagliflozin is excreted into the milk of lactating rats. 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 the breast-fed child, including the potential for bexagliflozin to affect postnatal renal development, advise patients that use of bexagliflozin is not recommended while breastfeeding.

In 9 clinical trials of bexagliflozin, 1047 (40.6%) patients 65 years and older, and 212 (8.2%) patients 75 years and older were exposed to bexagliflozin. One of the 9 trials enrolled patients with type 2 diabetes mellitus who had either established cardiovascular disease or were at increased risk for cardiovascular disease; this trial included a total of 571 (50%) patients who were 65 years and older and 113 (10%) patients who were 75 years and older treated with bexagliflozin. Among patients aged 65 years and older in this trial, volume depletion events were reported in 7.6%

and 9.8% of patients in the placebo and bexagliflozin groups, respectively. No overall differences in the effectiveness of bexagliflozin have been observed between patients aged 65 years and older and younger adult patients.