Brenzavvy (bexagliflozin)

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Bexagliflozin is administered orally as tablets.

Bexagliflozin should be taken in the morning with or without food; do not crush or chew the tablet.

If a dose of bexagliflozin is missed, take the missed dose as soon as possible. Do not double the next dose.

Withhold bexagliflozin for at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting. Resume bexagliflozin when the patient is clinically stable and has resumed oral intake.

Store bexagliflozin tablets at 20-25degreesC (excursions permitted between 15-30degreesC).

Bexagliflozin is mainly metabolized by uridine diphosphate-glucuronosyl transferase (UGT) 1A9, and, to a lesser extent, cytochrome P-450 (CYP) 3A.

Bexagliflozin is a substrate for P-glycoprotein (P-gp).

There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Antidiabetic Agents/Gymnema

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Gymnema has been shown to increase the number of insulin-secreting beta cells in animals. It has also been shown to increase the activity of enzymes responsible for glucose uptake and utilization and inhibit peripheral utilization of glucose.(1)

CLINICAL EFFECTS: Use of gymnema may result in decreased requirements of antidiabetic agents.(2-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Diabetic patients should be carefully monitored if gymnema is initiated or discontinued from concurrent therapy. The dosage of the patient's antidiabetic agent(s) may need to be adjusted.(2)

DISCUSSION: In a study in 22 non-insulin-dependent patients, patients had decreased blood glucose, glycosylated hemoglobin, and glycosylated plasma proteins during gymnema therapy. Patients were able to decrease the dosage of their conventional antidiabetic therapy and five patients were able to discontinue their conventional antidiabetic therapy.(3) In a study in 27 insulin-dependent patients, patients had decreased insulin requirements, fasting blood glucose, glycosylated hemoglobin, and glycosylated plasma protein levels.(4)

Sglt2 Inhibitors/Loop Diuretics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: SGLT2 inhibitors cause intravascular volume contraction through osmotic diuresis, which can result in hypotension in patients who are volume depleted from loop diuretic use.(1-7)

CLINICAL EFFECTS: Concurrent use of SGLT2 inhibitors with loop diuretics may result in dehydration, hypotension, and acute renal failure.(1-8)

PREDISPOSING FACTORS: This interaction may be more severe in patients who have a eGFR of less than 60 ml/min/1.73m2, are also taking ACE inhibitors or ARBs and/or NSAIDs, are on a low sodium diet, have low systolic blood pressure prior to initiating SGLT2 inhibitors, and/or are 65 years of age or older.(1-7)

PATIENT MANAGEMENT: Before initiating SGLT2 inhibitors in patients maintained on loop diuretics, assess volume status and correct if needed and also assess renal function. Patients receiving concurrent therapy should be monitored for hypotension and acute renal failure.(1-8)

DISCUSSION: In clinical trials of canagliflozin, volume depletion-related adverse effects were associated with the use of loop diuretics, moderate renal impairment (eGFR 30 ml/min/1.73m2 to less than 60 ml/min/1.73m2), and age 75 years and older. In a pool of eight Phase 3 clinical trials, 2.3% of all patients taking 100 mg of canagliflozin experienced at least one volume depletion-related event, compared to 3.2% of patients taking 100 mg of canagliflozin with a loop diuretic. 3.4% of all patients taking 300 mg of canagliflozin experienced at least one volume depletion-related event, compared to 8.8% of patients taking 300 mg of canagliflozin with a loop diuretic.(1,2) Cases of acute renal failure, most requiring hospitalization, have been reported in patients receiving canagliflozin and dapagliflozin. Twenty-six of 101 cases involved concurrent use of diuretics.(7) In a post-hoc analysis of the EMPEROR-Preserve trial, the combination of empagliflozin and diuretics was associated with a higher incidence of volume depletion events (HR 1.34; 95% CI, 1.13-1.59). The most commonly reported events were hypotension, syncope, and dehydration. Coadministration of diuretics and empagliflozin did not result in a difference in the incidence of acute renal failure, hyperkalemia, or adverse events leading to trial discontinuation (including fatal events) compared to empagliflozin alone. There was also no change in the benefit of empagliflozin for the primary end point of first hospitalization for heart failure or cardiovascular death.(8)

Sodium-Glucose Co-Transporter 2 (Sglt2) Inhibitors/Lithium

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors may increase the renal excretion of lithium by impairing the proximal tubular reabsorption of lithium.(1,2)

CLINICAL EFFECTS: Concurrent use of SGLT2 inhibitors may result in decreased levels and clinical effectiveness of lithium.(1-6)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Lithium levels should be monitored more frequently when starting or changing the dose of SGLT2 inhibitors. The dose of lithium may need to be adjusted.(3-6)

DISCUSSION: A 29 year old patient stabilized on lithium with good therapeutic response was started on empagliflozin on day 10 of lithium therapy. Three days later, lithium level was subtherapeutic. Empagliflozin was stopped. After 1 week, lithium levels returned to therapeutic range. Two days later, the patient had another trial of empagliflozin and again developed subtherapeutic lithium levels.(1) A post hoc analysis of 2 dapagliflozin trials (IMPROVE and DapKid) examined the effects of dapagliflozin on volume status in diabetic patients with albuminuric kidney disease. Lithium excretion, which served as a marker of proximal tubular sodium excretion, was found to increase by 19.6% (p < 0.01).(2)

*Hypersensitivity to bexagliflozin or any excipient in the formulation. Anaphylaxis and angioedema have been reported with sodium-glucose cotransporter 2 (SGLT2) inhibitors.

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

• 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
• Type 1 diabetes mellitus

• Hypoglycemic disorder

The most common adverse effects of bexagliflozin (>5% of patients) reported in clinical studies include female genital mycotic infections, urinary tract infection, and increased urination.

More Frequent

• Hypoglycemic disorder

Rare or Very Rare

• Acute kidney injury
• Diabetic ketoacidosis
• Necrotizing fasciitis of perineum or genital area
• Urosepsis

More Frequent

• Hypovolemia
• Polyuria
• Urinary tract infection
• Vulvovaginal candidiasis

Less Frequent

• Candidal balanitis
• Polydipsia
• Vulvovaginal pruritus

Rare or Very Rare

• Dizziness
• Skin rash

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Safety and effectiveness of bexagliflozin in pediatric patients have not been established.

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.

The manufacturer makes no specific dosage recommendations for geriatric patients.

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.