Bexagliflozin (Monograph)

Brand name: Brenzavvy
Drug class: Sodium-glucose Cotransporter 2 (SGLT2) Inhibitors

Introduction

Bexagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is an antidiabetic agent.

Uses for Bexagliflozin

Bexagliflozin has the following uses:

Bexagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Bexagliflozin is not recommended in patients with type 1 diabetes mellitus. The drug may increase the risk of diabetic ketoacidosis in these patients.

Bexagliflozin Dosage and Administration

General

Bexagliflozin is available in the following dosage form(s) and strength(s):

Tablets: 20 mg

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

Assess renal function prior to initiation of bexagliflozin and periodically thereafter as clinically indicated. Bexagliflozin is not recommended in patients with an eGFR less than 30 mL/min/1.73 m² and is contraindicated in patients on dialysis.

Assess volume status and correct volume depletion before initiating the drug.

Recommended dosage is 20 mg orally once daily, taken in the morning, with or without food. Do not crush or chew the tablet.

Related/similar drugs

metformin, Trulicity, Lantus, Tresiba, Victoza, Levemir

Cautions for Bexagliflozin

Contraindications

• Hypersensitivity to bexagliflozin or any excipient in the formulation.

• Patients on dialysis.

Warnings/Precautions

Ketoacidosis

Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization, have been identified in clinical trials and postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus who received SGLT2 inhibitors, including bexagliflozin. Fatal cases of ketoacidosis have been reported for patients taking SGLT2 inhibitors. In placebo-controlled trials of patients with type 1 diabetes, the risk of ketoacidosis was increased in patients who received SGLT2 inhibitors compared to patients who received placebo. Bexagliflozin is not indicated for the treatment of patients with type 1 diabetes mellitus.

Patients treated with bexagliflozin who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of blood glucose levels, as ketoacidosis associated with bexagliflozin may be present even if the blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected, bexagliflozin should be discontinued, the patient should be evaluated, and prompt treatment should be instituted. Treatment of ketoacidosis may require insulin, fluid, and carbohydrate replacement.

In many of the reported cases, and particularly in patients with type 1 diabetes, the presence of ketoacidosis was not immediately recognized, and the institution of treatment was delayed because the presenting blood glucose levels were below those typically expected for diabetic ketoacidosis (often less than 250 mg/dL). Signs and symptoms at presentation were consistent with dehydration and severe metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. In some but not all cases, factors predisposing to ketoacidosis, such as insulin dose reduction, acute febrile illness, reduced caloric intake, surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse were identified.

Before initiating bexagliflozin, consider factors in the patient history that may predispose to ketoacidosis, including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse.

For patients who undergo scheduled surgery, consider temporarily discontinuing bexagliflozin for at least 3 days prior to surgery. Consider monitoring for ketoacidosis and temporarily discontinuing bexagliflozin in clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or post-surgery). Ensure risk factors for ketoacidosis are resolved prior to restarting bexagliflozin.

Educate patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue bexagliflozin and seek medical attention immediately if signs and symptoms occur.

Lower Limb Amputation

An increased incidence of lower limb amputations occurred in bexagliflozin-treated patients compared to placebo-treated patients (8.3 versus 5.1 events per 1,000 patient-years) in a randomized, placebo-controlled trial evaluating patients with type 2 diabetes who had either established cardiovascular disease (CVD) or were at risk for CVD. Of the 23 bexagliflozin-treated patients who had amputations, 15 were amputations of the toe and midfoot and 8 were amputations above and below the knee. Some patients had multiple amputations.

Lower limb infections, gangrene, ischemia, and osteomyelitis were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of prior amputation, peripheral vascular disease, and neuropathy.

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.

Volume Depletion

Bexagliflozin can cause intravascular volume contraction which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. There have been postmarketing reports of acute kidney injury, sometimes requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m²), elderly patients, patients with low systolic blood pressure, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating bexagliflozin in patients with one or more of these characteristics, assess volume status and renal function. In patients with volume depletion, correct this condition before initiating bexagliflozin. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy.

Urosepsis and Pyelonephritis

There have been reports of serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization in patients receiving SGLT2 inhibitors, including bexagliflozin. Treatment with SGLT2 inhibitors, including bexagliflozin, increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated.

Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

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.

Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)

Reports of necrotizing fasciitis of the perineum (Fournier’s Gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death.

Patients treated with bexagliflozin presenting with pain or tenderness, erythema, or swelling in the genital or perineal areas, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue bexagliflozin, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.

Genital Mycotic Infections

Bexagliflozin increases the risk of genital mycotic infections. Patients who have a history of genital mycotic infections or who are uncircumcised are more likely to develop genital mycotic infections. Monitor and treat appropriately.

Specific Populations

Pregnancy

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.

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.

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.

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.

Lactation

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. 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.

Pediatric Use

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

Geriatric Use

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 (CVD) or were at increased risk for CVD, and had a total of 571 (50%) patients treated with bexagliflozin who were 65 years and older, and 113 (10%) patients treated with bexagliflozin who were 75 years and older. No overall differences in the effectiveness of bexagliflozin have been observed between patients 65 years of age and older and younger adult patients. Among patients 65 years of age 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.

Renal Impairment

Bexagliflozin is contraindicated in patients receiving dialysis and is not recommended in patients with an eGFR less than 30 mL/min/1.73 m² due to the decline of the glucose lowering effect of bexagliflozin and reduction in urine output in these patients. The recommended dosage for patients with an eGFR greater than or equal to 30 mL/min/1.73 m² is the same as the recommended dosage for patients with normal renal function.

The safety and efficacy of bexagliflozin in adults with type 2 diabetes mellitus and moderate renal impairment (eGFR between 30 and 60 mL/min/1.73 m²) were evaluated in a randomized placebo-controlled trial. Efficacy and safety studies with bexagliflozin did not enroll patients with an eGFR less than 30 mL/min/1.73 m².

Bexagliflozin-treated patients with renal impairment may be more likely to experience adverse reactions associated with the drug, including female genital mycotic infection, increased urination, and thirst, and may be at higher risk for volume depletion and acute kidney injury.

Hepatic Impairment

Bexagliflozin has 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.

Common Adverse Effects

Most common adverse reactions (incidence >5%) are female genital mycotic infections, urinary tract infection, and increased urination.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

See the following table for clinically significant interactions with bexagliflozin.

Actions

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.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Medication Guide).

• Inform patients that ketoacidosis is a serious life-threatening condition and that cases of ketoacidosis have been reported during use of bexagliflozin, sometimes associated with illness or surgery among other risk factors. Instruct patients to check ketones (when possible) if symptoms of ketoacidosis occur, even if blood glucose is not elevated. If symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness or labored breathing) occur, instruct patients to discontinue bexagliflozin and seek medical care immediately.

• Inform patients of the potential for an increased risk of amputations with bexagliflozin. Counsel patients on the importance of routine preventive foot care. Instruct patients to monitor for any new pain or tenderness, sores or ulcers, or infections involving the leg or foot and to seek medical advice immediately if such signs or symptoms develop.

• Inform patients that symptomatic hypotension may occur with bexagliflozin and advise them to contact their healthcare provider if they experience such symptoms. Inform patients that dehydration may increase the risk of hypotension, and to maintain adequate fluid intake.

• Inform patients of the potential for urinary tract infections, which may be serious. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice if such symptoms occur.

• Inform patients that the incidence of hypoglycemia may increase when bexagliflozin is added to insulin and/or an insulin secretagogue and that a lower dose of insulin or insulin secretagogue may be required to reduce the risk of hypoglycemia.

• Inform patients that necrotizing infections of the perineum (Fournier’s Gangrene) have occurred with bexagliflozin. Counsel patients to promptly seek medical attention if they develop pain or tenderness, redness or swelling of the genitals or the area from the genitals to the anus, accompanied by a fever above 100.4°F or malaise.

• Inform female patients that vaginal yeast infections may occur and provide them with information on the signs and symptoms of vaginal yeast infections. Advise them of treatment options and when to seek medical advice.

• Inform male patients that yeast infections of the penis (e.g., balanitis or balanoposthitis) may occur, especially in uncircumcised males and patients with prior infections. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice.

• Advise pregnant patients and females of reproductive potential of the potential risk to a fetus with bexagliflozin treatment. Instruct patients to inform their healthcare provider if pregnant or planning to become pregnant.

• Advise patients that breastfeeding is not recommended during treatment with bexagliflozin.

• Inform patients that their urine will test positive for glucose while taking bexagliflozin due to its mechanism of action.

• Instruct patients to take bexagliflozin only as prescribed. If a dose is missed, it should be taken as soon as possible. Advise patients not to double their next dose.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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