Version May 2024
Dosage guidance:
Clinical considerations: Correct hypovolemia, if present, prior to initiating treatment. May require a gradual dose reduction of insulin and/or insulin secretagogues (eg, sulfonylureas, meglitinides) to avoid hypoglycemia (Ref).
Diabetes mellitus, type 2, treatment:
Note: May be used as an adjunctive agent or alternative monotherapy for patients in whom initial therapy with lifestyle intervention and metformin failed or who cannot take metformin (Ref).
Oral: 20 mg once daily in the morning.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
eGFR ≥30 mL/minute/1.73 m2: No dosage adjustment necessary.
eGFR <30 mL/minute/1.73 m2: Use is not recommended.
Patients on dialysis: Impact of hemodialysis is not known; use is not recommended (has not been studied).
Mild or moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.
Severe impairment (Child-Pugh class C): Use is not recommended (has not been studied).
Refer to adult dosing.
Cases of acute kidney injury (AKI) have been reported in patients receiving sodium-glucose cotransporter 2 (SGLT2) inhibitors (specifically canagliflozin and dapagliflozin), including cases that have required hospitalization and dialysis (Ref). In addition, increased serum creatinine and decreased estimated GFR (eGFR) have been reported with bexagliflozin. In one clinical study in patients with type 2 diabetes mellitus and stage 3a/3b chronic kidney disease, a reversible increase in serum creatinine (+0.08 mg/dL) and decrease in eGFR (-2.41 mL/minute/1.73 m2) was observed in patients treated with bexagliflozin. AKI events were rarely reported in this study and all events were defined as stage I AKI. Long-term studies of other SGLT2 inhibitors suggest an overall reduction in the risk of AKI and kidney-related serious adverse events (Ref). As evidence mounts for positive effects of these agents on long-term kidney outcomes and possible reduction in the incidence of AKI, clinicians will need to weigh the potential risk of AKI with the overall benefit of these agents (Ref).
Mechanism: Dose-related; related to the pharmacologic action. SGLT2 inhibition causes increased excretion of glucose and sodium, thereby resulting in an osmotic diuresis; the subsequent hyperosmolarity and volume contraction may increase the risk of AKI. Glucose in the urine may be reabsorbed by glucose transporters in exchange for uric acid, resulting in uricosuria and associated crystal-dependent and -independent damage. Lastly, SGLT2 inhibition results in increased fructose generation; the metabolism of fructose may lead to increased uric acid, oxidative stress, and the release of chemokines, thus causing local tubular injury and inflammation (Ref).
On the other hand, bexagliflozin may confer some protection against AKI. Proposed mechanisms based on animal studies regarding the beneficial effects of SGLT2 inhibition on AKI include improved kidney cortical oxygen tension, tubular cell integrity, and tubular albumin reabsorption (Ref); in addition, improved cardiac function may be related to improved kidney function (Ref).
Onset: Varied; in one study, increases in serum creatinine and decreases in eGFR were seen within 6 weeks of bexagliflozin initiation, which tended to stabilize after ~12 weeks (Ref).
Risk factors:
• Preexisting risk factors for AKI (eg, hypovolemia, chronic kidney insufficiency, heart failure, use of concomitant medications [eg, diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs])
Bone fracture has been reported with bexagliflozin in clinical studies in certain patient populations (patients with type 2 diabetes and stage 3a/3b chronic kidney disease (Ref) and patients with type 2 diabetes mellitus with either established cardiovascular (CVD) or increased CVD risk). In the overall population, longer-term data may be necessary to clarify risk of bone fractures with bexagliflozin.
Onset: Delayed; fractures were observed within the first 6 months of therapy.
Sodium glucose cotransporter 2 (SGLT2) inhibitors, including bexagliflozin, may cause events consistent with hypovolemia, including symptomatic hypotension, syncope, and dehydration. In bexagliflozin clinical trials, systolic blood pressure (SBP) was reduced by -3.8 to -12.9 mm Hg (Ref).
Mechanism: Dose-related; related to the pharmacologic action. Inhibition of SGLT2 causes an increase in the excretion of glucose and sodium, thereby resulting in an osmotic diuresis and intravascular volume contraction (Ref).
Onset: Varied; reduced SBP has been observed within the first 6 weeks of therapy (Ref); timing is impacted by volume status (eg, reduced oral intake, fluid losses) and concomitant use of medications known to impact volume status or blood pressure (eg, diuretics, angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]) (Ref).
Risk factors:
• Kidney impairment (ie, eGFR <60 mL/minute/1.73 m2)
• Older adults
• Concomitant use of antihypertensives (eg, diuretics, ACE inhibitors, ARBs)
• Preexisting low systolic blood pressure
• Reduced oral intake or increased fluid losses
Sodium-glucose cotransporter 2 (SGLT2) inhibitors, including bexagliflozin, have been associated with increased risk of genitourinary fungal infection (eg, vaginal mycosis, vulvovaginal candidiasis, vulvovaginitis, candida balanitis, balanoposthitis) and urinary tract infections, including severe cases of urinary tract infection with sepsis and pyelonephritis requiring hospitalization. Additionally, rare but serious and potentially fatal cases of necrotizing fasciitis (perineum) (ie, Fournier gangrene) have been reported with SGLT2 inhibitors (Ref).
Mechanism: Dose-related; related to the pharmacologic action. Patients with diabetes are more prone to urinary tract and genital infections, potentially due to glucosuria-induced bacterial growth, increased adherence of bacteria to the uroepithelium, and altered immune function (Ref). Because SGLT2 inhibitors increase urinary excretion of glucose, it has been hypothesized that these agents further increase the risk of these infections (Ref).
Onset: Varied; available literature suggests that increased risk of genital infection may be apparent within the first month of SGLT2 inhibitor therapy and remain elevated throughout the course of therapy (Ref); Fournier gangrene may have an average onset of 9 months (range: 5 days to 49 months) (Ref).
Risk factors:
• Diabetes and/or uncontrolled hyperglycemia (Ref)
• Older adults
• Prior history of these types of infections (Ref)
• Females (Ref)
• Uncircumcised males (increased risk for genital infections) (Ref)
Cases of ketoacidosis have been reported in patients with type 1 and type 2 diabetes mellitus receiving sodium-glucose cotransporter 2 (SGLT2) inhibitors, including bexagliflozin (Ref).
In some cases, patients have presented with normal or only modestly elevated blood glucose (<250 mg/dL), which can lead to misdiagnosis, prevent timely initiation of treatment, and negatively influence duration of illness (Ref). In addition, SGLT2 inhibitor-mediated increases in urinary glucose loss may persist for several days after discontinuation which may impact duration of illness in patients who develop ketoacidosis (Ref).
Mechanism: Dose-related; related to the pharmacologic action. Several mechanisms have been proposed centered on increased ketone body production and reabsorption. Because SGLT2 inhibitors decrease urinary excretion of ketone bodies and decrease blood glucose in an insulin-independent manner, plasma glucose and urine ketone concentrations may be lower than what is typically expected in classic presentations of diabetic ketoacidosis (Ref).
Onset: Varied; timing is often impacted by the onset of metabolically stressful events (eg, surgery, extensive exercise, myocardial infarction [MI], stroke, severe infections, prolonged fasting) (Ref).
Risk factors:
• Patients with diabetes who are insulin deficient (eg, latent autoimmune diabetes in adults, type 1 diabetes, or some patients with long-standing type 2 diabetes) (Ref)
• Metabolically stressful events (eg, surgery, extensive exercise, MI, stroke, severe infections, prolonged fasting) (Ref)
• Presence of other risk factors that may predispose a patient to ketoacidosis (eg, pancreatic insulin deficiency, dose decreases or missed doses of insulin, caloric restriction, alcohol abuse, acute febrile illness, surgery, ketogenic diet, volume depletion, or any other extreme stress event)
• History of pancreatitis or pancreatic surgery
An increase in lower limb amputations has been observed in patients treated with bexagliflozin. In a clinical trial in patients with type 2 diabetes and established cardiovascular disease (CVD) or risk factors for CVD, the incidence of nontraumatic lower limb amputations was 2% in the bexagliflozin-treated population, compared to 1.2% in placebo-treated patients. Amputations observed involved the toe, midfoot, or less frequently the leg (above or below the knee); lower limb infections, gangrene, ischemia, and osteomyelitis were the most common precipitating factors.
Risk factors:
• Preexisting risk factors for amputation (eg, prior amputation, peripheral vascular disease, neuropathy, diabetic foot ulcers, cardiovascular disease) (Ref)
• Age ≥65 years (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults and may include percentages reported as part of a combination regimen with metformin.
1% to 10%:
Endocrine & metabolic: Hypoglycemia (2%), increased LDL cholesterol (2%), increased thirst (3%)
Genitourinary: Diuresis (7%; including nocturia, polyuria, urinary frequency, and urinary urgency), male genital disease (2%; including balanoposthitis, localized fungal infection [genital], and tinea [tinea cruris]), urinary tract infection (6%; including urinary tract infection with sepsis) (table 1), vaginal mycosis (6%; including vulvovaginal candidiasis) (table 2), vulvovaginal pruritus (3%)
|
Drug (Bexagliflozin) |
Placebo |
Number of Patients (Bexagliflozin) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|
|
6% |
4% |
372 |
300 |
Monotherapy or in combination with metformin |
|
Drug (Bexagliflozin) |
Placebo |
Number of Patients (Bexagliflozin) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|
|
6% |
0% |
372 |
300 |
Monotherapy or in combination with metformin |
Hematologic & oncologic: Increased hematocrit (1%), increased hemoglobin (3%)
Frequency not defined:
Dermatologic: Dermatitis, skin rash
Endocrine & metabolic: Ketoacidosis
Neuromuscular & skeletal: Bone fracture (Allegretti 2019)
Renal: Decreased estimated GFR (eGFR) (Allegretti 2019), increased serum creatinine (Allegretti 2019), pyelonephritis
Hypersensitivity to bexagliflozin or any component of the formulation.
Disease-related concerns:
• Bariatric surgery:
– Altered absorption: Absorption may be altered given the anatomic and transit changes created by gastric bypass and sleeve gastrectomy surgery (Mechanick 2020; Melissas 2013).
– Dehydration: Evaluate, correct, and maintain postsurgical fluid requirements and volume status prior to initiating therapy and closely monitor the patient for the duration of therapy; volume depletion and related adverse events (eg, hypotension, orthostatic hypotension, syncope) have occurred. Fluid intake may be more difficult after gastric bypass, sleeve gastrectomy, and gastric band (Mechanick 2020).
– Euglycemic diabetic ketoacidosis: Discontinue therapy 3 to 5 days prior to surgery (Bobart 2016). Postoperatively, assess volume status, caloric intake, and need for diabetes treatment and withhold antidiabetic medication if type 2 diabetes is in remission. Ketoacidosis has been reported in patients with type 1 and type 2 diabetes on SGLT2 inhibitors. In some cases, normal or only modestly elevated blood glucose was present (<250 mg/dL) (van Niekerk 2018). Risk factors include significant reduction in insulin, caloric restriction, stress of surgery, and infection.
Special populations:
• Older adult: Older adults may be predisposed to symptoms related to intravascular volume depletion (eg, hypotension, orthostatic hypotension, dizziness, syncope, dehydration) and renal impairment or failure.
Other warnings/precautions:
• Appropriate use: Not for use in patients with diabetic ketoacidosis or for glycemic control in patients with type 1 diabetes mellitus.
• Hospitalized patients: Use of SGLT2 inhibitors is not routinely recommended for glycemic control in hospitalized patients (ADA 2023).
• Surgical procedures: Consider temporary discontinuation ≥3 days prior to surgery; ensure risk factors for ketoacidosis are resolved prior to reinitiating therapy.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Brenzavvy: 20 mg [contains fd&c blue #1 (brill blue) aluminum lake, fd&c blue #2 (indigo carm) aluminum lake]
Generic: 20 mg
Yes
Tablets (Bexagliflozin Oral)
20 mg (per each): $13.16
Tablets (Brenzavvy Oral)
20 mg (per each): $1.56
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Oral: Administer in the morning without regard to meals. Do not crush or chew.
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/214373s001lbl.pdf#page=22, must be dispensed with this medication.
Diabetes mellitus, type 2, treatment: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Limitations of use: Not recommended in patients with diabetic ketoacidosis or to improve glycemic control in patients with type 1 diabetes mellitus.
Bexagliflozin may be confused with bexarotene.
Brenzavvy may be confused with Brenzys (Canadian brand name for etanercept).
Beers Criteria: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are identified in the Beers Criteria as potentially inappropriate medications to be used with caution in patients 65 years and older due to increased risk of urogenital infections, especially in women during the first month of use. In addition, a higher risk of euglycemic diabetic ketoacidosis has been observed in older adults (Beers Criteria [AGS 2023]).
Substrate of CYP3A4 (minor), UGT1A9; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Androgens: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Beta-Blockers (Beta1 Selective): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Beta-Blockers (Nonselective): May enhance the hypoglycemic effect of Antidiabetic Agents. Beta-Blockers (Nonselective) may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Bortezomib: May enhance the therapeutic effect of Antidiabetic Agents. Bortezomib may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Etilefrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy
Insulins: Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors may enhance the hypoglycemic effect of Insulins. Management: Consider a decrease in insulin dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Risk D: Consider therapy modification
Lithium: Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors may decrease the serum concentration of Lithium. Risk C: Monitor therapy
Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Pegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Prothionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Quinolones: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Quinolones may diminish the therapeutic effect of Agents with Blood Glucose Lowering Effects. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Risk C: Monitor therapy
Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Salicylates: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Sulfonylureas: Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with a sodium-glucose cotransporter 2 (SGLT2) inhibitor and monitor patients for hypoglycemia. Risk D: Consider therapy modification
Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
UGT1A9 Inducers: May decrease the serum concentration of Bexagliflozin. Risk C: Monitor therapy
Sodium-glucose cotransporter 2 inhibitors are not recommended for patients with type 2 diabetes mellitus planning to become pregnant. Patients who could become pregnant should use effective contraception during therapy. Transition to a preferred therapy should be initiated prior to conception and contraception should be continued until glycemic control is achieved (ADA 2023; Alexopoulos 2019; Egan 2020).
Due to adverse effects on renal development observed in animal studies, the manufacturer does not recommend use during the second and third trimesters of pregnancy.
Poorly controlled diabetes during pregnancy is associated with an increased risk of adverse maternal and fetal outcomes, including diabetic ketoacidosis, preeclampsia, spontaneous abortion, preterm delivery, delivery complications, major malformations, stillbirth, and macrosomia. To prevent adverse outcomes, prior to conception and throughout pregnancy, maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ADA 2023).
Agents other than bexagliflozin are currently recommended to treat diabetes mellitus during pregnancy (ADA 2023).
It is not known if bexagliflozin is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, including possible risk to kidney development, breastfeeding is not recommended by the manufacturer.
Blood glucose; renal function (baseline and periodically during treatment); volume status (eg, BP, hematocrit, electrolytes); genital mycotic infections and urinary tract infection; necrotizing fasciitis (fever or malaise along with genital or perianal pain, tenderness, erythema, or swelling); hypersensitivity reactions; BP; lower limb and feet (sores, ulcers, infection); signs/symptoms of ketoacidosis (eg, nausea/vomiting, abdominal pain, malaise, shortness of breath), confirm diagnosis by direct measurement of blood ketones and arterial pH (measurement of serum bicarbonate or urinary ketones may not be adequate) (AACE [Handelsman 2016]).
HbA 1c: Monitor at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; monitor quarterly in patients in whom treatment goals have not been met, or with therapy change. Note: In patients prone to glycemic variability (eg, patients with insulin deficiency), or in patients whose HbA1c is discordant with serum glucose levels or symptoms, consider evaluating HbA1c in combination with blood glucose levels and/or a glucose management indicator (ADA 2023; KDIGO 2020).
Recommendations for glycemic control in patients with diabetes:
Nonpregnant adults (AACE [Samson 2023], ADA 2023):
HbA1c: <7% (a more aggressive [<6.5%] or less aggressive [<8%] HbA1c goal may be targeted based on patient-specific characteristics). Note: In patients using a continuous glucose monitoring system, a goal of time in range >70% with time below range <4% is recommended and is similar to a goal HbA1c <7%.
Preprandial capillary blood glucose: 80 to 130 mg/dL (SI: 4.4 to 7.2 mmol/L) (more or less stringent goals may be appropriate based on patient-specific characteristics).
Peak postprandial capillary blood glucose (~1 to 2 hours after a meal): <180 mg/dL (SI: <10 mmol/L) (more or less stringent goals may be appropriate based on patient-specific characteristics).
Older adults (≥65 years of age) (ADA 2023):
Note: Consider less strict targets in patients who are using insulin and/or insulin secretagogues (sulfonylureas, meglitinides) (ES [LeRoith 2019]).
HbA1c: <7% to 7.5% (healthy); <8% (complex/intermediate health). Note: Individualization may be appropriate based on patient and caregiver preferences and/or presence of cognitive impairment. In patients with very complex or poor health (ie, limited remaining life expectancy), consider making therapy decisions based on avoidance of hypoglycemia and symptomatic hyperglycemia rather than HbA1c level.
Preprandial capillary blood glucose: 80 to 130 mg/dL (SI: 4.4 to 7.2 mmol/L) (healthy); 90 to 150 mg/dL (SI: 5 to 8.3 mmol/L) (complex/intermediate health); 100 to 180 mg/dL (SI: 5.6 to 10 mmol/L) (very complex/poor health).
Bedtime capillary blood glucose: 80 to 180 mg/dL (SI: 4.4 to 10 mmol/L) (healthy); 100 to 180 mg/dL (SI: 5.6 to 10 mmol/L) (complex/intermediate health); 110 to 200 mg/dL (SI: 6.1 to 11.1 mmol/L) (very complex/poor health).
Classification of hypoglycemia (ADA 2023):
Level 1: 54 to 70 mg/dL (SI: 3 to 3.9 mmol/L); hypoglycemia alert value; initiate fast-acting carbohydrate (eg, glucose) treatment.
Level 2: <54 mg/dL (SI: <3 mmol/L); threshold for neuroglycopenic symptoms; requires immediate action.
Level 3: Hypoglycemia associated with a severe event characterized by altered mental and/or physical status requiring assistance.
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.
Distribution: Vd: 262 L.
Protein binding: ~93%.
Metabolism: Primarily metabolized through UGT1A9 and, to a lesser extent, CYP3A to inactive metabolites.
Half-life elimination: ~12 hours.
Time to peak (plasma): 2 to 4 hours; extended to 5 hours (median) if taken after a high-fat, high-calorie meal.
Excretion: Feces (51.1%, majority as unchanged drug); urine (40.5%, majority as inactive metabolite).
Clearance: 19.1 L/hour.
Altered kidney function: AUC is increased in patients with impaired kidney function. In mild (eGFR 60 to 89 mL/minute/1.73 m2), moderate (eGFR 30 to 59 mL/minute/1.73 m2), and severe (eGFR <30 mL/minute/1.73 m2), bexagliflozin AUC was increased 7%, 34%, and 54%, respectively.
Hepatic impairment: In patients with moderate hepatic impairment (Child-Pugh class B), AUC increased by 28% and Cmax increased by 6.3%.
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