BRENZAVVY Tablet Ref.[107226] Active ingredients: Bexagliflozin

5.1 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis

In patients with type 1 diabetes mellitus, BRENZAVVY significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received sodium glucose transporter 2 (SGLT2) inhibitors compared to patients who received placebo. BRENZAVVY is not indicated for glycemic control in patients with type 1 diabetes mellitus.

Type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are also risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors.

Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse.

Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 3 days after discontinuing BRENZAVVY [see Clinical Pharmacology (12.2)]; however, there have been postmarketing reports of ketoacidosis and/or glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors.

Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue BRENZAVVY, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting BRENZAVVY.

Withhold BRENZAVVY, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume BRENZAVVY when the patient is clinically stable and has resumed oral intake [see Dosage and Administration (2.3)].

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

5.2 Lower Limb Amputation

An increased incidence of lower limb amputations occurred in BRENZAVVY-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 (Trial 6). Additional amputation data from Trial 6 are shown in Table 2 [see Adverse Reactions (6.1)]. Of the 23 BRENZAVVY-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 BRENZAVVY, 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 BRENZAVVY for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue BRENZAVVY if these complications occur.

5.3 Volume Depletion

BRENZAVVY can cause intravascular volume contraction which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine [see Adverse Reactions (6.1)]. There have been postmarketing reports of acute kidney injury, some 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) [see Use in Specific Populations (8.6)], 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 BRENZAVVY in patients with one or more of these characteristics, assess volume status and renal function [see Dosage and Administration (2.1)]. In patients with volume depletion, correct this condition before initiating BRENZAVVY. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy.

5.4 Urosepsis and Pyelonephritis

There have been reports of serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization in patients receiving SGLT2 inhibitors, including BRENZAVVY. Treatment with SGLT2 inhibitors, including BRENZAVVY, increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see Adverse Reactions (6.1)].

5.5 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

Insulin and insulin secretagogues (e.g., sulfonylureas) are known to cause hypoglycemia. BRENZAVVY may increase the risk of hypoglycemia when used in combination with insulin and/or an insulin secretagogue [see Adverse Reactions (6.1)]. A lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with BRENZAVVY.

5.6 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 BRENZAVVY 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 BRENZAVVY, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.

5.7 Genital Mycotic Infections

BRENZAVVY increases the risk of genital mycotic infections [see Adverse Reactions (6.1)]. 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.

The following important adverse reactions are described below and elsewhere in the labeling:

• Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis [see Warnings and Precautions (5.1)]
• Lower Limb Amputation [see Warnings and Precautions (5.2)]
• Volume Depletion [see Warnings and Precautions (5.3)]
• Urosepsis and Pyelonephritis [see Warnings and Precautions (5.4)]
• Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.5)]
• Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) [see Warnings and Precautions (5.6)]
• Genital Mycotic Infections [see Warnings and Precautions (5.7)]

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 BRENZAVVY 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) [see Clinical Studies (14.2, 14.3)] and a 12-week, placebo-controlled, dose-ranging, monotherapy trial (only the data from the 20 mg dosage of BRENZAVVY per day were included in this pool). In these pooled trials, patients received placebo (N=300) or BRENZAVVY 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 BRENZAVVY in these trials. These adverse reactions occurred more commonly in BRENZAVVY-treated patients than placebo-treated patients, and occurred in at least 2% of BRENZAVVY-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 BRENZAVVY-treated patients than placebo-treated patients and occurred in at least 2% of BRENZAVVY-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), BRENZAVVY (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), BRENZAVVY (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), BRENZAVVY (N=216).

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

BRENZAVVY 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) [see Clinical Studies (14.5)]. Patients on standard of care therapy for diabetes management were randomized to receive add-on therapy with either placebo (N=567) or BRENZAVVY 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 BRENZAVVY 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 BRENZAVVY-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 BRENZAVVY, 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 BRENZAVVY, 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 BRENZAVVY, 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 BRENZAVVY, 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 BRENZAVVY, 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 BRENZAVVY, 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 BRENZAVVY, respectively. Patients treated with BRENZAVVY 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 BRENZAVVY 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 BRENZAVVY, one event of rash and one event of dermatitis was confirmed to be attributable to BRENZAVVY exposure by withdrawal and rechallenge. The rash and dermatitis events occurred on day 37 and day 3 of exposure to BRENZAVVY, 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 BRENZAVVY, respectively.

Sepsis

BRENZAVVY 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 BRENZAVVY-treated patients in the trial, respectively. Of these, 1 sepsis event among placebo-treated patients and 3 sepsis events among BRENZAVVY-treated patients were related to urinary tract infections.

Laboratory Abnormalities

Changes in Serum Creatinine and eGFR

Initiation of BRENZAVVY 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 BRENZAVVY, 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 BRENZAVVY arms, respectively). Acute hemodynamic changes may play a role in the early renal function changes observed with BRENZAVVY 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 BRENZAVVY (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 BRENZAVVY 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 BRENZAVVY. In the same pool, mean changes from baseline to Week 24 in hematocrit were -0.6% with placebo and 1.3% with BRENZAVVY 20 mg. Fewer patients had >2 g/dL increases in hemoglobin from baseline for placebo (0.5%) compared to BRENZAVVY (4.9%). Increases in hemoglobin >3 g/dL from baseline were observed in 0% of placebo-treated patients compared to 0.7% of BRENZAVVY-treated patients.

See Table 4 for clinically significant interactions with BRENZAVVY.

Table 4. Clinically Significant Interactions with BRENZAVVY:

Risk Summary

Based on animal data showing adverse renal effects, BRENZAVVY is not recommended during the second and third trimesters of pregnancy.

The available data on use of BRENZAVVY 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 BRENZAVVY 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.

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

In 9 clinical trials of BRENZAVVY, 1047 (40.6%) patients 65 years and older, and 212 (8.2%) patients 75 years and older were exposed to BRENZAVVY [see Clinical Studies (14)].

One of the 9 trials enrolled patients with type 2 diabetes mellitus who had either established CVD or were at increased risk for CVD (Trial 6), and had a total of 571 (50%) patients treated with BRENZAVVY who were 65 years and older, and 113 (10%) patients treated with BRENZAVVY who were 75 years and older [see Clinical Studies (14.5)]. No overall differences in the effectiveness of BRENZAVVY have been observed between patients 65 years of age and older and younger adult patients. Among patients aged 65 and older in this trial, volume depletion events were reported in 7.6% and 9.8% of patients in the placebo and BRENZAVVY groups, respectively [see Warnings and Precautions (5.3)].

BRENZAVVY 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 BRENZAVVY and reduction in urine output in these patients [see Clinical Pharmacology (12.3)]. 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 [see Dosage and Administration (2.1)].

The safety and efficacy of BRENZAVVY in adults with type 2 diabetes mellitus and moderate renal impairment (eGFR between 30 and 60 mL/min/1.73 m²) were evaluated in Trial 5 [see Clinical Studies (14.4)]. Efficacy and safety studies with BRENZAVVY did not enroll patients with an eGFR less than 30 mL/min/1.73 m².

BRENZAVVY-treated patients with renal impairment may be more likely to experience adverse reactions associated with BRENZAVVY treatment, including female genital mycotic infection, increased urination, and thirst, and may be at higher risk for volume depletion and acute kidney injury [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].

BRENZAVVY 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 [see Clinical Pharmacology (12.3)].