DRUG INTERACTIONS-(details)

 Clinical Impact UGT Enzyme Inducers may significantly reduce exposure to BRENZAVVY and lead to decreased efficacy

. Intervention Consider adding another antihyperglycemic agent in patients who require additional glycemic control.

Concomitant Use with Insulin and Insulin Secretagogues Clinical Impact The risk of hypoglycemia is increased when BRENZAVVY is used in combination with insulin and/or an insulin secretagogue.

Intervention A lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with BRENZAVVY

 Lithium Clinical Impact Concomitant use with SGLT2 inhibitors such as BRENZAVVY may decrease serum lithium concentrations.

Intervention Monitor serum lithium concentration more frequently upon BRENZAVVY initiation and discontinuation.

Positive Urine Glucose Test Clinical Impact SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests.

Intervention Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control. Interference with 1,5-anhydroglucitol (1,5-AG)

Assay Clinical Impact Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors.

Intervention Monitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor glycemic control

BRIEF SUMMARY-

BEXAGLIFLOZIN-(Jan 2023)

Indicn- To  improve glycemic  control in adults with  type 2 diabetes as an adjunct to diet and  excercise                                                                         

Comp- Tablets: 20 mg   Recommended dose: 20 mg once daily, taken in the morning, with or without food. Do not crush or chew the tablet.

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

CI- Hypersensitivity to bexagliflozin or any excipient . Patients on dialysis

WARNINGS- Ketoacidosis: Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level. If suspected, discontinue, evaluate, and treat promptly.

Pat inform- Hypersensitivity to bexagliflozin or any excipient iPatients on dialysis

Instruct patients to check ketones (when possibleKetoacidosis-                                       

Inform patients that ketoacidosis is a serious life-threatening condition and that cases of ketoacidosis have been reported during use , sometimes associated with illness or surgery among other risk factors.) if symptoms of ketoacidosis occur, even if blood glucose is not elevated. If symptoms of ketoacidosis 

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U.S.  APPROVED DRUGS DURING 2023                                        

Serial No 2

Name-        BRENZAVVY

Acive  Ingredient -  Bexagliflozin

Pharmacological clssificiation-        To  improve glycemic  control in adults with                                                                    type 2 diabetes as an adjunct to diet and                                                                         excercise                                                                         

 Date of Approval-         1/6/2023

HIGHLIGHTS OF PRESCRIBING INFORMATION-

These highlights do not include all the information needed to use                BRENZAVVY™ safely and effectively.

See full prescribing information for BRENZAVVY. BRENZAVVY (bexagliflozin) tablets, for oral use

Initial U.S. Approval: 2023

INDICATIONS AND USAGE-

 BRENZAVVY is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

 Limitation of Use: Not recommended in patients with type 1 diabetes mellitus. May increase the risk of diabetic ketoacidosis in these patients

ADVERSE REACTIONS-

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

CONTRAINDICATIONS-

 Hypersensitivity to bexagliflozin or any excipient in BRENZAVVY ? Patients on dialysis

WARNINGS AND PRECAUTIONS

 Ketoacidosis: Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level. If suspected, discontinue, evaluate, and treat promptly.

Before initiating, consider risk factors for ketoacidosis. Patients may require monitoring and temporary discontinuation of therapy in clinical situations known to predispose to ketoacidosis

 Lower limb amputation: Consider factors that may increase the risk for amputations before initiating BRENZAVVY.

Monitor patients for signs and symptoms of infection or ulcers of the lower limbs, and discontinue if these occur 

Volume depletion: May result in acute kidney injury. Before initiating BRENZAVVY, assess and correct volume status in patients with impaired renal function or low systolic blood pressure, elderly patients or patients on diuretics. Monitor for signs and symptoms during therapy

 Urosepsis and pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated.

 Hypoglycemia: Consider a lower dose of insulin or insulin secretagogue to reduce risk of hypoglycemia when used in combination with BRENZAVVY

 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Serious, life-threatening cases have occurred in both females and males treated with SGLT2 inhibitors.

Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment 

 Genital mycotic infection: Monitor and treat as appropriate. -

DOSAGE AND ADMINISTRATION

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

 Assess renal function before initiating BRENZAVVY and as clinically indicated. Correct volume depletion before initiating (2.1) ? Not recommended if eGFR less than 30 mL/min/1.73 m2 .

DOSAGE FORMS AND STRENGTHS=

 Tablets: 20 mg

PATIENT COUNSELING INFORMATION

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

Instruct patients to check ketones (when possibleKetoacidosis-                                                                                                            Inform patients that ketoacidosis is a serious life-threatening condition and that cases of ketoacidosis have been reported during use of BRENZAVVY, sometimes associated with illness or surgery among other risk factors.) 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 BRENZAVVY and seek medical care immediately\

Lower Limb Amputation-

Inform patients of the potential for an increased risk of amputations with BRENZAVVY.

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

Volume Depletion-

Inform patients that symptomatic hypotension may occur with BRENZAVVY 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.

 Serious Urinary Tract Infections=

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

Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues-

Inform patients that the incidence of hypoglycemia may increase when BRENZAVVY 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

Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)-

Inform patients that necrotizing infections of the perineum (Fournier’s Gangrene) have occurred with BRENZAVVY.

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

Genital Mycotic Infections in Females (e.g., Vulvovaginitis)-

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

 Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis)-

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

Pregnancy Advise pregnant patients and females of reproductive potential of the potential risk to a fetus with treatment with BRENZAVVY.

Instruct patients to inform their healthcare provider if pregnant or planning to become pregnant

Lactation -

Advise patients that breastfeeding is not recommended during treatment with BRENZAVVY [see Use in Specific Populations

Laboratory Tests=

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

Missed Dose-

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

Distributed by: TheracosBio, LLC 225 Cedar Hill Street, Suite 200 Marlborough, MA 01752 USA BRENZAVVY is a trademark of TheracosBio, LLC Other brands listed are the trademarks of their respective owners and are not trademarks of TheracosBio, LLC Copyright © 2023 TheracosBio, LLC All rights reserved. Reference ID: 5112979 Page 22

CLINICAL PHARMACOLOGY-

1. 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.

2. Pharmacodynamics-

 Urinary Glucose Excretion and Urinary Volume Dose-dependent increases in urinary glucose excretion (UGE) accompanied by increases in urine volume were observed in healthy subjects and in adults with type 2 diabetes mellitus following single- and multiple-dose administration of bexagliflozin.

3. Pharmacokinetics- 

The pharmacokinetics of bexagliflozin are similar in healthy subjects and adults with type 2 diabetes mellitus. Following dosing in the fasted state, mean Cmax and AUC0-8 were 134 ng/mL and 1,162 ng·h/mL, respectively.

Bexagliflozin does not exhibit time-dependent pharmacokinetics and accumulates in plasma up to ~20% following multiple dosing.

Absorption-

Following oral administration of BRENZAVVY, peak plasma concentrations of bexagliflozin were reached between 2 – 4 hours post-dose and can be delayed if taken after a meal or by medications that slow gastric emptying.

Effect of Food Administration of BRENZAVVY after consumption of a standard high-fat, high-caloric meal increased Cmax and AUC by 31% and 10%, respectively, compared to dosing in the fasted state.

The median Tmax was increased to 5 hours. The effects of food on bexagliflozin pharmacokinetics are not considered clinically relevant [see Dosage and Administration

 Distribution-

Bexagliflozin is approximately 93% bound to plasma protein. Neither renal nor hepatic impairment substantially alters protein binding. The apparent volume of distribution is 262 L.

Elimination Metabolism-

Bexagliflozin is mainly metabolized by UGT1A9 and, to a lesser extent, CYP3A. In plasma the most abundant metabolite is the pharmacologically inactive 3'-O-glucuronide, which was found to constitute 32.2% of the parent compound AUC in a radiolabeled tracer study. None of the metabolites are expected to have clinically relevant pharmacological effects.

Excretion

The apparent oral clearance of bexagliflozin is 19.1 L/h by population pharmacokinetic modeling. The apparent terminal elimination half-life of bexagliflozin was approximately 12 hours.

Following administration of an oral [ 14C]-bexagliflozin solution to healthy subjects, 91.6% of input radioactivity was recovered, 51.1% in feces, the majority as bexagliflozin, and 40.5% in urine, largely as the 3'-O-glucuronide.

Specific Populations -

Patients with Renal Impairment-                                                                                    In a clinical pharmacology study in patients with type 2 diabetes mellitus and mild (eGFR 60 to 89 mL/min/1.73 m2 ), moderate (eGFR 30 to 59 mL/min/1.73 m2 ), and severe (eGFR less than 30 mL/min/1.73 m2 ) renal impairment, the AUC of bexagliflozin was 7%, 34% and 54% greater than in patients with normal renal function, respectively, after administration of a single 20 mg dose of BRENZAVVY.

These increases in bexagliflozin AUC are not considered clinically meaningful.

Patients with Hepatic Impairment-

In patients with moderate hepatic impairment (Child-Pugh class B), the AUC of bexagliflozin increased by 28%, and Cmax increased by 6.3% compared to subjects with normal hepatic function. These increases in bexagliflozin AUC and Cmax are not considered clinically meaningful.

There is no clinical experience in patients with ChildPugh class C (severe) hepatic impairment 

Effects of Age, Body Weight, Sex, and Race Based on a population pharmacokinetic analysis, age, body weight, sex and race do not have a clinically relevant effect on the pharmacokinetics of bexagliflozin.

Drug Interaction Studies-

In vitro Assessment of Drug Interactions Based on in vitro studies, bexagliflozin is not expected to inhibit CYP450 isoenzymes (CYPs) 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4, or induce CYPs 1A2, 2C19 and 3A4 at clinically relevant plasma concentrations.

Bexagliflozin is not expected to inhibit drug transporters including breast cancer resistance protein (BRCP), bile salt export pump (BSEP), organic anion transporting polypeptides (OATP1B1, OATP1B3), anion transporters (OAT1, OAT3), organic cation transporters (OCT1, OCT2), and multidrug and toxin extrusion transporters (MATE1, MATE2-K) at clinically relevant plasma concentrations.

USE IN SPECIFIC POPULATIONS

1. Pregnancy 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).

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 periconceptional 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.

2. Lactation 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 

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.

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

4.Geriatric Use

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 .

No overall differences in the effectiveness of BRENZAVVY have been observed between Reference ID: 5112979 Page 9 o~ A 0 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)].

5. Renal Impairment-

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

6. Hepatic Impairment-

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

 OVERDOSAG

In the event of an overdose of BRENZAVVY, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. Employ the usual supportive measures as dictated by the patient’s clinical status.

Removal of bexagliflozin by hemodialysis has not been studied.