bexagliflozin

Bexacat is indicated to improve glycemic control in otherwise healthy cats with diabetes mellitus not previously treated with insulin.

Elanco TM Bexacat TM (bexagliflozin tablets)

Mechanism of Action Bexagliflozin is an inhibitor of sodium-glucose cotransporter 2 (SGLT2), the renal transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. By inhibiting SGLT2, bexagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, thereby increasing urinary glucose excretion. Pharmacokinetics In a laboratory pilot study conducted to determine the prandial state of maximum exposure, systemic exposure for bexagliflozin was greater in the fasted state than in the fed state by 82% for the mean maximum observed plasma concentration (Cmax), and by 54% for the mean area under the plasma concentration versus time curve (AUC) from dosing (time 0) to the last quantifiable concentration (AUC0-last), respectively. In a well-controlled margin of safety study (see Target Animal Safety ), mean Cmax was approximately dose-proportional over a dosage range of 5 mg/kg (1X) to 25 mg/kg (5X). Mean AUC from time 0 to 24 hours exposure was approximately dose-proportional over a dosage range of 5 to 15 mg/kg, but more than dose-proportional at 15 to 25 mg/kg. An increase in exposure (AUC0-24 and Cmax), was observed in female cats compared to male cats on all evaluation days. Median time to reach peak plasma concentration (Tmax) was approximately 0.5 hours (range 0.5 to 2 hours) and mean half-life (T1/2) was approximately 5 hours across all dose groups. There was no accumulation of bexagliflozin following daily dosing of 5, 15, and 25 mg/kg in healthy non-diabetic cats. However, field studies showed that some diabetic cats had persistent bexagliflozin blood levels after discontinuation of the drug, which may be related to a decrease in liver function in some cats (see Animal Safety Warnings ).

Elanco TM Bexacat TM (bexagliflozin tablets)

•Do not use Bexacat in cats with diabetes mellitus who have previously been treated with insulin, who are receiving insulin, or in cats with insulin-dependent diabetes mellitus. The use of Bexacat in cats with insulin-dependent diabetes mellitus, or the withdrawal of insulin and initiation of Bexacat, is associated with an increased risk of diabetic ketoacidosis or euglycemic diabetic ketoacidosis and death. •Due to risk of severe adverse reactions, do not use Bexacat in cats with evidence of hepatic disease or reduced renal function.

Elanco TM Bexacat TM (bexagliflozin tablets)

User Safety Warnings Not for use in humans. Keep out of reach of children. Consult a physician in case of accidental ingestion by humans. Animal Safety Warnings •Bexacat should not be initiated in cats with: oAnorexia, dehydration, or lethargy at the time of diagnosis of diabetes mellitus, as it may indicate the presence of other concurrent disease and increase the risk of diabetic ketoacidosis. oAn fPL level > 5.3 mcg/L, diagnostic imaging consistent with pancreatitis, a history of pancreatitis, or current clinical signs suggestive of pancreatitis. oLaboratory values consistent with diabetic ketoacidosis, including elevated urine or serum ketones, and metabolic acidosis (high anion gap, or decreased bicarbonate, pH, or partial pressure carbon dioxide [PaCO2] levels). oA BHBA > 37 mg/dL, or if BHBA is > 25 mg/dL and the cat has a history of renal disease or metabolic acidosis. •Persistent plasma bexagliflozin concentrations and reduced clearance of Bexacat, represented as the presence of plasma half-lives in excess of 24 hours, may result in prolonged clinical effects such as glucosuria and/or euglycemia despite discontinuation of Bexacat in some cats with hepatic disease and/or reduced renal function, including cats with clinically undetectable disease at the time of Bexacat initiation. Reduced clearance of Bexacat may contribute to persistent glucosuria, resulting in an osmotic diuresis and dehydration that requires appropriate hydration support. These cats may require hospitalization, which may be protracted, for sequalae such as diabetic ketoacidosis, euglycemic diabetic ketoacidosis, or hepatic lipidosis. •Cats should be screened for urinary tract infections and treated, if indicated, when initiating Bexacat. Treatment with Bexacat may increase the risk for urinary tract infections (see Adverse Reactions ). Cats treated with Bexacat should be monitored for urinary tract infections and treated promptly. Consider discontinuation of Bexacat in cats with recurrent urinary tract infections. •Bexacat may cause increased serum calcium concentrations. Bexacat should be discontinued in cats with persistent increases in serum total calcium or ionized calcium because of increased risk of forming calcium containing uroliths (see Adverse Reactions ). •Long term use of Bexacat may increase the risk of urothelial carcinoma (see Adverse Reactions ). •Keep Bexacat in a secure location out of reach of dogs, cats, and other animals to prevent accidental ingestion or overdose.

Elanco TM Bexacat TM (bexagliflozin tablets)

Field Study Eighty-four cats with newly diagnosed diabetes mellitus were enrolled in a 180-day multicenter field effectiveness and safety study. Safety data were evaluated in 84 cats treated with at least one dose of Bexacat. All cats received one tablet, once daily, regardless of body weight or blood glucose level. Seventy-two of the 84 enrolled cats completed the study. The most common adverse reactions included elevated blood urea nitrogen (BUN), vomiting, elevated urine specific gravity (USG), elevated serum fPL, diarrhea, anorexia, lethargy, and dehydration. The adverse reactions seen during the field study are summarized in Table 1 below. Table 1. Adverse Reactions (n=84) * Most cats had elevations < 1.5 times the upper limit of normal (ULN). † Elevations were predominantly attributable to dehydration and/or glucosuria. ‡ Most cats had one or more isolated elevations, followed by a return to previous values. § Of nine cats with elevations ≥ 1.5X ULN, 2 cats developed diabetic ketoacidosis and were transitioned to insulin. One cat developed diabetic ketoacidosis and hepatic lipidosis resulting in death (euthanasia). One cat developed anemia, progressive weight loss and fPL elevations resulting in death. ** Observations included hiding, agitation, aggression, vocalization, and anxious behavior. Adverse Reaction Number (%) Elevated BUN* 46 (54.8) Vomiting 42 (50.0) Elevated USG† 33 (39.3) Elevated fPL‡ 33 (39.3) Diarrhea 32 (38.1) Anorexia 31 (37.0) Lethargy 17 (20.2) Dehydration 16 (19.0) Elevated symmetrical dimethylarginine (SDMA) 13 (15.5) Weight loss 13 (15.5) Urinary tract infection 12 (14.3) Elevated ALT and/or AST§ 11 (13.1) Hypercalcemia 8 (9.5) Behavioral changes** 6 (7.1) Proteinuria 5 (6.0) Elevated creatinine 4 (4.8) Elevated creatine kinase 4 (4.8) Inappropriate urination 4 (4.8) Death 3 (3.6) Diabetic ketoacidosis 3 (3.6) Pancreatitis 3 (3.6) Euglycemic diabetic ketoacidosis 2 (2.4) Hepatic lipidosis 2 (2.4) Elevated alkaline phosphatase 2 (2.4) Elevated total bilirubin 2 (2.4) Constipation 2 (2.4) Nine serious adverse reactions associated with Bexacat administration occurred during the study, including three cats who died or were euthanized. Of the three cats who died or were euthanized, two cats became clinically ill within 5 doses of Bexacat administration (range 3 to 5 doses). One cat with euglycemic diabetic ketoacidosis and hepatic lipidosis was euthanized due to further deterioration of its clinical condition, despite supportive treatment. One cat demonstrating anorexia, lethargy, dehydration, azotemia, and hypokalemia was euthanized without supportive treatment. One cat, who demonstrated a lack of effectiveness, anemia and hepatic lipidosis died on Day 77 despite supportive treatment and additional diagnostics. Six of the nine cats had serious adverse reactions that did not result in death or euthanasia. Five cats were treated for their clinical conditions and transitioned to insulin. Serious adverse reactions in these cats were associated with the following conditions (number of cats): euglycemic diabetic ketoacidosis (1); lack of effectiveness, diabetic ketoacidosis, elevated liver parameters (1); diabetic ketoacidosis (1); diabetic ketoacidosis and pyelonephritis (1); and lack of effectiveness, weight loss, dehydration (1). One cat with constipation and pancreatitis received supportive treatment and remained on Bexacat (bexagliflozin tablets). Pilot Field Study Eighty-nine cats with newly diagnosed diabetes mellitus were enrolled in a 56-day multicenter pilot field effectiveness and safety study, with continued use for up to 180 days. All cats received one tablet, once daily, regardless of body weight or blood glucose level. Safety data were evaluated for all 89 cats treated with at least one dose of bexagliflozin. The most common adverse reactions included elevated blood urea nitrogen (BUN), elevated urine specific gravity (USG), elevated serum feline pancreas-specific lipase, vomiting, diarrhea/loose stool, hyporexia/anorexia, lethargy, elevated serum alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), and urinary tract infections. The adverse reactions seen in the pilot study are summarized in Table 2 below. Table 2. Adverse Reactions (n=89) * Most cats had elevations ≤ 1.5X upper limit of normal (ULN). † Elevations were predominantly attributable to dehydration and/or glucosuria. ‡ Most cats had one or more isolated elevations, followed by a return to previous values. § Most elevations were ≤ 2X ULN. One cat had marked ALT and AST (9X and 6X upper limit of normal, respectively) elevations on Day 28. Following discontinuation of bexagliflozin, the liver enzymes decreased within 24 hours and returned to within reference range in 10 days. ** Observations included hiding, hyperactivity, vocalization, and abnormal behavior. Adverse Reaction Number (%) Elevated BUN* 51 (57.3) Elevated USG† 43 (48.3) Elevated fPL‡ 39 (43.8) Vomiting 39 (43.8) Diarrhea/Loose Stool 29 (32.6) Hyporexia/Anorexia 28 (31.4) Lethargy 16 (18.0) Elevated ALT and/or AST§ 13 (14.6) Urinary tract infection 13 (14.6) Dehydration 10 (11.2) Elevated symmetrical dimethylarginine (SDMA) 10 (11.2) Behavioral changes** 9 (10.1) Ketosis/Ketonuria 8 (9.0) Weight loss 8 (9.0) Proteinuria 8 (9.0) Pancreatitis 7 (7.9) Death 6 (6.7) Anemia 6 (6.7) Hepatopathy 6 (6.7) Hypercalcemia 4 (4.5) Elevated creatine kinase 4 (4.5) Inappropriate urination 4 (4.5) Peritonitis 3 (3.4) Constipation 3 (3.4) Elevated creatinine 2 (2.2) Euglycemic diabetic ketoacidosis 2 (2.2) Diabetic ketoacidosis 2 (2.2) Hemolytic anemia 2 (2.2) Elevated total bilirubin 2 (2.2) Twenty cats (22%) had at least one blood glucose value < 65 mg/dL recorded during 8-hour blood glucose curves. No clinical signs of hypoglycemia were observed and bexagliflozin dosing was not adjusted in any cat due to documented hypoglycemia. Nine serious adverse reactions associated with bexagliflozin administration occurred during the study, including six cats who died or were euthanized. Of the six cats who died or were euthanized, five became clinically ill within receiving 5 doses of bexagliflozin (range 1 to 5 doses). Four of the cats were euthanized due to further deterioration of their clinical condition despite supportive treatment. One cat died despite supportive treatment. Deaths were associated with the following conditions (number of cats): necrotizing pancreatitis and pancreatic abscess (1), pancreatitis and hepatic lipidosis (1), euglycemic diabetic ketoacidosis and severe hepatic lipidosis (1), pancreatitis and hepatic abscesses (1), diabetic ketoacidosis (1), and persistent polyuria and polydipsia and quality of life concerns (1). Three of nine serious adverse reactions that did not result in death or euthanasia included the following (number of cats): acute hepatocellular injury (1), immune-mediated hemolytic anemia (1), and euglycemic diabetic ketoacidosis with concurrent pancreatitis and hepatopathy (1). Two cats with serious adverse reactions demonstrated persistent bexagliflozin blood plasma levels and elimination half-lives after discontinuation of bexagliflozin. One cat with renal and liver values within the reference range at screening was euthanized due to a continued decline in clinical condition despite treatment for euglycemic diabetic ketoacidosis and severe hepatic lipidosis. The second cat, noted to have IRIS (International Renal Interest Society) stage II renal disease and liver values within the reference range at screening, recovered following treatment for marked liver enzyme elevations above the reference range on Day 28. Extended Use Field Study One hundred twenty-five cats with diabetes mellitus that had previously completed a bexagliflozin field study were enrolled in a multicenter extended use field study. Cats were enrolled in the study for a range of 7 to 1064 days, with a mean of 329 days. Safety data were evaluated for all 125 cats treated with at least one dose of Bexacat (bexagliflozin tablets). All cats received one tablet, once daily, regardless of body weight or blood glucose level. Forty-nine of the 125 enrolled cats were withdrawn from the study due to adverse reactions, serious adverse reactions, death/euthanasia, lack of effectiveness, suspected diabetic remission, withdrawal of owner consent, or lost to follow up. The most common adverse reactions were similar to those noted in the previous field studies and included elevated USG (35.2%), vomiting (27.2%), elevated fPL (26.4%), anorexia (24.0%), diarrhea (22.4%), urinary tract infections (17.6%), lethargy (16.8%), and death (16.0%). Twenty serious adverse reactions associated with Bexacat administration occurred during the study, all resulting in death or euthanasia. Clinical signs of hypoglycemia were observed in two of these cats. Deaths were associated with the following conditions (number of cats), with some cats experiencing multiple comorbidities (necropsy was not granted in all cases): euglycemic diabetic ketoacidosis (8); diabetic ketoacidosis (4); hepatic lipidosis (5); pancreatic necrosis/peripancreatic fat saponification (3); urothelial carcinoma (2); hypercalcemia, recurrent calcium containing cystic calculi (1); lack of effectiveness, weight loss, anorexia (1); lethargy, weight loss, pallor (1); chronic renal disease, glomerulonephritis (1); chronic enteropathy (1); hypoglycemia, possible pancreatitis (1).

Elanco TM Bexacat TM (bexagliflozin tablets)

Always provide the Client Information Sheet with the prescription. Dosing Instructions Administer one tablet by mouth to cats weighing 6.6 lbs (3.0 kg) or greater once daily, at approximately the same time each day, with or without food, and regardless of blood glucose level. Monitoring •Sudden onset of hyporexia/anorexia, lethargy, dehydration, or weight loss in cats receiving Bexacat should prompt immediate discontinuation of Bexacat and assessment for diabetic ketoacidosis, regardless of blood glucose level. •During treatment with Bexacat, blood glucose, fructosamine, serum β-hydroxybutyrate (BHBA), serum feline pancreas-specific lipase (fPL), liver parameters, serum cholesterol and triglycerides; and body weight and clinical signs should be routinely monitored. oIncreasing or persistently elevated feline pancreas-specific lipase or liver parameters should prompt further evaluation for pancreatitis and/or hepatic disease and consideration for discontinuing Bexacat. oBHBA is the predominate ketoacid in diabetic ketoacidosis. Bexacat should be discontinued if a notable reduction in BHBA is not observed after initiation of Bexacat, or if BHBA persistently rises after an initial reduction. oCats with increasing or persistently elevated cholesterol and triglyceride levels may be at an increased risk for developing diabetic ketoacidosis or euglycemic diabetic ketoacidosis. oBexacat should be discontinued if poor glycemic control, as described below, develops. •During the first 8 weeks after initiation of Bexacat, assessment of glycemic control and clinical improvement should be evaluated. oA physical examination, an 8-hour blood glucose curve, serum fructosamine and body weight should be assessed at 2, 4 and 8 weeks. oCats demonstrating poor glycemic control, including weight loss, an average blood glucose concentration from an 8-hour blood glucose curve ≥ 250 mg/dL, and/or a fructosamine indicating poor glycemic control should be closely monitored. oBexacat should be discontinued, and initiation of insulin considered in cats demonstrating poor glycemic control, as described above, at 8 weeks. •Cats may present with diabetic ketoacidosis and a normal blood glucose concentration (euglycemic diabetic ketoacidosis). Delay in recognition and treatment of diabetic ketoacidosis and euglycemic diabetic ketoacidosis may result in increased morbidity and mortality. •Development of diabetic ketoacidosis and euglycemic diabetic ketoacidosis requires the following actions: oDiscontinuation of Bexacat oPrompt initiation of insulin therapy oAdministration of dextrose or other carbohydrate source, regardless of blood glucose concentration oAppropriate nutritional support should be promptly initiated to prevent or treat hepatic lipidosis. For more information refer to CONTRAINDICATIONS and WARNINGS.

ORAL

Elanco TM Bexacat TM (bexagliflozin tablets)