Farxiga™ - Dapagliflozin Manufacturer: Bristol-Meyer Squibb FDA Approval Date: January 8, 2014

Farxiga™ - Dapagliflozin Clinical Application Indications: Adjunct to diet and exercise to improve glycemic control in Type 2 Diabetes Place in therapy: Alternative to existing add-on therapies by improving glycemic control without associated weight gain or hypoglycemic risk

Farxiga™ - Dapagliflozin Clinical Application Contraindications: History of serous hypersensitivity reaction Severe renal impairment, ESRD, dialysis Warnings and Precautions May cause symptomatic hypotension Impairment in renal function may occur Risk of hypoglycemia when used with insulin or insulin secretagogues Increased risk of genital mycotic infections May cause increased LDL-C elevation

Farxiga™ - Dapagliflozin Clinical Application Pregnancy: Category C Adverse events observed in animal studies Lactation: Excretion in breast milk unknown; use is not recommended

Farxiga™ - Dapagliflozin Drug Facts Pharmacology: Selectively inhibits sodium-glucose cotransporter 2 (SGLT-2) in the proximal renal tubules, reduces absorption of filtered glucose from the tubular lumen, increases urinary excretion of glucose

Farxiga™ - Dapagliflozin Drug Facts Pharmacokinetics A Tmax 2 hrs; absorption not affected by food D 91% protein bound M Extensive, primarily mediated by UGT1A9; CYP-mediated (minor) E Primarily via urine (75%) and feces (21%)

Farxiga™ - Dapagliflozin Drug Interactions Drug Interactions – Object Drugs: Duloxetine  Hypoglycemic agents  The hypoglycemic effect of Farxiga may be enhanced when used in combination with other drugs such as MAO inhibitors, salicylates, SSRIs, and other hypoglycemic agents.   Loop diuretics and thiazide diuretics may diminish the therapeutic effect of Farxiga. Lastly, drugs such as steroids and somatropin may diminish the hypoglycemic effect of Farxiga.

Farxiga™ - Dapagliflozin Drug Interactions Drug Interactions – Precipitant Drugs: Corticosteroids  Loop diuretics  MAO Inhibitors  Salicylates  SSRIs  Thiazide diuretics  The hypoglycemic effect of Farxiga may be enhanced when used in combination with other drugs such as MAO inhibitors, salicylates, SSRIs, and other hypoglycemic agents.   Loop diuretics and thiazide diuretics may diminish the therapeutic effect of Farxiga. Lastly, drugs such as steroids and somatropin may diminish the hypoglycemic effect of Farxiga.

Farxiga™ - Dapagliflozin Adverse Effects Female genital mycotic infections (6.9%) [1.5%] UTI (4.3%) [3.7%] Male genital mycotic infections (2.7%)[0.3%] Back pain (4.2%) [3.2%] Nasopharyngitis (6.3%) [6.2%] Dyslipidemia (2.5%) [1.5%] Increased urination (3.8%) [1.7%] Dysuria (2.1%) [0.7%] Pain in extremity (1.7%) [1.4%] Constipation (1.9%) [1.5%]

Farxiga™ - Dapagliflozin Monitoring Parameters Efficacy Monitoring: Blood glucose, Hgb A1c Toxicity Monitoring: Renal function, LDL-C

Farxiga™ - Dapagliflozin Prescription Information Dosing: 5-10 mg once daily Cost: $347 for 30-day supply Source: Medi-Span (via Lexi-comp online) Accessed 3/13/2014

Farxiga™ - Dapagliflozin Literature Review A multicenter, double-blind, randomized, active-controlled, noninferiority, phase 3 study [Dapagliflozin + metformin] vs. [Glipizide + metformin] Primary endpoint Absolute change in HbA1c from baseline to week 52 Provide background from other trials comparing Farxiga Nauck, et al. Diabetes Care 2011; 34:2015-22.

Farxiga™ - Dapagliflozin Literature Review Secondary Endpoints Absolute change in total body weight (TBW) Proportion of patients reporting at least one episode of hypoglycemia Proportion of patients achieving a TBW decrease ≥5% Nauck, et al. Diabetes Care 2011; 34:2015-22.

Farxiga™ - Dapagliflozin Literature Review Age ≥ 18 yrs (mean age 59) 6.5% < HbA1c ≤ 10% (mean 7.7%) 57% receiving metformin monotherapy ≥ 1500 mg/day Median metformin dose at randomization 2000 mg/day Men and women aged 18 or older with inadequately controlled T2DM while receiving metformin or metformin and one other OAD administered up to half-maximal dose for at least 8 wks before enrollment. Nauck, et al. Diabetes Care 2011; 34:2015-22.

Farxiga™ - Dapagliflozin Literature Review Primary outcome: HbA1c adjusted mean change from baseline at week 52 for Farxiga was -0.52 (95% CI -0.60 to -0.44) vs. -0.52 (-0.60 to -0.44) for glipizide; hence, the Farxiga A1c mean difference from glipizide at week 52 was 0.00 (-0.11 to 0.11). HbA1c change with Farxiga was statistically noninferior to that with glipizide at week 52. Although the initial drop in A1c during the titration period with glipizide was greater than that observed with Farxiga, efficacy for glipizide waned during the maintenance period but remained stable for dapagliflozin. Nauck, et al. Diabetes Care 2011; 34:2015-22.

Farxiga™ - Dapagliflozin Literature Review Secondary outcome: Farxiga produced weight loss, whereas glipizide led to weight gain, resulting in an absolute mean difference of 4.65kg (p<0.001) at week 52. Nauck, et al. Diabetes Care 2011; 34:2015-22.

Farxiga™ - Dapagliflozin Literature Review Secondary outcomes: The adjusted proportion of patients experiencing at least one hypoglycemic episode by week 52 was more than 10-fold lower with Farxiga than with glipizide. Farxiga showed a significantly greater proportion of patients with a body weight reduction of >/= 5% at week 52. Nauck, et al. Diabetes Care 2011; 34:2015-22.

Farxiga™ - Dapagliflozin Literature Review Conclusions Comparable long-term efficacy of dapagliflozin with glipizide with fewer hypoglycemic episodes along with sustained weight loss Dapagliflozin is a potential valuable alternative to sulfonylureas as add-on therapy when metformin monotherapy fails to maintain adequate glycemic control Nauck, et al. Diabetes Care 2011; 34:2015-22.

Farxiga™ - Dapagliflozin Summary Farxiga, dapagliflozin, is the second in class agent that selectively inhibits SGLT2 receptor which modulates reabsorption of glucose in the kidney, resulting in excretion of glucose in the urine Indicated as an adjunct to diet and exercise to improve glycemic control in adults with Type 2 Diabetes Initially dosed 5 mg once daily in the morning Most common side effects include genital infections, urinary tract infections, and nasopharyngitis Alternative to existing add-on therapies by improving glycemic control without associated weight gain or hypoglycemic risk

Farxiga™ - Dapagliflozin References http://www.farxiga.com Farxiga package insert. Bristol-Meyers Squibb. January 2014. Farxiga. Lexicomp Drug Information. Accessed through UpToDate. Accessed on March 13, 2014. Nauck MA, et al. Dapagliflozin versus glipizide as add-on therapy in patients with Type 2 Diabetes who have inadequate glycemic control with metformin. Diabetes Care 2011; 34:2015-2022. Bailey CJ, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, double-blind, placebo-controlled trial. Lancet 2010; 375:2223-33.