Invokana  - Canagliflozin

1. Invokana - Canagliflozin Manufacturer: Janssen Pharmaceuticals FDA Approval Date: 3/2013

2. Invokana - canagliflozinClinical Application • Indications: • Diabetes mellitus type 2 as an adjunct to diet and exercise (monotherapy or in combination with metformin and/or sulfonylurea) • Place in therapy: • New third-line agent after metformin and sulfonylurea failure • Possibly in front of DPP-IV inhibitors like sitagliptin

3. Invokana - canagliflozin Clinical Application • Contraindications: • History of serious hypersensitivity reactions • Severe renal impairment (GFR < 30 ml/min, ESRD / on dialysis) • Warnings • Genital mycotic infections (uncircumcised men or prior mycotic infections increase risk • Hyperkalemia • Hypersensitivity (generalized urticarial) (discontinue if occurs) • Hypoglycemia • Precautions • Use with caution in elderly patients as symptomatic hypotension may occur

4. Invokana - canagliflozin Clinical Application • Pregnancy: • Category C • Lactation: • Use caution. Unknown if excreted in breast milk (Not Recommended)

5. Invokana - canagliflozin Drug Facts • Sodium-glucose co-transporter 2 (SGLT2) inhibitor • SGLT2 is expressed in the proximal renal tubules and is responsible for the majority of reabsorption of filtered glucose from the tubular lumen • Reabsorption of filtered glucose and renal threshold for glucose (RTG) are reduced which results in increased urinary glucose excretion

6. Invokana - canagliflozin Drug Facts • Pharmacokinetics • A – Bioavailability ~65% (not affected by food); TMax ~1-2 hrs • D – ~99% protein-bound (mainly albumin) • M – O-glucuronidation by UGT1A9 and UGT2B to 2 inactive metabolites (Minor oxidation through CYP3A4) • E – Feces (41.5% unchanged), Urine 35% (< 1% unchanged); T1/2 ~10.6-13.1 hours

7. Invokana - canagliflozin Drug Interactions • Drug Interactions – Object Drugs • Digoxin • Increased AUC by 20% and Cmax by 36% when administered with canagliflozin 300 mg

8. Invokana - canagliflozin Drug Interactions • Drug Interactions – Precipitant Drugs • Canagliflozin is a substrate of UGT 1A9 and UGT2B • UGT Enzyme Inducers  AUC of canagliflozin by ~50% • Rifampin • Ritonavir • Phenobarbital • Phenytoin

9. Invokana - canagliflozin Adverse Effects • Common Adverse Effects: • Serious Adverse Effects: • Hypoglycemia (3.6%%)[2.6%] • Pancreatitis • Moderate renal impairment (18-22.5%)

10. Invokana - canagliflozin Monitoring Parameters • Efficacy Monitoring • Blood glucose • A1c • Toxicity Monitoring • Renal function • Blood glucose • Potassium, Magnesium, Phosphate • LDL-C • Genital mycotic infections • Blood pressure

11. Invokana - canagliflozin Prescription Information • 100 mg orally once daily initially • May increase to 300 mg once daily if additional glycemic control required • In setting of renal insufficiency (estimated GFR of 45-59 mL/min) a max dose of 100 mg once daily is recommended • Not indicated in severe renal impairment (GFR < 45, ESRD / dialysis) • Cost – $ 316 accessed 05/30/2013

12. Invokana - canagliflozin Literature Review: • Active-controlled study vs. sitagliptin combination with metformin + a sulfonylurea (n=755) in patients inadequately controlled on 2 drug therapy • Sitagliptin 100 mg once daily + metformin and a sulfonylurea (n=378) • A1c baseline: 8.13% (mean) • Canagliflozin 300 mg once daily + metformin and a sulfonylurea (n=377) • A1c baseline: 8.12 (mean) Schernthaner. Diabetes Care. 2013 Apr 5. Epub, PMD: 23564919

13. Invokana - canagliflozin Literature Review: • Primary endpoint: • Change in A1c from baseline through week 52 • Secondary endpoints: • Percent of patients with A1c < 7.0% • Percent body weight change • Change in SBP Schernthaner. Diabetes Care. 2013 Apr 5. Epub, PMD: 23564919

14. Invokana - canagliflozin Literature Review: • Results • Primary Endpoint: A1c change from baseline • Canagliflozin group: - 1.03 • Sitagliptini group: - 0.66 • P-value: < 0.05 (95% CI: -0.50 to -0.25) • Canagliflozin + metformin considered noninferior to sitagliptin due to upper limit of CI being less than prescepcified noninferiority margin of < 0.3% Schernthaner. Diabetes Care. 2013 Apr 5. Epub, PMD: 23564919

15. Invokana - canagliflozin Literature Review: • Results Secondary endpoints • Percent of patients @ A1c goal < 7.0% • 48% for canagliflozin vs. 35% for sitagliptin group • Incidence of Hypoglycemia • 43.2% canagliflozin group vs. 40.7% sitagliptin group • Percent body weight change • -2.8% canagliflozin group vs. +0.3% sitagliptin group • P-value: < 0.001 (95% CI: -3.3 to -2.2) • SBP change from baseline • -5.9 mmHg canagliflozin vs. + 0.9 mmHg sitagliptin • 95% CI: -7.6 to -4.2% Schernthaner. Diabetes Care. 2013 Apr 5. Epub, PMD: 23564919

16. Invokana - canagliflozin Summary • Invokava, canagliflozin, is a new once daily alternative for the maintenance treatment of Type 2 diabetes mellitus • Canagliflozin is the first and only medication in the class of Sodium-glucose co-transporter 2 (SGLT2) inhibitor • Usual dose is 100 mg orally once daily initially • May increase to 300 mg once daily • Max dose of 100 mg daily is recommended for GFR of 45-59 mL/min • Canagliflozin use may result in increased genitialmycotic infections • Canagliflozin may have a place in therapy as a new third-line agent after metformin and sulfonylurea failure (possibly in front of DPP-IV inhibitors like sitagliptin

17. Invokana - canagliflozin References • http://www.invokana.com/ • Canagliflozin package insert. Janssen Pharmaceuticals. March 2013. • Stenlof K, et al. Efficacy ansafety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes, Obesity and Metabolism. 2012; 15:372-382. • Lexicomp: canagliflozin. Accessed May 29, 2013. • Micromedex: canagliflozin. Accessed May 29, 2013.