1. Pharmacokinetics. When is steady state achieved? Steady-state was reached after 4 to 5 days of once-daily dosing with Sulisent 100 mg to 300mg.

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4 1. Pharmacokinetics How is Sulisent metabolized? Sulisent has a novel mechanism of action that targets the kidneys and allows for excess glucose excretion resulting in urinary calorie loss. Sulisent is an inhibitor of sodium-glucose co-transporter 2 (SGLT2), which mediates the majority of the reabsorption of glucose in the kidneys. Sulisent is well absorbed (65%), highly albumin bound (99%), and is eliminated mostly in the urine and feces. UGT (UDP-glucuronosyl transferase) enzymes assist in metabolism. O-glucuronidation is the major metabolic elimination pathway for Sulisent, which is mainly glucuronidated by UGT1A9 and UGT2B4 to two inactive O-glucuronide metabolites. CYP3A4-mediated (oxidative) metabolism of Sulisent is minimal (approximately 7%) in humans When is steady state achieved? Steady-state was reached after 4 to 5 days of once-daily dosing with Sulisent 100 mg to 300mg. Ref: Plosker GL. Canagliflozin: a review of its use in patients with type 2 diabetes mellitus. Drugs May;74(7): Pharmacodynamics What is the mechanism of action of Sulisent? The rate of renal glucose reabsorption is elevated in people with type 2 diabetes due to upregulation of both expression and function of sodium-glucose cotransporters 2 (SGLT-2). Sulisent is a selective inhibitor of SGLT2, thereby decreasing renal glucose reabsorption and lowering the renal threshold for glucose (RTG), increasing urinary glucose excretion and, in turn, lowering blood glucose levels. Ref: Chao EC. SGLT-2 Inhibitors: A New Mechanism for Glycemic Control. Clin Diabetes Jan;32(1):4-11. Plosker GL. Canagliflozin: a review of its use in patients with type 2 diabetes mellitus. Drugs May;74(7): What is renal threshold for glucose? Sodium-glucose cotransporters (SGLTs), namely SGLT-1 and SGLT-2, facilitate reabsorption of glucose back into the plasma. The renal glucose threshold (RTG) is the plasma glucose concentration above which the glucose reabsorption capacity of the kidney is exceeded as the SGLT becomes saturated and urinary glucose excretion (UGE) occurs. Ref: Chao EC. SGLT-2 Inhibitors: A New Mechanism for Glycemic Control. Clin Diabetes Jan;32(1):4-11. Plosker GL. Canagliflozin: a review of its use in patients with type 2 diabetes mellitus. Drugs May;74(7): How much does Sulisent lower the renal threshold for glucose (RTG)? From a starting value of approximately 240 mg/dl, Sulisent reduced RTG to approximately mg/dl over 24 hours in type 2 diabetes patients. These RTG values are above the plasma glucose level at which symptoms of hypoglycaemia typically develop and, on the basis of this, Sulisent is not expected to increase the risk of hypoglycaemia. Ref: Plosker GL. Canagliflozin: a review of its use in patients with type 2 diabetes mellitus. Drugs May;74(7): Efficacy How does Sulisent affect fasting plasma glucose (FPG) and postprandial plasma glucose (PPG)? In patients with type 2 diabetes, treatment with Sulisent produced clinically and statistically significant improvements in A1C, fasting plasma glucose (FPG), and 2-hour postprandial glucose (PPG), compared to placebo. In a 26-week placebo-controlled clinical study, the placebo adjusted reduction in FPG and PPG reported with Sulisent as monotherapy was 36 mg/dl and 48 mg/dl. How does Sulisent affect HbA1c? Sulisent was effective in reducing A1C in a broad range of patients regardless of disease duration and concomitant use of antihyperglycemic agents to treat type 2 diabetes. Statistically significant improvements in glycemic control relative to placebo were observed with Sulisent when given as monotherapy, as initial add-on therapy with metformin or a sulfonylurea, add-on therapy with metformin and a sulfonylurea, metformin and pioglitazone, or add-on therapy with insulin (with or without other antihyperglycemic agents). In a 26-week placebo-controlled clinical study, the placebo adjusted reduction in HbA1c reported with Sulisent as monotherapy was 0.91%. Canagliflozin Tablets 100 mg

5 What type of efficacy was seen with elderly patients? Sulisent demonstrated statistically significant A1c reductions, FPG and body weight in a 26-week placebo-controlled study of 714 patients aged 55 to 80 years who were inadequately controlled on current antihyperglycemic agents. Mean A1c change from baseline: - Sulisent 100mg showed mean A1c change from baseline of (p<0.001) - Sulisent 300mg showed mean A1c change from baseline of (p<0.001) Ref: Bode B, Stenlof K, Sullivan D, et al. Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus: a randomized trial. Hosp Pract (Minneap). 2013;41(2): Use in Special Population Can Sulisent be prescribed in patients with renal impairment? In patients with an estimated glomerular filtration rate (egfr) 45 to < 60 ml/min/1.73 m2 [CrCl 45 to < 60 ml/min], the dose of Sulisent is limited to 100 mg once daily. Sulisent should not be initiated in patients with an egfr < 45 ml/min/1.73 m2 [CrCl < 45 ml/min]. Sulisent should be discontinued when egfr is persistently < 45 ml/min/1.73 m2 [CrCl < 45 ml/min] (see Warnings and Precautions and Adverse Reactions). Sulisent should not be used in patients with an egfr < 45 ml/min/1.73 m2 [CrCl < 45 ml/min] as it would not be effective in these patient populations. Can Sulisent be prescribed in patients with hepatic impairment? Mild or moderate hepatic impairment (Child-Pugh class A and B) had no clinically significant effect on the pharmacokinetic profile of Sulisent, but the drug is not recommended for use in patients with severe hepatic disease (Child-Pugh class C) because of the lack of clinical experience with Sulisent in these patients. Ref: Plosker GL. Canagliflozin: a review of its use in patients with type 2 diabetes mellitus. Drugs May;74(7): Cardiovascular Safety What is the cardiovascular safety data on Sulisent? The preliminary CV safety data from phase 2/3 studies including CANVAS trial suggest no increased CV risk. A pre-specified interim meta-analysis of phase II and III clinical trials with canagliflozin in 9,632 patients with type 2 diabetes, including 4,327 patients with increased cardiovascular risk who are participating in CANVAS, showed a hazard ratio of 0.91 (95 % CI ) for canagliflozin 100 and 300 mg/day (combined) versus placebo for the composite primary endpoint (time to event), which included cardiovascular death, non-fatal stroke, nonfatal myocardial infarction and unstable angina requiring hospitalization. In addition, administration of canagliflozin at therapeutic or supratherapeutic dosages was not associated with any meaningful changes in the corrected QT interval in an appropriately designed randomized trial in 60 healthy subjects. Ref: Plosker GL. Canagliflozin: a review of its use in patients with type 2 diabetes mellitus. Drugs May;74(7): What is the effect of Sulisent on blood pressure? In an analysis of four 26-week, placebo-controlled studies (N=2313), mean reductions in systolic blood pressure relative to placebo were observed with Sulisent 100 mg (-3.9 mmhg), Sulisent 300 mg (-5.3 mmhg), and placebo (-0.1 mmhg) regardless of antihypertensive medication use at baseline. In this same population, there was a smaller effect on diastolic blood pressure with mean changes of -2.1 mmhg with Sulisent 100 mg, -2.5 mmhg with Sulisent 300 mg, and -0.3 mmhg with placebo, regardless of antihypertensive medication use at baseline. There was no discernible change in heart rate. What is the effect of Sulisent on lipid parameters? In an integrated analysis of four placebo-controlled studies of 26 weeks, patients with type 2 diabetes treated with both doses of Sulisent had increased serum levels of total cholesterol, LDL-C (low density lipoprotein cholesterol), and HDL-C (high-density lipoprotein cholesterol) compared to small changes in placebo, while serum levels of triglycerides decreased compared to placebo. At Week 26, the LDL-C/HDL-C ratio minimally changed compared to baseline in all three treatment groups. Canagliflozin Tablets 100 mg

6 6. Drug Interaction What are the key drug interactions? In clinical studies, the effects of other drugs on canagliflozin were assessed. Ciclosporin, hydrochlorothiazide, oral contraceptives (ethinyl estradiol and levonorgestrel), metformin, and probenecid had no clinically relevant effect on the pharmacokinetics of canagliflozin. Co-administration with rifampicin, a nonselective inducer of several UGT enzymes and drug transporters decreased canagliflozin exposure. These decreases in exposure to canagliflozin may decrease efficacy. If a combined inducer of these UGTs and drug transport systems (e.g., rifampicin, phenytoin, barbituates, phenobarbitol, ritonavir, carbamazepine, efavirenz, St John s wort [Hypericum perforatum]) must be co-administered with Sulisent, monitor HbA1c in patients receiving Sulisent 100 mg once daily. In patients with an egfr 45 to < 60 ml/min/1.73 m2 [CrCl 45 to < 60 ml/min], taking Sulisent 100 mg who are receiving concurrent therapy with a UGT enzyme inducer and who require additional glycemic control, other antihyperglycemic therapies should be considered. Patients taking digoxin or other cardiac glycosides (e.g., digitoxin) should be monitored appropriately Sulisent can increase Cmax of digoxin by 36%. Can Sulisent be used with other antihyperglycemic agents? Sulisent has been studied as monotherapy, as add-on therapy with metformin, sulfonylurea, metformin and sulfonylurea, metformin and a thiazolidinedione (pioglitazone), and as add-on therapy with insulin (with or without other antihyperglycemic agents). Hence, it can be combined with most of the available antihyperglycemic agents. Is there any dose adjustments required for sulfonylurea or insulin when used in combination with Sulisent? When Sulisent is used as add-on therapy with insulin or an insulin secretagogue (e.g., sulfonylurea), a lower dose of insulin or the insulin secretagogue may be considered to reduce the risk of hypoglycemia. 7. Adverse Effects What are the common adverse events associated with Sulisent? Genital mycotic infections are a common adverse event associated with canagliflozin and occur more frequently in females than in males. In clinical trials, the incidence of genital mycotic infections was higher with canagliflozin than with placebo, although most infections were mild to moderate in severity and responded to topical and/or oral antifungal therapies, none were serious and few led to discontinuation. The majority of genital mycotic infections were treated with topical antifungal treatments, either prescribed by a healthcare professional or self-treated while continuing therapy with Sulisent. Also, urinary tract infections were more frequently reported for Sulisent 100 mg and 300 mg (5.9% versus 4.3%, respectively) compared to 4.0% with placebo. Most infections were mild to moderate with no increase in the occurrence of serious adverse events. Subjects responded to standard treatments while continuing canagliflozin treatment. The incidence of recurrent infections was not increased with canagliflozin. Ref: Sulisent Prescribing Information. Plosker GL. Canagliflozin: a review of its use in patients with type 2 diabetes mellitus. Drugs May;74(7): Can Sulisent be used with DPP4 inhibitors or GLP-1 analoges? As per the ADA/EASD 2015 guidelines SGLT2 inhibitors can be used in combination with DPP4 inhibitors and GLP-1 analoges Ref: Inzucchi SE, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care Jan;38(1): What type of genital infections are seen in males and females? Vulvovaginal candidiasis (including vulvovaginitis and vulvovaginal mycotic infection) was reported in 10.4% and 11.4% of female patients treated with Sulisent 100 mg and Sulisent 300 mg, respectively, compared to 3.2% in placebo-treated female patients. Most reports of vulvovaginal candidiasis occurred during the first four months of treatment with canagliflozin. Candidal balanitis or balanoposthitis was reported in 4.2% and 3.7% of male patients treated with Sulisent 100 mg and Sulisent 300 mg, respectively, compared to 0.6% in placebo-treated male patients. Canagliflozin Tablets 100 mg

7 Among male patients taking Sulisent, 0.9% had more than one infection. Overall, 0.5% of male patients discontinued Sulisent due to candidial balanitis or balanoposthitis. Phimosis was reported in 0.3% of uncircumcised males in a pooled analysis of 8 controlled trials. Which patients are more prone to genital mycotic infection? Male and female patients with a history of genital mycotic infections were more likely to develop an infection. Genital mycotic infections occurred more frequently in males who were uncircumcised than in those who were circumcised. Ref: 1. Sulisent Prescribing Information dated 28 July Plosker GL. Canagliflozin: a review of its use in patients with type 2 diabetes mellitus. Drugs May;74(7): What precautions should be taken to prevent genital mycotic infections in males? In general, good hygiene is always recommended, and cleaning beneath the foreskin with soap and water is advised in uncircumcised patients. Inform male patients, especially those not circumcised, of the potential for infection, and provide them with information on the signs and symptoms. Advise patients of treatment options and when to seek medical advice. Ref: Penis health: identify and prevent problems. Mayo Clinic Web site. Accessed July 23, 2015 What precautions should be taken to prevent genital mycotic infections in females? Inform female patients of the potential risk for vulvovaginal candidiasis and provide them with information on signs and symptoms. To help prevent vaginal yeast infections, patients can: Avoid scented hygiene products like bubble bath, sprays, pads, and tampons Change tampons and pads often during your period Avoid tight underwear or clothes made of synthetic fibers Wear cotton underwear and pantyhose with a cotton crotch Change out of wet swimsuits and exercise clothes as soon as you can Avoid hot tubs and very hot baths Does Sulisent increases the risk of hypoglycemia? When used alone or as add-on therapy with antihyperglycemic agents not associated with hypoglycemia, Sulisent showed a low incidence of hypoglycemia. Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. When Sulisent was used as add-on therapy with insulin or an insulin secretagogue (e.g., sulfonylurea), the incidence of hypoglycemia was increased over that of placebo. Is there a significant increase in urine volume with Sulisent? In clinical studies, moderate increases (generally < ml) in daily urine volume were seen that attenuated over several days of dosing. What are the volume-depletion related Side Effects (S/Es)? In placebo-controlled clinical studies of Sulisent, increases in adverse reactions related to reduced intravascular volume (e.g. postural dizziness, orthostatic hypotension, or hypotension) were seen more commonly with the 300 mg dose and occurred most frequently in the first three months. Patients most susceptible to adverse reactions related to reduced intravascular volume include patients with moderate renal impairment, elderly patients, patients on loop diuretics and patients with low systolic blood pressure. The incidences of reduced intravascular volume-related adverse reactions were similar across Sulisent 100 mg, 300 mg and placebo groups (1.2%, 1.3% and 1.1%), respectively. The incidences of these adverse reactions with Sulisent in the two active-controlled studies were similar to comparators. Ref: Vaginal yeast infection fact sheet. Womenshealth.gov Web site. Accessed July 23, Canagliflozin Tablets 100 mg

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