INVOKANA 300mg tablets medication leaflet

Invokana 100 mg film-coated tablets

Invokana 300 mg film-coated tablets

Invokana 100 mg film-coated tablets

Each tablet contains canagliflozin hemihydrate, equivalent to 100 mg canagliflozin.

Each tablet contains 39.2 mg lactose.

Invokana 300 mg film-coated tablets

Each tablet contains canagliflozin hemihydrate, equivalent to 300 mg canagliflozin.

Each tablet contains 117.78 mg lactose.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Invokana 100 mg film-coated tablets

The tablet is yellow, capsule-shaped, approximately 11 mm in length, immediate-release andfilm-coated, with “CFZ” on one side and “100” on the other side.

Invokana 300 mg film-coated tablets

The tablet is white, capsule-shaped, approximately 17 mm in length, immediate-release andfilm-coated, with “CFZ” on one side and “300” on the other side.

Invokana is indicated for the treatment of adults with insufficiently controlled type 2 diabetes mellitusas an adjunct to diet and exercise:

- as monotherapy when metformin is considered inappropriate due to intolerance orcontraindications

- in addition to other medicinal products for the treatment of diabetes.

For study results with respect to combination of therapies, effects on glycaemic control, cardiovascularand renal events, and the populations studied, see sections 4.4, 4.5 and 5.1.

The recommended starting dose of canagliflozin is 100 mg once daily. In patients toleratingcanagliflozin 100 mg once daily who have an estimated glomerular filtration rate(eGFR) ≥ 60 mL/min/1.73 m2 or CrCl ≥ 60 mL/min and need tighter glycaemic control, the dose canbe increased to 300 mg once daily (see section 4.4). For dose adjustment recommendations accordingto eGFR refer to table 1.

Care should be taken when increasing the dose in patients ≥ 75 years of age, patients with knowncardiovascular disease, or other patients for whom the initial canagliflozin-induced diuresis poses arisk (see section 4.4). In patients with evidence of volume depletion, correcting this condition prior toinitiation of canagliflozin is recommended (see section 4.4).

When canagliflozin is used as add-on therapy with insulin or an insulin secretagogue(e.g., sulphonylurea), a lower dose of insulin or the insulin secretagogue may be considered to reducethe risk of hypoglycaemia (see sections 4.5 and 4.8).

Renal function and risk of volume depletion should be taken into account (see section 4.4).

For treatment of diabetic kidney disease as add on to standard of care (eg ACE-inhibitors or ARBs), adose of 100 mg canagliflozin once daily should be used (see table 1). Because the glycaemic loweringefficacy of canagliflozin is reduced in patients with moderate renal impairment and likely absent inpatients with severe renal impairment, if further glycaemic control is needed, the addition of otheranti-hyperglycaemic agents should be considered. For dose adjustment recommendations according toeGFR refer to table 1.

Table 1: Dose adjustment recommendationsaeGFR (mL/min/1.73 m2) Total daily dose of canagliflozinor CrCl (mL/min)

Initiate with 100 mg.

≥ 60

In patients tolerating 100 mg and requiring additionalglycaemic control, the dose can be increased to 300 mg.

30 to < 60b Use 100 mg.

Continue 100 mg for patients already taking Invokanad.

< 30b, c

Invokana should not be initiated.a See sections 4.4, pct. 4.8, 5.1, and 5.2.b If further glycaemic control is needed, the addition of other anti hyperglycaemic agents should be consideredc With urinary albumin/creatinine ratio ˃ 300 mg/gd Continue dosing until dialysis or renal transplantation.

For patients with mild or moderate hepatic impairment, no dose adjustment is required.

Canagliflozin has not been studied in patients with severe hepatic impairment and is not recommendedfor use in these patients (see section 5.2).

The safety and efficacy of canagliflozin in children under 18 years of age have not yet beenestablished. No data are available.

For oral use

Invokana should be taken orally once a day, preferably before the first meal of the day. Tablets shouldbe swallowed whole.

If a dose is missed, it should be taken as soon as the patient remembers; however, a double doseshould not be taken on the same day.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

The efficacy of canagliflozin for glycaemic control is dependent on renal function, and efficacy isreduced in patients who have moderate renal impairment and likely absent in patients with severerenal impairment (see section 4.2).

In patients with an eGFR < 60 mL/min/1.73 m2 or CrCl < 60 mL/min, a higher incidence of adversereactions associated with volume depletion (e.g., postural dizziness, orthostatic hypotension,hypotension) was reported, particularly with the 300 mg dose. In addition, in such patients moreevents of elevated potassium and greater increases in serum creatinine and blood urea nitrogen (BUN)were reported (see section 4.8).

Therefore, the canagliflozin dose should be limited to 100 mg once daily in patients witheGFR < 60 mL/min/1.73 m2 or CrCl < 60 mL/min (see section 4.2).

Regardless of pretreatment eGFR, patients on canagliflozin experienced an initial fall in eGFR thatthereafter attenuated over time (see sections 4.8 and 5.1).

Monitoring of renal function is recommended as follows:

- Prior to initiation of canagliflozin and at least annually, thereafter (see sections 4.2, pct. 4.8, 5.1, and5.2)

- Prior to initiation of concomitant medicinal products that may reduce renal function andperiodically thereafter.

There is experience with canagliflozin for the treatment of diabetic kidney disease(eGFR ≥30 mL/min/1.73 m2) both with and without albuminuria. While both groups of patientsbenefitted, patients with albuminuria may benefit more from treatment with canagliflozin.

Use in patients at risk for adverse reactions related to volume depletion

Due to its mechanism of action, canagliflozin, by increasing urinary glucose excretion (UGE) inducesan osmotic diuresis, which may reduce intravascular volume and decrease blood pressure (seesection 5.1). In controlled clinical studies of canagliflozin, increases in adverse reactions related tovolume depletion (e.g., postural dizziness, orthostatic hypotension, or hypotension) were seen morecommonly with the 300 mg dose and occurred most frequently in the first three months (seesection 4.8).

Caution should be exercised in patients for whom a canagliflozin-induced drop in blood pressure couldpose a risk, such as patients with known cardiovascular disease, patients with aneGFR < 60 mL/min/1.73 m2, patients on anti-hypertensive therapy with a history of hypotension,patients on diuretics, or elderly patients (≥ 65 years of age) (see sections 4.2 and 4.8).

Due to volume depletion, generally small mean decreases in eGFR were seen within the first 6 weeksof treatment initiation with canagliflozin. In patients susceptible to greater reductions in intravascularvolume as described above, larger decreases in eGFR (> 30%) were sometimes seen, whichsubsequently improved, and infrequently required interruption of treatment with canagliflozin (seesection 4.8).

Patients should be advised to report symptoms of volume depletion. Canagliflozin is not recommendedfor use in patients receiving loop diuretics (see section 4.5) or who are volume depleted, e.g., due toacute illness (such as gastrointestinal illness).

For patients receiving canagliflozin, in case of intercurrent conditions that may lead to volumedepletion (such as a gastrointestinal illness), careful monitoring of volume status (e.g., physicalexamination, blood pressure measurements, laboratory tests including renal function tests), and serumelectrolytes is recommended. Temporary interruption of treatment with canagliflozin may beconsidered for patients who develop volume depletion while on canagliflozin therapy until thecondition is corrected. If interrupted, consideration should be given to more frequent glucosemonitoring.

Rare cases of diabetic ketoacidosis (DKA), including life-threatening and fatal cases, have beenreported in patients treated with SGLT2 inhibitors, including canagliflozin. In a number of cases, thepresentation of the condition was atypical with only moderately increased blood glucose values, below14 mmol/L (250 mg/dL). It is not known if DKA is more likely to occur with higher doses ofcanagliflozin. Risk of DKA appears to be higher in patients with moderately to severely decreasedrenal function who require insulin.

The risk of diabetic ketoacidosis must be considered in the event of non-specific symptoms such asnausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusualfatigue or sleepiness. Patients should be assessed for ketoacidosis immediately if these symptomsoccur, regardless of blood glucose level.

In patients where DKA is suspected or diagnosed, treatment with Invokana should be discontinuedimmediately.

Treatment should be interrupted in patients who are hospitalised for acute serious medical illnesses.

Withhold Invokana, if possible, for an appropriate period of time (days) prior to major surgery,including abdominal and bariatric, or any other invasive procedures associated with prolonged fasting.

Monitoring for serum ketones is recommended. Consider alternative anti-hyperglycaemic therapy,including insulin.

Measurement of blood ketone levels is preferred to urine. Treatment with Invokana may be restartedwhen the ketone values are normal and the patient’s condition has stabilised.

Before initiating Invokana, factors in the patient history that may predispose to ketoacidosis should beconsidered.

Diabetic ketoacidosis may be prolonged after discontinuation of Invokana in some patients, i.e. it maylast longer than expected from the plasma half-life of canagliflozin (see section 5.2). Prolongedglucosuria has been observed along with persistent DKA. Canagliflozin-independent factors might beinvolved in prolonged periods of DKA. Insulin deficiency may contribute to prolonged diabeticketoacidosis and has to be corrected when verified.

Patients who may be at higher risk of DKA include patients with a low beta-cell function reserve (e.g.,type 2 diabetes patients with low C-peptide or latent autoimmune diabetes in adults (LADA) orpatients with a history of pancreatitis), patients with conditions that lead to restricted food intake orsevere dehydration, patients for whom insulin doses are reduced and patients with increased insulinrequirements due to acute medical illness, surgery or alcohol abuse. SGLT2 inhibitors should be usedwith caution in these patients.

Restarting SGLT2 inhibitor treatment in patients with previous DKA while on SGLT2 inhibitortreatment is not recommended unless another clear precipitating factor is identified and resolved.

The safety and efficacy of canagliflozin in patients with type 1 diabetes have not been established andcanagliflozin should not be used for treatment of patients with type 1 diabetes. Limited data fromclinical studies suggest that DKA occurs with common frequency when patients with type 1 diabetesare treated with SGLT2 inhibitors.

In long-term clinical studies of canagliflozin in patients with type 2 diabetes with establishedcardiovascular disease (CVD) or at least 2 risk factors for CVD, Invokana was associated with anincreased risk of lower limb amputation versus placebo (0.63 vs 0.34 events per 100 patient-years,respectively), and this increase occurred primarily in the toe and midfoot (see section 4.8). In along-term clinical study in patients with type 2 diabetes and diabetic kidney disease, no difference inlower limb amputation risk was observed in patients treated with canagliflozin 100 mg relative toplacebo. In this study precautionary measures as outlined below were applied. As an underlyingmechanism has not been established, risk factors, apart from general risk factors, for amputation areunknown.

Before initiating Invokana, consider factors in the patient history that may increase the risk foramputation. As precautionary measures, consideration should be given to carefully monitoring patientswith a higher risk for amputation events and counselling patients about the importance of routinepreventative foot care and maintaining adequate hydration. Consideration may also be given tostopping treatment with Invokana in patients who develop events which may precede amputation suchas lower-extremity skin ulcer, infection, osteomyelitis or gangrene.

Post-marketing cases of necrotising fasciitis of the perineum, (also known as Fournier’s gangrene),have been reported in female and male patients taking SGLT2 inhibitors. This is a rare but serious andpotentially life-threatening event that requires urgent surgical intervention and antibiotic treatment.

Patients should be advised to seek medical attention if they experience a combination of symptoms ofpain, tenderness, erythema, or swelling in the genital or perineal area, with fever or malaise. Be awarethat either uro-genital infection or perineal abscess may precede necrotising fasciitis. If Fournier’sgangrene is suspected, Invokana should be discontinued and prompt treatment (including antibioticsand surgical debridement) should be instituted.

Haematocrit increase was observed with canagliflozin treatment (see section 4.8); therefore, carefulmonitoring in patients with already elevated haematocrit is warranted.

Elderly patients may be at a greater risk for volume depletion, are more likely to be treated withdiuretics, and to have impaired renal function. In patients ≥ 75 years of age, a higher incidence ofadverse reactions associated with volume depletion (e.g., postural dizziness, orthostatic hypotension,hypotension) was reported. In addition, in such patients greater decreases in eGFR were reported (seesections 4.2 and 4.8).

Genital mycotic infections

Consistent with the mechanism of sodium glucose co-transporter 2 (SGLT2) inhibition with increased

UGE, vulvovaginal candidiasis in females and balanitis or balanoposthitis in males were reported inclinical studies with canagliflozin (see section 4.8). Male and female patients with a history of genitalmycotic infections were more likely to develop an infection. Balanitis or balanoposthitis occurredprimarily in uncircumcised male patients which in some instances resulted in phimosis and/orcircumcision. The majority of genital mycotic infections were treated with topical antifungaltreatments, either prescribed by a healthcare professional or self-treated while continuing therapy with

Invokana.

Urinary tract infections

Post-marketing cases of complicated urinary tract infections including pyelonephritis and urosepsishave been reported in patients treated with canagliflozin, frequently leading to treatment interruption.

Temporary interruption of canagliflozin should be considered in patients with complicated urinarytract infections.

Cardiac failure

Experience in New York Heart Association (NYHA) class III is limited, and there is no experience inclinical studies with canagliflozin in NYHA class IV.

Due to its mechanism of action, patients taking canagliflozin will test positive for glucose in theirurine.

The tablets contain lactose.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, orglucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium-free’.

Canagliflozin may add to the effect of diuretics and may increase the risk of dehydration andhypotension (see section 4.4).

Insulin and insulin secretagogues, such as sulphonylureas, can cause hypoglycaemia. Therefore, alower dose of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycaemiawhen used in combination with canagliflozin (see sections 4.2 and 4.8).

Effects of other medicinal products on canagliflozin

The metabolism of canagliflozin is primarily via glucuronide conjugation mediated by UDPglucuronosyl transferase 1A9 (UGT1A9) and 2B4 (UGT2B4). Canagliflozin is transported by

P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP).

Enzyme inducers (such as St. John’s wort [Hypericum perforatum], rifampicin, barbiturates,phenytoin, carbamazepine, ritonavir, efavirenz) may decrease the exposure to canagliflozin. Followingco-administration of canagliflozin with rifampicin (an inducer of various active transporters andmedicinal product-metabolising enzymes), 51% and 28% decreases in canagliflozin systemic exposure(AUC) and peak concentration (Cmax) were observed. These decreases in exposure to canagliflozinmay decrease efficacy.

If a combined inducer of these UGT enzymes and transport proteins must be co-administered withcanagliflozin, monitoring of glycaemic control to assess response to canagliflozin is appropriate. If aninducer of these UGT enzymes must be co-administered with canagliflozin, increasing the dose to300 mg once daily may be considered if patients are currently tolerating canagliflozin 100 mg oncedaily, have an eGFR ≥ 60 mL/min/1.73 m2 or CrCl ≥ 60 mL/min, and require additional glycaemiccontrol. In patients with an eGFR 45 mL/min/1.73 m2 to < 60 mL/min/1.73 m2 or CrCl 45 mL/min to< 60 mL/min taking canagliflozin 100 mg who are receiving concurrent therapy with a UGT enzymeinducer and who require additional glycaemic control, other glucose-lowering therapies should beconsidered (see sections 4.2 and 4.4).

Cholestyramine may potentially reduce canagliflozin exposure. Dosing of canagliflozin should occurat least 1 hour before or 4-6 hours after administration of a bile acid sequestrant to minimise possibleinterference with their absorption.

Interaction studies suggest that the pharmacokinetics of canagliflozin are not altered by metformin,hydrochlorothiazide, oral contraceptives (ethinyl estradiol and levonorgestrol), ciclosporin, and/orprobenecid.

Effects of canagliflozin on other medicinal products

The combination of canagliflozin 300 mg once daily for 7 days with a single dose of digoxin 0.5 mgfollowed by 0.25 mg daily for 6 days resulted in a 20% increase in AUC and a 36% increase in Cmax ofdigoxin, probably due to inhibition of P-gp. Canagliflozin has been observed to inhibit P-gp in vitro.

Patients taking digoxin or other cardiac glycosides (e.g., digitoxin) should be monitored appropriately.

The concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations.

Monitor serum lithium concentration more closely during treatment with canagliflozin, especiallyduring initiation and dosage changes.

Dabigatran

The effect of concomitant administration of canagliflozin (a weak P-gp inhibitor) on dabigatranetexilate (a P-gp substrate) has not been studied. As dabigatran concentrations may be increased in thepresence of canagliflozin, monitoring (looking for signs of bleeding or anaemia) should be exercisedwhen dabigatran is combined with canagliflozin.

Simvastatin

The combination of canagliflozin 300 mg once daily for 6 days with a single dose of simvastatin(CYP3A4 substrate) 40 mg resulted in a 12% increase in AUC and a 9% increase in Cmax ofsimvastatin and an 18% increase in AUC and a 26% increase in Cmax of simvastatin acid. Theincreases in simvastatin and simvastatin acid exposures are not considered clinically relevant.

Inhibition of BCRP by canagliflozin cannot be excluded at an intestinal level and increased exposuremay therefore occur for medicinal products transported by BCRP, e.g. certain statins like rosuvastatinand some anti-cancer medicinal products.

In interaction studies, canagliflozin at steady-state had no clinically relevant effect on thepharmacokinetics of metformin, oral contraceptives (ethinyl estradiol and levonorgestrol),glibenclamide, paracetamol, hydrochlorothiazide, or warfarin.

Medicinal product/Laboratory test interference1,5-AG assay

Increases in urinary glucose excretion with Invokana can falsely lower 1,5-anhydroglucitol (1,5-AG)levels and make measurements of 1,5-AG unreliable in assessing glycaemic control. Therefore,1,5-AG assays should not be used for assessment of glycaemic control in patients on canagliflozin. Forfurther detail, it may be advisable to contact the specific manufacturer of the 1,5-AG assay.

There are no data from the use of canagliflozin in pregnant women. Studies in animals have shownreproductive toxicity (see section 5.3).

Canagliflozin should not be used during pregnancy. When pregnancy is detected, treatment withcanagliflozin should be discontinued.

It is unknown whether canagliflozin and/or its metabolites are excreted in human milk. Availablepharmacodynamic/toxicological data in animals have shown excretion of canagliflozin/metabolites inmilk, as well as pharmacologically mediated effects in breast-feeding offspring and juvenile ratsexposed to canagliflozin (see section 5.3). A risk to newborns/infants cannot be excluded.

Canagliflozin should not be used during breast-feeding.

The effect of canagliflozin on fertility in humans has not been studied. No effects on fertility wereobserved in animal studies (see section 5.3).

Canagliflozin has no or negligible influence on the ability to drive and use machines. However,patients should be alerted to the risk of hypoglycaemia when canagliflozin is used as add-on therapywith insulin or an insulin secretagogue, and to the elevated risk of adverse reactions related to volumedepletion, such as postural dizziness (see sections 4.2, pct. 4.4 and 4.8).

The safety of canagliflozin was evaluated in 22,645 patients with type 2 diabetes, including13,278 patients treated with canagliflozin and 9,367 patients treated with comparator in15 double-blind, controlled phase 3 and phase 4 clinical studies. A total of 10,134 patients weretreated in two dedicated cardiovascular studies for a mean exposure duration of 149 weeks (223 weeksin CANVAS and 94 weeks in CANVAS-R), and 8,114 patients were treated in 12 double blind,controlled phase 3 and phase 4 clinical studies, for a mean exposure duration of 49 weeks. In adedicated renal outcomes study, a total of 4,397 patients with type 2 diabetes and diabetic kidneydisease had a mean exposure duration of 115 weeks.

The primary assessment of safety and tolerability was conducted in a pooled analysis (n = 2,313) offour 26-week placebo-controlled clinical studies (monotherapy and add-on therapy with metformin,metformin and a sulphonylurea, and metformin and pioglitazone). The most commonly reportedadverse reactions during treatment were hypoglycaemia in combination with insulin or asulphonylurea, vulvovaginal candidiasis, urinary tract infection, and polyuria or pollakiuria(i.e., urinary frequency). Adverse reactions leading to discontinuation of ≥ 0.5% of allcanagliflozin-treated patients in these studies were vulvovaginal candidiasis (0.7% of female patients)and balanitis or balanoposthitis (0.5% of male patients). Additional safety analyses (includinglong-term data) from data across the entire canagliflozin programme (placebo- and active-controlledstudies) were conducted to assess reported adverse reactions in order to identify adverse reactions(table 2) (see sections 4.2 and 4.4).

Adverse reactions in table 2 are based on the pooled analysis of the placebo- and active-controlledstudies described above. Adverse reactions reported from world-wide postmarketing use ofcanagliflozin are also included in this tabulation. Adverse reactions listed below are classifiedaccording to frequency and system organ class. Frequency categories are defined according to thefollowing convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to< 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated fromthe available data).

Table 2: Tabulated list of adverse reactions (MedDRA) from placebo-e andactive-controlled studiese and from postmarketing experience

System organ class Adverse reaction

Frequency

Infections and infestationsvery common Vulvovaginal candidiasisb, jcommon Balanitis or balanoposthitisb, k, Urinary tractinfectionc (pyelonephritis and urosepsis havebeen reported postmarketing)not known Necrotising fasciitis of the perineum (Fournier’sgangrene)d

Immune system disordersrare Anaphylactic reaction

Metabolism and nutrition disordersvery common Hypoglycaemia in combination with insulin orsulphonylureacuncommon Dehydrationarare Diabetic ketoacidosisb

Nervous system disordersuncommon Dizziness posturala, Syncopea

Vascular disordersuncommon Hypotensiona, Orthostatic hypotensiona

Gastrointestinal disorderscommon Constipation, Thirstf, Nausea

Skin and subcutaneous tissue disordersuncommon Photosensitivity, Rashg, Urticariarare Angioedema

Musculoskeletal and connective tissue disordersuncommon Bone fractureh

Renal and urinary disorderscommon Polyuria or Pollakiuriaiuncommon Renal failure (mainly in the context of volumedepletion)

Investigationscommon Dyslipidaemial, Haematocrit increasedb, muncommon Blood creatinine increasedb, n, Blood ureaincreasedb, o, Blood potassium increasedb, p,

Blood phosphate increasedq

Surgical and medical proceduresuncommon Lower limb amputations (mainly of the toe andmidfoot) especially in patients at high risk forheart diseaseba Related to volume depletion; see section 4.4 and description of adverse reaction (AR) below.b See section 4.4 and description of AR below.c See description of AR below.d See section 4.4.e Safety data profiles from individual pivotal studies (including studies in moderately renally impaired patients; olderpatients [≥ 55 years of age to ≤ 80 years of age]; patients with increased CV- and renal-risk) were generally consistentwith the adverse reactions identified in this table.

f Thirst includes the terms thirst, dry mouth, and polydipsia.g Rash includes the terms rash erythematous, rash generalised, rash macular, rash maculopapular, rash papular, rashpruritic, rash pustular, and rash vesicular.h Related to bone fracture; see description of AR below.i Polyuria or pollakiuria includes the terms polyuria, pollakiuria, micturition urgency, nocturia, and urine outputincreased.j Vulvovaginal candidiasis includes the terms vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginitis,vaginal infection, vulvitis, and genital infection fungal.k Balanitis or balanoposthitis includes the terms balanitis, balanoposthitis, balanitis candida, and genital infectionfungal.l Mean percent increases from baseline for canagliflozin 100 mg and 300 mg versus placebo, respectively, were totalcholesterol 3.4% and 5.2% versus 0.9%; HDL-cholesterol 9.4% and 10.3% versus 4.0%; LDL-cholesterol 5.7% and9.3% versus 1.3%; non-HDL-cholesterol 2.2% and 4.4% versus 0.7%; triglycerides 2.4% and 0.0% versus 7.6%.

m Mean changes from baseline in haematocrit were 2.4% and 2.5% for canagliflozin 100 mg and 300 mg, respectively,compared to 0.0% for placebo.

n Mean percent changes from baseline in creatinine were 2.8% and 4.0% for canagliflozin 100 mg and 300 mg,respectively, compared to 1.5% for placebo.

o Mean percent changes from baseline in blood urea nitrogen were 17.1% and 18.0% for canagliflozin 100 mg and300 mg, respectively, compared to 2.7% for placebo.

p Mean percent changes from baseline in blood potassium were 0.5% and 1.0% for canagliflozin 100 mg and 300 mg,respectively, compared to 0.6% for placebo.

q Mean percent changes from baseline in serum phosphate were 3.6% and 5.1% for canagliflozin 100 mg and 300 mg,compared to 1.5% for placebo.

In a long-term renal outcomes study in patients with type 2 diabetes and diabetic kidney disease,incidence rates of adjudicated events of diabetic ketoacidosis (DKA) were 0.21 (0.5%, 12/2,200) and0.03 (0.1%, 2/2,197) per 100 patient-years of follow-up with canagliflozin 100 mg and placebo,respectively; of the 14 patients with DKA, 8 (7 on canagliflozin 100 mg and 1 on placebo) had apretreatment eGFR of 30 to ˂ 45 mL/min/1.73 m2 (see section 4.4).

Lower limb amputation

In patients with type 2 diabetes who had established cardiovascular disease or at least two risk factorsfor cardiovascular disease, canagliflozin was associated with an increased risk of lower limbamputation as observed in the Integrated CANVAS Program comprised of CANVAS and

CANVAS-R, two large, long-term, randomised, placebo-controlled trials evaluating 10,134 patients.

The imbalance occurred as early as the first 26 weeks of therapy. Patients in CANVAS and

CANVAS-R were followed for an average of 5.7 and 2.1 years, respectively. Regardless of treatmentwith canagliflozin or placebo, the risk of amputation was highest in patients with a baseline history ofprior amputation, peripheral vascular disease, and neuropathy. The risk of lower limb amputation wasnot dose-dependent. The amputation results for the Integrated CANVAS Program are shown intable 3.

There was no difference in risk of lower limb amputations associated with the use of canagliflozin100 mg relative to placebo (1.2 vs 1.1 events per 100 patient-years, respectively [HR: 1.11; 95%

CI 0.79, 1.56]) in CREDENCE, a long-term renal outcomes study of 4,397 patients with type 2diabetes and diabetic kidney disease (see section 4.4). In other type 2 diabetes studies withcanagliflozin, which enrolled a general diabetic population of 8,114 patients, no difference in lowerlimb amputation risk was observed relative to control.

Table 3: Integrated analysis of amputations in CANVAS AND CANVAS-R

Placebo canagliflozin

N = 4344 N = 5790

Total number of subjects with events, n47 (1.1) 140 (2.4)(%)

Incidence rate (per 100 patient-years) 0.34 0.63

HR (95% CI) vs. placebo 1.97 (1.41, 2.75)

Minor Amputation, n (%)* 34/47 (72.3) 99/140 (70.7)

Major Amputation, n (%)† 13/47 (27.7) 41/140 (29.3)

Note: Incidence is based on the number of patients with at least one amputation, and not the total number of amputationevents. A patient’s follow-up is calculated from Day 1 to the first amputation event date. Some patients had more than oneamputation. The percentage of minor and major amputations is based on the highest level amputation for each patient.

* Toe and midfoot† Ankle, below knee and above knee

Of the subjects, within the CANVAS Program, who had an amputation, the toe and midfoot were themost frequent sites (71%) in both treatment groups (table 3). Multiple amputations (some involvingboth lower limbs) were observed infrequently and in similar proportions in both treatment groups.

Lower limb infections, diabetic foot ulcers, peripheral arterial disease, and gangrene, were the mostcommon medical events associated with the need for an amputation in both treatment groups (seesection 4.4).

Adverse reactions related to volume depletion

In the pooled analysis of the four 26-week, placebo-controlled studies, the incidence of all adversereactions related to volume depletion (e.g., postural dizziness, orthostatic hypotension, hypotension,dehydration, and syncope) was 1.2% for canagliflozin 100 mg, 1.3% for canagliflozin 300 mg, and1.1% for placebo. The incidence with canagliflozin treatment in the two active-controlled studies wassimilar to comparators.

In one of the dedicated long-term cardiovascular studies (CANVAS), where patients were generallyolder with a higher rate of diabetes complications, the incidence rates of adverse reactions related tovolume depletion were 2.3 with canagliflozin 100 mg, 2.9 with canagliflozin 300 mg, and 1.9 withplacebo, events per 100 patient-years.

To assess risk factors for these adverse reactions, a larger pooled analysis (N = 12,441) of patientsfrom 13 controlled phase 3 and phase 4 studies including both doses of canagliflozin was conducted.

In this pooled analysis, patients on loop diuretics, patients with a baseline eGFR 30 mL/min/1.73 m2 to< 60 mL/min/1.73 m2, and patients ≥ 75 years of age had generally higher incidences of these adversereactions. For patients on loop diuretics, the incidence rates were 5.0 on canagliflozin 100 mg and 5.7on canagliflozin 300 mg compared to 4.1 events per 100 patient-years of exposure in the controlgroup. For patients with a baseline eGFR 30 mL/min/1.73 m2 to < 60 mL/min/1.73 m2, the incidencerates were 5.2 on canagliflozin 100 mg and 5.4 on canagliflozin 300 mg compared to 3.1 events per100 patient-years of exposure in the control group. In patients ≥ 75 years of age, the incidence rateswere 5.3 on canagliflozin 100 mg and 6.1 on canagliflozin 300 mg compared to 2.4 events per100 patient-years of exposure in the control group (see sections 4.2 and 4.4).

In a long-term renal outcomes study in patients with type 2 diabetes and diabetic kidney disease,incidence rate of events related to volume depletion was 2.84 and 2.35 events per 100 patient-years forcanagliflozin 100 mg and placebo, respectively. The incidence rate was observed to increase withdecreasing eGFR. In subjects with eGFR 30 to <45 mL/min/1.73 m2, the incidence rate of volumedepletion was higher in the canagliflozin group (4.91 events per 100 patient-years) compared to theplacebo group (2.60 events per 100 patient-years); however, in the subgroups eGFR ≥45 to <60 andeGFR 60 to <90 mL/min/1.73 m2, the between-group incidence rate was similar.

In the dedicated cardiovascular study and the larger pooled analysis, as well as in a dedicated renaloutcomes study, discontinuations due to adverse reactions related to volume depletion and seriousadverse reactions related to volume depletion were not increased with canagliflozin.

Hypoglycaemia in add-on therapy with insulin or insulin secretagogues

The frequency of hypoglycaemia was low (approximately 4%) among treatment groups, includingplacebo, when used as monotherapy or as an add-on to metformin. When canagliflozin was added toinsulin therapy, hypoglycaemia was observed in 49.3%, 48.2%, and 36.8% of patients treated withcanagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively, and severe hypoglycaemiaoccurred in 1.8%, 2.7%, and 2.5% of patients treated with canagliflozin 100 mg, canagliflozin 300 mg,and placebo, respectively. When canagliflozin was added to a sulphonylurea therapy, hypoglycaemiawas observed in 4.1%, 12.5%, and 5.8% of patients treated with canagliflozin 100 mg, canagliflozin300 mg, and placebo, respectively (see sections 4.2 and 4.5).

Genital mycotic infections

Vulvovaginal candidiasis (including vulvovaginitis and vulvovaginal mycotic infection) was reportedin 10.4% and 11.4% of female patients treated with canagliflozin 100 mg and canagliflozin 300 mg,respectively, compared to 3.2% in placebo-treated female patients. Most reports of vulvovaginalcandidiasis occurred during the first four months of treatment with canagliflozin. Among femalepatients taking canagliflozin, 2.3% experienced more than one infection. Overall, 0.7% of all femalepatients discontinued canagliflozin due to vulvovaginal candidiasis (see section 4.4). In the CANVAS

Program, median duration of the infection was longer in the canagliflozin group compared to theplacebo group.

Candidal balanitis or balanoposthitis occurred in male patients at a rate of 2.98 and 0.79 events per100 patient-years on canagliflozin and placebo, respectively. Among male patients takingcanagliflozin, 2.4% had more than one infection. Discontinuation of canagliflozin by male patients dueto candidal balanitis or balanoposthitis occurred at a rate of 0.37 events per 100 patient-years.

Phimosis was reported at a rate of 0.39 and 0.07 events per 100 patient-years on canagliflozin andplacebo, respectively. Circumcision was performed at rates of 0.31 and 0.09 events per100 patient-years on canagliflozin and placebo, respectively (see section 4.4).

Urinary tract infections

In clinical studies, urinary tract infections were more frequently reported for canagliflozin 100 mg and300 mg (5.9% versus 4.3%, respectively) compared to 4.0% with placebo. Most infections were mildto moderate with no increase in the occurrence of serious adverse reactions. In these studies, subjectsresponded to standard treatments while continuing canagliflozin treatment.

However, post-marketing cases of complicated urinary tract infections including pyelonephritis andurosepsis have been reported in patients treated with canagliflozin, frequently leading to treatmentinterruption.

Bone fracture

In a cardiovascular study (CANVAS) of 4,327 treated subjects with established or at least two riskfactors for cardiovascular disease, the incidence rates of all adjudicated bone fracture were 1.6, 1.8,and 1.1 per 100 patient-years of follow-up to canagliflozin 100 mg, canagliflozin 300 mg, andplacebo, respectively, with the fracture imbalance initially occurring within the first 26 weeks oftherapy.

In two other long-term studies and in studies conducted in the general diabetes population, nodifference in fracture risk was observed with canagliflozin relative to control. In a secondcardiovascular study (CANVAS-R) of 5,807 treated subjects with established or at least two riskfactors for cardiovascular disease, the incidence rates of all adjudicated bone fracture were 1.1 and1.3 events per 100 patient-years of follow-up to canagliflozin and placebo, respectively.

In a long-term renal outcomes study of 4,397 treated subjects with type 2 diabetes and diabetic kidneydisease, the incidence rates of all adjudicated bone fracture were 1.2 events per 100 patient-years offollow-up for both canagliflozin 100 mg and placebo. In other type 2 diabetes studies withcanagliflozin, which enrolled a general diabetes population of 7,729 patients and where bone fractureswere adjudicated, the incidence rates of all adjudicated bone fracture were 1.2 and 1.1 per100 patient-years of follow-up to canagliflozin and control, respectively. After 104 weeks oftreatment, canagliflozin did not adversely affect bone mineral density.

In a pooled analysis of 13 placebo-controlled and active-controlled studies, the safety profile ofcanagliflozin in elderly patients was generally consistent with younger patients. Patients ≥ 75 years ofage had a higher incidence of adverse reactions related to volume depletion (such as posturaldizziness, orthostatic hypotension, hypotension) with incidence rates of 5.3, 6.1, and 2.4 events per100 patient-years of exposure for canagliflozin 100 mg, canagliflozin 300 mg, and in the controlgroup, respectively. Decreases in eGFR (-3.4 and -4.7 mL/min/1.73 m2) were reported withcanagliflozin 100 mg and canagliflozin 300 mg, respectively, compared to the control group(-4.2 mL/min/1.73 m2). Mean baseline eGFR was 62.5, 64.7, and 63.5 mL/min/1.73 m2 forcanagliflozin 100 mg, canagliflozin 300 mg, and the control group, respectively (see sections 4.2 and4.4).

Renal impairment in patients with insufficiently controlled type 2 diabetes mellitus

Patients with a baseline eGFR < 60 mL/min/1.73 m2 had a higher incidence of adverse reactionsassociated with volume depletion (e.g., postural dizziness, orthostatic hypotension, hypotension) withincidence rates of 5.3, 5.1, and 3.1 events per 100 patient-years of exposure for canagliflozin 100 mg,canagliflozin 300 mg, and placebo, respectively (see sections 4.2 and 4.4).

The overall incidence rate of elevated serum potassium was higher in patients with moderate renalimpairment with incidence rates of 4.9, 6.1, and 5.4 events per 100 patient-years of exposure forcanagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively. In general, elevations weretransient and did not require specific treatment.

In patients with moderate renal impairment, increases in serum creatinine of 9.2 µmol/L and BUN ofapproximately 1.0 mmol/L were observed with both doses of canagliflozin.

The incidence rates for larger decreases in eGFR (> 30%) at any time during treatment were 7.3, 8.1,and 6.5 events per 100 patient-years of exposure for canagliflozin 100 mg, canagliflozin 300 mg, andplacebo, respectively. At the last post-baseline value, incidence rates of such decreases were 3.3 forpatients treated with canagliflozin 100 mg, 2.7 for canagliflozin 300 mg, and 3.7 events per100 patient-years of exposure for placebo (see section 4.4).

Patients treated with canagliflozin regardless of baseline eGFR experienced an initial fall in meaneGFR. Thereafter, eGFR was maintained or gradually increased during continued treatment. MeaneGFR returned to baseline after treatment discontinuation suggesting that haemodynamic changes mayplay a role in these renal function changes.

Renal impairment in patients with diabetic kidney disease in type 2 diabetes mellitus

In a long-term renal outcomes study in patients with type 2 diabetes and diabetic kidney disease, theincidence of renal-related events occurred frequently in both groups but less frequent in thecanagliflozin group (5.71 events per 100 patient-years) compared with the placebo group (7.91 eventsper 100 patient-years). Serious and severe renal-related events were also lower in the canagliflozingroup versus placebo. The incidence rates of renal-related events were lower with canagliflozinrelative to placebo across all three eGFR strata; the highest incidence rate of renal-related events wasseen in the eGFR 30 to <45 mL/min/1.73 m2 stratum (9.47 vs 12.80 events per 100 patient-years forcanagliflozin versus placebo, respectively).

In the long-term renal outcomes study, no difference in serum potassium, no increase in adverseevents of hyperkalaemia, and no absolute (> 6.5 mEq/L) or relative (> upper limit of normal and> 15% increase from baseline) increases in serum potassium were observed with canagliflozin 100 mgrelative to placebo.

In general, there were no imbalances between treatment groups observed for abnormalities ofphosphate, overall or in either eGFR category (45 to < 60 or 30 to < 45 mL/min/1.73 m2[CrCl 45 to < 60 or 30 to < 45 mL/min]).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Single doses up to 1,600 mg of canagliflozin in healthy subjects and canagliflozin 300 mg twice dailyfor 12 weeks in patients with type 2 diabetes were generally well-tolerated.

In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., removeunabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute clinicalmeasures if required. Canagliflozin was negligibly removed during a 4-hour haemodialysis session.

Canagliflozin is not expected to be dialysable by peritoneal dialysis.

Pharmacotherapeutic group: Drugs used in diabetes, blood glucose lowering drugs, excluding insulins.

ATC code: A10BK02.

The SGLT2 transporter, expressed in the proximal renal tubules, is responsible for the majority of thereabsorption of filtered glucose from the tubular lumen. Patients with diabetes have been shown tohave elevated renal glucose reabsorption which may contribute to persistent elevated blood glucoseconcentrations. Canagliflozin is an orally-active inhibitor of SGLT2. By inhibiting SGLT2,canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RTG),and thereby increases UGE, lowering elevated plasma glucose concentrations by thisinsulin-independent mechanism in patients with type 2 diabetes. The increased UGE with SGLT2inhibition also translates to an osmotic diuresis, with the diuretic effect leading to a reduction insystolic blood pressure; the increase in UGE results in a loss of calories and therefore a reduction inbody weight, as has been demonstrated in studies of patients with type 2 diabetes.

Canagliflozin’s action to increase UGE directly lowering plasma glucose is independent of insulin.

Improvement in homeostasis model assessment for beta-cell function (HOMA beta-cell) and improvedbeta-cell insulin secretion response to a mixed-meal challenge has been observed in clinical studieswith canagliflozin.

In phase 3 studies, pre-meal administration of canagliflozin 300 mg provided a greater reduction inpostprandial glucose excursion than observed with the 100 mg dose. This effect at the 300 mg dose ofcanagliflozin may, in part, be due to local inhibition of intestinal SGLT1 (an important intestinalglucose transporter) related to transient high concentrations of canagliflozin in the intestinal lumenprior to medicinal product absorption (canagliflozin is a low potency inhibitor of the SGLT1transporter). Studies have shown no glucose malabsorption with canagliflozin.

Canagliflozin increases the delivery of sodium to the distal tubule by blocking SGLT2-dependentglucose and sodium reabsorption thereby increasing tubuloglomerular feedback, which is associatedwith a reduction in intraglomerular pressure and a decrease in hyperfiltration in preclinical models ofdiabetes and clinical studies.

Following single and multiple oral doses of canagliflozin to patients with type 2 diabetes,dose-dependent decreases in RTG and increases in UGE were observed. From a starting value of RTGof approximately 13 mmol/L, maximal suppression of 24-hour mean RTG was seen with the 300 mgdaily dose to approximately 4 mmol/L to 5 mmol/L in patients with type 2 diabetes in phase 1 studies,suggesting a low risk for treatment-induced hypoglycaemia. The reductions in RTG led to increased

UGE in subjects with type 2 diabetes treated with either 100 mg or 300 mg of canagliflozin rangingfrom 77 g/day to 119 g/day across the phase 1 studies; the UGE observed translates to a loss of308 kcal/day to 476 kcal/day. The reductions in RTG and increases in UGE were sustained over a26-week dosing period in patients with type 2 diabetes. Moderate increases (generally < 400 mL to500 mL) in daily urine volume were seen that attenuated over several days of dosing. Urinary uric acidexcretion was transiently increased by canagliflozin (increased by 19% compared to baseline on day 1and then attenuating to 6% on day 2 and 1% on day 13). This was accompanied by a sustainedreduction in serum uric acid concentration of approximately 20%.

In a single-dose study in patients with type 2 diabetes, treatment with 300 mg before a mixed mealdelayed intestinal glucose absorption and reduced postprandial glucose through both a renal and anon-renal mechanism.

Improvement in glycaemic control and reduction of cardiovascular and renal morbidity and mortalityare integral parts of the treatment of type 2 diabetes.

Glycaemic efficacy and safety

A total of 10,501 patients with type 2 diabetes participated in ten double-blind, controlled clinicalefficacy and safety studies conducted to evaluate the effects of Invokana on glycaemic control. Theracial distribution was 72% White, 16% Asian, 5% Black, and 8% other groups. 17% of patients were

Hispanic. 58% of patients were male. Patients had an overall mean age of 59.5 years (range 21 yearsto 96 years), with 3,135 patients ≥ 65 years of age and 513 patients ≥ 75 years of age. 58% of patientshad a body mass index (BMI) ≥ 30 kg/m2. In the clinical development programme, 1,085 patients witha baseline eGFR 30 mL/min/1.73 m2 to < 60 mL/min/1.73 m2 were evaluated.

Placebo-controlled studies

Canagliflozin was studied as monotherapy, dual therapy with metformin, dual therapy with asulphonylurea, triple therapy with metformin and a sulphonylurea, triple therapy with metformin andpioglitazone, and as an add-on therapy with insulin (table 4). In general, canagliflozin producedclinically and statistically significant (p < 0.001) results relative to placebo in glycaemic control,including HbA1c, the percentage of patients achieving HbA1c < 7%, change from baseline fastingplasma glucose (FPG), and 2-hour postprandial glucose (PPG). In addition, reductions in body weightand systolic blood pressure relative to placebo were observed.

Furthermore, canagliflozin was studied as triple therapy with metformin and sitagliptin and dosed witha titration regimen, using a starting dose of 100 mg and titrated to 300 mg as early as week 6 inpatients requiring additional glycaemic control who had appropriate eGFR and were toleratingcanagliflozin 100 mg (table 4). Canagliflozin dosed with a titration regimen produced clinically andstatistically significant (p < 0.001) results relative to placebo in glycaemic control, including HbA1cand change from baseline fasting plasma glucose (FPG), and a statistically significant (p < 0.01)improvement in the percentage of patients achieving HbA1c < 7%. In addition, reductions in bodyweight and systolic blood pressure relative to placebo were observed.

Table 4: Efficacy results from placebo-controlled clinical studiesa

Monotherapy (26 weeks)

Canagliflozin100 mg 300 mg Placebo(N = 195) (N = 197) (N = 192)

HbA1c (%)

Baseline (mean) 8.06 8.01 7.97

Change from baseline (adjusted

- 0.77 -1.03 0.14mean)

Difference from placebo (adjusted -0.91b -1.16b

N/Acmean) (95% CI) (-1.09; -0.73) (-1.34; -0.98)

Patients (%) achieving HbA1c < 7% 44.5b 62.4b 20.6

Baseline (mean) in kg 85.9 86.9 87.5% change from baseline (adjusted

- 2.8 -3.9 -0.6mean)

Difference from placebo (adjusted -2.2b -3.3b

N/Acmean) (95% CI) (-2.9; -1.6) (-4.0; -2.6)

Dual therapy with metformin (26 weeks)

Canagliflozin + metformin Placebo +100 mg 300 mg metformin(N = 368) (N = 367) (N = 183)

HbA1c (%)

Baseline (mean) 7.94 7.95 7.96

Change from baseline (adjusted

- 0.79 -0.94 -0.17mean)

Difference from placebo (adjusted -0.62b -0.77b

N/Acmean) (95% CI) (-0.76; -0.48) (-0.91; -0.64)

Patients (%) achieving HbA1c < 7% 45.5b 57.8b 29.8

Baseline (mean) in kg 88.7 85.4 86.7% change from baseline (adjusted

- 3.7 -4.2 -1.2mean)

Difference from placebo (adjusted -2.5b -2.9b

N/Acmean) (95% CI) (-3.1; -1.9) (-3.5; -2.3)

Triple therapy with metformin and sulphonylurea (26 weeks)

Canagliflozin + metformin Placebo +and sulphonylurea metformin and100 mg 300 mg sulphonylurea(N = 157) (N = 156) (N = 156)

HbA1c (%)

Baseline (mean) 8.13 8.13 8.12

Change from baseline (adjusted

- 0.85 -1.06 -0.13mean)

Difference from placebo (adjusted -0.71b -0.92b

N/Acmean) (95% CI) (-0.90; -0.52) (-1.11; -0.73)

Patients (%) achieving HbA1c < 7% 43.2b 56.6b 18.0

Baseline (mean) in kg 93.5 93.5 90.8% change from baseline (adjusted

- 2.1 -2.6 -0.7mean)

Difference from placebo (adjusted -1.4b -2.0b

N/Acmean) (95% CI) (-2.1; -0.7) (-2.7; -1.3)

Add-on therapy with insulind (18 weeks)

Canagliflozin + insulin Placebo +100 mg 300 mg insulin(N = 566) (N = 587) (N = 565)

HbA1c (%)

Baseline (mean) 8.33 8.27 8.20

Change from baseline (adjusted

- 0.63 -0.72 0.01mean)

Difference from placebo (adjustedmean) -0.65b -0.73b N/Ac(95% CI) (-0.73; -0.56) (-0.82; -0.65)

Patients (%) achieving HbA1c < 7% 19.8b 24.7b 7.7

Baseline (mean) in kg 96.9 96.7 97.7% change from baseline (adjusted

- 1.8 -2.3 0.1mean)

Difference from placebo (adjusted -1.9b -2.4b

N/Acmean) (97.5% CI) (-2.2; -1.5) (-2.8; -2.0)

Triple therapy with metformin and sitagliptine (26 weeks)

Canagliflozin + Placebo +metformin and sitaglipting metformin and sitagliptin(N = 107) (N = 106)

HbA1c (%)

Baseline (mean) 8.53 8.38

Change from baseline (adjusted

- 0.91 -0.01mean)

Difference from placebo (adjusted

- 0.89bmean)(-1.19; -0.59)(95% CI)

Patients (%) achieving HbA f1c < 7% 32 12

Fasting Plasma Glucose (mg/dL)

Baseline (mean) 186 180

Change from baseline (adjusted

- 30 -3mean)

Difference from placebo (adjusted -27bmean) (95% CI) (-40; -14)

Body Weight

Baseline (mean) in kg 93.8 89.9% change from baseline (adjusted

- 3.4 -1.6mean)

Difference from placebo (adjusted -1.8bmean) (95% CI) (-2.7; -0.9)a Intent-to-treat population using last observation in study prior to glycaemic rescue therapy.b p < 0.001 compared to placebo.c Not applicable.d Canagliflozin as add-on therapy to insulin (with or without other glucose-lowering medicinal products).e Canagliflozin 100 mg uptitrated to 300 mgf p < 0.01 compared to placebog 90.7% of subjects in the canagliflozin group uptitrated to 300 mg

In addition to the studies presented above, glycaemic efficacy results observed in an 18-week dualtherapy sub-study with a sulphonylurea and a 26-week triple therapy study with metformin andpioglitazone were generally comparable with those observed in other studies.

Active-controlled studies

Canagliflozin was compared to glimepiride as dual therapy with metformin and compared tositagliptin as triple therapy with metformin and a sulphonylurea (table 5). Canagliflozin 100 mg asdual therapy with metformin produced similar reductions in HbA1c from baseline and 300 mgproduced superior (p < 0.05) reductions in HbA1c compared to glimepiride, thus demonstratingnon-inferiority. A lower proportion of patients treated with canagliflozin 100 mg (5.6%) andcanagliflozin 300 mg (4.9%) experienced at least one episode/event of hypoglycaemia over 52 weeksof treatment compared to the group treated with glimepiride (34.2%). In a study comparingcanagliflozin 300 mg to sitagliptin 100 mg in triple therapy with metformin and a sulphonylurea,canagliflozin demonstrated non-inferior (p < 0.05) and superior (p < 0.05) reduction in HbA1c relativeto sitagliptin. The incidence of hypoglycaemia episodes/events with canagliflozin 300 mg andsitagliptin 100 mg was 40.7% and 43.2%, respectively. Significant improvements in body weight andreductions in systolic blood pressure compared to both glimepiride and sitagliptin were also observed.

Table 5: Efficacy results from active-controlled clinical studiesa

Compared to glimepiride as dual therapy with metformin (52 weeks)

Canagliflozin + metformin Glimepiride(titrated) +100 mg 300 mg metformin(N = 483) (N = 485) (N = 482)

HbA1c (%)

Baseline (mean) 7.78 7.79 7.83

Change from baseline (adjusted mean) -0.82 -0.93 -0.81

Difference from glimepiride (adjusted -0.01b -0.12b

N/Acmean) (95% CI) (−0.11; 0.09) (−0.22; −0.02)

Patients (%) achieving HbA1c < 7% 53.6 60.1 55.8

Baseline (mean) in kg 86.8 86.6 86.6% change from baseline (adjusted mean) -4.2 -4.7 1.0

Difference from glimepiride (adjusted -5.2b -5.7b

N/Acmean) (95% CI) (−5.7; −4.7) (−6.2; −5.1)

Compared to sitagliptin as triple therapy with metformin and sulphonylurea (52 weeks)

Sitagliptin100 mg +

Canagliflozin 300 mg + metformin andmetformin and sulphonylurea sulphonylurea(N = 377) (N = 378)

HbA1c (%)

Baseline (mean) 8.12 8.13

Change from baseline (adjusted mean) -1.03 -0.66

Difference from sitagliptin (adjusted -0.37b

N/Acmean) (95% CI) (-0.50; -0.25)

Patients (%) achieving HbA1c < 7% 47.6 35.3

Baseline (mean) in kg 87.6 89.6% change from baseline (adjusted mean) -2.5 0.3

Difference from sitagliptin (adjusted -2.8d

N/Acmean) (95% CI) (-3.3; -2.2)a Intent-to-treat population using last observation in study prior to glycaemic rescue therapy.b p < 0.05.c Not applicable.d p < 0.001.

Canagliflozin as initial combination therapy with metformin

Canagliflozin was evaluated in combination with metformin as initial combination therapy in patientswith type 2 diabetes failing diet and exercise. Canagliflozin 100 mg and canagliflozin 300 mg incombination with metformin XR resulted in a statistically significant greater improvement in HbA1Ccompared to their respective canagliflozin doses (100 mg and 300 mg) alone or metformin XR alone(table 6).

Table 6: Results from 26-week active-controlled clinical study of canagliflozin as initialcombination therapy with metformin*

Canagliflozin100 mg + Canagliflozin

Metformin Canagliflozin Canagliflozin Metformin 300 mg +

Efficacy XR 100 mg 300 mg XR Metformin XR

Parameter (N = 237) (N = 237) (N = 238) (N = 237) (N = 237)

HbA1c (%)

Baseline(mean) 8.81 8.78 8.77 8.83 8.90

Change frombaseline(adjustedmean) -1.30 -1.37 -1.42 -1.77 -1.78

Differencefromcanagliflozin100 mg(adjustedmean) -0.40‡(95% CI) † (-0.59, -0.21)

Differencefromcanagliflozin300 mg(adjustedmean) (95% -0.36‡

CI) † (-0.56, -0.17)

Differencefrommetformin XR(adjustedmean) (95% -0.06‡ -0.11‡ -0.46‡ -0.48‡

CI) † (-0.26, 0.13) (-0.31, 0.08) (-0.66, -0.27) (-0.67, -0.28)

Percent ofpatientsachieving

HbA < 7% 43 39 43 50§§ 57§§1c

Body Weight

Baseline(mean) in kg 92.1 90.3 93.0 88.3 91.5% changefrom baseline(adjustedmean) -2.1 -3.0 -3.9 -3.5 -4.2

Differencefrommetformin XR(adjustedmean) -0.9§§ -1.8§ -1.4‡ -2.1‡(95% CI)† (-1.6, -0.2) (-2.6, -1.1) (-2.1, -0.6) (-2.9, -1.4)

* Intent-to-treat population† Least squares mean adjusted for covariates including baseline value and stratification factor‡ Adjusted p = 0.001§ Adjusted p < 0.01§§ Adjusted p < 0.05

In three studies conducted in special populations (older patients, patients with an eGFR of30 mL/min/1.73 m2 to < 50 mL/min/1.73 m2 and patients with or at high risk for cardiovasculardisease), canagliflozin was added to patients’ current stable diabetes treatments (diet, monotherapy, orcombination therapy).

A total of 714 patients ≥ 55 years of age to ≤ 80 years of age (227 patients 65 years of age to< 75 years of age and 46 patients 75 years of age to ≤ 80 years of age) with inadequate glycaemiccontrol on current diabetes treatment (glucose-lowering medicinal products and/or diet and exercise)participated in a double-blind, placebo-controlled study over 26 weeks. Statistically significant(p < 0.001) changes from baseline HbA1c relative to placebo of -0.57% and -0.70% were observed for100 mg and 300 mg, respectively (see sections 4.2 and 4.8).

Patients with eGFR < 60 mL/min/1.73 m2

In a pooled analysis of patients (N = 721) with a baseline eGFR 45 mL/min/1.73 m2 to< 60 mL/min/1.73 m2, canagliflozin provided clinically meaningful reduction in HbA1c compared toplacebo, with -0.47% for canagliflozin 100 mg and -0.52% for canagliflozin 300 mg. Patients with abaseline eGFR 45 mL/min/1.73 m2 to < 60 mL/min/1.73 m2 treated with canagliflozin 100 mg and300 mg exhibited mean improvements in percent change in body weight relative to placebo of -1.8%and -2.0%, respectively.

In a pooled analysis of patients (N = 348) with a baseline eGFR < 45 mL/min/1.73 m2, canagliflozinprovided a modest reduction in HbA1c compared to placebo, with -0.23% for canagliflozin 100 mgand -0.39% for canagliflozin 300 mg.

The majority of patients with a baseline eGFR < 60 mL/min/1.73 m2 were on insulin and/or asulphonylurea. Consistent with the expected increase of hypoglycaemia when a medicinal product notassociated with hypoglycaemia is added to insulin and/or sulphonylurea, an increase in hypoglycaemiaepisodes/events was seen when canagliflozin was added to insulin and/or a sulphonylurea (seesection 4.8).

In four placebo-controlled studies, treatment with canagliflozin as monotherapy or add-on therapywith one or two oral glucose-lowering medicinal products resulted in mean changes from baselinerelative to placebo in FPG of -1.2 mmol/L to -1.9 mmol/L for canagliflozin 100 mg and -1.9 mmol/Lto -2.4 mmol/L for canagliflozin 300 mg, respectively. These reductions were sustained over thetreatment period and near maximal after the first day of treatment.

Postprandial glucose

Using a mixed-meal challenge, canagliflozin as monotherapy or add-on therapy with one or two oralglucose-lowering medicinal products reduced postprandial glucose (PPG) from baseline relative toplacebo by -1.5 mmol/L to -2.7 mmol/L for canagliflozin 100 mg and -2.1 mmol/L to -3.5 mmol/L for300 mg, respectively, due to reductions in the pre-meal glucose concentration and reducedpostprandial glucose excursions.

Canagliflozin 100 mg and 300 mg as monotherapy and as dual or triple add-on therapy resulted instatistically significant reductions in the percentage of body weight at 26 weeks relative to placebo. Intwo 52-week active-controlled studies comparing canagliflozin to glimepiride and sitagliptin,sustained and statistically significant mean reductions in the percentage of body weight forcanagliflozin as add-on therapy to metformin were -4.2% and -4.7% for canagliflozin 100 mg and300 mg, respectively, compared to the combination of glimepiride and metformin (1.0%) and -2.5%for canagliflozin 300 mg in combination with metformin and a sulphonylurea compared to sitagliptinin combination with metformin and a sulphonylurea (0.3%).

A subset of patients (N = 208) from the active-controlled dual therapy study with metformin whounderwent dual energy X-ray densitometry (DXA) and abdominal computed tomography (CT) scansfor evaluation of body composition demonstrated that approximately two-thirds of the weight losswith canagliflozin was due to loss of fat mass with similar amounts of visceral and abdominalsubcutaneous fat being lost. Two hundred eleven (211) patients from the clinical study in olderpatients participated in a body composition substudy using DXA body composition analysis. Thisdemonstrated that approximately two-thirds of the weight loss associated with canagliflozin was dueto loss of fat mass relative to placebo. There were no meaningful changes in bone density in trabecularand cortical regions.

In placebo-controlled studies, treatment with canagliflozin 100 mg and 300 mg resulted in meanreductions in systolic blood pressure of -3.9 mmHg and -5.3 mmHg, respectively, compared toplacebo (-0.1 mmHg) and a smaller effect on diastolic blood pressure with mean changes forcanagliflozin 100 mg and 300 mg of -2.1 mmHg and -2.5 mmHg, respectively, compared to placebo(-0.3 mmHg). There was no notable change in heart rate.

Patients with baseline HbA1c > 10% to ≤ 12%

A substudy of patients with baseline HbA1c > 10% to ≤ 12% with canagliflozin as monotherapyresulted in reductions from baseline in HbA1c (not placebo-adjusted) of -2.13% and -2.56% forcanagliflozin 100 mg and 300 mg, respectively.

Cardiovascular outcomes in the CANVAS Program

The effect of canagliflozin on cardiovascular events in adults with type 2 diabetes who had establishedcardiovascular (CV) disease or were at risk for CVD (two or more CV risk factors), was evaluated inthe CANVAS Program (integrated analysis of the CANVAS and the CANVAS-R study). Thesestudies were multi-centre, multi-national, randomised, double-blind, parallel group, with similarinclusion and exclusion criteria and patient populations. The CANVAS Program compared the risk ofexperiencing a Major Adverse Cardiovascular Event (MACE) defined as the composite ofcardiovascular death, nonfatal myocardial infarction and nonfatal stroke, between canagliflozin andplacebo on a background of standard of care treatments for diabetes and atherosclerotic cardiovasculardisease.

In CANVAS, subjects were randomly assigned 1:1:1 to canagliflozin 100 mg, canagliflozin 300 mg,or matching placebo. In CANVAS-R, subjects were randomly assigned 1:1 to canagliflozin 100 mg ormatching placebo, and titration to 300 mg was permitted (based on tolerability and glycaemic needs)after Week 13. Concomitant antidiabetic and atherosclerotic therapies could be adjusted, according tothe standard care for these diseases.

A total of 10,134 patients were treated (4,327 in CANVAS and 5,807 in CANVAS-R; total of 4,344randomly assigned to placebo and 5,790 to canagliflozin) for a mean exposure duration of 149 weeks(223 weeks in CANVAS and 94 weeks in CANVAS-R). Vital status was obtained for 99.6% ofsubjects across the studies. The mean age was 63 years and 64% were male. Sixty-six percent ofsubjects had a history of established cardiovascular disease, with 56% having a history of coronarydisease, 19% with cerebrovascular disease, and 21% with peripheral vascular disease; 14% had ahistory of heart failure.

The mean HbA1c at baseline was 8.2% and mean duration of diabetes was 13.5 years.

Patients were required to have an eGFR > 30 mL/min/1.73 m2 at study entry. Baseline renal functionwas normal or mildly impaired in 80% of patients and moderately impaired in 20% of patients (meaneGFR 77 mL/min/1.73 m2). At baseline, patients were treated with one or more antidiabetic medicinalproduct including metformin (77%), insulin (50%), and sulfonylurea (43%).

The primary endpoint in the CANVAS Program was the time to first occurrence of a MACE.

Secondary endpoints within a sequential conditional hypothesis testing were all-cause mortality andcardiovascular mortality.

Patients in the pooled canagliflozin groups (pooled analysis of canagliflozin 100 mg, canagliflozin300 mg, and canagliflozin up-titrated from 100 mg to 300 mg) had a lower rate of MACE as comparedto placebo: 2.69 versus 3.15 patients per 100 patient-years (HR of the pooled analysis: 0.86; 95% CI(0.75, 0.97).

Based on the Kaplan-Meier plot for the first occurrence of MACE, shown below, the reduction in

MACE in the canagliflozin group was observed as early as Week 26 and was maintained throughoutthe remainder of the study (see Figure 1).

Figure 1: Time to first occurrence of MACE

There were 2,011 patients with eGFR 30 to < 60 mL/min/1.73 m2. The MACE findings in the 30 to< 60 mL/min/1.73 m2, 30 to < 45 mL/min/1.73 m2 and 45 to < 60 mL/min/1.73 m2 subgroups wereconsistent with the overall findings.

Each MACE component positively contributed to the overall composite, as shown in Figure 2. Resultsfor the 100 mg and 300 mg canagliflozin doses were consistent with results for the combined dosegroups.

Figure 2: Treatment effect for the primary composite endpoint and its components1 P value for superiority (2-sided) = 0.0158.

All-cause mortality in the CANVAS Program

In the combined canagliflozin group, the HR for all-cause mortality versus placebo was 0.87; 95% CI(0.74, 1.01).

Heart failure requiring hospitalisation in the CANVAS Program

Canagliflozin reduced the risk for heart failure requiring hospitalisation compared to placebo (HR:0.67; 95% CI (0.52, 0.87)).

Renal endpoints in the CANVAS Program

For time to first adjudicated nephropathy event (doubling of serum creatinine, need forrenal-replacement therapy, and renal death), the HR was 0.53 (95% CI: 0.33, 0.84) for canagliflozin(0.15 events per 100 patient-years) versus placebo (0.28 events per 100 patient-years). In addition,canagliflozin reduced progression of albuminuria by 25.8% versus placebo 29.2% (HR: 0.73; 95% CI:0.67, 0.79) in patients with baseline normo- or micro-albuminuria.

Renal outcomes in the CREDENCE study

The effect of canagliflozin 100 mg on renal events in adults with type 2 diabetes and diabetic kidneydisease (DKD) with estimated glomerular filtration rate (eGFR) 30 to < 90 mL/min/1.73 m2 andalbuminuria (˃ 300 to 5000 mg/g of creatinine), was evaluated in the Canagliflozin and Renal Eventsin Diabetes with Established Nephropathy Clinical Evaluation Trial (CREDENCE). This was amulti-centre, multi-national, randomised, double-blind, event-driven, placebo-controlled,parallel-group study. The CREDENCE study compared the risk of experiencing DKD defined as thecomposite of end-stage kidney disease, doubling of serum creatinine, and renal or cardiovasculardeath, between canagliflozin 100 mg and placebo on a background of standard of care treatments for

DKD, including angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker(ARB). Canagliflozin 300 mg was not investigated in this study.

In CREDENCE, subjects were randomly assigned 1:1 to canagliflozin 100 mg or placebo, stratified byscreening eGFR 30 to <45, 45 to <60, 60 to <90 mL/min/1.73 m2. Treatment with canagliflozin100 mg was continued in patients until the initiation of dialysis or in the event of renal transplantation.

A total of 4,397 subjects were treated and exposed for a mean of 115 weeks. The mean age was63 years and 66% were male.

The mean baseline HbA1c was 8.3% and baseline median urine albumin/creatinine was 927 mg/g. Themost frequent antihyperglycaemic agents (AHA) used at baseline were insulin (65.5%), biguanides(57.8%), and sulfonylureas (28.8%). Nearly all subjects (99.9%) were on ACEi or ARB atrandomisation. About 92% of the subjects were on cardiovascular therapies (not including

ACEi/ARBs) at baseline, with approximately 60% taking an anti-thrombotic agent (includingacetylsalicylic acid) and 69% on statins.

The mean baseline eGFR was 56.2 mL/min/1.73 m2 and approximately 60% of the population had abaseline eGFR of < 60 mL/min/1.73 m2. The proportion of subjects with prior CV disease was 50.4%;14.8% had a history of heart failure.

The primary composite endpoint in the CREDENCE study was the time to first occurrence of ESKD(defined as an eGFR < 15 mL/min/1.73 m2, initiation of chronic dialysis or renal transplant), doublingof serum creatinine, and renal or CV death.

Canagliflozin 100 mg significantly reduced the risk of first occurrence of the primary compositeendpoint of ESKD, doubling of serum creatinine, and renal or CV death [p<0.0001; HR: 0.70; 95%

CI: 0.57, 0.84] (see Figure 4). Treatment effect was consistent across subgroups, including all threeeGFR strata and subjects with or without a history of CV disease.

Based on the Kaplan-Meier plot for the time to first occurrence of the primary composite endpointshown below, the treatment effect was evident beginning from Week 52 with canagliflozin 100 mgand was maintained through the end of study (see Figure 3).

Canagliflozin 100 mg significantly reduced the risk of cardiovascular secondary endpoints, as shownin Figure 4.

Figure 3: CREDENCE: Time to first occurrence of the primary composite endpoint

* 95% RCI (Repeated Confidence Interval) for the primary endpoint with family-wise type I error-rate controlled at a2-sided significance level of 0.05.

Figure 4: Treatment effect for the primary composite endpoint and its components and secondaryendpoints

As shown in Figure 5, the eGFR in placebo-treated patients demonstrated a progressive linear declineover time; in contrast, the canagliflozin group showed an acute decrease at Week 3, followed by anattenuated decline over time; after Week 52, the LS mean decrease in eGFR was smaller in thecanagliflozin group than in the placebo group, and the treatment effect was maintained through the endof treatment.

Figure 5: LS mean change from baseline in eGFR over time (on-treatment analysis set)

In CREDENCE, the incidence rate for renal-related adverse events was lower in the canagliflozin100 mg group compared with the placebo group (5.71 and 7.91 per 100 patient-years in canagliflozin100 mg and placebo, respectively).

The European Medicines Agency has deferred the obligation to submit the results of studies withcanagliflozin in one or more subsets of the paediatric population in type 2 diabetes (see section 4.2 forinformation on paediatric use).

The pharmacokinetics of canagliflozin are essentially similar in healthy subjects and patients withtype 2 diabetes. After single-dose oral administration of 100 mg and 300 mg in healthy subjects,canagliflozin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 hourto 2 hours post-dose. Plasma Cmax and AUC of canagliflozin increased in a dose-proportional mannerfrom 50 mg to 300 mg. The apparent terminal half-life (t1/2) (expressed as mean ± standard deviation)was 10.6 ± 2.13 hours and 13.1 ± 3.28 hours for the 100 mg and 300 mg doses, respectively.

Steady-state was reached after 4 days to 5 days of once-daily dosing with canagliflozin 100 mg to300 mg. Canagliflozin does not exhibit time-dependent pharmacokinetics, and accumulated in plasmaup to 36% following multiple doses of 100 mg and 300 mg.

The mean absolute oral bioavailability of canagliflozin is approximately 65%. Co-administration of ahigh-fat meal with canagliflozin had no effect on the pharmacokinetics of canagliflozin; therefore,

Invokana may be taken with or without food. However, based on the potential to reduce postprandialplasma glucose excursions due to delayed intestinal glucose absorption, it is recommended that

Invokana be taken before the first meal of the day (see sections 4.2 and 5.1).

The mean steady-state volume of distribution of canagliflozin following a single intravenous infusionin healthy subjects was 83.5 litres, suggesting extensive tissue distribution. Canagliflozin isextensively bound to proteins in plasma (99%), mainly to albumin. Protein binding is independent ofcanagliflozin plasma concentrations. Plasma protein binding is not meaningfully altered in patientswith renal or hepatic impairment.

O-glucuronidation is the major metabolic elimination pathway for canagliflozin, which is mainlyglucuronidated by UGT1A9 and UGT2B4 to two inactive O-glucuronide metabolites.

CYP3A4-mediated (oxidative) metabolism of canagliflozin is minimal (approximately 7%) in humans.

In in vitro studies, canagliflozin neither inhibited cytochrome P450 CYP1A2, CYP2A6, CYP2C19,

CYP2D6, or CYP2E1, CYP2B6, CYP2C8, CYP2C9, nor induced CYP1A2, CYP2C19, CYP2B6,

CYP3A4 at higher than therapeutic concentrations. No clinically relevant effect on CYP3A4 wasobserved in vivo (see section 4.5).

Following administration of a single oral [14C]canagliflozin dose to healthy subjects, 41.5%, 7.0%, and3.2% of the administered radioactive dose was recovered in faeces as canagliflozin, a hydroxylatedmetabolite, and an O-glucuronide metabolite, respectively. Enterohepatic circulation of canagliflozinwas negligible.

Approximately 33% of the administered radioactive dose was excreted in urine, mainly as

O-glucuronide metabolites (30.5%). Less than 1% of the dose was excreted as unchangedcanagliflozin in urine. Renal clearance of canagliflozin 100 mg and 300 mg doses ranged from1.30 mL/min to 1.55 mL/min.

Canagliflozin is a low-clearance substance, with a mean systemic clearance of approximately192 mL/min in healthy subjects following intravenous administration.

A single-dose, open-label study evaluated the pharmacokinetics of canagliflozin 200 mg in subjectswith varying degrees of renal impairment (classified using CrCl based on the Cockroft-Gault equation)compared to healthy subjects. The study included 8 subjects with normal renal function(CrCl ≥ 80 mL/min), 8 subjects with mild renal impairment (CrCl 50 mL/min to < 80 mL/min),8 subjects with moderate renal impairment (CrCl 30 mL/min to < 50 mL/min), and 8 subjects withsevere renal impairment (CrCl < 30 mL/min) as well as 8 subjects with ESKD on haemodialysis.

The Cmax of canagliflozin was moderately increased by 13%, 29%, and 29% in subjects with mild,moderate, and severe renal failure, respectively, but not in subjects on haemodialysis. Compared tohealthy subjects, plasma AUC of canagliflozin was increased by approximately 17%, 63%, and 50%in subjects with mild, moderate, and severe renal impairment, respectively, but was similar for ESKDsubjects and healthy subjects.

Canagliflozin was negligibly removed by haemodialysis.

Relative to subjects with normal hepatic function, the geometric mean ratios for Cmax and AUC∞ ofcanagliflozin were 107% and 110%, respectively, in subjects with Child-Pugh class A (mild hepaticimpairment) and 96% and 111%, respectively, in subjects with Child-Pugh class B (moderate) hepaticimpairment following administration of a single 300 mg dose of canagliflozin.

These differences are not considered to be clinically meaningful. There is no clinical experience inpatients with Child-Pugh class C (severe) hepatic impairment.

Age had no clinically meaningful effect on the pharmacokinetics of canagliflozin based on apopulation pharmacokinetic analysis (see sections 4.2, pct. 4.4, and 4.8).

A paediatric phase 1 study examined the pharmacokinetics and pharmacodynamics of canagliflozin inchildren and adolescents ≥ 10 to < 18 years of age with type 2 diabetes mellitus. The observedpharmacokinetic and pharmacodynamic responses were consistent with those found in adult subjects.

Pharmacogenetics

Both UGT1A9 and UGT2B4 are subject to genetic polymorphism. In a pooled analysis of clinicaldata, increases in canagliflozin AUC of 26% were observed in UGT1A9*1/*3 carriers and 18% in

UGT2B4*2/*2 carriers. These increases in canagliflozin exposure are not expected to be clinicallyrelevant. The effect of being homozygote (UGT1A9*3/*3, frequency < 0.1%) is probably moremarked, but has not been investigated.

Gender, race/ethnicity, or body mass index had no clinically meaningful effect on thepharmacokinetics of canagliflozin based on a population pharmacokinetic analysis.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, and genotoxicity.

Canagliflozin showed no effects on fertility and early embryonic development in the rat at exposuresup to 19 times the human exposure at the maximum recommended human dose (MRHD).

In an embryo-foetal development study in rats, ossification delays of metatarsal bones were observedat systemic exposures 73 times and 19 times higher than the clinical exposures at the 100 mg and300 mg doses. It is unknown whether ossification delays can be attributed to effects of canagliflozinon calcium homeostasis observed in adult rats. Ossification delays were also observed for thecombination of canagliflozin and metformin, which were more prominent than for metformin alone atcanagliflozin exposures 43 times and 12 times higher than clinical exposures at 100 mg and 300 mgdoses.

In a pre- and postnatal development study, canagliflozin administered to female rats from gestationday 6 to lactation day 20 resulted in decreased body weights in male and female offspring atmaternally toxic doses > 30 mg/kg/day (exposures ≥ 5.9 times the human exposure to canagliflozin atthe MHRD). Maternal toxicity was limited to decreased body weight gain.

A study in juvenile rats administered canagliflozin from day 21 through day 90 postnatal did not showincreased sensitivity compared to effects observed in adults rats. However, dilatation of the renalpelvis was noticed with a No Observed Effect Level (NOEL) at exposures 2.4 times and 0.5 times theclinical exposures at 100 mg and 300 mg doses, respectively, and did not fully reverse within theapproximately 1-month recovery period. Persistent renal findings in juvenile rats can most likely beattributed to reduced ability of the developing rat kidney to handle canagliflozin-increased urinevolumes, as functional maturation of the rat kidney continues through 6 weeks of age.

Canagliflozin did not increase the incidence of tumours in male and female mice in a 2-year study atdoses of 10, 30, and 100 mg/kg. The highest dose of 100 mg/kg provided up to 14 times the clinicaldose of 300 mg based on AUC exposure. Canagliflozin increased the incidence of testicular Leydigcell tumours in male rats at all doses tested (10, 30, and 100 mg/kg); the lowest dose of 10 mg/kg isapproximately 1.5 times the clinical dose of 300 mg based on AUC exposure. The higher doses ofcanagliflozin (100 mg/kg) in male and female rats increased the incidence of pheochromocytomas andrenal tubular tumours. Based on AUC exposure, the NOEL of 30 mg/kg/day for pheochromocytomasand renal tubular tumours is approximately 4.5 times the exposure at the daily clinical dose of 300 mg.

Based on preclinical and clinical mechanistic studies, Leydig cell tumours, renal tubule tumours, andpheochromocytomas are considered to be rat-specific. Canagliflozin-induced renal tubule tumours andpheochromocytomas in rats appear to be caused by carbohydrate malabsorption as a consequence ofintestinal SGLT1 inhibitory activity of canagliflozin in the gut of rats; mechanistic clinical studieshave not demonstrated carbohydrate malabsorption in humans at canagliflozin doses of up to 2-timesthe maximum recommended clinical dose. The Leydig cell tumours are associated with an increase inluteinizing hormone (LH), which is a known mechanism of Leydig cell tumour formation in rats. In a12-week clinical study, unstimulated LH did not increase in male patients treated with canagliflozin.

Microcrystalline cellulose

Hydroxypropylcellulose

Croscarmellose sodium

Magnesium stearate

Invokana 100 mg film-coated tablets

Poly(vinyl alcohol)

Titanium dioxide (E171)

Macrogol 3350

Talc

Iron oxide yellow (E172)

Invokana 300 mg film-coated tablets

Poly(vinyl alcohol)

Titanium dioxide (E171)

Macrogol 3350

Talc

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

Polyvinyl chloride/Aluminium (PVC/Alu) perforated unit dose blister.

Pack sizes of 10 x 1, 30 x 1, 90 x 1, and 100 x 1 film-coated tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

Invokana 100 mg film-coated tablets

EU/1/13/884/001 (10 film-coated tablets)

EU/1/13/884/002 (30 film-coated tablets)

EU/1/13/884/003 (90 film-coated tablets)

EU/1/13/884/004 (100 film-coated tablets)

Invokana 300 mg film-coated tablets

EU/1/13/884/005 (10 film-coated tablets)

EU/1/13/884/006 (30 film-coated tablets)

EU/1/13/884/007 (90 film-coated tablets)

EU/1/13/884/008 (100 film-coated tablets)

Date of first authorisation: 15 November 2013

Date of latest renewal: 26 July 2018

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.