VOKANAMET 150mg / 850mg tablets medication leaflet

Vokanamet 50 mg/850 mg film-coated tablets

Vokanamet 50 mg/1,000 mg film-coated tablets

Vokanamet 150 mg/850 mg film-coated tablets

Vokanamet 150 mg/1,000 mg film-coated tablets

Vokanamet 50 mg/850 mg film-coated tablets

Each tablet contains canagliflozin hemihydrate, equivalent to 50 mg of canagliflozin, and 850 mg ofmetformin hydrochloride.

Vokanamet 50 mg/1,000 mg film-coated tablets

Each tablet contains canagliflozin hemihydrate, equivalent to 50 mg of canagliflozin, and 1,000 mg ofmetformin hydrochloride.

Vokanamet 150 mg/850 mg film-coated tablets

Each tablet contains canagliflozin hemihydrate, equivalent to 150 mg of canagliflozin, and 850 mg ofmetformin hydrochloride.

Vokanamet 150 mg/1,000 mg film-coated tablets

Each tablet contains canagliflozin hemihydrate, equivalent to 150 mg of canagliflozin, and 1,000 mgof metformin hydrochloride.

For the full list of excipients, see section 6.1.

Film-coated tablet.

Vokanamet 50 mg/850 mg film-coated tablets

The tablet is pink, capsule-shaped, 20 mm in length, film-coated, and debossed with “CM” on one sideand “358” on the other side.

Vokanamet 50 mg/1,000 mg film-coated tablets

The tablet is beige, capsule-shaped, 21 mm in length, film-coated, and debossed with “CM” on oneside and “551” on the other side.

Vokanamet 150 mg/850 mg film-coated tablets

The tablet is light yellow, capsule-shaped, 21 mm in length, film-coated, and debossed with “CM” onone side and “418” on the other side.

Vokanamet 150 mg/1,000 mg film-coated tablets

The tablet is purple, capsule-shaped, 22 mm in length, film-coated, and debossed with “CM” on oneside and “611” on the other side.

Vokanamet is indicated in adults with type 2 diabetes mellitus as an adjunct to diet and exercise:

- in patients insufficiently controlled on their maximally tolerated doses of metformin alone

- in combination with other medicinal products for the treatment of diabetes, in patientsinsufficiently controlled with metformin and these medicinal products

- in patients already being treated with the combination of canagliflozin and metformin asseparate tablets.

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

Adults with normal renal function (estimated glomerular filtration rate [eGFR] ≥ 90 mL/min/1.73 m2)

The dose of glucose-lowering therapy with Vokanamet should be individualised on the basis of thepatient’s current regimen, effectiveness, and tolerability, using the recommended daily dose of 100 mgor 300 mg canagliflozin and not exceeding the maximum recommended daily dose ofmetformin orally.

For patients inadequately controlled on maximal tolerated dose of metformin

For patients not adequately controlled on metformin, the recommended starting dose of Vokanametshould provide canagliflozin dosed at 50 mg twice daily plus the dose of metformin already beingtaken or the nearest therapeutically appropriate dose. For patients who are tolerating a Vokanametdose containing canagliflozin 50 mg who need tighter glycaemic control, the dose can be increased to

Vokanamet containing 150 mg canagliflozin twice daily (see below and section 4.4).

For patients switching from separate tablets of canagliflozin and metformin

For patients switching from separate tablets of canagliflozin and metformin, Vokanamet should beinitiated at the same total daily dose of canagliflozin and metformin already being taken or the nearesttherapeutically appropriate dose of metformin.

Dose titration with canagliflozin (added to the optimal dose of metformin) should be considered beforethe patient is switched to Vokanamet.

In patients tolerating Vokanamet containing canagliflozin 50 mg who need tighter glycaemic control,increasing the dose to Vokanamet containing canagliflozin 150 mg may be considered.

Care should be taken when increasing the dose of Vokanamet containing 50 mg of canagliflozin to150 mg of canagliflozin in patients ≥ 75 years of age, patients with known cardiovascular disease, orother patients for whom the initial canagliflozin-induced diuresis poses a risk (see section 4.4). Inpatients with evidence of volume depletion, correcting this condition prior to initiation of Vokanametis recommended (see section 4.4).

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

Elderly (≥ 65 years old)

Because metformin is eliminated in part by the kidney and elderly patients are more likely to havedecreased renal function, Vokanamet should be used with caution as age increases. Regularassessment of renal function is necessary to aid in prevention of metformin-associated lactic acidosis,particularly in elderly patients. The risk of volume depletion associated with canagliflozin should betaken into account (see sections 4.3 and 4.4).

Vokanamet is contraindicated in patients with severe renal failure (eGFR < 30 mL/min) (seesection 4.3).

An eGFR should be assessed before initiation of treatment with metformin containing products and atleast annually thereafter. In patients at increased risk of further progression of renal impairment and inthe elderly, renal function should be assessed more frequently, e.g. every 3-6 months.

The maximum daily dose of metformin should preferably be divided into 2-3 daily doses.

Risk factors that may increase the risk of lactic acidosis (see section 4.4) should be reviewed beforeconsidering initiation of metformin in patients with eGFR < 60 mL/min/1.73 m2.

If no adequate strength of Vokanamet is available, individual monocomponents should be used insteadof the fixed dose combination (see table 1).

Table 1: Dose adjustment recommendationseGFR Metformin CanagliflozinmL/min/1.73 m260-89 Maximum daily dose is 3,000 mg Maximum total daily dose is 300 mg.

Dose reduction may be considered inrelation to declining renal function.

45-59 Maximum daily dose is 2,000 mg Canagliflozin should not be initiated.

The starting dose is at most half of the Patients tolerating canagliflozin canmaximum dose. continue use at a maximum totaldaily dose of 100 mg.30-44 Maximum daily dose is 1,000 mg. Canagliflozin should not be used.

The starting dose is at most half of themaximum dose.

< 30 Metformin is contraindicated. Canagliflozin has not been studied insevere renal impairment.

Vokanamet is contraindicated in patients with hepatic impairment due to the active substancemetformin (see sections 4.3 and 5.2). There is no clinical experience with Vokanamet in patients withhepatic impariment.

The safety and efficacy of Vokanamet in children under 18 years of age have not been established. Nodata are available.

For oral use

Vokanamet should be taken orally twice daily with meals to reduce the gastrointestinal undesirableeffects associated with metformin. Tablets are to be swallowed whole.

If a dose is missed, it should be taken as soon as the patient remembers unless it is time for the nextdose in which case patients should skip the missed dose and take the medicinal product at the nextregularly scheduled time.

- Hypersensitivity to the active substances or any of the excipients listed in section 6.1;

- Any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis);

- Diabetic pre-coma;

- Severe renal failure (eGFR < 30 mL/min/1.73 m2) (see sections 4.2 and 4.4);

- Acute conditions with the potential to alter renal function such as: dehydration, severe infection,shock (see section 4.4);

- Acute or chronic disease which may cause tissue hypoxia such as: cardiac or respiratory failure,recent myocardial infarction, shock;

- Hepatic impairment, acute alcohol intoxication, alcoholism (see sections 4.2 and 4.5).

Lactic acidosis

Lactic acidosis, a very rare but serious metabolic complication, most often occurs at acute worseningof renal function or cardiorespiratory illness or sepsis. Metformin accumulation occurs at acuteworsening of renal function and increases the risk of lactic acidosis.

In case of dehydration (severe diarrhoea or vomiting, fever or reduced fluid intake), Vokanametshould be temporarily discontinued and contact with a healthcare professional is recommended.

Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics andnon-steroidal anti-inflammatory drugs [NSAIDs]) should be initiated with caution in

Vokanamet-treated patients. Other risk factors for lactic acidosis are excessive alcohol intake, hepaticinsufficiency, inadequately controlled diabetes, ketosis, prolonged fasting and any conditionsassociated with hypoxia, as well as concomitant use of medicinal products that may cause lacticacidosis (see sections 4.3 and 4.5).

Patients and/or care-givers should be informed of the risk of lactic acidosis. Lactic acidosis ischaracterised by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermiafollowed by coma. In case of suspected symptoms, the patient should stop taking Vokanamet and seekimmediate medical attention. Diagnostic laboratory findings are decreased blood pH (< 7.35),increased plasma lactate levels (> 5 mmol/L) and an increased anion gap and lactate/pyruvate ratio.

The risk of lactic acidosis must be considered in the event of non-specific signs such as muscle crampswith digestive disorders as abdominal pain and severe asthenia.

Decreased renal function in elderly patients is frequent and asymptomatic. Special caution should beexercised in situations where renal function may become impaired; for example, when initiatingantihypertensive or diuretic therapy and when starting treatment with a NSAID.

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 daily in patients witheGFR < 60 mL/min/1.73 m2 or CrCl < 60 mL/min and canagliflozin should not be used for thepurpose of glycaemic control in patients with an eGFR persistently < 45 mL/min/1.73 m2 or

CrCl < 45 mL/min (see section 4.2).

Administration of iodinated contrast agent

Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy,resulting in metformin accumulation and an increased risk of lactic acidosis. Vokanamet should bediscontinued prior to, or at the time of the imaging procedure and not restarted until at least 48 hoursafter, provided that renal function has been re-evaluated and found to be stable (see sections 4.2and 4.5).

As Vokanamet contains metformin, Vokanamet must be discontinued at the time of surgery undergeneral, spinal, or epidural anaesthesia. Therapy may be restarted no earlier than 48 hours followingsurgery or resumption of oral nutrition and provided that renal function has been re-evaluated andfound to be stable.

Vitamin B12 decrease/deficiency

Metformin may reduce vitamin B12 serum levels. The risk of low vitamin B12 levels increases withincreasing metformin dose, treatment duration, and/or in patients with risk factors known to causevitamin B12 deficiency. In case of suspicion of vitamin B12 deficiency (such as anaemia orneuropathy), vitamin B12 serum levels should be monitored. Periodic vitamin B12 monitoring could benecessary in patients with risk factors for vitamin B12 deficiency. Metformin therapy should becontinued for as long as it is tolerated and not contra-indicated and appropriate corrective treatment forvitamin B12 deficiency provided in line with current clinical guidelines.

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 a daily dose of 300 mg canaliflozin and occurred most frequently in the first threemonths (see section 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 Vokanamet, in case of intercurrent conditions that may lead to volume depletion(such as a gastrointestinal illness), careful monitoring of volume status (e.g., physical examination,blood pressure measurements, laboratory tests including renal function tests), and serum electrolytes isrecommended. Temporary interruption of treatment with Vokanamet may be considered for patientswho develop volume depletion while on Vokanamet therapy until the condition is corrected. Ifinterrupted, consideration should be given to more frequent glucose monitoring.

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 Vokanamet should be discontinuedimmediately.

Treatment should be interrupted in patients who are hospitalised for major surgical procedures or acuteserious medical illnesses. Monitoring of ketones is recommended in these patients.

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

Before initiating Vokanamet, factors in the patient history that may predispose to ketoacidosis shouldbe considered.

Diabetic ketoacidosis may be prolonged after discontinuation of Vokanamet in some patients, i.e. itmay last 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 and

Vokanamet 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, canagliflozin 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 Vokanamet, 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 Vokanamet in patients who develop events which may precede amputationsuch as 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, Vokanamet 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 (≥ 65 years old)

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 with canagliflozin therapy. In addition, in such patients greater decreases ineGFR were reported (see sections 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

Vokanamet.

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 canagliflozin’s mechanism of action, patients taking Vokanamet will test positive for glucosein their urine.

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

Pharmacokinetic drug interaction studies with Vokanamet have not been performed; however, suchstudies have been conducted with the individual active substances (canagliflozin and metformin).

Co-administration of canagliflozin (300 mg once daily) and metformin (2,000 mg once daily) had noclinically relevant effect on the pharmacokinetics of either canagliflozin or metformin.

Canagliflozin

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

Canagliflozin is not recommended for use in patients receiving loop diuretics.

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 Vokanamet (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 give rise to decreased exposure of canagliflozin.

Following co-administration of canagliflozin with rifampicin (an inducer of various active transportersand medicinal product-metabolising enzymes), 51% and 28% decreases in canagliflozin systemicexposure (area under the curve, AUC) and peak concentration (Cmax) were observed. These decreasesin exposure to canagliflozin may 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 to

Vokanamet containing 150 mg twice daily may be considered if patients are currently toleratingcanagliflozin 50 mg twice daily and require additional glycaemic control (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 canagliflozin 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

Vokanamet. For further detail, it may be advisable to contact the specific manufacturer of the 1,5-AGassay.

Alcohol

Alcohol intoxication is associated with an increased risk of lactic acidosis (particularly in cases offasting, malnutrition, or hepatic impairment) due to the metformin active substance of Vokanamet (seesection 4.4). Consumption of alcohol and medicinal products containing alcohol should be avoided.

Iodinated contrast agents

The intravascular administration of iodinated contrast agents in radiological studies may lead to renalfailure, resulting in metformin accumulation and a risk of lactic acidosis. Therefore, Vokanamet mustbe discontinued prior to, or at the time of the imaging procedure and not restarted until at least48 hours after, provided that renal function has been re-evaluated and found to be stable (seesections 4.2 and 4.4).

Cationic medicinal products

Cationic medicinal products that are eliminated by renal tubular secretion (e.g., cimetidine) mayinteract with metformin by competing for common renal tubular transport systems. A study conductedin seven normal healthy volunteers showed that cimetidine, administered as 400 mg twice daily,increased metformin AUC by 50% and Cmax by 81%. Therefore, close monitoring of glycaemiccontrol, dose adjustment within the recommended posology and changes in diabetic treatment shouldbe considered when cationic medicinal products that are eliminated by renal tubular secretion areco-administered (see sections 4.4 and 5.1).

Combinations requiring precautions for use

Some medicinal products can adversely affect renal function which may increase the risk of lacticacidosis, e.g. NSAIDs, including selective cyclo-oxygenase (COX) II inhibitors, ACE inhibitors,angiotensin II receptor antagonists and diuretics, especially loop diuretics. When starting or using suchproducts in combination with Vokanamet, close monitoring of renal function is necessary.

Glucocorticoids (given by systemic and local routes), beta-2-agonists, and diuretics have intrinsichyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoringperformed, especially at the beginning of treatment with such medicinal products. If necessary, thedose of glucose-lowering medicinal products should be adjusted during therapy with the othermedicinal product and on its discontinuation.

Due to their potential to decrease renal function, diuretics (especially loop diuretics) may increase therisk of lactic acidosis associated with metformin.

There are no data from the use of canagliflozin alone or Vokanamet in pregnant women. Studies inanimals with canagliflozin have shown reproductive toxicity (see section 5.3).

A limited amount of data from the use of metformin in pregnant women does not indicate an increasedrisk of congenital malformations. Animal studies with metformin do not indicate harmful effects withrespect to pregnancy, embryonic or foetal development, parturition, or postnatal development (seesection 5.3).

Vokanamet should not be used during pregnancy. When pregnancy is detected, treatment with

Vokanamet should be discontinued.

No studies in lactating animals have been conducted with the combined active substances of

Vokanamet. It is unknown whether canagliflozin and/or its metabolites are excreted in human milk.

Available pharmacodynamic/toxicological data in animals have shown excretion ofcanagliflozin/metabolites in milk, as well as pharmacologically mediated effects in breast-feedingoffspring and juvenile rats exposed to canagliflozin (see section 5.3). Metformin is excreted intohuman breast milk in small amounts. A risk to newborns/infants cannot be excluded. Vokanametshould not be used during breast-feeding.

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

Vokanamet has no or negligible influence on the ability to drive and use machines. However, patientsshould be alerted to the risk of hypoglycaemia when Vokanamet is used as add-on therapy with insulinor an insulin secretagogue, and to the elevated risk of adverse reactions related to volume depletion,such as postural dizziness (see sections 4.2, pct. 4.4, and 4.8).

Canagliflozin

The safety of canagliflozin was evaluated in 22,645 patients with type 2 diabetes, including theevaluation of canagliflozin in combination with metformin in 16,334 patients. In addition, an 18-weekdouble-blind, placebo-controlled phase 2 study with twice daily dosing (canagliflozin 50 mg or150 mg as add-on therapy with metformin 500 mg) was conducted in 279 patients in which186 patients were treated with canagliflozin as add-on therapy with metformin.

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 events in order to identify adverse reactions (seetable 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.

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 a long-term renal outcomes study of 4,397 patients with type 2 diabetes and diabetickidney disease (see section 4.4). In other type 2 diabetes studies with canagliflozin, which enrolled ageneral diabetic population of 8,114 patients, no difference in lower limb amputation risk wasobserved relative to control.

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

Placebo canagliflozin

N = 4,344 N = 5,790

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 (see table 3). Multiple amputations (someinvolving both lower limbs) were observed infrequently and in similar proportions in both treatmentgroups.

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 once daily, 1.3% for canagliflozin300 mg once daily, and 1.1% for placebo. The incidence with canagliflozin treatment in the twoactive-controlled studies was similar 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 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 once daily, canagliflozin 300 mg once daily, and placebo, respectively, andsevere hypoglycaemia occurred in 1.8%, 2.7%, and 2.5% of patients treated with canagliflozin 100 mgonce daily, canagliflozin 300 mg once daily, and placebo, respectively. When canagliflozin was addedto a sulphonylurea therapy, hypoglycaemia was observed in 4.1%, 12.5%, and 5.8% of patients treatedwith canagliflozin 100 mg once daily, canagliflozin 300 mg once daily, and placebo, respectively (seesections 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 once daily and canagliflozin300 mg once daily, respectively, compared to 3.2% in placebo-treated female patients. Most reports ofvulvovaginal candidiasis occurred during the first four months of treatment with canagliflozin. Amongfemale patients taking canagliflozin, 2.3% experienced more than one infection. Overall, 0.7% of allfemale patients 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 comparedto the placebo 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 once daily (5.9% versus 4.3%, respectively) compared to 4.0% with placebo. Most infectionswere mild to moderate with no increase in the occurrence of serious adverse reactions. In these studies,subjects responded 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.

Elderly (≥ 65 years old)

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 once daily, canagliflozin 300 mg once daily,and in the control group, respectively. Decreases in eGFR (-3.4 and -4.7 mL/min/1.73 m2) werereported with canagliflozin 100 mg and canagliflozin 300 mg, respectively, compared to the controlgroup (-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).

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.

Table 4 presents adverse reactions by SOC and by frequency category reported in patients whoreceived metformin as monotherapy and that were not observed in patients receiving canagliflozin.

Frequency categories are based on information available from the metformin Summary of Product

Characteristics.

Table 4: The frequency of metformin adverse reactions identified from clinical study andpostmarketing data

System organ class Adverse reaction

Frequency

Metabolism and nutrition disorderscommon Vitamin B12 decrease/deficiencyavery rare Lactic acidosis

Nervous system disorderscommon Taste disturbance

Gastrointestinal disordersvery common Gastro-intestinal symptomsb

Skin and subcutaneous tissue disordersvery rare Erythema, Pruritis, Urticaria

Hepatobiliary disordersvery rare Liver function test abnormal, Hepatitisa Metformin may commonly reduce vitamin B12 serum levels, which may result in clinically significant vitamin B12deficiency (e.g., megaloblastic anaemia). The risk of low vitamin B12 levels increases with increasing metformin dose,treatment duration, and/or in patients with risk factors known to cause vitamin B12 deficiency. Periodic monitoring ofvitamin B12 levels is recommended in these patients.

b Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite occur mostfrequently during initiation of therapy and resolve spontaneously in most cases.

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.

Canagliflozin

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.

Hypoglycaemia has not been seen with metformin hydrochloride doses of up to 85 g; although, lacticacidosis has occurred in such circumstances. High overdose of metformin or concomitant risks maylead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in hospital. Themost effective method to remove lactate and metformin is haemodialysis.

In the event of an overdose of Vokanamet, it is reasonable to employ the usual supportive measures,e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, andinstitute clinical measures as dictated by the patient’s clinical status. The most effective method toremove lactate and metformin is haemodialysis. Canagliflozin was negligibly removed during a 4-hourhaemodialysis session. Canagliflozin is not expected to be dialysable by peritoneal dialysis.

Pharmacotherapeutic group: Drugs used in diabetes, combinations of blood glucose lowering drugs,

ATC code: A10BD16.

Vokanamet combines two oral glucose-lowering medicinal products with different and complementarymechanisms of action to improve glycaemic control in patients with type 2 diabetes: canagliflozin, aninhibitor of SGLT2 transporter, and metformin hydrochloride, a member of the biguanide class.

Canagliflozin

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 once daily provided a greaterreduction in postprandial glucose excursion than observed with the 100 mg once daily dose. Thiseffect at the 300 mg dose of canagliflozin may, in part, be due to local inhibition of intestinal SGLT1(an important intestinal glucose transporter) related to transient high concentrations of canagliflozin inthe intestinal lumen prior to medicinal product absorption (canagliflozin is a low potency inhibitor ofthe SGLT1 transporter). Studies have shown no glucose malabsorption with canagliflozin.

Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandialplasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.

Metformin may act via three mechanisms:

- by reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis

- in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilisation

- and delay of intestinal glucose absorption.

Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metforminincreases the transport capacity of the membrane glucose transporters GLUT-1 and GLUT-4.

In humans, independently of its action on glycaemia, metformin has favourable effects on lipidmetabolism. This has been shown at therapeutic doses in controlled, medium-term, or long-termclinical studies: metformin reduces total cholesterol, LDL-C, and triglyceride levels.

Pharmacodynamic effects of canagliflozin

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 once daily of canagliflozinranging from 77 g/day to 119 g/day across the phase 1 studies; the UGE observed translates to a lossof 308 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.

Both improvement in glycaemic control and reduction of cardiovascular morbidity and mortality arean integral part of the treatment of type 2 diabetes.

The co-administration of canagliflozin and metformin has been studied in patients with type 2 diabetesinadequately controlled on metformin either alone or in combination with other glucose-loweringmedicinal products.

There have been no clinical efficacy studies conducted with Vokanamet; however, bioequivalence of

Vokanamet to canagliflozin and metformin co-administered as individual tablets was demonstrated inhealthy subjects.

Canagliflozin

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 canagliflozin on glycaemic control,including 5,151 patients treated with canagliflozin in combination with metformin. The racialdistribution of patients who received canagliflozin was 72% White, 16% Asian, 5% Black, and8% other groups. 17% of patients were Hispanic. 58% of patients were male. Patients had an overallmean age of 59.5 years (range 21 years to 96 years), with 3,135 patients ≥ 65 years of age and513 patients ≥ 75 years of age. 58% of patients had a body mass index (BMI) ≥ 30 kg/m2. In theclinical development programme, 1,085 patients with a baseline eGFR 30 mL/min/1.73 m2 to< 60 mL/min/1.73 m2 were evaluated.

Placebo-controlled studies

Canagliflozin was studied as dual therapy with metformin, dual therapy with a sulphonylurea, tripletherapy with metformin and a sulphonylurea, triple therapy with metformin and pioglitazone, as anadd-on therapy with insulin, and as monotherapy (table 5). In general, canagliflozin producedclinically and statistically significant (p < 0.001) results relative to placebo in glycaemic control,including glycosylated haemoglobin (HbA1c), the percentage of patients achieving HbA1c < 7%,change from baseline fasting plasma glucose (FPG), and 2-hour postprandial glucose (PPG). Inaddition, reductions in body weight and 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 5). 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 FPG, and a statistically significant (p < 0.01) improvement in the percentageof patients achieving HbA1c < 7%. In addition, reductions in body weight and systolic blood pressurerelative to placebo were observed.

Table 5: Efficacy results from placebo-controlled clinical studiesa

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 mean) -0.79 -0.94 -0.17

Difference from placebo (adjusted -0.62b -0.77b

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

Patients (%) achieving HbA < 7% 45.5b 57.8b1c 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 and Placebo +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 mean) -0.85 -1.06 -0.13

Difference from placebo (adjusted -0.71b -0.92b

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

Patients (%) achieving HbA b1c < 7% 43.2 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 mean) -0.63 -0.72 0.01

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

Patients (%) achieving HbA < 7% 19.8b 24.7b1c 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 andmetformin and sitagliptinsitaglipting(N = 106)(N = 107)

HbA1c (%)

Baseline (mean) 8.53 8.38

Change from baseline (adjusted mean) -0.91 -0.01

Difference from placebo (adjusted

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

Patients (%) achieving HbA1c < 7% 32f 12

Fasting plasma glucose (mg/dL)

Baseline (mean) 186 180

Change from baseline (adjusted mean) -30 -3

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

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.

A dedicated study demonstrated that co-administration of canagliflozin 50 mg and 150 mg dosed twicedaily as dual therapy with metformin produced clinically and statistically significant results relative toplacebo in glycaemic control, including HbA1c, the percentage of patients achieving HbA1c < 7%,change from baseline FPG, and in reductions in body weight as shown in table 6.

Table 6: Efficacy results from placebo-controlled clinical study of canagliflozin dosed twicedailya

Canagliflozin50 mg 150 mg Placebotwice daily twice daily (N = 93)(N = 93) (N = 93)

HbA1c (%)

Baseline (mean) 7.63 7.53 7.66

Change from baseline (adjusted mean) -0.45 -0.61 -0.01

Difference from placebo (adjusted -0.44b -0.60b

N/Acmean) (95% CI) (-0.637; -0.251) (-0.792; -0.407)

Patients (%) achieving HbA d1c < 7% 47.8 57.1b 31.5

Baseline (mean) in kg 90.59 90.44 90.37% change from baseline (adjusted

- 2.8 -3.2 -0.6mean)

Difference from placebo (adjusted -2.2b -2.6b

N/Acmean) (95% CI) (-3.1; -1.3) (-3.5; -1.7)a Intent-to-treat population using last observation in study.b p < 0.001 compared to placebo.c Not applicable.d p = 0.013 compared to placebo.

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 7). Canagliflozin 100 mg oncedaily as dual 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 once daily (5.6%)and canagliflozin 300 mg once daily (4.9%) experienced at least one episode/event of hypoglycaemiaover 52 weeks of treatment compared to the group treated with glimepiride (34.2%). In a studycomparing canagliflozin 300 mg once daily to sitagliptin 100 mg in triple therapy with metformin anda sulphonylurea, canagliflozin demonstrated non-inferior (p < 0.05) and superior (p < 0.05) reductionin HbA1c relative to sitagliptin. The incidence of hypoglycaemia episodes/events with canagliflozin300 mg once daily and sitagliptin 100 mg was 40.7% and 43.2%, respectively. Significantimprovements in body weight and reductions in systolic blood pressure compared to both glimepirideand sitagliptin were also observed.

Table 7: Efficacy results from active-controlled clinical studiesa

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

Canagliflozin + metformin Glimepiride(titrated) +100 mg 300 mgmetformin(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 (adjustedmean) -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)

Canagliflozin 300 mg + Sitagliptin 100 mg +metformin and metformin andsulphonylurea 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/Amean) (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 (adjustedmean) -2.5 0.3

Difference from sitagliptin (adjusted -2.8d

N/Amean) (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 8).

Table 8: Results from 26-week active-controlled clinical study of canagliflozin as initialcombination therapy with metformin*

Canagliflozin Canagliflozin100 mg + 300 mg +

Metformin Canagliflozin Canagliflozin metformin metformin

Efficacy XR 100 mg 300 mg XR XRparameter (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(adjusted mean) -1.30 -1.37 -1.42 -1.77 -1.78

Difference fromcanagliflozin100 mg(adjusted mean) -0.40‡(95% CI) † (-0.59, -0.21)

Difference fromcanagliflozin300 mg(adjusted mean) -0.36‡(95% CI) † (-0.56, -0.17)

Difference frommetformin XR(adjusted mean) -0.06‡ -0.11‡ -0.46‡ -0.48‡(95% CI) † (-0.26, 0.13) (-0.31, 0.08) (-0.66, -0.27) (-0.67, -0.28)

Percent ofpatientsachieving HbA1c< 7% 43 39 43 50§§ 57§§

Baseline (mean)in kg 92.1 90.3 93.0 88.3 91.5% change frombaseline(adjusted mean) -2.1 -3.0 -3.9 -3.5 -4.2

Difference frommetformin XR(adjusted mean) -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 (elderly 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 once daily and 300 mg once daily, respectively (see sections 4.2 and 4.8).

Patients with eGFR 45 mL/min/1.73 m2 to < 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.

The majority of patients with a baseline eGFR 45 mL/min/1.73 m2 to < 60 mL/min/1.73 m2 were oninsulin and/or a sulphonylurea (85% [614/721]). Consistent with the expected increase ofhypoglycaemia when a medicinal product not associated with hypoglycaemia is added to insulinand/or sulphonylurea, an increase in hypoglycaemia episodes/events was seen when canagliflozin wasadded to insulin and/or a sulphonylurea (see section 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 once dailyand -1.9 mmol/L to -2.4 mmol/L for canagliflozin 300 mg once daily, respectively. These reductionswere sustained over the treatment 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 from baseline relative to placeboby -1.5 mmol/L to -2.7 mmol/L for canagliflozin 100 mg once daily and -2.1 mmol/L to -3.5 mmol/Lfor canagliflozin 300 mg once daily, respectively, due to reductions in the pre-meal glucoseconcentration and reduced postprandial glucose excursions.

Canagliflozin 100 mg and 300 mg once daily in dual or triple add-on therapy with metformin resultedin statistically significant reductions in the percentage of body weight at 26 weeks relative to placebo.

In two 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 once daily, respectively, compared to the combination of glimepiride and metformin (1.0%)and -2.5% for canagliflozin 300 mg once daily in combination with metformin and a sulphonylureacompared to sitagliptin in 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. 211 patients from the clinical study in older patients participated in a bodycomposition substudy using DXA body composition analysis. This demonstrated that approximatelytwo-thirds of the weight loss associated with canagliflozin was due to loss of fat mass relative toplacebo. There were no meaningful changes in bone density in trabecular and 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.

Baseline renal function was normal or mildly impaired in 80% of patients and moderately impaired in20% of patients (mean eGFR 77 mL/min/1.73 m2). At baseline, patients were treated with one or moreantidiabetic medicinal products 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 thissubgroup were consistent 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 combined canagliflozin group, the HR for all-cause mortality versus placebo was 0.87 (0.74,1.01).

Heart failure requiring hospitalisation

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 serumcreatinine, need for renal-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 per100 patient-years). In addition, canagliflozin reduced progression of albuminuria 25.8% versusplacebo 29.2% (HR: 0.73; 95% CI: 0.67, 0.79) in patients with baseline normo- or micro-albuminuria.

Canagliflozin 100 mg has also been studied in adults with type 2 diabetes and diabetic kidney diseasewith estimated glomerular filtration rate (eGFR) 30 to < 90 mL/min/1.73 m2 and albuminuria(˃ 33.9 to 565.6 mg/mmol of creatinine). No information in this patient population is available for thecanagliflozin/metformin fixed dose combination.

The prospective randomised (UKPDS) study has established the long-term benefit of intensive bloodglucose control in type 2 diabetes. Analysis of the results for overweight patients treated withmetformin after failure of diet alone showed:

- a significant reduction of the absolute risk of any diabetesrelated complication in the metformingroup (29.8 events/1,000 patient-years) versus diet alone (43.3 events/1,000 patient-years),p = 0.0023, and versus the combined sulphonylurea and insulin monotherapy groups(40.1 events/1,000 patient-years), p = 0.0034

- a significant reduction of the absolute risk of any diabetes-related mortality: metformin7.5 events/1,000 patient-years, diet alone 12.7 events/1,000 patient-years, p = 0.017

- a significant reduction of the absolute risk of overall mortality: metformin13.5 events/1,000 patient-years versus diet alone 20.6 events/1,000 patient-years, (p = 0.011),and versus the combined sulphonylurea and insulin monotherapy groups18.9 events/1,000 patient-years (p = 0.021)

- a significant reduction in the absolute risk of myocardial infarction: metformin11 events/1,000 patient-years, diet alone 18 events/1,000 patient-years, (p = 0.01).

The European Medicines Agency has waived the obligation to submit the results of studies with

Vokanamet in all subsets of the paediatric population in type 2 diabetes (see section 4.2 forinformation on paediatric use).

Vokanamet

Bioequivalence studies in healthy subjects demonstrated that Vokanamet 50 mg/850 mg,50 mg/1,000 mg, 150 mg/850 mg, and 150 mg/1,000 mg combination tablets are bioequivalent toco-administration of corresponding doses of canagliflozin and metformin as individual tablets.

Administration of Vokanamet 150 mg/1,000 mg with food resulted in no change in overall exposure ofcanagliflozin. There was no change in metformin AUC; however, mean peak plasma concentration ofmetformin was decreased by 16% when administered with food. A delayed time to peak plasmaconcentration was observed for both components (2 hours for canagliflozin and 1 hour for metformin)under fed conditions. These changes are not likely to be clinically relevant. As metformin isrecommended to be administered with a meal to reduce the incidence of gastrointestinal adversereactions, it is recommended that Vokanamet be taken with a meal to reduce gastrointestinalintolerability associated with metformin.

Canagliflozin

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,canagliflozin may be taken with or without food (see section 4.2).

The mean steady-state volume of distribution (Vd) of canagliflozin following a single intravenousinfusion in 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 end-stage kidney disease(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.

Elderly (≥ 65 years old)

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.

After an oral dose of metformin hydrochloride tablet, Cmax is reached in approximately 2.5 hours(Tmax). Absolute bioavailability of a 500 mg or 850 mg metformin hydrochloride tablet isapproximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered infaeces was 20-30%.

After oral administration, metformin absorption is saturable and incomplete. It is assumed that thepharmacokinetics of metformin absorption are non-linear.

At the recommended metformin doses and dosing schedules, steady-state plasma concentrations arereached within 24-48 hours and are generally less than 1 μg/mL. In controlled clinical studies, Cmax didnot exceed 5 μg/mL, even at maximum doses.

Food decreases the extent and slightly delays the absorption of metformin. Following oraladministration of an 850 mg tablet, a 40% lower plasma peak concentration, a 25% decrease in AUC,and a 35-minute prolongation of time to peak plasma concentration were observed. The clinicalrelevance of these findings is unknown.

Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lowerthan the plasma peak and appears at approximately the same time. The red blood cells most likelyrepresent a secondary compartment of distribution. The mean Vd ranged between 63-276 litres.

Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.

Renal clearance of metformin is > 400 mL/min, indicating that metformin hydrochloride is eliminatedby glomerular filtration and tubular secretion. Following an oral dose, the apparent terminalelimination half-life is approximately 6.5 hours.

When renal function is impaired, renal clearance is decreased in proportion to that of creatinine andthus the elimination half-life is prolonged, leading to increased levels of metformin in plasma.

Single dose study: After single doses of metformin hydrochloride 500 mg, paediatric patients haveshown a similar pharmacokinetic profile to that observed in healthy adults.

Multiple dose study: Data are restricted to one study. After repeated doses of 500 mg twice daily for7 days in paediatric patients, the peak Cmax and AUC0-t were reduced by approximately 33% and 40%,respectively compared to diabetic adults who received repeated doses of 500 mg twice daily for14 days. As the dose is individually titrated based on glycaemic control, this is of limited clinicalrelevance.

Canagliflozin

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.

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 1 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 0.6 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 inluteinising 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.

Preclinical data reveal no special hazard for humans based on conventional studies on safety,pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and fertility.

Environmental Risk Assessment: no environmental impact is anticipated from the clinical use of eitherof the active substances canagliflozin or metformin in Vokanamet.

Canagliflozin/metformin

In a study on embryo-fetal development in rats, metformin alone (300 mg/kg/day) causedabsent/incomplete ossification, while canagliflozin alone (60 mg/kg/day) had no effects. Whencanagliflozin/metformin was administered at 60/300 mg/kg/day (exposure levels 11 and 13 times theclinical exposure for canagliflozin and metformin, respectively, at 300/2,000 mg doses), the effectswere more pronounced compared to metformin alone.

Microcrystalline cellulose

Hypromellose

Croscarmellose sodium

Magnesium stearate

Vokanamet 50 mg/850 mg film-coated tablets

Macrogol (3350)

Poly(vinyl alcohol)

Talc

Titanium dioxide (E171)

Iron oxide red (E172)

Iron oxide black (E172)

Vokanamet 50 mg/1,000 mg film-coated tablets

Macrogol (3350)

Poly(vinyl alcohol)

Talc

Titanium dioxide (E171)

Iron oxide red (E172)

Iron oxide yellow (E172)

Vokanamet 150 mg/850 mg film-coated tablets

Macrogol (3350)

Poly(vinyl alcohol)

Talc

Titanium dioxide (E171)

Iron oxide yellow (E172)

Vokanamet 150 mg/1,000 mg film-coated tablets

Macrogol (3350)

Poly(vinyl alcohol)

Talc

Titanium dioxide (E171)

Iron oxide red (E172)

Iron oxide black (E172)

Not applicable.

3 years.

Do not store above 30°C.

HDPE bottle with child-resistant closure, induction seal, and desiccant.

The bottles contain 20 or 60 film-coated tablets.

Pack sizes:1 x 20 film-coated tablets1 x 60 film-coated tablets

Multipack containing 180 (3 x 60) 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

Vokanamet 50 mg/850 mg film-coated tablets

EU/1/14/918/001 (20 film-coated tablets)

EU/1/14/918/002 (60 film-coated tablets)

EU/1/14/918/003 (180 film-coated tablets)

Vokanamet 50 mg/1,000 mg film-coated tablets

EU/1/14/918/004 (20 film-coated tablets)

EU/1/14/918/005 (60 film-coated tablets)

EU/1/14/918/006 (180 film-coated tablets)

Vokanamet 150 mg/850 mg film-coated tablets

EU/1/14/918/007 (20 film-coated tablets)

EU/1/14/918/008 (60 film-coated tablets)

EU/1/14/918/009 (180 film-coated tablets)

Vokanamet 150 mg/1,000 mg film-coated tablets

EU/1/14/918/010 (20 film-coated tablets)

EU/1/14/918/011 (60 film-coated tablets)

EU/1/14/918/012 (180 film-coated tablets)

Date of first authorisation: 23 April 2014

Date of latest renewal: 18 December 2018

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

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