Invokana

1

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



2

1. NAME OF THE MEDICINAL PRODUCT

Invokana 100 mg film-coated tablets
Invokana 300 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Invokana 100 mg film-coated tablets

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

Excipient(s) with known effect
Each tablet contains 39.2 mg lactose.

Invokana 300 mg film-coated tablets

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

Excipient(s) with known effect
Each tablet contains 117.78 mg lactose.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet).

Invokana 100 mg film-coated tablets

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

Invokana 300 mg film-coated tablets

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

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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

- as monotherapy when metformin is considered inappropriate due to intolerance or 
contraindications

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

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



3

4.2 Posology and method of administration

Posology

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

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

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

Special populations

Elderly (≥ 65 years old)
Renal function and risk of volume depletion should be taken into account (see section 4.4).

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

Table 1: Dose adjustment recommendationsa

eGFR (mL/min/1.73 m2)
or CrCl (mL/min)

Total daily dose of canagliflozin

≥ 60

Initiate with 100 mg.

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

45 to < 60b
Initiate with 100 mg.

Continue 100 mg for patients already taking Invokana.

30 to < 45b, c
Initiate with 100 mg.

Continue 100 mg for patients already taking Invokana.

< 30b, c
Continue 100 mg for patients already taking Invokanad.

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

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



4

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

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

Method of administration

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

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

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Renal impairment

The efficacy of canagliflozin for glycaemic control is dependent on renal function, and efficacy is 
reduced in patients who have moderate renal impairment and likely absent in patients with severe 
renal 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 adverse 
reactions associated with volume depletion (e.g., postural dizziness, orthostatic hypotension, 
hypotension) was reported, particularly with the 300 mg dose. In addition, in such patients more 
events of elevated potassium and greater increases in serum creatinine and blood urea nitrogen (BUN) 
were reported (see section 4.8).

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

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

Monitoring of renal function is recommended as follows:
- Prior to initiation of canagliflozin and at least annually, thereafter (see sections 4.2, 4.8, 5.1, and 

5.2)
- Prior to initiation of concomitant medicinal products that may reduce renal function and 

periodically thereafter.

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) induces 
an osmotic diuresis, which may reduce intravascular volume and decrease blood pressure (see 
section 5.1). In controlled clinical studies of canagliflozin, increases in adverse reactions related to 
volume depletion (e.g., postural dizziness, orthostatic hypotension, or hypotension) were seen more 
commonly with the 300 mg dose and occurred most frequently in the first three months (see 
section 4.8).

Caution should be exercised in patients for whom a canagliflozin-induced drop in blood pressure could 
pose a risk, such as patients with known cardiovascular disease, patients with an 



5

eGFR < 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 weeks 
of treatment initiation with canagliflozin. In patients susceptible to greater reductions in intravascular 
volume as described above, larger decreases in eGFR (> 30%) were sometimes seen, which 
subsequently improved, and infrequently required interruption of treatment with canagliflozin (see 
section 4.8).

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

For patients receiving canagliflozin, 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 is recommended. Temporary interruption of treatment with canagliflozin may be 
considered for patients who develop volume depletion while on canagliflozin therapy until the 
condition is corrected. If interrupted, consideration should be given to more frequent glucose
monitoring.

Diabetic ketoacidosis

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

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

In patients where DKA is suspected or diagnosed, treatment with canagliflozin should be discontinued 
immediately.

Treatment should be interrupted in patients who are hospitalised for major surgical procedures or acute 
serious medical illnesses. Monitoring of ketones is recommended in these patients. Measurement of 
blood ketone levels is preferred to urine. Treatment with canagliflozin may be restarted when the 
ketone values are normal and the patient’s condition has stabilised.

Before initiating canagliflozin, factors in the patient history that may predispose to ketoacidosis should 
be considered.

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) or 
patients with a history of pancreatitis), patients with conditions that lead to restricted food intake or 
severe dehydration, patients for whom insulin doses are reduced and patients with increased insulin 
requirements due to acute medical illness, surgery or alcohol abuse. SGLT2 inhibitors should be used 
with caution in these patients.

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



6

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

Lower limb amputations

In long-term clinical studies of canagliflozin in patients with type 2 diabetes with established 
cardiovascular disease (CVD) or at least 2 risk factors for CVD, Invokana was associated with an 
increased 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 a 
long-term clinical study in patients with type 2 diabetes and diabetic kidney disease, no difference in 
lower limb amputation risk was observed in patients treated with canagliflozin 100 mg relative to 
placebo. In this study precautionary measures as outlined below were applied. As an underlying 
mechanism has not been established, risk factors, apart from general risk factors, for amputation are 
unknown.

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

Necrotising fasciitis of the perineum (Fournier’s 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 and 
potentially 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 of 
pain, tenderness, erythema, or swelling in the genital or perineal area, with fever or malaise. Be aware 
that either uro-genital infection or perineal abscess may precede necrotising fasciitis. If Fournier's 
gangrene is suspected, Invokana should be discontinued and prompt treatment (including antibiotics 
and surgical debridement) should be instituted.

Elevated haematocrit

Haematocrit increase was observed with canagliflozin treatment (see section 4.8); therefore, careful 
monitoring 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 with 
diuretics, and to have impaired renal function. In patients ≥ 75 years of age, a higher incidence of 
adverse reactions associated with volume depletion (e.g., postural dizziness, orthostatic hypotension, 
hypotension) was reported. In addition, in such patients greater decreases in eGFR were reported (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 in 
clinical studies with canagliflozin (see section 4.8). Male and female patients with a history of genital 
mycotic infections were more likely to develop an infection. Balanitis or balanoposthitis occurred 
primarily in uncircumcised male patients which in some instances resulted in phimosis and/or
circumcision. The majority of genital mycotic infections were treated with topical antifungal 



7

treatments, either prescribed by a healthcare professional or self-treated while continuing therapy with 
Invokana.

Cardiac failure

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

Urine laboratory assessments

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

Lactose intolerance

The tablets contain lactose.
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or 
glucose-galactose malabsorption should not take this medicinal product.

Sodium

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

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

Diuretics

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

Insulin and insulin secretagogues

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

Pharmacokinetic interactions

Effects of other medicinal products on canagliflozin

The metabolism of canagliflozin is primarily via glucuronide conjugation mediated by UDP 
glucuronosyl 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 transporters 
and medicinal product-metabolising enzymes), 51% and 28% decreases in canagliflozin systemic 
exposure (AUC) and peak concentration (Cmax) were observed. These decreases in exposure to 
canagliflozin may decrease efficacy.

If a combined inducer of these UGT enzymes and transport proteins must be co-administered with 
canagliflozin, monitoring of glycaemic control to assess response to canagliflozin is appropriate. If an 
inducer of these UGT enzymes must be co-administered with canagliflozin, increasing the dose to 



8

300 mg once daily may be considered if patients are currently tolerating canagliflozin 100 mg once 
daily, have an eGFR ≥ 60 mL/min/1.73 m2 or CrCl ≥ 60 mL/min, and require additional glycaemic 
control. In patients with an eGFR 45 mL/min/1.73 m2 to < 60 mL/min/1.73 m2 or CrCl 45 mL/min to
< 60 mL/min taking canagliflozin 100 mg who are receiving concurrent therapy with a UGT enzyme 
inducer and who require additional glycaemic control, other glucose-lowering therapies should be 
considered (see sections 4.2 and 4.4).

Cholestyramine may potentially reduce canagliflozin exposure. Dosing of canagliflozin should occur 
at least 1 hour before or 4-6 hours after administration of a bile acid sequestrant to minimise possible 
interference 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/or 
probenecid.

Effects of canagliflozin on other medicinal products

Digoxin
The combination of canagliflozin 300 mg once daily for 7 days with a single dose of digoxin 0.5 mg 
followed by 0.25 mg daily for 6 days resulted in a 20% increase in AUC and a 36% increase in Cmax of 
digoxin, 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.

Dabigatran
The effect of concomitant administration of canagliflozin (a weak P-gp inhibitor) on dabigatran 
etexilate (a P-gp substrate) has not been studied. As dabigatran concentrations may be increased in the 
presence of canagliflozin, monitoring (looking for signs of bleeding or anaemia) should be exercised 
when 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 of 
simvastatin and an 18% increase in AUC and a 26% increase in Cmax of simvastatin acid. The 
increases 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 exposure 
may therefore occur for medicinal products transported by BCRP, e.g. certain statins like rosuvastatin 
and some anti-cancer medicinal products.

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

Medicinal product/Laboratory test interference

1,5-AG assay

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



9

4.6 Fertility, pregnancy and lactation

Pregnancy

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

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

Breast-feeding

It is unknown whether canagliflozin and/or its metabolites are excreted in human milk. Available 
pharmacodynamic/toxicological data in animals have shown excretion of canagliflozin/metabolites in 
milk, as well as pharmacologically mediated effects in breast-feeding offspring and juvenile rats 
exposed to canagliflozin (see section 5.3). A risk to newborns/infants cannot be excluded. 
Canagliflozin should not be used during breast-feeding.

Fertility

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

The safety of canagliflozin was evaluated in 22,645 patients with type 2 diabetes, including 
13,278 patients treated with canagliflozin and 9,367 patients treated with comparator in 
15 double-blind, controlled phase 3 and phase 4 clinical studies. A total of 10,134 patients were 
treated in two dedicated cardiovascular studies for a mean exposure duration of 149 weeks (223 weeks 
in CANVAS and 94 weeks in CANVAS-R), and 8,114 patients were treated in 12 double blind, 
controlled phase 3 and phase 4 clinical studies, for a mean exposure duration of 49 weeks. In a 
dedicated renal outcomes study, a total of 4,397 patients with type 2 diabetes and diabetic kidney 
disease had a mean exposure duration of 115 weeks.

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



10

Tabulated list of adverse reactions

Adverse reactions in table 2 are based on the pooled analysis of the placebo- and active-controlled
studies described above. Adverse reactions reported from world-wide postmarketing use of 
canagliflozin are also included in this tabulation. Adverse reactions listed below are classified 
according to frequency and system organ class. Frequency categories are defined according to the 
following 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 from 
the available data).

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

System organ class
Frequency

Adverse reaction

Infections and infestations
very common Vulvovaginal candidiasisb, j

common Balanitis or balanoposthitisb, k, Urinary tract 
infectionc (pyelonephritis and urosepsis have 
been reported postmarketing)

not known Necrotising fasciitis of the perineum (Fournier’s 
gangrene)d

Immune system disorders
rare Anaphylactic reaction
Metabolism and nutrition disorders
very common Hypoglycaemia in combination with insulin or 

sulphonylureac

uncommon Dehydrationa

rare Diabetic ketoacidosisb

Nervous system disorders
uncommon Dizziness posturala, Syncopea

Vascular disorders
uncommon Hypotensiona, Orthostatic hypotensiona

Gastrointestinal disorders
common Constipation, Thirstf, Nausea
Skin and subcutaneous tissue disorders
uncommon Photosensitivity, Rashg, Urticaria

rare Angioedema
Musculoskeletal and connective tissue disorders
uncommon Bone fractureh

Renal and urinary disorders
common Polyuria or Pollakiuriai

uncommon Renal failure (mainly in the context of volume 
depletion)

Investigations
common Dyslipidemial, Haematocrit increasedb, m

uncommon Blood creatinine increasedb, n, Blood urea 
increasedb, o, Blood potassium increasedb, p, 
Blood phosphate increasedq



11

Surgical and medical procedures
uncommon Lower limb amputations (mainly of the toe and 

midfoot) especially in patients at high risk for 
heart diseaseb

a 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; older 

patients [≥ 55 years of age to ≤ 80 years of age]; patients with increased CV- and renal-risk) were generally consistent 
with 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, rash 

pruritic, 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 output 

increased.
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 infection 

fungal.
l Mean percent increases from baseline for canagliflozin 100 mg and 300 mg versus placebo, respectively, were total 

cholesterol 3.4% and 5.2% versus 0.9%; HDL-cholesterol 9.4% and 10.3% versus 4.0%; LDL-cholesterol 5.7% and 
9.3% 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 and 
300 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.

Description of selected adverse reactions

Diabetic ketoacidosis

In a long-term renal outcomes study in patients with type 2 diabetes and diabetic kidney disease, 
incidence rates of adjudicated events of diabetic ketoacidosis (DKA) were 0.21 (0.5%, 12/2,200) and 
0.03 (0.1%, 2/2,197) per 100 patient-years of follow-up with canagliflozin 100 mg and placebo, 
respectively; of the 14 patients with DKA, 8 (7 on canagliflozin 100 mg and 1 on placebo) had a 
pretreatment eGFR of 30 to ˂ 45 mL/min/1.73 m2 (see section 4.4).

Lower limb amputation

In patients with type 2 diabetes who had established cardiovascular disease or at least two risk factors 
for cardiovascular disease, canagliflozin was associated with an increased risk of lower limb 
amputation 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 treatment 
with canagliflozin or placebo, the risk of amputation was highest in patients with a baseline history of 
prior amputation, peripheral vascular disease, and neuropathy. The risk of lower limb amputation was
not dose-dependent. The amputation results for the Integrated CANVAS Program are shown in 
table 3.



12

There was no difference in risk of lower limb amputations associated with the use of canagliflozin 
100 mg relative to placebo (1.2 vs 1.1 events per 100 patient-years, respectively [HR: 1.11; 95% 
CI 0.79, 1.56]) in CREDENCE, a long-term renal outcomes study of 4,397 patients with type 2
diabetes and diabetic kidney disease (see section 4.4). In other type 2 diabetes studies with 
canagliflozin, which enrolled a general diabetic population of 8,114 patients, no difference in lower 
limb amputation risk was observed relative to control.

Table 3: Integrated analysis of amputations in CANVAS AND CANVAS-R
Placebo
N = 4344

canagliflozin
N = 5790

Total number of subjects with events, n 
(%)

47 (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 amputation 
events. A patient’s follow-up is calculated from Day 1 to the first amputation event date. Some patients had more than one 
amputation. 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 the 
most frequent sites (71%) in both treatment groups (table 3). Multiple amputations (some involving 
both lower limbs) were observed infrequently and in similar proportions in both treatment groups.

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

Adverse reactions related to volume depletion

In the pooled analysis of the four 26-week, placebo-controlled studies, the incidence of all adverse 
reactions related to volume depletion (e.g., postural dizziness, orthostatic hypotension, hypotension, 
dehydration, and syncope) was 1.2% for canagliflozin 100 mg, 1.3% for canagliflozin 300 mg, and 
1.1% for placebo. The incidence with canagliflozin treatment in the two active-controlled studies was 
similar to comparators.

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

To assess risk factors for these adverse reactions, a larger pooled analysis (N = 12,441) of patients 
from 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 adverse 
reactions. For patients on loop diuretics, the incidence rates were 5.0 on canagliflozin 100 mg and 5.7
on canagliflozin 300 mg compared to 4.1 events per 100 patient-years of exposure in the control 
group. For patients with a baseline eGFR 30 mL/min/1.73 m2 to < 60 mL/min/1.73 m2, the incidence
rates were 5.2 on canagliflozin 100 mg and 5.4 on canagliflozin 300 mg compared to 3.1 events per 
100 patient-years of exposure in the control group. In patients ≥ 75 years of age, the incidence rates 
were 5.3 on canagliflozin 100 mg and 6.1 on canagliflozin 300 mg compared to 2.4 events per 
100 patient-years of exposure in the control group (see sections 4.2 and 4.4).

In a long-term renal outcomes study in patients with type 2 diabetes and diabetic kidney disease, 
incidence rate of events related to volume depletion was 2.84 and 2.35 events per 100 patient-years for 
canagliflozin 100 mg and placebo, respectively. The incidence rate was observed to increase with 



13

decreasing eGFR. In subjects with eGFR 30 to <45 mL/min/1.73 m2, the incidence rate of volume 
depletion was higher in the canagliflozin group (4.91 events per 100 patient-years) compared to the 
placebo group (2.60 events per 100 patient-years); however, in the subgroups eGFR ≥45 to <60 and 
eGFR 60 to <90 mL/min/1.73 m2, the between-group incidence rate was similar.

In the dedicated cardiovascular study and the larger pooled analysis, as well as in a dedicated renal 
outcomes study, discontinuations due to adverse reactions related to volume depletion and serious 
adverse 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, including 
placebo, when used as monotherapy or as an add-on to metformin. When canagliflozin was added to 
insulin therapy, hypoglycaemia was observed in 49.3%, 48.2%, and 36.8% of patients treated with 
canagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively, and severe hypoglycaemia 
occurred in 1.8%, 2.7%, and 2.5% of patients treated with canagliflozin 100 mg, canagliflozin 300 mg, 
and placebo, respectively. When canagliflozin was added to a sulphonylurea therapy, hypoglycaemia 
was observed in 4.1%, 12.5%, and 5.8% of patients treated with canagliflozin 100 mg, canagliflozin 
300 mg, and placebo, respectively (see sections 4.2 and 4.5).

Genital mycotic infections

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

Candidal balanitis or balanoposthitis occurred in male patients at a rate of 2.98 and 0.79 events per 
100 patient-years on canagliflozin and placebo, respectively. Among male patients taking 
canagliflozin, 2.4% had more than one infection. Discontinuation of canagliflozin by male patients due 
to 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 and 
placebo, respectively. Circumcision was performed at rates of 0.31 and 0.09 events per 
100 patient-years on canagliflozin and placebo, respectively (see section 4.4).

Urinary tract infections

Urinary tract infections were more frequently reported for canagliflozin 100 mg and 300 mg (5.9% 
versus 4.3%, respectively) compared to 4.0% with placebo. Most infections were mild to moderate 
with no increase in the occurrence of serious adverse reactions. Subjects responded to standard 
treatments while continuing canagliflozin treatment.

Bone fracture

In a cardiovascular study (CANVAS) of 4,327 treated subjects with established or at least two risk 
factors 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, and 
placebo, respectively, with the fracture imbalance initially occurring within the first 26 weeks of 
therapy.

In two other long-term studies and in studies conducted in the general diabetes population, no 
difference in fracture risk was observed with canagliflozin relative to control. In a second 
cardiovascular study (CANVAS-R) of 5,807 treated subjects with established or at least two risk 



14

factors for cardiovascular disease, the incidence rates of all adjudicated bone fracture were 1.1 and 
1.3 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 kidney 
disease, the incidence rates of all adjudicated bone fracture were 1.2 events per 100 patient-years of 
follow-up for both canagliflozin 100 mg and placebo. In other type 2 diabetes studies with 
canagliflozin, which enrolled a general diabetes population of 7,729 patients and where bone fractures 
were adjudicated, the incidence rates of all adjudicated bone fracture were 1.2 and 1.1 per 
100 patient-years of follow-up to canagliflozin and control, respectively. After 104 weeks of 
treatment, canagliflozin did not adversely affect bone mineral density.

Special populations

Elderly (≥ 65 years old)
In a pooled analysis of 13 placebo-controlled and active-controlled studies, the safety profile of 
canagliflozin in elderly patients was generally consistent with younger patients. Patients ≥ 75 years of 
age had a higher incidence of adverse reactions related to volume depletion (such as postural 
dizziness, orthostatic hypotension, hypotension) with incidence rates of 5.3, 6.1, and 2.4 events per 
100 patient-years of exposure for canagliflozin 100 mg, canagliflozin 300 mg, and in the control 
group, respectively. Decreases in eGFR (-3.4 and -4.7 mL/min/1.73 m2) were reported with 
canagliflozin 100 mg and canagliflozin 300 mg, respectively, compared to the control group 
(-4.2 mL/min/1.73 m2). Mean baseline eGFR was 62.5, 64.7, and 63.5 mL/min/1.73 m2 for 
canagliflozin 100 mg, canagliflozin 300 mg, and the control group, respectively (see sections 4.2 and 
4.4).

Renal impairment in patients with insufficiently controlled type 2 diabetes mellitus
Patients with a baseline eGFR < 60 mL/min/1.73 m2 had a higher incidence of adverse reactions 
associated with volume depletion (e.g., postural dizziness, orthostatic hypotension, hypotension) with 
incidence 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 renal 
impairment with incidence rates of 4.9, 6.1, and 5.4 events per 100 patient-years of exposure for 
canagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively. In general, elevations were 
transient and did not require specific treatment.

In patients with moderate renal impairment, increases in serum creatinine of 9.2 µmol/L and BUN of 
approximately 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, and 
placebo, respectively. At the last post-baseline value, incidence rates of such decreases were 3.3 for
patients treated with canagliflozin 100 mg, 2.7 for canagliflozin 300 mg, and 3.7 events per 
100 patient-years of exposure for placebo (see section 4.4).

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

Renal impairment in patients with diabetic kidney disease in type 2 diabetes mellitus
In a long-term renal outcomes study in patients with type 2 diabetes and diabetic kidney disease, the 
incidence of renal-related events occurred frequently in both groups but less frequent in the 
canagliflozin group (5.71 events per 100 patient-years) compared with the placebo group (7.91 events 
per 100 patient-years). Serious and severe renal-related events were also lower in the canagliflozin 
group versus placebo. The incidence rates of renal-related events were lower with canagliflozin 
relative to placebo across all three eGFR strata; the highest incidence rate of renal-related events was 



15

seen in the eGFR 30 to <45 mL/min/1.73 m2 stratum (9.47 vs 12.80 events per 100 patient-years for 
canagliflozin versus placebo, respectively).

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

In general, there were no imbalances between treatment groups observed for abnormalities of 
phosphate, overall or in either eGFR category (45 to < 60 or 30 to < 45 mL/min/1.73 m2

[CrCl 45 to < 60 or 30 to < 45 mL/min]).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

4.9 Overdose

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

Therapy

In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove 
unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute clinical 
measures if required. Canagliflozin was negligibly removed during a 4-hour haemodialysis session. 
Canagliflozin is not expected to be dialysable by peritoneal dialysis.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in diabetes, blood glucose lowering drugs, excluding insulins.
ATC code: A10BK02.

Mechanism of action

The SGLT2 transporter, expressed in the proximal renal tubules, is responsible for the majority of the 
reabsorption of filtered glucose from the tubular lumen. Patients with diabetes have been shown to 
have elevated renal glucose reabsorption which may contribute to persistent elevated blood glucose 
concentrations. 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 this 
insulin-independent mechanism in patients with type 2 diabetes. The increased UGE with SGLT2 
inhibition also translates to an osmotic diuresis, with the diuretic effect leading to a reduction in 
systolic blood pressure; the increase in UGE results in a loss of calories and therefore a reduction in 
body 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 improved 
beta-cell insulin secretion response to a mixed-meal challenge has been observed in clinical studies 
with canagliflozin.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


16

In phase 3 studies, pre-meal administration of canagliflozin 300 mg provided a greater reduction in 
postprandial glucose excursion than observed with the 100 mg dose. This effect 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 in the intestinal lumen 
prior to medicinal product absorption (canagliflozin is a low potency inhibitor of the SGLT1
transporter). Studies have shown no glucose malabsorption with canagliflozin.

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

Pharmacodynamic effects

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 RTG
of approximately 13 mmol/L, maximal suppression of 24-hour mean RTG was seen with the 300 mg 
daily dose to approximately 4 mmol/L to 5 mmol/L in patients with type 2 diabetes in phase 1 studies, 
suggesting a low risk for treatment-induced hypoglycaemia. The reductions in RTG led to increased 
UGE in subjects with type 2 diabetes treated with either 100 mg or 300 mg of canagliflozin ranging 
from 77 g/day to 119 g/day across the phase 1 studies; the UGE observed translates to a loss of 
308 kcal/day to 476 kcal/day. The reductions in RTG and increases in UGE were sustained over a 
26-week dosing period in patients with type 2 diabetes. Moderate increases (generally < 400 mL to 
500 mL) in daily urine volume were seen that attenuated over several days of dosing. Urinary uric acid 
excretion was transiently increased by canagliflozin (increased by 19% compared to baseline on day 1 
and then attenuating to 6% on day 2 and 1% on day 13). This was accompanied by a sustained 
reduction 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 meal 
delayed intestinal glucose absorption and reduced postprandial glucose through both a renal and a 
non-renal mechanism.

Clinical efficacy and safety

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

Glycaemic efficacy and safety
A total of 10,501 patients with type 2 diabetes participated in ten double-blind, controlled clinical 
efficacy and safety studies conducted to evaluate the effects of Invokana on glycaemic control. The 
racial distribution was 72% White, 16% Asian, 5% Black, and 8% other groups. 17% of patients were 
Hispanic. 58% of patients were male. Patients had an overall mean age of 59.5 years (range 21 years 
to 96 years), with 3,135 patients ≥ 65 years of age and 513 patients ≥ 75 years of age. 58% of patients 
had a body mass index (BMI) ≥ 30 kg/m2. In the clinical 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 monotherapy, dual therapy with metformin, dual therapy with a 
sulphonylurea, triple therapy with metformin and a sulphonylurea, triple therapy with metformin and 
pioglitazone, and as an add-on therapy with insulin (table 4). In general, canagliflozin produced 
clinically and statistically significant (p < 0.001) results relative to placebo in glycaemic control, 
including HbA1c, the percentage of patients achieving HbA1c < 7%, change from baseline fasting
plasma glucose (FPG), and 2-hour postprandial glucose (PPG). In addition, reductions in body weight 
and systolic blood pressure relative to placebo were observed.



17

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

Table 4: Efficacy results from placebo-controlled clinical studiesa

Monotherapy (26 weeks)
Canagliflozin

Placebo
(N = 192)

100 mg
(N = 195)

300 mg
(N = 197)

HbA1c (%)
Baseline (mean) 8.06 8.01 7.97
Change from baseline (adjusted 
mean)

-0.77 -1.03 0.14

Difference from placebo (adjusted 
mean) (95% CI)

-0.91b

(-1.09; -0.73)
-1.16b

(-1.34; -0.98)
N/Ac

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

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

-2.8 -3.9 -0.6

Difference from placebo (adjusted 
mean) (95% CI)

-2.2b

(-2.9; -1.6)
-3.3b

(-4.0; -2.6)
N/Ac

Dual therapy with metformin (26 weeks)
Canagliflozin + metformin Placebo + 

metformin
(N = 183)

100 mg
(N = 368)

300 mg
(N = 367)

HbA1c (%)
Baseline (mean) 7.94 7.95 7.96
Change from baseline (adjusted 
mean)

-0.79 -0.94 -0.17

Difference from placebo (adjusted 
mean) (95% CI)

-0.62b

(-0.76; -0.48)
-0.77b

(-0.91; -0.64)
N/Ac

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

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

-3.7 -4.2 -1.2

Difference from placebo (adjusted 
mean) (95% CI)

-2.5b

(-3.1; -1.9)
-2.9b

(-3.5; -2.3)
N/Ac

Triple therapy with metformin and sulphonylurea (26 weeks)
Canagliflozin + metformin

and sulphonylurea
Placebo + 

metformin and 
sulphonylurea

(N = 156)
100 mg

(N = 157)
300 mg

(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 
mean) (95% CI)

-0.71b

(-0.90; -0.52)
-0.92b

(-1.11; -0.73)
N/Ac

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



18

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

-2.1 -2.6 -0.7

Difference from placebo (adjusted 
mean) (95% CI)

-1.4b

(-2.1; -0.7)
-2.0b

(-2.7; -1.3)
N/Ac

Add-on therapy with insulind (18 weeks)
Canagliflozin + insulin Placebo + 

insulin
(N = 565)

100 mg
(N = 566)

300 mg
(N = 587)

HbA1c (%)
Baseline (mean) 8.33 8.27 8.20
Change from baseline (adjusted 
mean)

-0.63 -0.72 0.01

Difference from placebo (adjusted 
mean)
(95% CI)

-0.65b

(-0.73; -0.56)
-0.73b

(-0.82; -0.65)
N/Ac

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

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

-1.8 -2.3 0.1

Difference from placebo (adjusted 
mean) (97.5% CI)

-1.9b

(-2.2; -1.5)
-2.4b

(-2.8; -2.0)
N/Ac

Triple therapy with metformin and sitagliptine (26 weeks)
Canagliflozin +

metformin and sitaglipting

(N = 107)

Placebo +
metformin and sitagliptin

(N = 106)
HbA1c (%)

Baseline (mean) 8.53 8.38
Change from baseline (adjusted 
mean)

-0.91 -0.01

Difference from placebo (adjusted 
mean)
(95% CI)

-0.89b

(-1.19; -0.59)

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 
mean) (95% CI)

-27b

(-40; -14)
Body Weight

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

-3.4 -1.6

Difference from placebo (adjusted 
mean) (95% CI)

-1.8b

(-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 mg
f p < 0.01 compared to placebo
g 90.7% of subjects in the canagliflozin group uptitrated to 300 mg



19

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

Active-controlled studies

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

Table 5: Efficacy results from active-controlled clinical studiesa

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

(titrated) + 
metformin
(N = 482)

100 mg
(N = 483)

300 mg
(N = 485)

HbA1c (%)
Baseline (mean) 7.78 7.79 7.83
Change from baseline (adjusted mean) -0.82 -0.93 -0.81
Difference from glimepiride (adjusted
mean) (95% CI)

-0.01b

(−0.11; 0.09)
-0.12b

(−0.22; −0.02)
N/Ac

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

Baseline (mean) in kg 86.8 86.6 86.6
% change from baseline (adjusted mean) -4.2 -4.7 1.0
Difference from glimepiride (adjusted 
mean) (95% CI)

-5.2b

(−5.7; −4.7)
-5.7b

(−6.2; −5.1)
N/Ac

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

Canagliflozin 300 mg + 
metformin and sulphonylurea

(N = 377)

Sitagliptin 
100 mg + 

metformin and 
sulphonylurea

(N = 378)
HbA1c (%)

Baseline (mean) 8.12 8.13
Change from baseline (adjusted mean) -1.03 -0.66
Difference from sitagliptin (adjusted 
mean) (95% CI)

-0.37b

(-0.50; -0.25)
N/Ac

Patients (%) achieving HbA1c < 7% 47.6 35.3
Body weight

Baseline (mean) in kg 87.6 89.6
% change from baseline (adjusted mean) -2.5 0.3
Difference from sitagliptin (adjusted 
mean) (95% CI)

-2.8d

(-3.3; -2.2)
N/Ac



20

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 patients 
with type 2 diabetes failing diet and exercise. Canagliflozin 100 mg and canagliflozin 300 mg in 
combination with metformin XR resulted in a statistically significant greater improvement in HbA1C
compared to their respective canagliflozin doses (100 mg and 300 mg) alone or metformin XR alone 
(table 6).

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

Efficacy 
Parameter

Metformin 
XR

(N = 237)

Canagliflozin 
100 mg

(N = 237)

Canagliflozin 
300 mg

(N = 238)

Canagliflozin 
100 mg + 

Metformin 
XR

(N = 237)

Canagliflozin 
300 mg + 

Metformin 
XR

(N = 237)
HbA1c (%)

Baseline (mean) 8.81 8.78 8.77 8.83 8.90
Change from 
baseline 
(adjusted mean) -1.30 -1.37 -1.42 -1.77 -1.78
Difference from 
canagliflozin 
100 mg 
(adjusted mean) 
(95% CI) †

-0.40‡

(-0.59, -0.21)
Difference from 
canagliflozin 
300 mg 
(adjusted mean) 
(95% CI) †

-0.36‡

(-0.56, -0.17)
Difference from 
metformin XR 
(adjusted mean) 
(95% CI) †

-0.06‡

(-0.26, 0.13)
-0.11‡

(-0.31, 0.08)
-0.46‡

(-0.66, -0.27)
-0.48‡

(-0.67, -0.28)
Percent of 
patients 
achieving HbA1c
< 7% 43 39 43 50§§ 57§§

Body Weight
Baseline (mean) 
in kg 92.1 90.3 93.0 88.3 91.5
% change from 
baseline 
(adjusted mean) -2.1 -3.0 -3.9 -3.5 -4.2
Difference from 
metformin XR 
(adjusted mean) 
(95% CI)†

-0.9§§

(-1.6, -0.2)
-1.8§

(-2.6, -1.1)
-1.4‡

(-2.1, -0.6)
-2.1‡

(-2.9, -1.4)



21

* 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

Special populations

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

Elderly
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 glycaemic
control 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 for 
100 mg and 300 mg, 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 to 
placebo, with -0.47% for canagliflozin 100 mg and -0.52% for canagliflozin 300 mg. Patients with a 
baseline eGFR 45 mL/min/1.73 m2 to < 60 mL/min/1.73 m2 treated with canagliflozin 100 mg and 
300 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 on 
insulin and/or a sulphonylurea (85% [614/721]). Consistent with the expected increase of 
hypoglycaemia when a medicinal product not associated with hypoglycaemia is added to insulin 
and/or sulphonylurea, an increase in hypoglycaemia episodes/events was seen when canagliflozin was 
added to insulin and/or a sulphonylurea (see section 4.8).

Fasting plasma glucose

In four placebo-controlled studies, treatment with canagliflozin as monotherapy or add-on therapy 
with one or two oral glucose-lowering medicinal products resulted in mean changes from baseline 
relative to placebo in FPG of -1.2 mmol/L to -1.9 mmol/L for canagliflozin 100 mg and -1.9 mmol/L 
to -2.4 mmol/L for canagliflozin 300 mg, respectively. These reductions were 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 oral 
glucose-lowering medicinal products reduced postprandial glucose (PPG) from baseline relative to 
placebo by -1.5 mmol/L to -2.7 mmol/L for canagliflozin 100 mg and -2.1 mmol/L to -3.5 mmol/L for 
300 mg, respectively, due to reductions in the pre-meal glucose concentration and reduced 
postprandial glucose excursions.

Body weight

Canagliflozin 100 mg and 300 mg as monotherapy and as dual or triple add-on therapy resulted in 
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 for 



22

canagliflozin as add-on therapy to metformin were -4.2% and -4.7% for canagliflozin 100 mg and 
300 mg, respectively, compared to the combination of glimepiride and metformin (1.0%) and -2.5% 
for canagliflozin 300 mg in combination with metformin and a sulphonylurea compared to 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 who 
underwent dual energy X-ray densitometry (DXA) and abdominal computed tomography (CT) scans 
for evaluation of body composition demonstrated that approximately two-thirds of the weight loss 
with canagliflozin was due to loss of fat mass with similar amounts of visceral and abdominal 
subcutaneous fat being lost. Two hundred eleven (211) patients from the clinical study in older 
patients participated in a body composition substudy using DXA body composition analysis. This 
demonstrated that approximately two-thirds of the weight loss associated with canagliflozin was due 
to loss of fat mass relative to placebo. There were no meaningful changes in bone density in trabecular 
and cortical regions.

Blood pressure

In placebo-controlled studies, treatment with canagliflozin 100 mg and 300 mg resulted in mean 
reductions in systolic blood pressure of -3.9 mmHg and -5.3 mmHg, respectively, compared to 
placebo (-0.1 mmHg) and a smaller effect on diastolic blood pressure with mean changes for 
canagliflozin 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 monotherapy 
resulted in reductions from baseline in HbA1c (not placebo-adjusted) of -2.13% and -2.56% for 
canagliflozin 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 established 
cardiovascular (CV) disease or were at risk for CVD (two or more CV risk factors), was evaluated in 
the CANVAS Program (integrated analysis of the CANVAS and the CANVAS-R study). These 
studies were multi-centre, multi-national, randomised, double-blind, parallel group, with similar 
inclusion and exclusion criteria and patient populations. The CANVAS Program compared the risk of 
experiencing a Major Adverse Cardiovascular Event (MACE) defined as the composite of
cardiovascular death, nonfatal myocardial infarction and nonfatal stroke, between canagliflozin and 
placebo on a background of standard of care treatments for diabetes and atherosclerotic cardiovascular 
disease.

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 or 
matching 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 to 
the 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 4,344 
randomly 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% of 
subjects across the studies. The mean age was 63 years and 64% were male. Sixty-six percent of 
subjects had a history of established cardiovascular disease, with 56% having a history of coronary 
disease, 19% with cerebrovascular disease, and 21% with peripheral vascular disease; 14% had a 
history of heart failure.

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



23

Baseline renal function was normal or mildly impaired in 80% of patients and moderately impaired in 
20% of patients (mean eGFR 77 mL/min/1.73 m2). At baseline, patients were treated with one or more 
antidiabetic medicinal product 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 and 
cardiovascular mortality.

Patients in the pooled canagliflozin groups (pooled analysis of canagliflozin 100 mg, canagliflozin 
300 mg, and canagliflozin up-titrated from 100 mg to 300 mg) had a lower rate of MACE as compared 
to 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 throughout 
the 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 this 
subgroup were consistent with the overall findings.

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

Figure 2: Treatment effect for the primary composite endpoint and its components

1 P value for superiority (2-sided) = 0.0158.



24

All-cause mortality in the CANVAS Program

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

Heart failure requiring hospitalization in the CANVAS Program

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

Renal endpoints in the CANVAS Program

For time to first adjudicated nephropathy event (doubling of serum creatinine, need 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 per 100 patient-years). In addition, 
canagliflozin reduced progression of albuminuria 25.8% versus placebo 29.2% (HR: 0.73; 95% CI: 
0.67, 0.79) in patients with baseline normo- or micro-albuminuria.

Renal outcomes in the CREDENCE study

The effect of canagliflozin 100 mg on renal events in adults with type 2 diabetes and diabetic kidney 
disease (DKD) with estimated glomerular filtration rate (eGFR) 30 to < 90 mL/min/1.73 m2 and 
albuminuria (˃ 300 to 5000 mg/g of creatinine), was evaluated in the Canagliflozin and Renal Events 
in Diabetes with Established Nephropathy Clinical Evaluation Trial (CREDENCE). This was a 
multi-centre, multi-national, randomised, double-blind, event-driven, placebo-controlled, 
parallel-group study. The CREDENCE study compared the risk of experiencing DKD defined as the 
composite of end-stage kidney disease, doubling of serum creatinine, and renal or cardiovascular 
death, between canagliflozin 100 mg and placebo on a background of standard of care treatments for 
DKD, including angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker 
(ARB). Canagliflozin 300 mg was not investigated in this study.

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

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

The mean baseline HbA1c was 8.3% and baseline median urine albumin/creatinine was 927 mg/g. The 
most frequent antihyperglycaemic agents (AHA) used at baseline were insulin (65.5%), biguanides 
(57.8%), and sulfonylureas (28.8%). Nearly all subjects (99.9%) were on ACEi or ARB at 
randomisation. About 92% of the subjects were on cardiovascular therapies (not including 
ACEi/ARBs) at baseline, with approximately 60% taking an anti-thrombotic agent (including 
acetylsalicylic acid) and 69% on statins.

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

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

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



25

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

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

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

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

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



26

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

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

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

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



27

Paediatric population

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

5.2 Pharmacokinetic properties

The pharmacokinetics of canagliflozin are essentially similar in healthy subjects and patients with 
type 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 hour 
to 2 hours post-dose. Plasma Cmax and AUC of canagliflozin increased in a dose-proportional manner 
from 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 to 
300 mg. Canagliflozin does not exhibit time-dependent pharmacokinetics, and accumulated in plasma 
up to 36% following multiple doses of 100 mg and 300 mg.

Absorption

The mean absolute oral bioavailability of canagliflozin is approximately 65%. Co-administration of a 
high-fat meal with canagliflozin had no effect on the pharmacokinetics of canagliflozin; therefore, 
Invokana may be taken with or without food. However, based on the potential to reduce postprandial 
plasma glucose excursions due to delayed intestinal glucose absorption, it is recommended that 
Invokana be taken before the first meal of the day (see sections 4.2 and 5.1).

Distribution

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

Biotransformation

O-glucuronidation is the major metabolic elimination pathway for canagliflozin, which is mainly 
glucuronidated 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 was 
observed in vivo (see section 4.5).

Elimination

Following administration of a single oral [14C]canagliflozin dose to healthy subjects, 41.5%, 7.0%, and 
3.2% of the administered radioactive dose was recovered in faeces as canagliflozin, a hydroxylated 
metabolite, and an O-glucuronide metabolite, respectively. Enterohepatic circulation of canagliflozin 
was 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 unchanged 
canagliflozin in urine. Renal clearance of canagliflozin 100 mg and 300 mg doses ranged from 
1.30 mL/min to 1.55 mL/min.



28

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

Special populations

Renal impairment
A single-dose, open-label study evaluated the pharmacokinetics of canagliflozin 200 mg in subjects 
with 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 with 
severe renal impairment (CrCl < 30 mL/min) as well as 8 subjects with ESKD on haemodialysis.

The Cmax of canagliflozin was moderately increased by 13%, 29%, and 29% in subjects with mild, 
moderate, and severe renal failure, respectively, but not in subjects on haemodialysis. Compared to 
healthy 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 ESKD 
subjects and healthy subjects.

Canagliflozin was negligibly removed by haemodialysis.

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

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

Elderly (≥ 65 years old)
Age had no clinically meaningful effect on the pharmacokinetics of canagliflozin based on a 
population pharmacokinetic analysis (see sections 4.2, 4.4, and 4.8).

Paediatric population

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

Other special populations

Pharmacogenetics
Both UGT1A9 and UGT2B4 are subject to genetic polymorphism. In a pooled analysis of clinical 
data, 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 clinically 
relevant. The effect of being homozygote (UGT1A9*3/*3, frequency < 0.1%) is probably more 
marked, but has not been investigated.

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

5.3 Preclinical safety data

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



29

Canagliflozin showed no effects on fertility and early embryonic development in the rat at exposures 
up 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 observed 
at systemic exposures 73 times and 19 times higher than the clinical exposures at the 100 mg and 
300 mg doses. It is unknown whether ossification delays can be attributed to effects of canagliflozin 
on calcium homeostasis observed in adult rats. Ossification delays were also observed for the 
combination of canagliflozin and metformin, which were more prominent than for metformin alone at 
canagliflozin exposures 43 times and 12 times higher than clinical exposures at 100 mg and 300 mg 
doses.

In a pre- and postnatal development study, canagliflozin administered to female rats from gestation 
day 6 to lactation day 20 resulted in decreased body weights in male and female offspring at 
maternally toxic doses > 30 mg/kg/day (exposures ≥ 5.9 times the human exposure to canagliflozin at 
the 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 show 
increased sensitivity compared to effects observed in adults rats. However, dilatation of the renal 
pelvis was noticed with a No Observed Effect Level (NOEL) at exposures 2.4 times and 0.6 times the 
clinical exposures at 100 mg and 300 mg doses, respectively, and did not fully reverse within the 
approximately 1-month recovery period. Persistent renal findings in juvenile rats can most likely be 
attributed to reduced ability of the developing rat kidney to handle canagliflozin-increased urine 
volumes, 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 at 
doses of 10, 30, and 100 mg/kg. The highest dose of 100 mg/kg provided up to 14 times the clinical 
dose of 300 mg based on AUC exposure. Canagliflozin increased the incidence of testicular Leydig 
cell tumours in male rats at all doses tested (10, 30, and 100 mg/kg); the lowest dose of 10 mg/kg is 
approximately 1.5 times the clinical dose of 300 mg based on AUC exposure. The higher doses of 
canagliflozin (100 mg/kg) in male and female rats increased the incidence of pheochromocytomas and 
renal tubular tumours. Based on AUC exposure, the NOEL of 30 mg/kg/day for pheochromocytomas 
and 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, and 
pheochromocytomas are considered to be rat-specific. Canagliflozin-induced renal tubule tumours and 
pheochromocytomas in rats appear to be caused by carbohydrate malabsorption as a consequence of 
intestinal SGLT1 inhibitory activity of canagliflozin in the gut of rats; mechanistic clinical studies 
have not demonstrated carbohydrate malabsorption in humans at canagliflozin doses of up to 2-times 
the maximum recommended clinical dose. The Leydig cell tumours are associated with an increase in 
luteinizing hormone (LH), which is a known mechanism of Leydig cell tumour formation in rats. In a 
12-week clinical study, unstimulated LH did not increase in male patients treated with canagliflozin.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

Lactose
Microcrystalline cellulose
Hydroxypropylcellulose
Croscarmellose sodium
Magnesium stearate



30

Film-coating

Invokana 100 mg film-coated tablets

Poly(vinyl alcohol)
Titanium dioxide (E171)
Macrogol 3350
Talc
Iron oxide yellow (E172)

Invokana 300 mg film-coated tablets

Poly(vinyl alcohol)
Titanium dioxide (E171)
Macrogol 3350
Talc

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Polyvinyl chloride/Aluminium (PVC/Alu) perforated unit dose blister.
Pack sizes of 10 x 1, 30 x 1, 90 x 1, and 100 x 1 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7. MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

8. MARKETING AUTHORISATION NUMBER(S)

Invokana 100 mg film-coated tablets

EU/1/13/884/001 (10 film-coated tablets)
EU/1/13/884/002 (30 film-coated tablets)
EU/1/13/884/003 (90 film-coated tablets)



31

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

Invokana 300 mg film-coated tablets

EU/1/13/884/005 (10 film-coated tablets)
EU/1/13/884/006 (30 film-coated tablets)
EU/1/13/884/007 (90 film-coated tablets)
EU/1/13/884/008 (100 film-coated tablets)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 15 November 2013
Date of latest renewal: 26 July 2018

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.



32

ANNEX II

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT



33

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer responsible for batch release

Janssen-Cilag S.p.A.
Via C. Janssen
Borgo San Michele
04100 Latina
Italy

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal products subject to medical prescription.

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

 Periodic safety update reports (PSURs)

The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT

 Risk management plan (RMP)

The marketing authorization holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation 
and any agreed subsequent updates of the RMP.

An updated RMP should be submitted:
 At the request of the European Medicines Agency;
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached.



34

ANNEX III

LABELLING AND PACKAGE LEAFLET



35

A. LABELLING



36

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

Invokana 100 mg film-coated tablets
Invokana 300 mg film-coated tablets
canagliflozin

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains canagliflozin hemihydrate, equivalent to 100 mg canagliflozin.
Each tablet contains canagliflozin hemihydrate, equivalent to 300 mg canagliflozin.

3. LIST OF EXCIPIENTS

Lactose.
See the package leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

Film-coated tablet.
10 x 1 film-coated tablets
30 x 1 film-coated tablets
90 x 1 film-coated tablets
100 x 1 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP



37

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/13/884/001 (100 mg – 10x1 film-coated tablets)
EU/1/13/884/002 (100 mg – 30x1 film-coated tablets)
EU/1/13/884/003 (100 mg – 90x1 film-coated tablets)
EU/1/13/884/004 (100 mg – 100x1 film-coated tablets)
EU/1/13/884/005 (300 mg – 10x1 film-coated tablets)
EU/1/13/884/006 (300 mg – 30x1 film-coated tablets)
EU/1/13/884/007 (300 mg – 90x1 film-coated tablets)
EU/1/13/884/008 (300 mg – 100x1 film-coated tablets)

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

invokana 100 mg
invokana 300 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC
SN
NN



38

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTERS

1. NAME OF THE MEDICINAL PRODUCT

Invokana 100 mg tablets
Invokana 300 mg tablets
canagliflozin

2. NAME OF THE MARKETING AUTHORISATION HOLDER

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER



39

B. PACKAGE LEAFLET



40

Package leaflet: Information for the patient

Invokana 100 mg film-coated tablets
Invokana 300 mg film-coated tablets

canagliflozin

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor, pharmacist or nurse.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.

What is in this leaflet
1. What Invokana is and what it is used for
2. What you need to know before you take Invokana
3. How to take Invokana
4. Possible side effects
5. How to store Invokana
6. Contents of the pack and other information

1. What Invokana is and what it is used for

Invokana contains the active substance canagliflozin which belongs to a group of medicines called 
“blood-glucose lowering drugs.”

Invokana is used:
 to treat adults with type 2 diabetes.

This medicine works by increasing the amount of sugar removed from your body in your urine. This 
reduces the amount of sugar in your blood and can help prevent heart disease in patients with type 2 
diabetes mellitus (T2DM). It also helps to slow down deterioration of kidney function in patients with
T2DM by a mechanism beyond blood glucose lowering.

Invokana can be used by itself or along with other medicines you may be using to treat your type 2 
diabetes (such as metformin, insulin, a DPP-4 inhibitor [such as sitagliptin, saxagliptin, or linagliptin], 
a sulphonylurea [such as glimepiride or glipizide], or pioglitazone) that lower blood sugar levels. You 
may already be taking one or more of these to treat your type 2 diabetes.

It is also important to keep following advice about diet and exercise given by your doctor or nurse.

What is type 2 diabetes?
Type 2 diabetes is a condition in which your body does not make enough insulin, and the insulin that 
your body produces does not work as well as it should. Your body can also make too much sugar. 
When this happens, sugar (glucose) builds up in the blood. This can lead to serious medical conditions 
such as heart disease, kidney disease, blindness, and amputation.

2. What you need to know before you take Invokana

Do not take Invokana
 if you are allergic to canagliflozin or any of the other ingredients of this medicine (listed in 

section 6).



41

Warnings and precautions
Talk to your doctor, pharmacist or nurse before taking Invokana, and during treatment:
 about what you can do to prevent dehydration (see section 4 for signs of dehydration).
 if you have type 1 diabetes because Invokana should not be used to treat this condition.
 if you experience rapid weight loss, feeling sick or being sick, stomach pain, excessive thirst, 

fast and deep breathing, confusion, unusual sleepiness or tiredness, a sweet smell to your breath, 
a sweet or metallic taste in your mouth or a different odour to your urine or sweat, talk to a 
doctor or go to the nearest hospital immediately. These symptoms could be a sign of “diabetic 
ketoacidosis” – a rare but serious, sometimes life-threatening problem you can get with diabetes 
because of increased levels of “ketone bodies” in your urine or blood, seen in tests. The risk of 
developing diabetic ketoacidosis may be increased with prolonged fasting, excessive alcohol 
consumption, dehydration, sudden reductions in insulin dose, or a higher need of insulin due to 
major surgery or serious illness.

 if you have diabetic ketoacidosis (a complication of diabetes with high blood sugar, rapid 
weight loss, nausea, or vomiting). Invokana should not be used to treat this condition.

 if you have severe kidney problems or are on dialysis.
 if you have severe liver problems.
 if you have ever had serious heart disease or if you have had a stroke.
 if you are on medicines to lower your blood pressure (anti-hypertensives) or have ever had low 

blood pressure (hypotension). More information is given below in “Other medicines and 
Invokana”.

 if you have had a lower limb amputation.
 It is important to check your feet regularly and adhere to any other advice regarding foot care 

and adequate hydration given by your healthcare professional. You should notify your doctor
immediately if you notice any wounds or discolouration, or if you experience any tenderness or 
pain in your feet. Some studies indicate that taking canagliflozin may have contributed to the 
risk of lower limb amputation (mainly toe and midfoot amputations).

 Talk to your doctor immediately if you develop a combination of symptoms of pain, tenderness, 
redness, or swelling of the genitals or the area between the genitals and the anus with fever or
feeling generally unwell. These symptoms could be a sign of a rare but serious or even 
life-threatening infection, called necrotising fasciitis of the perineum or Fournier’s gangrene 
which destroys the tissue under the skin. Fournier’s gangrene has to be treated immediately.

 if you have signs of a genital yeast infection such as irritation, itching, unusual discharge or 
odour.

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist, or nurse before 
taking this medicine.

Kidney function
Your kidneys will be tested by a blood test before you start taking and while you are on this medicine.

Urine glucose
Because of how this medicine works, your urine will test positive for sugar (glucose) while you are on 
this medicine.

Children and adolescents
Invokana is not recommended for children and adolescents under 18 years.

Other medicines and Invokana
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other 
medicines. This is because this medicine can affect the way some other medicines work. Also, some 
other medicines can affect the way this medicine works.

In particular, tell your doctor if you are taking any of the following medicines:



42

 other antidiabetics - either insulin or a sulphonylurea (such as glimepiride or glipizide) – your 
doctor may want to reduce your dose in order to avoid your blood sugar level from getting too 
low (hypoglycaemia)

 medicines used to lower your blood pressure (anti-hypertensives), including diuretics
(medicines used to remove levels of excess water in the body, also known as water tablets) since 
this medicine can also lower your blood pressure by removing levels of excess water in the 
body. Possible signs of losing too much fluid from your body are listed in section 4.

 St. John’s wort (an herbal medicine to treat depression)
 carbamazepine, phenytoin, or phenobarbital (medicines used to control seizures)
 efavirenz or ritonavir (a medicine used to treat HIV infection)
 rifampicin (an antibiotic used to treat tuberculosis)
 cholestyramine (medicine used to reduce cholesterol levels in the blood). See section 3, “Taking 

this medicine”.
 digoxin or digitoxin (medicines used for certain heart problems). The level of digoxin or 

digitoxin in your blood may need to be checked if taken with Invokana.
 dabigatran (blood thinner medicine that lowers the risk of blood clot formation).

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking or continuing to take this medicine. Invokana
should not be used during pregnancy. Talk to your doctor about the best way to discontinue Invokana 
and control your blood sugar as soon as you know that you are pregnant.

You should not take this medicine if you are breast-feeding. Talk to your doctor about whether to stop 
taking this medicine or to stop breast-feeding.

Driving and using machines
Invokana has no or negligible influence on the ability to drive, cycle, and use tools or machines.
However, dizziness or lightheadedness has been reported, which may affect your ability to drive, 
cycle, or use tools or machines.

Taking Invokana with other medicines for diabetes called sulphonylureas (such as glimepiride or 
glipizide) or insulin can increase the risk of having low blood sugar (hypoglycaemia). Signs include
blurred vision, tingling lips, trembling, sweating, pale looking, a change in mood, or feeling anxious or
confused. This may affect your ability to drive, cycle, and use any tools or machines. Tell your doctor 
as soon as possible if you get any of the signs of low blood sugar.

Invokana contains lactose
If you have been told by your doctor that you have an intolerance to some sugars, talk to your doctor 
before taking this medicine.

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

3. How to take Invokana

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor
or pharmacist if you are not sure.

How much to take
 The starting dose of Invokana is one 100 mg tablet each day. Your doctor will decide whether to 

increase your dose to 300 mg.
 Your doctor may limit your dose to 100 mg if you have a kidney problem.
 Your doctor will prescribe the strength that is right for you.



43

Taking this medicine
 Swallow the tablet whole with water.
 You can take your tablet with or without food. It is best to take your tablet before the first meal 

of the day.
 Try to take it at the same time each day. This will help you remember to take it.
 If your doctor has prescribed canagliflozin along with any bile acid sequestrant such as 

cholestyramine (medicines for lowering cholesterol) you should take canagliflozin at least 
1 hour before or 4 hours to 6 hours after the bile acid sequestrant.

Your doctor may prescribe Invokana together with another glucose-lowering medicine. Remember to 
take all medicines as directed by your doctor to achieve the best results for your health.

Diet and exercise
To control your diabetes, you still need to follow the advice about diet and exercise from your doctor, 
pharmacist or nurse. In particular, if you are following a diabetic weight control diet, continue to 
follow it while you are taking this medicine.

If you take more Invokana than you should
If you take more of this medicine than you should, talk to a doctor or go to the nearest hospital
immediately.

If you forget to take Invokana
 If you forget to take a dose, take it as soon as you remember. However, if it is nearly time for 

the next dose, skip the missed dose.
 Do not take a double dose (two doses on the same day) to make up for a forgotten dose.

If you stop taking Invokana
Your blood sugar levels may rise if you stop taking this medicine. Do not stop taking this medicine 
without talking to your doctor first.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Stop taking Invokana and talk to a doctor or go to the nearest hospital immediately if you have 
any of the following serious side effects:

Severe allergic reaction (rare, may affect up to 1 in 1,000 people)
Possible signs of severe allergic reaction may include:
 swelling of the face, lips, mouth, tongue, or throat that may lead to difficulty breathing or 

swallowing.

Diabetic ketoacidosis (rare, may affect up to 1 in 1,000 people)
These are the signs of diabetic ketoacidosis (see also section 2):
 increased levels of “ketone bodies” in your urine or blood
 rapid weight loss
 feeling sick or being sick
 stomach pain
 excessive thirst
 fast and deep breathing
 confusion
 unusual sleepiness or tiredness



44

 a sweet smell to your breath, a sweet or metallic taste in your mouth or a different odour to your 
urine or sweat.

This may occur regardless of blood glucose level. Diabetic ketoacidosis may occur more frequently as 
the kidney function gets worse. The doctor may decide to temporarily or permanently stop the 
treatment with Invokana.

Dehydration (uncommon, may affect up to 1 in 100 people)
 loss of too much fluid from your body (dehydration). This happens more often in elderly people 

(aged 75 and over), people with kidney problems, and people taking water tablets (diuretics).
Possible signs of dehydration are:
- feeling light-headed or dizzy
- passing out (fainting) or feeling dizzy or faint when you stand up
- very dry or sticky mouth, feeling very thirsty
- feeling very weak or tired
- passing little or no urine
- fast heartbeat.

Tell your doctor as soon as possible if you have any of the following side effects:
Hypoglycaemia (very common, may affect more than 1 in 10 people)
 low blood sugar levels (hypoglycaemia) - when taking this medicine with insulin or a 

sulphonylurea (such as glimepiride or glipizide).
Possible signs of low blood sugar are:
- blurred vision
- tingling lips
- trembling, sweating, pale looking
- a change in mood or feeling anxious or confused.

Your doctor will tell you how to treat low blood sugar levels and what to do if you have any of the 
signs above.

Urinary tract infections (common, may affect up to 1 in 10 people)
 These are signs of a severe infection of the urinary tract, e.g.:

- fever and/or chills
- burning sensation when passing water (urinating)
- pain in your back or side.

Although uncommon, if you see blood in your urine, tell your doctor immediately.

Other side effects:
Very common (may affect more than 1 in 10 people)
 vaginal yeast infection.

Common (may affect up to 1 in 10 people)
 rash or redness of the penis or foreskin (yeast infection)
 changes in urination (including urinating more frequently or in larger amounts, urgent need to 

urinate, need to urinate at night)
 constipation
 feeling thirsty
 nausea
 blood tests may show changes in blood fat (cholesterol) levels and increases in amount of red 

blood cells in your blood (haematocrit).

Uncommon (may affect up to 1 in 100 people)
 rash or red skin – this may be itchy and include raised bumps, oozing fluid or blisters
 hives



45

 blood tests may show changes related to kidney function (increased creatinine or urea) or 
increased potassium

 blood tests may show increases in your blood phosphate level
 bone fracture
 kidney failure (mainly as a consequence of loss of too much fluid from your body).
 lower limb amputations (mainly of the toe) especially if you are at high risk of heart disease.
 phimosis – difficulty pulling back the foreskin around the tip of the penis.
 skin reactions after exposure to sunlight.

Not known (frequency cannot be estimated from the available data)
 necrotising fasciitis of the perineum or Fournier’s gangrene, a serious soft tissue infection of the 

genitals or the area between the genitals and the anus.

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects, you can help provide more information on the 
safety of this medicine.

5. How to store Invokana

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the blister and carton after EXP. The 
expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not use Invokana if the packaging is damaged or shows signs of tampering.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Invokana contains
 The active substance is canagliflozin.

- Each tablet contains canagliflozin hemihydrate, equivalent to 100 mg or 300 mg of
canagliflozin.

 The other ingredients are:
- tablet core: lactose (see section 2 ‘Invokana contains lactose’), microcrystalline cellulose, 

hydroxypropylcellulose, croscarmellose sodium and magnesium stearate.
- film-coating: poly(vinyl alcohol), titanium dioxide (E171), macrogol 3350 and talc. The 

100 mg tablet also contains iron oxide yellow (E172).

What Invokana looks like and contents of the pack
 Invokana 100 mg film-coated tablets (tablets) are yellow, capsule-shaped, 11 mm long, with 

“CFZ” on one side and “100” on the other side.
 Invokana 300 mg film-coated tablets (tablets) are white, capsule-shaped, 17 mm long, with 

“CFZ” on one side and “300” on the other side.

Invokana is available in PVC/aluminium perforated unit dose blisters. The pack sizes are cartons of 
10 x 1, 30 x 1, 90 x 1, or 100 x 1 tablets.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


46

Not all pack sizes may be marketed.

Marketing Authorisation Holder
Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

Manufacturer
Janssen-Cilag SpA
Via C. Janssen
Borgo San Michele
04100 Latina
Italy

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
Mundipharma BV
Tél/Tel: +32 15 45 11 80
info@mundipharma.be

Lietuva
UAB "JOHNSON & JOHNSON"
Tel: +370 5 278 68 88
lt@its.jnj.com

България
ТП Мундифарма Гезелшафт М.Б.Х.
Тел.: +359 2 962 13 56
mundipharma@mundipharma.bg

Luxembourg/Luxemburg
Mundipharma Comm VA
Tél/Tel: +32 15 45 11 80
info@mundipharma.be

Česká republika
Mundipharma GesmbH. Austria - organizační 
složka ČR
Tel: +420 222 318 221
office@mundipharma.cz

Magyarország
Janssen-Cilag Kft.
Tel.: +36 1 884 2858
janssenhu@its.jnj.com

Danmark
Mundipharma A/S
Tlf: +45 45 17 48 00
mundipharma@mundipharma.dk

Malta
AM MANGION LTD.
Tel: +356 2397 6000

Deutschland
Janssen-Cilag GmbH
Tel: +49 2137 955-955
jancil@its.jnj.com

Nederland
Mundipharma Pharmaceuticals B.V.
Tel: +31 33 450 82 70
info@mundipharma.nl

Eesti
UAB "JOHNSON & JOHNSON" Eesti filiaal
Tel: +372 617 7410
ee@its.jnj.com

Norge
Mundipharma AS
Tlf: +47 67 51 89 00
post@mundipharma.no

Ελλάδα
Janssen-Cilag Φαρμακευτική Α.Ε.Β.Ε.
Tηλ: +30 210 80 90 000

Österreich
Mundipharma Gesellschaft m.b.H.
Tel: +43 1 523 25 05 -0
office@mundipharma.at



47

España
Mundipharma Pharmaceuticals, S.L.
Tel: +34 91 3821870
infomed@mundipharma.es

Polska
Mundipharma Polska Sp. z o.o.
Tel.: +48 22 866 87 12
biuro@mundipharma.pl

France
Janssen-Cilag
Tél: 0 800 25 50 75 / +33 1 55 00 40 03
medisource@its.jnj.com

Portugal
Mundipharma Farmacêutica Lda
Tel: +351 21 90 13 162
Portugal.regulatory@mundipharma.pt

Hrvatska
Johnson & Johnson S.E. d.o.o.
Tel: +385 1 6610 700
jjsafety@JNJCR.JNJ.com

România
Johnson & Johnson România SRL
Tel: +40 21 207 1800

Ireland
Mundipharma Pharmaceuticals Limited
Tel: +353 1 2063800

Slovenija
Johnson & Johnson d.o.o.
Tel: +386 1 401 18 00
Janssen_safety_slo@its.jnj.com

Ísland
Janssen-Cilag AB
Sími: +354 535 7000
janssen@vistor.is

Slovenská republika
Mundipharma Ges.m.b.H.-o.z.
Tel: +421 2 6381 1611
mundipharma@mundipharma.sk

Italia
Mundipharma Pharmaceuticals Srl
Tel: +39 02 3182881
infomedica@mundipharma.it

Suomi/Finland
Mundipharma Oy
Puh/Tel: +358 9 8520 2065
info@mundipharma.dk

Κύπρος
Mundipharma Pharmaceuticals Ltd
Τηλ: +357 22 815656
Drug.Safety@mundipharma.com.cy

Sverige
Mundipharma AB
Tel: +46 31 773 75 30
info@mundipharma.se

Latvija
UAB "JOHNSON & JOHNSON" filiāle Latvijā
Tel: +371 678 93561
lv@its.jnj.com

United Kingdom
Napp Pharmaceuticals Limited,
Tel: +44 1223 424444

This leaflet was approved in {month YYYY}.

Other sources of information
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET