There are no data from the use of canagliflozin alone or canagliflozin/metformin in pregnant women. Studies in animals with canagliflozin have shown reproductive toxicity.

A limited amount of data from the use of metformin in pregnant women does not indicate an increased risk of congenital malformations. Animal studies with metformin do not indicate harmful effects with respect to pregnancy, embryonic or foetal development, parturition, or postnatal development.

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

No studies in lactating animals have been conducted with the combined active substances of canagliflozin/metformin combination. 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. Metformin is excreted into human breast milk in small amounts. A risk to newborns/infants cannot be excluded. Canagliflozin/metformin should not be used during breast-feeding.

Fertility

The effect of canagliflozin/metformin on fertility in humans has not been studied. No effects of canagliflozin or metformin on fertility were observed in animal studies.

Canagliflozin/metformin combination 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/metformin 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.

Canagliflozin

Summary of the safety profile

The safety of canagliflozin was evaluated in 22,645 patients with type 2 diabetes, including the evaluation of canagliflozin in combination with metformin in 16,334 patients. In addition, an 18-week double-blind, placebo-controlled phase 2 study with twice daily dosing (canagliflozin 50 mg or 150 mg as add-on therapy with metformin 500 mg) was conducted in 279 patients in which 186 patients were treated with canagliflozin as add-on therapy with metformin.

The primary assessment of safety and tolerability was conducted in a pooled analysis (N=2,313) 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 events in order to identify adverse reactions (see table 1).

Tabulated list of adverse reactions

Adverse reactions in table 1 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 1. Tabulated list of adverse reactions (MedDRA) from placebo^e and active-controlled studies^e and from postmarketing experience:

^a Related to volume depletion; see description of adverse reaction (AR) below.
^b See description of AR below.
^c See description of AR below.
^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.
° 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 cangliflozin 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

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 2.

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 a long-term renal outcomes study of 4,397 patients with type 2 diabetes and diabetic kidney disease. 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 2. Integrated analysis of amputations in CANVAS and CANVAS-R:

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 (see table 2). 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.

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 once daily, 1.3% for canagliflozin 300 mg once daily, 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.

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 once daily, canagliflozin 300 mg once daily, and placebo, respectively, and severe hypoglycaemia occurred in 1.8%, 2.7%, and 2.5% of patients treated with canagliflozin 100 mg once daily, canagliflozin 300 mg once daily, 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 once daily, canagliflozin 300 mg once daily, and placebo, respectively.

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 once daily and canagliflozin 300 mg once daily, 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. 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.

Urinary tract infections

In clinical studies, urinary tract infections were more frequently reported for canagliflozin 100 mg and 300 mg once daily (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. In these studies, subjects responded to standard treatments while continuing canagliflozin treatment.

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

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

Renal impairment

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.

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.

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.

Metformin

Table 3 presents adverse reactions by SOC and by frequency category reported in patients who received metformin as monotherapy and that were not observed in patients receiving canagliflozin. Frequency categories are based on information available from the metformin Summary of Product Characteristics.

Table 3. The frequency of metformin adverse reactions identified from clinical study and postmarketing data:

^a Metformin may commonly reduce vitamin B₁₂ serum levels, which may result in clinically significant vitamin B₁₂ deficiency (e.g., megaloblastic anaemia). The risk of low vitamin B₁₂ levels increases with increasing metformin dose, treatment duration, and/or in patients with risk factors known to cause vitamin B₁₂ deficiency. Periodic monitoring of vitamin B₁₂ levels is recommended in these patients.
^b Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite occur most frequently during initiation of therapy and resolve spontaneously in most cases.

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.