Invokana Adverse Reactions

Summary of the safety profile: The safety of canagliflozin was evaluated in 10,285 patients with type 2 diabetes, including 3,139 patients treated with canagliflozin 100 mg and 3,506 patients treated with canagliflozin 300 mg, who received medicinal product in nine double-blind, controlled phase 3 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 (see Table 3) (see Dosage & Administration and Precautions).
Tabulated list of adverse reactions: Adverse reactions in Table 5 are based on the pooled analysis of the placebo- and active-controlled studies described previously. 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). (See Table 5.)

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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 Precautions).
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 6.
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, 1.561]) 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. (See Table 6.)

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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 6). 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 Precautions).
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 Dosage & Administration and Precautions).
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 decreasing eGFR. In subjects with eGFR 30 to <45mL/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 <90mL/min/1.73 m², the between-group incidence 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 Dosage & Administration and Interactions).
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 Precautions). 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 Precautions).
Urinary tract infections: In clinical studies, 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. 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, 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 Dosage & Administration and Precautions).
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 Dosage & Administration and Precautions).
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 Precautions).
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 frequently 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 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 hyperkalemia, 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]).