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The following adverse reactions are also discussed elsewhere in the labeling:

  • Lactic Acidosis [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
  • Hypotension [see WARNINGS AND PRECAUTIONS]
  • Impairment in Renal Function [see WARNINGS AND PRECAUTIONS]
  • Hyperkalemia [see WARNINGS AND PRECAUTIONS]
  • Impaired Hepatic Function [see WARNINGS AND PRECAUTIONS]
  • Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin [see WARNINGS AND PRECAUTIONS]
  • Genital Mycotic Infections [see WARNINGS AND PRECAUTIONS]
  • Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
  • Vitamin B12 Deficiency [see WARNINGS AND PRECAUTIONS]
  • Increases in Low-Density Lipoprotein (LDL-C) [see WARNINGS AND PRECAUTIONS]

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Pool of Placebo-Controlled Trials

Canagliflozin

The data in Table 1 is derived from four 26-week placebo-controlled trials. In one trial canagliflozin was used as monotherapy and in three trials canagliflozin was used as add-on therapy with metformin (with or without other agents) [see Clinical Studies]. These data reflect exposure of 1667 patients to canagliflozin and a mean duration of exposure to canagliflozin of 24 weeks with 1275 subjects exposed to a combination of canagliflozin and metformin. Patients received canagliflozin 100 mg (N=833), canagliflozin 300 mg (N=834) or placebo (N=646) once daily. The mean daily dose of metformin was 2138 mg (SD 337.3) for the 1275 subjects in the three placebo-controlled metformin add-on studies. The mean age of the population was 56 years and 2% were older than 75 years of age. Fifty percent (50%) of the population was male and 72% were Caucasian, 12% were Asian, and 5% were Black or African American. At baseline the population had diabetes for an average of 7.3 years, had a mean HbA1C of 8.0% and 20% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 88 mL/min/1.73 m²).

Table 1 shows common adverse reactions associated with the use of canagliflozin. These adverse reactions were not present at baseline, occurred more commonly on canagliflozin than on placebo, and occurred in at least 2% of patients treated with either canagliflozin 100 mg or canagliflozin 300 mg.

Table 1: A dverse Reactions From Pool of Four 26-Week Placebo-Controlled Studies Reported in ≥ 2% of Canagliflozin-Treated Patients*

Adverse Reaction Placebo
N=646
Canagliflozin 100 mg
N=833
Canagliflozin 300 mg
N=834
Female genital mycotic infections† 3.2% 10.4% 11.4%
Urinary tract infections‡ 4.0% 5.9% 4.3%
Increased urination§ 0.8% 5.3% 4.6%
Male genital mycotic infections¶ 0.6% 4.2% 3.7%
Vulvovaginal pruritus 0.0% 1.6% 3.0%
Thirst# 0.2% 2.8% 2.3%
Constipation 0.9% 1.8% 2.3%
Nausea 1.5% 2.2% 2.3%
* The four placebo-controlled trials included one monotherapy trial and three addon combination trials with metformin, metformin and sulfonylurea, or metformin and pioglitazone.
† Female genital mycotic infections include the following adverse reactions: Vulvovaginal candidiasis, Vulvovaginal mycotic infection, Vulvovaginitis, Vaginal infection, Vulvitis, and Genital infection fungal. Percentages calculated with the number of female subjects in each group as denominator: placebo (N=312), canagliflozin 100 mg (N=425), and canagliflozin 300 mg (N=430).
‡ Urinary tract infections include the following adverse reactions: Urinary tract infection, Cystitis, Kidney infection, and Urosepsis.
§ Increased urination includes the following adverse reactions: Polyuria, Pollakiuria, Urine output increased, Micturition urgency, and Nocturia.
¶ Male genital mycotic infections include the following adverse reactions: Balanitis or Balanoposthitis, Balanitis candida, and Genital infection fungal. Percentages calculated with the number of male subjects in each group as denominator: placebo (N=334), canagliflozin 100 mg (N=408), and canagliflozin 300 mg (N=404).
# Thirst includes the following adverse reactions: Thirst, Dry mouth, and Polydipsia.

Abdominal pain was also more commonly reported in patients taking canagliflozin 100 mg (1.8%), 300 mg (1.7%) than in patients taking placebo (0.8%).

Canagliflozin and Metformin

The incidence and type of adverse reactions in the three 26-week

placebo-controlled metformin add-on studies, representing a majority of data from the four 26-week placebo-controlled trials, was similar to the adverse reactions described in Table 1. There were no additional adverse reactions identified in the pooling of these three placebo-controlled studies that included metformin relative to the four placebo-controlled studies.

Pool of Placebo- and Active-Controlled Trials - Canagliflozin

The occurrence of adverse reactions for canagliflozin was evaluated in a larger pool of patients participating in placebo- and active-controlled trials.

The data combined eight clinical trials and reflect exposure of 6177 patients to canagliflozin. The mean duration of exposure to canagliflozin was 38 weeks with 1832 individuals exposed to canagliflozin for greater than 50 weeks. Patients received canagliflozin 100 mg (N=3092), canagliflozin 300 mg (N=3085) or comparator (N=3262) once daily. The mean age of the population was 60 years and 5% were older than 75 years of age. Fifty-eight percent (58%) of the population was male and 73% were Caucasian, 16% were Asian, and 4% were Black or African American. At baseline, the population had diabetes for an average of 11 years, had a mean HbA1C of 8.0% and 33% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 81 mL/min/1.73 m²).

The types and frequency of common adverse reactions observed in the pool of eight clinical trials were consistent with those listed in Table 1. In this pool, canagliflozin was also associated with the adverse reactions of fatigue (1.7% with comparator, 2.2% with canagliflozin 100 mg, and 2.0% with canagliflozin 300 mg) and loss of strength or energy (i.e., asthenia) (0.6% with comparator, 0.7% with canagliflozin 100 mg, and 1.1% with canagliflozin 300 mg).

In the pool of eight clinical trials, the incidence rate of pancreatitis (acute or chronic) was 0.9, 2.7, and 0.9 per 1000 patient-years of exposure to comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively.

In the pool of eight clinical trials with a longer mean duration of exposure to canagliflozin (68 weeks), the incidence rate of bone fracture was 14.2, 18.7, and 17.6 per 1000 patient years of exposure to comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Upper extremity fractures occurred more commonly on canagliflozin than comparator.

In the pool of eight clinical trials, hypersensitivity-related adverse reactions (including erythema, rash, pruritus, urticaria, and angioedema) occurred in 3.0%, 3.8%, and 4.2% of patients receiving comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Five patients experienced serious adverse reactions of hypersensitivity with canagliflozin, which included 4 patients with urticaria and 1 patient with a diffuse rash and urticaria occurring within hours of exposure to canagliflozin. Among these patients, 2 patients discontinued canagliflozin. One patient with urticaria had recurrence when canagliflozin was re-initiated.

Photosensitivity-related adverse reactions (including photosensitivity reaction, polymorphic light eruption, and sunburn) occurred in 0.1%, 0.2%, and 0.2% of patients receiving comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively.

Other adverse reactions occurring more frequently on canagliflozin than on comparator were:

Volume Depletion-Related Adverse Reactions

Canagliflozin results in an osmotic diuresis, which may lead to reductions in intravascular volume. In clinical studies, treatment with canagliflozin was associated with a dose-dependent increase in the incidence of volume depletion-related adverse reactions (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration). An increased incidence was observed in patients on the 300 mg dose. The three factors associated with the largest increase in volume depletion-related adverse reactions were the use of loop diuretics, moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m²), and age 75 years and older (Table 2) [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, and Use in Specific Populations].

Table 2: Proportion of Patients With at Least One Volume Depletion-Related Adverse Reaction (Pooled Results from 8 Clinical Trials)

Baseline characteristic Comparator Group* % Canagliflozin 100 mg % Canagliflozin 300 mg %
Overall population 1.5% 2.3% 3.4%
75 years of age and older† 2.6% 4.9% 8.7%
eGFR less than 60 mL/min/1.73 m²† 2.5% 4.7% 8.1%
Use of loop diuretic† 4.7% 3.2% 8.8%
* Includes placebo and active-comparator groups
† Patients could have more than 1 of the listed risk factors

Impairment in Renal Function

Canagliflozin is associated with a dose-dependent increase in serum creatinine and a concomitant fall in estimated GFR (Table 3). Patients with moderate renal impairment at baseline had larger mean changes.

Table 3: Changes in Serum Creatinine and eGFR Associated with Canagliflozin in the Pool of Four Placebo-Controlled Trials and Moderate Renal Impairment Trial

  Placebo N=646 canagliflozin 100 mg N=833 canagliflozin 300 mg N=834
Pool of Four Placebo-Controlled Trials Baseline Creatinine (mg/dL) 0.84 0.82 0.82
eGFR (mL/ min/1.73 m²) 87.0 88.3 88.8
Week 6 Change Creatinine (mg/dL) 0.01 0.03 0.05
eGFR (mL/min/1.73 m²) -1.6 -3.8 -5.0
End of Treatment Change* Creatinine (mg/dL) 0.01 0.02 0.03
eGFR (mL/min/1.73 m²) -1.6 -2.3 -3.4
  Placebo N=90 canagliflozin 100 mg N=90 canagliflozin 300 mg N=89
Moderate Renal Impairment Trial Baseline Creatinine (mg/dL) 1.61 1.62 1.63
eGFR (mL/min/1.73 m²) 40.1 39.7 38.5
Week 3 Change Creatinine (mg/dL) 0.03 0.18 0.28
eGFR (mL/min/1.73 m²) -0.7 -4.6 -6.2
End of Treatment Change* Creatinine (mg/dL) 0.07 0.16 0.18
eGFR (mL/min/1.73 m²) -1.5 -3.6 -4.0
* Week 26 in mITT LOCF population

In the pool of four placebo-controlled trials where patients had normal or mildly impaired baseline renal function, the proportion of patients who experienced at least one event of significant renal function decline, defined as an eGFR below 80 mL/min/1.73 m² and 30% lower than baseline, was 2.1% with placebo, 2.0% with canagliflozin 100 mg, and 4.1% with canagliflozin 300 mg. At the end of treatment, 0.5% with placebo, 0.7% with canagliflozin 100 mg, and 1.4% with canagliflozin 300 mg had a significant renal function decline.

In a trial carried out in patients with moderate renal impairment with a baseline eGFR of 30 to less than 50 mL/min/1.73 m² (mean baseline eGFR 39 mL/min/1.73 m²), the proportion of patients who experienced at least one event of significant renal function decline, defined as an eGFR 30% lower than baseline, was 6.9% with placebo, 18% with canagliflozin 100 mg, and 22.5% with canagliflozin 300 mg. At the end of treatment, 4.6% with placebo, 3.4% with canagliflozin 100 mg, and 2.2% with canagliflozin 300 mg had a significant renal function decline.

In a pooled population of patients with moderate renal impairment (N=1085) with baseline eGFR of 30 to less than 60 mL/min/1.73 m² (mean baseline eGFR 48 mL/min/1.73 m²), the overall incidence of these events was lower than in the dedicated trial but a dose-dependent increase in incident episodes of significant renal function decline compared to placebo was still observed.

Use of canagliflozin has been associated with an increased incidence of renal-related adverse reactions (e.g., increased blood creatinine, decreased glomerular filtration rate, renal impairment, and acute renal failure), particularly in patients with moderate renal impairment.

In the pooled analysis of patients with moderate renal impairment, the incidence of renal-related adverse reactions was 3.7% with placebo, 8.9% with canagliflozin 100 mg, and 9.3% with canagliflozin 300 mg. Discontinuations due to renal-related adverse events occurred in 1.0% with placebo, 1.2% with canagliflozin 100 mg, and 1.6% with canagliflozin 300 mg [see WARNINGS AND PRECAUTIONS].

Genital Mycotic Infections

In the pool of four placebo-controlled clinical trials, female genital mycotic infections (e.g., vulvovaginal mycotic infection, vulvovaginal candidiasis, and vulvovaginitis) occurred in 3.2%, 10.4%, and 11.4% of females treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections on canagliflozin. Female patients who developed genital mycotic infections on canagliflozin were more likely to experience recurrence and require treatment with oral or topical antifungal agents and anti-microbial agents [see WARNINGS AND PRECAUTIONS].

In the pool of four placebo-controlled clinical trials, male genital mycotic infections (e.g., candidal balanitis, balanoposthitis) occurred in 0.6%, 4.2%, and 3.7% of males treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Male genital mycotic infections occurred more commonly in uncircumcised males and in males with a prior history of balanitis or balanoposthitis. Male patients who developed genital mycotic infections on canagliflozin were more likely to experience recurrent infections (22% on canagliflozin versus none on placebo), and require treatment with oral or topical antifungal agents and anti-microbial agents than patients on comparators. In the pooled analysis of 8 controlled trials, phimosis was reported in 0.3% of uncircumcised male patients treated with canagliflozin and 0.2% required circumcision to treat the phimosis [see WARNINGS AND PRECAUTIONS].

Hypoglycemia

In canagliflozin clinical trials, hypoglycemia was defined as any event regardless of symptoms, where biochemical hypoglycemia was documented (any glucose value below or equal to 70 mg/dL). Severe hypoglycemia was defined as an event consistent with hypoglycemia where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained). In individual clinical trials [see Clinical Studies], episodes of hypoglycemia occurred at a higher rate when canagliflozin was co-administered with insulin or sulfonylureas (Table 4) [see WARNINGS AND PRECAUTIONS].

Table 4: I ncidence of Hypoglycemia* in Controlled Clinical Studies

Monotherapy (26 weeks) Placebo
(N=192)
canagliflozin 100 mg
(N=195)
canagliflozin 300 mg
(N=197)
Overall [N (%)] 5(2.6) 7 (3.6) 6(3.0)
in combination with metformin (26 weeks) Placebo + metformin (N=183) canagliflozin 100 mg + metformin (N=368) canagliflozin 300 mg + metformin (N=367)
Overall [N (%)] 3(1.6) 16 (4.3) 17 (4.6)
Severe [N (%)]† 0 (0) 1 (0.3) 1 (0.3)
in combination with metformin (18 weeks) ‡ Placebo (N=93) canagliflozin 100 mg (N=93) canagliflozin 300 mg (N=93)
Overall [N (%)] 3(3.2) 4 (4.3) 3(3.2)
in combination with metformin + sulfonylurea (26 weeks) Placebo + metformin + sulfonylurea (N=156) canagliflozin 100 mg + metformin + sulfonylurea (N=157) canagliflozin 300 mg + metformin + sulfonylurea (N=156)
Overall [N (%)] 24 (15.4) 43 (27.4) 47 (30.1)
Severe [N (%)]† 1 (0.6) 1 (0.6) 0
in combination with metformin + Pioglitazone (26 weeks) Placebo + metformin + Pioglitazone (N=115) canagliflozin 100 mg + metformin + Pioglitazone (N=113) canagliflozin 300 mg + metformin + Pioglitazone (N=114)
Overall [N (%)] 3(2.6) 3(2.7) 6(5.3)
in combination with insulin (18 weeks) Placebo (N=565) canagliflozin 100 mg (N=566) canagliflozin 300 mg (N=587)
Overall [N (%)] 208 (36.8) 279(49.3) 285 (48.6)
Severe [N (%)]† 14 (2.5) 10 (1.8) 16 (2.7)
in combination with insulin and metformin (18 weeks) § Placebo (N=145) canagliflozin 100 mg (N=139) canagliflozin 300 mg (N=148)
Overall [N (%)] 66 (45.5) 58 (41.7) 70 (47.3)
Severe [N (%)]† 4(2.8) 1 (0.7) 3 (2.0)
* Number of patients experiencing at least one event of hypoglycemia based on either biochemically documented episodes or severe hypoglycemic events in the intent-to-treat population
† Severe episodes of hypoglycemia were defined as those where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained)
‡ Phase 2 clinical study with twice daily dosing (50 mg or 150 mg twice daily in combination with metformin)
§ Subgroup of patients (N=279) from insulin substudy on canagliflozin in combination with metformin and insulin (with or without other antiglycemic agents)

Metformin

The most common adverse reactions (5% or greater incidence) due to initiation of metformin are diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.

Long-term treatment with metformin has been associated with a decrease in vitamin B12, which may very rarely result in clinically significant vitamin B12 deficiency (e.g., megaloblastic anemia) [see WARNINGS AND PRECAUTIONS].

Laboratory Tests

Increases in Serum Potassium

In pooled data from four placebo-controlled trials with canagliflozin, the mean change in serum potassium levels was 0.5% and 1.0% with canagliflozin 100 mg and canagliflozin 300 mg, respectively, compared to 0.6% with placebo. Episodes of elevated serum potassium (greater than 5.4 mEq/L and 15% above baseline) were seen in 4.4% of patients treated with canagliflozin 100 mg, 7.0% of patients treated with canagliflozin 300 mg, and 4.8% of patients treated with placebo. Dose-related, transient mean increases in serum potassium were observed early after initiation of canagliflozin (i.e., within 3 weeks) in a trial of patients with moderate renal impairment. In this trial, increases in serum potassium of greater than 5.4 mEq/L and 15% above baseline occurred in 16.1%, 12.4%, and 27.0% of patients treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. More severe elevations (i.e., equal or greater than 6.5 mEq/L) occurred in 1.1%, 2.2%, and 2.2% of patients treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. In patients with moderate renal impairment, increases in potassium were more commonly seen in those with elevated potassium at baseline and in those using medications that reduce potassium excretion, such as potassium-sparing diuretics, angiotensin-converting-enzyme inhibitors, and angiotensin-receptor blockers [see WARNINGS AND PRECAUTIONS].

Increases in Serum Magnesium

Dose-related increases in serum magnesium were observed early after initiation of canagliflozin (within 6 weeks) and remained elevated throughout treatment. In the pool of four placebo-controlled trials, the mean change in serum magnesium levels was 8.1% and 9.3% with canagliflozin 100 mg and canagliflozin 300 mg, respectively, compared to - 0.6% with placebo. In a trial of patients with moderate renal impairment, serum magnesium levels increased by 0.2%, 9.2%, and 14.8% with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively.

Increases in Serum Phosphate

Dose-related increases in serum phosphate levels were observed with canagliflozin. In the pool of four placebo-controlled trials, the mean percent change in serum phosphate levels were 3.6% and 5.1% with canagliflozin 100 mg and canagliflozin 300 mg, respectively, compared to 1.5% with placebo. In a trial of patients with moderate renal impairment, the mean serum phosphate levels increased by 1.2%, 5.0%, and 9.3% with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively.

Increases in Low-Density Lipoprotein Cholesterol (LDL-C) and non-High-Density Lipoprotein Cholesterol (non-HDL-C)

In the pool of four placebo-controlled trials, dose-related increases in LDL-C with canagliflozin were observed. Mean changes (percent changes) from baseline in LDL-C relative to placebo were 4.4 mg/dL (4.5%) and 8.2 mg/dL (8.0%) with canagliflozin 100 mg and canagliflozin 300 mg, respectively. The mean baseline LDL-C levels were 104 to 110 mg/dL across treatment groups [see WARNINGS AND PRECAUTIONS].

Dose-related increases in non-HDL-C with canagliflozin were observed. Mean changes (percent changes) from baseline in non-HDL-C relative to placebo were 2.1 mg/dL (1.5%) and 5.1 mg/dL (3.6%) with canagliflozin 100 mg and 300 mg, respectively. The mean baseline non-HDL-C levels were 140 to 147 mg/dL across treatment groups.

Increases in Hemoglobin

In the pool of four placebo-controlled trials, mean changes (percent changes) from baseline in hemoglobin were - 0.18 g/dL (-1.1%) with placebo, 0.47 g/dL (3.5%) with canagliflozin 100 mg, and 0.51 g/dL (3.8%) with canagliflozin 300 mg. The mean baseline hemoglobin value was approximately 14.1 g/dL across treatment groups. At the end of treatment, 0.8%, 4.0%, and 2.7% of patients treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively, had hemoglobin levels above the upper limit of normal.