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The following important adverse reactions are described below and elsewhere in the labeling:

  • Use in Patients with Renal Impairment [see WARNINGS AND PRECAUTIONS]
  • Hypotension [see WARNINGS AND PRECAUTIONS]
  • Use with Medications Known to Cause Hypoglycemia [see WARNINGS AND PRECAUTIONS]
  • Vitamin B12 Concentrations [see WARNINGS AND PRECAUTIONS]
  • Genital Mycotic Infections [see WARNINGS AND PRECAUTIONS]
  • Increases in Low-Density Lipoprotein Cholesterol (LDL-C) [see WARNINGS AND PRECAUTIONS]
  • Bladder Cancer [see WARNINGS AND PRECAUTIONS]

Clinical Trials 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 rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Dapagliflozin and Metformin Hydrochloride

Data from a prespecified pool of patients from 8 short-term, placebo-controlled studies of dapagliflozin coadministered with metformin immediate- or extended-release was used to evaluate safety. This pool included several add-on studies (metformin alone and in combination with a dipeptidyl peptidase-4 [DPP4] inhibitor and metformin, or insulin and metformin, 2 initial combination with metformin studies, and 2 studies of patients with cardiovascular disease [CVD] and type 2 diabetes who received their usual treatment [with metformin as background therapy]). For studies that included background therapy with and without metformin, only patients who received metformin were included in the 8-study placebo-controlled pool. Across these 8 studies 983 patients were treated once daily with dapagliflozin 10 mg and metformin and 1185 were treated with placebo and metformin. These 8 studies provide a mean duration of exposure of 23 weeks. The mean age of the population was 57 years and 2% were older than 75 years. Fifty-four percent (54%) of the population was male; 88% White, 6% Asian, and 3% Black or African American. At baseline, the population had diabetes for an average of 8 years, mean hemoglobin A1c (HbA1c) was 8.4%, and renal function was normal or mildly impaired in 90% of patients and moderately impaired in 10% of patients.

The overall incidence of adverse events for the 8-study, short-term, placebo-controlled pool in patients treated with dapagliflozin 10 mg and metformin was 60.3% compared to 58.2% for the placebo and metformin group. Discontinuation of therapy due to adverse events in patients who received dapagliflozin 10 mg and metformin was 4% compared to 3.3% for the placebo and metformin group. The most commonly reported events leading to discontinuation and reported in at least 3 patients treated with dapagliflozin 10 mg and metformin were renal impairment (0.7%), increased blood creatinine (0.2%), decreased renal creatinine clearance (0.2%), and urinary tract infection (0.2%).

Table 1 shows common adverse reactions associated with the use of dapagliflozin and metformin. These adverse reactions were not present at baseline, occurred more commonly on dapagliflozin and metformin than on placebo, and occurred in at least 2% of patients treated with either dapagliflozin 5 mg or dapagliflozin 10 mg.

Table 1: Adverse Reactions in Placebo-Controlled Studies Reported in ≥ 2% of Patients Treated with Dapagliflozin and Metformin

Adverse Reaction % of Patients
Pool of 8 Placebo-Controlled Studies
Placebo and Metformin
N=1185
Dapagliflozin 5 mg and Metformin
N=410
Dapagliflozin 10 mg and Metformin
N=983
Female genital mycotic infections* 1.5 9.4 9.3
Nasopharyngitis 5.9 6.3 5.2
Urinary tract infections† 3.6 6.1 5.5
Diarrhea 5.6 5.9 4.2
Headache 2.8 5.4 3.3
Male genital mycotic infections‡ 0 4.3 3.6
Influenza 2.4 4.1 2.6
Nausea 2.0 3.9 2.6
Back pain 3.2 3.4 2.5
Dizziness 2.2 3.2 1.8
Cough 1.9 3.2 1.4
Constipation 1.6 2.9 1.9
Dyslipidemia 1.4 2.7 1.5
Pharyngitis 1.1 2.7 1.5
Increased urination§ 1.4 2.4 2.6
Discomfort with urination 1.1 2.2 1.6
* Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for females: vulvovaginal mycotic infection, vaginal infection, genital infection, vulvovaginitis, fungal genital infection, vulvovaginal candidiasis, vulval abscess, genital candidiasis, and vaginitis bacterial. (N for females: Placebo and metformin=534, dapagliflozin 5 mg and metformin=223, dapagliflozin 10 mg and metformin=430).
† Urinary tract infections include the following adverse reactions, listed in order of frequency reported: urinary tract infection, cystitis, pyelonephritis, urethritis, and prostatitis.
‡ Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for males: balanitis, fungal genital infection, balanitis candida, genital candidiasis, genital infection, posthitis, balanoposthitis. (N for males: Placebo and metformin=651, dapagliflozin 5 mg and metformin=187, dapagliflozin 10 mg and metformin=553).
§ Increased urination includes the following adverse reactions, listed in order of frequency reported: pollakiuria, polyuria, and urine output increased.

Metformin Hydrochloride

In placebo-controlled monotherapy trials of metformin extended-release, diarrhea and nausea/vomiting were reported in > 5% of metformin-treated patients and more commonly than in placebo-treated patients (9.6% versus 2.6% for diarrhea and 6.5% versus 1.5% for nausea/vomiting). Diarrhea led to discontinuation of study medication in 0.6% of the patients treated with metformin extended-release.

Pool of 12 Placebo-Controlled Studies for Dapagliflozin 5 and 10 mg

Dapagliflozin

The data in Table 2 are derived from 12 placebo-controlled studies ranging from 12 to 24 weeks. In 4 studies dapagliflozin was used as monotherapy, and in 8 studies dapagliflozin was used as add-on to background antidiabetic therapy or as combination therapy with metformin [see Clinical Studies].

These data reflect exposure of 2338 patients to dapagliflozin with a mean exposure duration of 21 weeks. Patients received placebo (N=1393), dapagliflozin 5 mg (N=1145), or dapagliflozin 10 mg (N=1193) once daily. The mean age of the population was 55 years and 2% were older than 75 years of age. Fifty percent (50%) of the population were male; 81% were White, 14% were Asian, and 3% were Black or African American. At baseline, the population had diabetes for an average of 6 years, had a mean HbA1c of 8.3%, and 21% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired in 92% of patients and moderately impaired in 8% of patients (mean eGFR 86 mL/min/1.73 m²).

Table 2 shows common adverse reactions associated with the use of dapagliflozin. These adverse reactions were not present at baseline, occurred more commonly on dapagliflozin than on placebo, and occurred in at least 2% of patients treated with either dapagliflozin 5 mg or dapagliflozin 10 mg.

Table 2: Adverse Reactions in Placebo-Controlled Studies Reported in ≥ 2% of Patients Treated with Dapagliflozin

Adverse Reaction % of Patients
Pool of 12 Placebo-Controlled Studies
Placebo
N=1393
Dapagliflozin 5 mg
N=1145
Dapagliflozin 10 mg
N=1193
Female genital mycotic infections* 1.5 8.4 6.9
Nasopharyngitis 6.2 6.6 6.3
Urinary tract infections† 3.7 5.7 4.3
Back pain 3.2 3.1 4.2
Increased urination‡ 1.7 2.9 3.8
Male genital mycotic infections§ 0.3 2.8 2.7
Nausea 2.4 2.8 2.5
Influenza 2.3 2.7 2.3
Dyslipidemia 1.5 2.1 2.5
Constipation 1.5 2.2 1.9
Discomfort with urination 0.7 1.6 2.1
Pain in extremity 1.4 2.0 1.7
* Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for females: vulvovaginal mycotic infection, vaginal infection, vulvovaginal candidiasis, vulvovaginitis, genital infection, genital candidiasis, fungal genital infection, vulvitis, genitourinary tract infection, vulval abscess, and vaginitis bacterial. (N for females: Placebo=677, dapagliflozin 5 mg=581, dapagliflozin 10 mg=598).
† Urinary tract infections include the following adverse reactions, listed in order of frequency reported: urinary tract infection, cystitis, Escherichia urinary tract infection, genitourinary tract infection, pyelonephritis, trigonitis, urethritis, kidney infection, and prostatitis.
‡ Increased urination includes the following adverse reactions, listed in order of frequency reported: pollakiuria, polyuria, and urine output increased.
§ Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for males: balanitis, fungal genital infection, balanitis candida, genital candidiasis, genital infection male, penile infection, balanoposthitis, balanoposthitis infective, genital infection, posthitis. (N for males: Placebo=716, dapagliflozin 5 mg=564, dapagliflozin 10 mg=595).

Pool of 13 Placebo-Controlled Studies for Dapagliflozin 10 mg

The safety and tolerability of dapagliflozin 10 mg was also evaluated in a larger placebocontrolled study pool. This pool combined 13 placebo-controlled studies, including 3 monotherapy studies, 9 add-on to background antidiabetic therapy studies, and an initial combination with metformin study. Across these 13 studies, 2360 patients were treated once daily with dapagliflozin 10 mg for a mean duration of exposure of 22 weeks. The mean age of the population was 59 years and 4% were older than 75 years. Fifty-eight percent (58%) of the population were male; 84% were White, 9% were Asian, and 3% were Black or African American. At baseline, the population had diabetes for an average of 9 years, had a mean HbA1c of 8.2%, and 30% had established microvascular disease. Baseline renal function was normal or mildly impaired in 88% of patients and moderately impaired in 11% of patients (mean Egfr 82 mL/min/1.73 m²).

Volume Depletion

Dapagliflozin causes an osmotic diuresis, which may lead to reductions in intravascular volume. Adverse reactions related to volume depletion (including reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension) are shown in Table 3 for the 12-study and 13-study, short-term, placebo-controlled pools [see WARNINGS AND PRECAUTIONS].

Table 3: Adverse Reactions of Volume Depletion* in Clinical Studies with Dapagliflozin

  Pool of 12 Placebo-Controlled Studies Pool of 13 Placebo-Controlled Studies
Placebo Dapagliflozin 5 mg Dapagliflozin 10 mg Placebo Dapagliflozin 10 mg
Overall population N (%) N=1393
5 (0.4%)
N=1145
7 (0.6%)
N=1193
9 (0.8%)
N=2295
17 (0.7%)
N=2360
27 (1.1%)
Patient Subgroup n (%)
  Patients on loop diuretics n=55
1 (1.8%)
n=40
0
n=31
3 (9.7%)
n=267
4 (1.5%)
n=236
6 (2.5%)
  Patients with moderate renal impairment with eGFR ≥ 30 and < 60 mL/min/1.73 m² n=107
2 (1.9%)
n=107
1 (0.9%)
n=89
1 (1.1%)
n=268
4 (1.5%)
n=265
5 (1.9%)
  Patients ≥ 65 years of age n=276
1 (0.4%)
n=216
1 (0.5%)
n=204
3 (1.5%)
n=711
6 (0.8%)
n=665
11 (1.7%)
* Volume depletion includes reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension.

Impairment of Renal Function

Use of dapagliflozin was associated with increases in serum creatinine and decreases in eGFR (see Table 4). In patients with normal or mildly impaired renal function at baseline, serum creatinine and eGFR returned to baseline values at Week 24. Renal-related adverse reactions, including renal failure and blood creatinine increase, were more frequent in patients treated with dapagliflozin (see Table 5). Elderly patients and patients with impaired renal function were more susceptible to these adverse reactions (see Table 5). Sustained decreases in eGFR were seen in patients with moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m²).

Table 4: Changes in Serum Creatinine and eGFR Associated with Dapagliflozin in the Pool of 12 Placebo-Controlled Studies and Moderate Renal Impairment Study

  Pool of 12 Placebo-Controlled Studies
Placebo
N=1393
Dapagliflozin 5 mg
N=1145
Dapagliflozin 10 mg
N=1193
Baseline Mean Serum Creatinine (mg/dL) 0.853 0.860 0.847
eGFR (mL/min/1.73 m²) 86.0 85.3 86.7
Week 1 Change Serum Creatinine (mg/dL) -0.003 0.029 0.041
eGFR (mL/min/1.73 m²) 0.4 -2.9 -4.1
Week 24 Change Serum Creatinine (mg/dL) -0.005 -0.001 0.001
eGFR (mL/min/1.73 m²) 0.8 0.8 0.3
  Moderate Renal Impairment Study
Placebo N=84 Dapagliflozin 5 mg N=83 Dapagliflozin 10 mg N=85
Baseline Mean Serum Creatinine (mg/dL) 1.46 1.53 1.52
eGFR (mL/min/1.73 m²) 45.6 44.2 43.9
Week 1 Change Serum Creatinine (mg/dL) 0.01 0.13 0.18
eGFR (mL/min/1.73 m²) 0.5 -3.8 -5.5
Week 24 Change Serum Creatinine (mg/dL) 0.02 0.08 0.16
eGFR (mL/min/1.73 m²) 0.03 -4.0 -7.4
Week 52 Change Serum Creatinine (mg/dL) 0.10 0.06 0.15
eGFR (mL/min/1.73 m²) -2.6 -4.2 -7.3

Table 5: Proportion of Patients with at Least One Renal Impairment- Related Adverse Reaction

Baseline Characteristic Pool of 6 Placebo-Controlled Studies (up to 104 weeks)* Pool of 9 Placebo-Controlled Studies (up to 104 weeks)†
Placebo Dapagliflozin 5 mg Dapagliflozin 10 mg Placebo Dapagliflozin 10 mg
Overall population Patients (%) with at least one event n=785
13 (1.7%)
n=767
14 (1.8%)
n=859
16 (1.9%)
n=1956
82 (4.2%)
n=2026
136 (6.7%)
65 years of age and older Patients (%) with at least one event n=190
4 (2.1%)
n=162
5 (3.1%)
n=159
6 (3.8%)
n=655
52 (7.9%)
n=620
87 (14.0%)
eGFR ≥ 30 and < 60 mL/min/1.73 m² Patients (%) with at least one event n=77
5 (6.5%)
n=88
7 (8.0%)
n=75
9 (12.0%)
n=249
40 (16.1%)
n=251
71 (28.3%)
65 years of age and older and eGFR ≥ 30 and < 60 mL/min/1.73 m² Patients (%) with at least one event n=41
2 (4.9%)
n=43
3 (7.0%)
n=35
4 (11.4%)
n=141
27 (19.1%)
n=134
47 (35.1%)
* Subset of patients from the pool of 12 placebo-controlled studies with long-term extensions.
† Subset of patients from the pool of 13 placebo-controlled studies with long-term extensions.

The safety of dapagliflozin was evaluated in a study of patients with moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m²). In this study 13 patients experienced bone fractures for treatment durations up to 104 weeks. No fractures occurred in the placebo group, 5 occurred in the dapagliflozin 5 mg group, and 8 occurred in the dapagliflozin 10 mg group. Eight of these 13 fractures were in patients who had a baseline eGFR of 30 to 45 mL/min/1.73 m². Eleven of the 13 fractures were reported within the first 52 weeks. There was no apparent pattern with respect to the anatomic site of fracture.

Hypoglycemia

The frequency of hypoglycemia by study [see Clinical Studies] is shown in Table 6. Hypoglycemia was more frequent when dapagliflozin was added to sulfonylurea or insulin [see WARNINGS AND PRECAUTIONS].

Table 6: Incidence of Major* and Minor† Hypoglycemia in Placebo-Controlled Studies

  Placebo Dapagliflozin 5 mg Dapagliflozin 10 mg
Add-on to Metformin* (24 weeks) N=137 N=137 N=135
  Major [n (%)] 0 0 0
  Minor [n (%)] 0 2 (1.5) 1 (0.7)
Active Control Add-on to Metformin versus Glipizide (52 weeks) N=408 - N=406
  Major [n (%)] 3 (0.7) - 0
  Minor [n (%)] 147 (36.0) - 7 (1.7)
Add-on to DPP4 inhibitor (with or without Metformin) (24 weeks) N=226 - N=225
  Major [n (%)] 0 - 1 (0.4)
  Minor [n (%)] 3 (1.3) - 4 (1.8)
Add-on to Insulin with or without other OADs‡ (24 weeks) N=197 N=212 N=196
  Major [n (%)] 1 (0.5) 1 (0.5) 1 (0.5)
  Minor [n (%)] 67 (34.0) 92 (43.4) 79 (40.3)
* Major episodes of hypoglycemia were defined as symptomatic episodes requiring external (third party) assistance due to severe impairment in consciousness or behavior with a capillary or plasma glucose value < 54 mg/dL and prompt recovery after glucose or glucagon administration.
† Minor episodes of hypoglycemia were defined as either a symptomatic episode with a capillary or plasma glucose measurement < 63 mg/dL regardless of need for external assistance, or an asymptomati capillary or plasma glucose measurement < 63 mg/dL that does not qualify as a major episode.
‡ OAD = oral antidiabetic therapy.

Genital Mycotic Infections

Genital mycotic infections were more frequent with dapagliflozin treatment. Genital mycotic infections were reported in 0.9% of patients on placebo, 5.7% on dapagliflozin 5 mg, and 4.8% on dapagliflozin 10 mg, in the 12-study placebo-controlled pool. Discontinuation from study due to genital infection occurred in 0% of placebo-treated patients and 0.2% of patients treated with dapagliflozin 10 mg. Infections were more frequently reported in females than in males (see Table 2). The most frequently reported genital mycotic infections were vulvovaginal mycotic infections in females and balanitis in males. Patients with a history of genital mycotic infections were more likely to have a genital mycotic infection during the study than those with no prior history (10.0%, 23.1%, and 25.0% versus 0.8%, 5.9%, and 5.0% on placebo, dapagliflozin 5 mg, and dapagliflozin 10 mg, respectively).

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., angioedema, urticaria, hypersensitivity) were reported with dapagliflozin treatment. Across the clinical program, serious anaphylactic reactions and severe cutaneous adverse reactions and angioedema were reported in 0.2% of comparator-treated patients and 0.3% of dapagliflozin-treated patients. If hypersensitivity reactions occur, discontinue use of dapagliflozin; treat per standard of care and monitor until signs and symptoms resolve.

Laboratory Tests

Increase in Hematocrit

Dapagliflozin

In the pool of 13 placebo-controlled studies, increases from baseline in mean hematocrit values were observed in dapagliflozin-treated patients starting at Week 1 and continuing up to Week 16, when the maximum mean difference from baseline was observed. At Week 24, the mean changes from baseline in hematocrit were -0.33% in the placebo group and 2.30% in the dapagliflozin 10 mg group. By Week 24, hematocrit values > 55% were reported in 0.4% of placebo-treated patients and 1.3% of dapagliflozin 10 mg–treated patients.

Increase in Serum Inorganic Phosphorus

Dapagliflozin

In the pool of 13 placebo-controlled studies, increases from baseline in mean serum phosphorus levels were reported at Week 24 in dapagliflozin 10 mg–treated patients compared with placebotreated patients (mean increases of 0.13 mg/dL versus -0.04 mg/dL, respectively). Higher proportions of patients with marked laboratory abnormalities of hyperphosphatemia ( ≥ 5.6 mg/dL if age 17-65 or ≥ 5.1 mg/dL if age ≥ 66) were reported in the dapagliflozin 10 mg group versus the placebo group at Week 24 (1.7% versus 0.9%, respectively).

Increase in Low-Density Lipoprotein Cholesterol Dapagliflozin

Dapagliflozin

In the pool of 13 placebo-controlled studies, changes from baseline in mean lipid values were reported in dapagliflozin-treated patients compared to placebo-treated patients. Mean percent change from baseline at Week 24 were 0.0% versus 2.5% for total cholesterol and -1.0% versus 2.9% for LDL cholesterol in the placebo and dapagliflozin 10 mg groups, respectively.

Vitamin B12 Concentrations

Metformin Hydrochloride

Metformin may lower serum vitamin B12 concentrations. Measurement of hematologic parameters on an annual basis is advised in patients on XIGDUO XR and any apparent abnormalities should be appropriately investigated and managed. [See WARNINGS AND PRECAUTIONS]