FDA label 1bc7cf83-520d-41e0-8255-5fcd83bfdfc7

5 WARNINGS AND PRECAUTIONS • Hypotension: Before initiating FARXIGA, assess volume status and correct hypovolemia in the elderly, in patients with renal impairment or low systolic blood pressure, and in patients on diuretics. Monitor for signs and symptoms during therapy. (5.1 , 6.1) • Impairment in renal function: Monitor renal function during therapy. (5.2) • Hypoglycemia: In patients taking insulin or an insulin secretagogue with FARXIGA, consider a lower dose of insulin or the insulin secretagogue to reduce the risk of hypoglycemia. (5.3) • Genital mycotic infections: Monitor and treat if indicated. (5.4) • Increased LDL-C: Monitor and treat per standard of care. (5.5) • Bladder Cancer: An imbalance in bladder cancers was observed in clinical trials. FARXIGA should not be used in patients with active bladder cancer and should be used with caution in patients with a prior history of bladder cancer. (5.6) • Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with FARXIGA or any other antidiabetic drug. (5.7) 5.1 Hypotension FARXIGA causes intravascular volume contraction. Symptomatic hypotension can occur after initiating FARXIGA [see Adverse Reactions (6.1) ] particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m 2 ), elderly patients, or patients on loop diuretics. Before initiating FARXIGA in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms of hypotension after initiating therapy. 5.2 Impairment in Renal Function FARXIGA increases serum creatinine and decreases eGFR. Elderly patients and patients with impaired renal function may be more susceptible to these changes. Adverse reactions related to renal function can occur after initiating FARXIGA [see Adverse Reactions (6.1) ]. Renal function should be evaluated prior to initiation of FARXIGA and monitored periodically thereafter. 5.3 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues Insulin and insulin secretagogues are known to cause hypoglycemia. FARXIGA can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse Reactions (6.1) ]. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when these agents are used in combination with FARXIGA. 5.4 Genital Mycotic Infections FARXIGA increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections [see Adverse Reactions (6.1) ]. Monitor and treat appropriately. 5.5 Increases in Low-Density Lipoprotein Cholesterol (LDL-C) Increases in LDL‑C occur with FARXIGA [see Adverse Reactions (6.1) ]. Monitor LDL‑C and treat per standard of care after initiating FARXIGA. 5.6 Bladder Cancer Across 22 clinical studies, newly diagnosed cases of bladder cancer were reported in 10/6045 patients (0.17%) treated with FARXIGA and 1/3512 patient (0.03%) treated with placebo/comparator. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 4 cases with FARXIGA and no cases with placebo/comparator. Bladder cancer risk factors and hematuria (a potential indicator of pre-existing tumors) were balanced between treatment arms at baseline. There were too few cases to determine whether the emergence of these events is related to FARXIGA. There are insufficient data to determine whether FARXIGA has an effect on pre-existing bladder tumors. Consequently, FARXIGA should not be used in patients with active bladder cancer. In patients with prior history of bladder cancer, the benefits of glycemic control versus unknown risks for cancer recurrence with FARXIGA should be considered. 5.7 Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with FARXIGA or any other antidiabetic drug.

6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: • Hypotension [see Warnings and Precautions (5.1) ] • Impairment in Renal Function [see Warnings and Precautions (5.2) ] • Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.3) ] • Genital Mycotic Infections [see Warnings and Precautions (5.4) ] • Increases in Low-Density Lipoprotein Cholesterol (LDL‑C) [see Warnings and Precautions (5.5) ] • Bladder Cancer [see Warnings and Precautions (5.6) ] • The most common adverse reactions associated with FARXIGA (5% or greater incidence) were female genital mycotic infections, nasopharyngitis, and urinary tract infections. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. Pool of 12 Placebo-Controlled Studies for FARXIGA 5 and 10 mg The data in Table 1 is derived from 12 placebo-controlled studies ranging from 12 to 24 weeks. In 4 studies FARXIGA was used as monotherapy, and in 8 studies FARXIGA was used as add-on to background antidiabetic therapy or as combination therapy with metformin [see Clinical Studies (14) ] . These data reflect exposure of 2338 patients to FARXIGA with a mean exposure duration of 21 weeks. Patients received placebo (N=1393), FARXIGA 5 mg (N=1145), or FARXIGA 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 hemoglobin A1c (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 m 2 ). Table 1 shows common adverse reactions associated with the use of FARXIGA. These adverse reactions were not present at baseline, occurred more commonly on FARXIGA than on placebo, and occurred in at least 2% of patients treated with either FARXIGA 5 mg or FARXIGA 10 mg. Table 1: Adverse Reactions in Placebo-Controlled Studies Reported in ≥2% of Patients Treated with FARXIGA Adverse Reaction % of Patients Pool of 12 Placebo-Controlled Studies Placebo N=1393 FARXIGA 5 mg N=1145 FARXIGA 10 mg N=1193 * 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, FARXIGA 5 mg=581, FARXIGA 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, FARXIGA 5 mg=564, FARXIGA 10 mg=595). 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 Pool of 13 Placebo-Controlled Studies for FARXIGA 10 mg The safety and tolerability of FARXIGA 10 mg was also evaluated in a larger placebo-controlled 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 FARXIGA 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 m 2 ). Volume Depletion FARXIGA 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 2 for the 12-study and 13-study, short-term, placebo-controlled pools [see Warnings and Precautions (5.1) ]. Table 2: Adverse Reactions of Volume Depletion* in Clinical Studies with FARXIGA Pool of 12 Placebo-Controlled Studies Pool of 13 Placebo-Controlled Studies Placebo FARXIGA 5 mg FARXIGA 10 mg Placebo FARXIGA 10 mg * Volume depletion includes reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension. 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 m 2 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%) Impairment of Renal Function Use of FARXIGA was associated with increases in serum creatinine and decreases in eGFR (see Table 3). 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 FARXIGA (see Table 4). Elderly patients and patients with impaired renal function were more susceptible to these adverse reactions (see Table 4). Sustained decreases in eGFR were seen in patients with moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m 2 ). Table 3: Changes in Serum Creatinine and eGFR Associated with FARXIGA in the Pool of 12 Placebo-Controlled Studies and Moderate Renal Impairment Study Pool of 12 Placebo-Controlled Studies Placebo N=1393 FARXIGA 5 mg N=1145 FARXIGA 10 mg N=1193 Baseline Mean Serum Creatinine (mg/dL) 0.853 0.860 0.847 eGFR (mL/min/1.73 m 2 ) 86.0 85.3 86.7 Week 1 Change Serum Creatinine (mg/dL) −0.003 0.029 0.041 eGFR (mL/min/1.73 m 2 ) 0.4 −2.9 −4.1 Week 24 Change Serum Creatinine (mg/dL) −0.005 −0.001 0.001 eGFR (mL/min/1.73 m 2 ) 0.8 0.8 0.3 Moderate Renal Impairment Study Placebo N=84 FARXIGA 5 mg N=83 FARXIGA 10 mg N=85 Baseline Mean Serum Creatinine (mg/dL) 1.46 1.53 1.52 eGFR (mL/min/1.73 m 2 ) 45.6 44.2 43.9 Week 1 Change Serum Creatinine (mg/dL) 0.01 0.13 0.18 eGFR (mL/min/1.73 m 2 ) 0.5 −3.8 −5.5 Week 24 Change Serum Creatinine (mg/dL) 0.02 0.08 0.16 eGFR (mL/min/1.73 m 2 ) 0.03 −4.0 −7.4 Week 52 Change Serum Creatinine (mg/dL) 0.10 0.06 0.15 eGFR (mL/min/1.73 m 2 ) −2.6 −4.2 −7.3 Table 4: Proportion of Patients with at Least One Renal Impairment-Related Adverse Reaction Pool of 6 Placebo-Controlled Studies (up to 104 weeks)* Pool of 9 Placebo-Controlled Studies (up to 104 weeks) † Baseline Characteristic Placebo FARXIGA 5 mg FARXIGA 10 mg Placebo FARXIGA 10 mg * 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. 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 m 2 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 m 2 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%) The safety of FARXIGA was evaluated in a study of patients with moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m 2 ) [see Clinical Studies (14) ]. 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 FARXIGA 5 mg group, and 8 occurred in the FARXIGA 10 mg group. Eight of these 13 fractures were in patients who had a baseline eGFR of 30 to 45 mL/min/1.73 m 2 . 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 (14) ] is shown in Table 5. Hypoglycemia was more frequent when FARXIGA was added to sulfonylurea or insulin [see Warnings and Precautions (5.3) ]. Table 5: Incidence of Major* and Minor † Hypoglycemia in Placebo-Controlled Studies Placebo FARXIGA 5 mg FARXIGA 10 mg * 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 asymptomatic capillary or plasma glucose measurement <63 mg/dL that does not qualify as a major episode. ‡ OAD = oral antidiabetic therapy. Monotherapy* (24 weeks) N=75 N=64 N=70 Major [n (%)] 0 0 0 Minor [n (%)] 0 0 0 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 Glimepiride* (24 weeks) N=146 N=145 N=151 Major [n (%)] 0 0 0 Minor [n (%)] 3 (2.1) 8 (5.5) 9 (6.0) Add-on to Pioglitazone* (24 weeks) N=139 N=141 N=140 Major [n (%)] 0 0 0 Minor [n (%)] 0 3 (2.1) 0 Add-on to DPP4 inhibitor (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) Genital Mycotic Infections Genital mycotic infections were more frequent with FARXIGA treatment. Genital mycotic infections were reported in 0.9% of patients on placebo, 5.7% on FARXIGA 5 mg, and 4.8% on FARXIGA 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 FARXIGA 10 mg. Infections were more frequently reported in females than in males (see Table 1). 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, FARXIGA 5 mg, and FARXIGA 10 mg, respectively). Hypersensitivity Reactions Hypersensitivity reactions (e.g., angioedema, urticaria, hypersensitivity) were reported with FARXIGA 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 FARXIGA-treated patients. If hypersensitivity reactions occur, discontinue use of FARXIGA; treat per standard of care and monitor until signs and symptoms resolve. Laboratory Tests Increase in Hematocrit In the pool of 13 placebo-controlled studies, increases from baseline in mean hematocrit values were observed in FARXIGA-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 FARXIGA 10 mg group. By Week 24, hematocrit values >55% were reported in 0.4% of placebo-treated patients and 1.3% of FARXIGA 10 mg–treated patients. Increase in Serum Inorganic Phosphorus In the pool of 13 placebo-controlled studies, increases from baseline in mean serum phosphorus levels were reported at Week 24 in FARXIGA-treated patients compared with placebo-treated patients (mean increase of 0.13 versus −0.04 mg/dL, respectively). Higher proportions of patients with marked laboratory abnormalities of hyperphosphatemia (≥5.6 mg/dL for age 17-65 years or ≥5.1 mg/dL for age ≥66 years) were reported on FARXIGA at Week 24 (0.9% versus 1.7% for placebo and FARXIGA 10 mg, respectively). Increase in Low-Density Lipoprotein Cholesterol In the pool of 13 placebo-controlled studies, changes from baseline in mean lipid values were reported in FARXIGA-treated patients compared to placebo-treated patients. Mean percent changes 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 FARXIGA 10 mg groups, respectively.

<table ID="_RefID0EKSAE" cellpadding="5.75pt" width="100%"> <caption>Table 1: Adverse Reactions in Placebo-Controlled Studies Reported in &#x2265;2% of Patients Treated with FARXIGA</caption> <col width="42%"/> <col width="12%"/> <col width="22%"/> <col width="24%"/> <thead> <tr> <th align="left" styleCode="Rrule Lrule Toprule " valign="top"> <content styleCode="bold">Adverse Reaction</content> </th> <th align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">% of Patients</content> </th> </tr> <tr> <th align="left" styleCode="Rrule Lrule " valign="top"/> <th align="center" colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <content styleCode="bold">Pool of 12 Placebo-Controlled Studies</content> </th> </tr> <tr> <th align="left" styleCode="Rrule Lrule Botrule " valign="top"/> <th align="center" styleCode="Rrule Lrule Botrule " valign="top"> <content styleCode="bold">Placebo</content> <content styleCode="bold">N=1393</content> </th> <th align="center" styleCode="Rrule Lrule Botrule " valign="top"> <content styleCode="bold">FARXIGA 5 mg</content> <content styleCode="bold">N=1145</content> </th> <th align="center" styleCode="Rrule Lrule Botrule " valign="top"> <content styleCode="bold">FARXIGA 10 mg</content> <content styleCode="bold">N=1193</content> </th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4" styleCode="Botrule" valign="top">* 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, FARXIGA 5 mg=581, FARXIGA 10 mg=598). ^&#x2020; Urinary tract infections include the following adverse reactions, listed in order of frequency reported: urinary tract infection, cystitis, <content styleCode="emphasis">Escherichia</content> urinary tract infection, genitourinary tract infection, pyelonephritis, trigonitis, urethritis, kidney infection, and prostatitis. ^&#x2021; Increased urination includes the following adverse reactions, listed in order of frequency reported: pollakiuria, polyuria, and urine output increased. ^&#xA7; 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, FARXIGA 5 mg=564, FARXIGA 10 mg=595).</td> </tr> </tfoot> <tbody> <tr> <td styleCode="Rrule Lrule Toprule Botrule "> <paragraph>Female genital mycotic infections*</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule "> <paragraph>1.5</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule "> <paragraph>8.4</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule "> <paragraph>6.9</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Nasopharyngitis</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>6.2</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>6.6</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>6.3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Urinary tract infections^&#x2020; </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>3.7</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>5.7</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>4.3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Back pain</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>3.2</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>3.1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>4.2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Increased urination^&#x2021; </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>1.7</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>2.9</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>3.8</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Male genital mycotic infections^&#xA7; </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>0.3</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>2.8</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>2.7</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Nausea</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>2.4</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>2.8</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>2.5</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Influenza</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>2.3</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>2.7</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>2.3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Dyslipidemia</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>1.5</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>2.1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>2.5</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Constipation</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>1.5</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>2.2</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>1.9</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Discomfort with urination </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>0.7</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>1.6</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>2.1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule "> <paragraph>Pain in extremity</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule "> <paragraph>1.4</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule "> <paragraph>2.0</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule "> <paragraph>1.7</paragraph> </td> </tr> </tbody> </table>

<table ID="_RefID0ET3AE" width="100%"> <caption>Table 2: Adverse Reactions of Volume Depletion* in Clinical Studies with FARXIGA</caption> <col width="45%"/> <col width="9%"/> <col width="11%"/> <col width="11%"/> <col width="11%"/> <col width="13%"/> <thead> <tr> <th align="left" styleCode="Rrule Lrule Toprule " valign="top"/> <th align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">Pool of 12 Placebo-Controlled</content> <content styleCode="bold">Studies</content> </th> <th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">Pool of 13 Placebo-Controlled</content> <content styleCode="bold">Studies</content> </th> </tr> <tr> <th align="left" styleCode="Rrule Lrule Botrule " valign="top"/> <th align="center" styleCode="Rrule Lrule Botrule " valign="top"> <content styleCode="bold">Placebo</content> </th> <th align="center" styleCode="Rrule Lrule Botrule " valign="top"> <content styleCode="bold">FARXIGA</content> <content styleCode="bold">5 mg</content> </th> <th align="center" styleCode="Rrule Lrule Botrule " valign="top"> <content styleCode="bold">FARXIGA</content> <content styleCode="bold">10 mg</content> </th> <th align="center" styleCode="Rrule Lrule Botrule " valign="top"> <content styleCode="bold">Placebo</content> </th> <th align="center" styleCode="Rrule Lrule Botrule " valign="top"> <content styleCode="bold">FARXIGA</content> <content styleCode="bold">10 mg</content> </th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="6" styleCode="Botrule" valign="top">* Volume depletion includes reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension.</td> </tr> </tfoot> <tbody> <tr> <td styleCode="Rrule Lrule Toprule Botrule "> <paragraph> <content styleCode="bold">Overall population N (%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule "> <paragraph>N=1393</paragraph> <paragraph>5 (0.4%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule "> <paragraph>N=1145</paragraph> <paragraph>7 (0.6%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule "> <paragraph>N=1193</paragraph> <paragraph>9 (0.8%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule "> <paragraph>N=2295</paragraph> <paragraph>17 (0.7%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule "> <paragraph>N=2360</paragraph> <paragraph>27 (1.1%)</paragraph> </td> </tr> <tr> <td colspan="6" styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">Patient Subgroup n (%)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Patients on loop diuretics</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>n=55 1 (1.8%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>n=40 0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>n=31 3 (9.7%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>n=267 4 (1.5%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>n=236 6 (2.5%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Patients with moderate renal impairment with eGFR &#x2265;30 and &lt;60 mL/min/1.73 m² </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>n=107 2 (1.9%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>n=107 1 (0.9%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>n=89 1 (1.1%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>n=268 4 (1.5%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>n=265 5 (1.9%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule "> <paragraph>Patients &#x2265;65 years of age</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule "> <paragraph>n=276 1 (0.4%)</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule "> <paragraph>n=216 1 (0.5%)</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule "> <paragraph>n=204 3 (1.5%)</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule "> <paragraph>n=711 6 (0.8%)</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule "> <paragraph>n=665 11 (1.7%)</paragraph> </td> </tr> </tbody> </table>

<table ID="_RefID0EREAG" width="100%"> <caption>Table 3: Changes in Serum Creatinine and eGFR Associated with FARXIGA in the Pool of 12 Placebo-Controlled Studies and Moderate Renal Impairment Study</caption> <col width="20%"/> <col width="29%"/> <col width="11%"/> <col width="20%"/> <col width="21%"/> <tbody> <tr> <td styleCode="Lrule Toprule "/> <td styleCode="Rrule Toprule "/> <td align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule "> <paragraph> <content styleCode="bold">Pool of 12 Placebo-Controlled Studies</content> </paragraph> </td> </tr> <tr> <td styleCode="Lrule Botrule "/> <td/> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">Placebo</content> <content styleCode="bold">N=1393</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">FARXIGA 5 mg</content> <content styleCode="bold">N=1145</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">FARXIGA 10 mg</content> <content styleCode="bold">N=1193</content> </paragraph> </td> </tr> <tr> <td rowspan="2" styleCode="Rrule Lrule Botrule "> <paragraph>Baseline Mean</paragraph> </td> <td styleCode="Rrule Lrule Botrule "> <paragraph>Serum Creatinine (mg/dL)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>0.853</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>0.860</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>0.847</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>eGFR (mL/min/1.73 m²)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>86.0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>85.3</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>86.7</paragraph> </td> </tr> <tr> <td rowspan="2" styleCode="Rrule Lrule Botrule "> <paragraph>Week 1 Change</paragraph> </td> <td styleCode="Rrule Lrule Botrule "> <paragraph>Serum Creatinine (mg/dL)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>&#x2212;0.003</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>0.029</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>0.041</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>eGFR (mL/min/1.73 m²)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>0.4</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>&#x2212;2.9</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>&#x2212;4.1</paragraph> </td> </tr> <tr> <td rowspan="2" styleCode="Rrule Lrule Botrule "> <paragraph>Week 24 Change</paragraph> </td> <td styleCode="Rrule Lrule Botrule "> <paragraph>Serum Creatinine (mg/dL)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>&#x2212;0.005</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>&#x2212;0.001</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>0.001</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>eGFR (mL/min/1.73 m²)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>0.8</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>0.8</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>0.3</paragraph> </td> </tr> <tr> <td styleCode="Lrule "/> <td/> <td align="center" colspan="3" styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">Moderate Renal Impairment Study</content> </paragraph> </td> </tr> <tr> <td styleCode="Lrule Botrule "/> <td/> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">Placebo</content> <content styleCode="bold">N=84</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">FARXIGA 5 mg</content> <content styleCode="bold">N=83</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">FARXIGA 10 mg</content> <content styleCode="bold">N=85</content> </paragraph> </td> </tr> <tr> <td rowspan="2" styleCode="Rrule Lrule Botrule "> <paragraph>Baseline Mean</paragraph> </td> <td styleCode="Rrule Lrule Botrule "> <paragraph>Serum Creatinine (mg/dL)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>1.46</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>1.53</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>1.52</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>eGFR (mL/min/1.73 m²)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>45.6</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>44.2</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>43.9</paragraph> </td> </tr> <tr> <td rowspan="2" styleCode="Rrule Lrule Botrule "> <paragraph>Week 1 Change</paragraph> </td> <td styleCode="Rrule Lrule Botrule "> <paragraph>Serum Creatinine (mg/dL)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>0.01</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>0.13</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>0.18</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>eGFR (mL/min/1.73 m²)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>0.5</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>&#x2212;3.8</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>&#x2212;5.5</paragraph> </td> </tr> <tr> <td rowspan="2" styleCode="Rrule Lrule Botrule "> <paragraph>Week 24 Change</paragraph> </td> <td styleCode="Rrule Lrule Botrule "> <paragraph>Serum Creatinine (mg/dL)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>0.02</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>0.08</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>0.16</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>eGFR (mL/min/1.73 m²)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>0.03</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>&#x2212;4.0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>&#x2212;7.4</paragraph> </td> </tr> <tr> <td rowspan="2" styleCode="Rrule Lrule Botrule "> <paragraph>Week 52 Change</paragraph> </td> <td styleCode="Rrule Lrule Botrule "> <paragraph>Serum Creatinine (mg/dL)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>0.10</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>0.06</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule "> <paragraph>0.15</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule "> <paragraph>eGFR (mL/min/1.73 m²)</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule "> <paragraph>&#x2212;2.6</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule "> <paragraph>&#x2212;4.2</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule "> <paragraph>&#x2212;7.3</paragraph> </td> </tr> </tbody> </table>