FARXIGA (Page 2 of 13)

5.2 Volume Depletion

FARXIGA can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. There have been post-marketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including FARXIGA. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating FARXIGA in patients with one or more of these characteristics, assess volume status and renal function. Monitor for signs and symptoms of hypotension, and renal function after initiating therapy.

5.3 Urosepsis and Pyelonephritis

Serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization have been reported in patients receiving SGLT2 inhibitors, including FARXIGA. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see Adverse Reactions (6)].

5.4 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

Insulin and insulin secretagogues are known to cause hypoglycemia. FARXIGA may 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.

5.5 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)

Reports of necrotizing fasciitis of the perineum (Fournier’s Gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including FARXIGA. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death.

Patients treated with FARXIGA presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue FARXIGA, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.

5.6 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.

6 ADVERSE REACTIONS

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

Ketoacidosis in Patients with Diabetes Mellitus [see Warnings and Precautions (5.1)]
Volume Depletion [see Warnings and Precautions (5.2)]
Urosepsis and Pyelonephritis [see Warnings and Precautions (5.3)]
Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.4)]
Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) [see Warnings and Precautions (5.5)]
Genital Mycotic Infections [see Warnings and Precautions (5.6)]

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.

FARXIGA has been evaluated in clinical trials in patients with type 2 diabetes mellitus, in patients with heart failure, and in patients with chronic kidney disease. The overall safety profile of FARXIGA was consistent across the studied indications. Severe hypoglycemia and diabetic ketoacidosis (DKA) were observed only in patients with diabetes mellitus.

Clinical Trials in Patients with Type 2 Diabetes Mellitus

Pool of 12 Placebo-Controlled Studies for FARXIGA 5 and 10 mg for Glycemic Control

The data in Table 1 is derived from 12 glycemic control placebo-controlled studies in patients with type 2 diabetes mellitus 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 (14.1)].

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 m2).

Table 2 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 2: Adverse Reactions in Placebo-Controlled Studies of Glycemic Control 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, and 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 for Glycemic Control

FARXIGA 10 mg was also evaluated in a larger glycemic control placebo-controlled study pool in patients with type 2 diabetes mellitus. 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 m2).

Volume Depletion

FARXIGA causes an osmotic diuresis, which may lead to a reduction in intravascular volume. Adverse reactions related to volume depletion (including reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension) in patients with type 2 diabetes mellitus for the 12-study and 13-study, short-term, placebo-controlled pools and for the DECLARE study are shown in Table 3 [see Warnings and Precautions (5.2)].

Table 3: Adverse Reactions Related to Volume Depletion * in Clinical Studies in Patients with Type 2 Diabetes Mellitus with FARXIGA
*
Volume depletion includes reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension.

Pool of 12 Placebo-Controlled Studies

Pool of 13 Placebo-Controlled Studies

DECLARE Study

Placebo

FARXIGA5 mg

FARXIGA10 mg

Placebo

FARXIGA 10 mg

Placebo

FARXIGA10 mg

Overall population N (%)

N=13935(0.4%)

N=11457(0.6%)

N=11939(0.8%)

N=229517(0.7%)

N=236027(1.1%)

N=8569207(2.4%)

N=8574213 (2.5%)

Patient Subgroup n (%)

Patients on loop diuretics

n=551 (1.8%)

n=400

n=313 (9.7%)

n=2674 (1.5%)

n=2366 (2.5%)

n=93457(6.1%)

n=86657(6.6%)

Patients with moderate renal impairment with eGFR ≥30 and <60 mL/min/1.73 m2

n=1072(1.9%)

n=1071(0.9%)

n=891(1.1%)

n=2684(1.5%)

n=2655(1.9%)

n=65830(4.6%)

n=60435(5.8%)

Patients ≥65 years of age

n=2761(0.4%)

n=2161(0.5%)

n=2043(1.5%)

n=7116(0.8%)

n=66511(1.7%)

n=3950121(3.1%)

n=3948117(3.0%)

Hypoglycemia

The frequency of hypoglycemia by study in patients with type 2 diabetes mellitus [see Clinical Studies (14.1)] is shown in Table 4. Hypoglycemia was more frequent when FARXIGA was added to sulfonylurea or insulin [see Warnings and Precautions (5.4)].

Table 4: Incidence of Severe Hypoglycemia * and Hypoglycemia with Glucose < 54 mg/dL in Controlled Glycemic Control Clinical Studies in Patients with Type 2 Diabetes Mellitus
Placebo/Active Control FARXIGA5 mg FARXIGA10 mg
*
Severe episodes of hypoglycemia were defined as episodes of severe impairment in consciousness or behavior, requiring external (third party) assistance, and with prompt recovery after intervention regardless of glucose level.
Episodes of hypoglycemia with glucose <54 mg/dL (3 mmol/L) were defined as reported episodes of hypoglycemia meeting the glucose criteria that did not also qualify as a severe episode.
OAD = oral antidiabetic therapy.

Monotherapy (24 weeks)

N=75

N=64

N=70

Severe [n (%)]

0

0

0

Glucose <54 mg/dL [n (%)]

0

0

0

Add-on to Metformin (24 weeks)

N=137

N=137

N=135

Severe [n (%)]

0

0

0

Glucose <54 mg/dL [n (%)]

0

0

0

Add-on to Glimepiride (24 weeks)

N=146

N=145

N=151

Severe [n (%)]

0

0

0

Glucose <54 mg/dL [n (%)]

1 (0.7)

3 (2.1)

5 (3.3)

Add-on to Metformin and a Sulfonylurea (24 Weeks)

N=109

N=109

Severe [n (%)]

0

0

Glucose <54 mg/dL [n (%)]

3 (2.8)

7 (6.4)

Add-on to Pioglitazone (24 weeks)

N=139

N=141

N=140

Severe [n (%)]

0

0

0

Glucose <54 mg/dL [n (%)]

0

1 (0.7)

0

Add-on to DPP4 inhibitor (24 weeks)

N=226

N=225

Severe [n (%)]

0

1 (0.4)

Glucose <54 mg/dL [n (%)]

1 (0.4)

1 (0.4)

Add-on to Insulin with or without other OADs (24 weeks)

N=197

N=212

N=196

Severe [n (%)]

1 (0.5)

2 (0.9)

2 (1.0)

Glucose <54 mg/dL [n (%)]

43 (21.8)

55 (25.9)

45 (23.0)

In the DECLARE study [see Clinical Studies (14.2)] , severe events of hypoglycemia were reported in 58 (0.7%) out of 8574 patients treated with FARXIGA and 83 (1.0%) out of 8569 patients treated with placebo.

Genital Mycotic Infections

In the glycemic control trials, 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). In the DECLARE study [see Clinical Studies (14.2)] , serious genital mycotic infections were reported in <0.1% of patients treated with FARXIGA and <0.1% of patients treated with placebo. Genital mycotic infections that caused study drug discontinuation were reported in 0.9% of patients treated with FARXIGA and <0.1% of patients treated with placebo.

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., angioedema, urticaria, hypersensitivity) were reported with FARXIGA treatment. In glycemic control studies, 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.

Ketoacidosis in Patients with Diabetes Mellitus

In the DECLARE study [see Warnings and Precautions (5.1) and Clinical Studies (14.2)], events of diabetic ketoacidosis (DKA) were reported in 27 out of 8574 patients in the FARXIGA-treated group and 12 out of 8569 patients in the placebo group. The events were evenly distributed over the study period.

Laboratory Tests

Increases in Serum Creatinine and Decreases in eGFR

Initiation of SGLT2 inhibitors, including FARXIGA causes a small increase in serum creatinine and decrease in eGFR. These changes in serum creatinine and eGFR generally occur within two weeks of starting therapy and then stabilize regardless of baseline kidney function. Changes that do not fit this pattern should prompt further evaluation to exclude the possibility of acute kidney injury [see Warnings and Precautions (5.2)]. In two studies that included patients with type 2 diabetes mellitus with moderate renal impairment, the acute effect on eGFR reversed after treatment discontinuation, suggesting acute hemodynamic changes may play a role in the renal function changes observed with FARXIGA.

Increase in Hematocrit

In the pool of 13 placebo-controlled studies of glycemic control, 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 Low-Density Lipoprotein Cholesterol

In the pool of 13 placebo-controlled studies of glycemic control, 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. In the DECLARE study [see Clinical Studies (14.2)] , mean changes from baseline after 4 years were 0.4 mg/dL versus -4.1 mg/dL for total cholesterol, and -2.5 mg/dL versus -4.4 mg/dL for LDL cholesterol, in FARXIGA-treated and the placebo groups, respectively.

Decrease in Serum Bicarbonate

In a study of concomitant therapy of FARXIGA 10 mg with exenatide extended-release (on a background of metformin), four patients (1.7%) on concomitant therapy had a serum bicarbonate value of less than or equal to 13 mEq/L compared to one each (0.4%) in the FARXIGA and exenatide-extended release treatment groups [see Warnings and Precautions (5.1)].

DAPA-HF Heart Failure Study

No new adverse reactions were identified in the DAPA-HF heart failure study.

DAPA-CKD Chronic Kidney Disease Study

No new adverse reactions were identified in the DAPA-CKD study in patients with chronic kidney disease.

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