Farxiga (Dapagliflozin Propanediol) - Side Effects and Adverse Reactions

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 ].

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 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 m²).

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 ].

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 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%)

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 m²).

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 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	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 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 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 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%)

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 m²) [see Clinical Studies ]. 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 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 5. Hypoglycemia was more frequent when FARXIGA was added to sulfonylurea or insulin [see Warnings and Precautions ].

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.