Farxiga (oral)

Overdose

There were no reports of overdose during the clinical development program for FARXIGA.

In the event of an overdose, contact the Poison Control Center. It is also reasonable to employ supportive measures, as dictated by the patient's clinical status. The removal of dapagliflozin by hemodialysis has not been studied.

Contraindications

• History of a serious hypersensitivity reaction to FARXIGA .
• Severe renal impairment, (eGFR less than 30 mL/min/1.73 m²) end-stage renal disease (ESRD), or patients on dialysis.

Undesirable effects

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

• Hypotension
• Ketoacidosis
• Acute Kidney Injury and Impairment in Renal Function
• Urosepsis and Pyelonephritis
• Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
• Genital Mycotic Infections
• Increases in Low-Density Lipoprotein Cholesterol (LDL-C)
• Bladder Cancer

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.

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
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, 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).

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.

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

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

Baseline Characteristic	Pool of 6 Placebo-Controlled Studies (up to 104 weeks)*	Pool of 9 Placebo-Controlled Studies (up to 104 weeks)†
Placebo	FARXIGA 5 mg	FARXIGA 10 mg	Placebo	FARXIGA 10 mg
Overall population	n=785	n=767	n=859	n=1956	n=2026
Patients (%) with at least one event	13 (1.7%)	14 (1.8%)	16 (1.9%)	82 (4.2%)	136 (6.7%)
65 years of age and older	n=190	n=162	n=159	n=655	n=620
Patients (%) with at least one event	4 (2.1%)	5 (3.1%)	6 (3.8%)	52 (7.9%)	87 (14.0%)
eGFR ≥ 30 and <60 mL/min/1.73 m²	n=77	n=88	n=75	n=249	n=251
Patients (%) with at least one event	5 (6.5%)	7 (8.0%)	9 (12.0%)	40 (16.1%)	71 (28.3%)
65 years of age and older and eGFR ≥ 30 and <60 mL/min/1.73 m²	n=41	n=43	n=35	n=141	n=134
Patients (%) with at least one event	2 (4.9%)	3 (7.0%)	4 (11.4%)	27 (19.1%)	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 FARXIGA 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 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 is shown in Table 5. Hypoglycemia was more frequent when FARXIGA was added to sulfonylurea or insulin.

Table 5: Incidence of Major* and Minor† Hypoglycemia in Controlled Clinical Studies

	Placebo/Active Control	FARXIGA 5 mg	FARXIGA 10 mg
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 Metformin and a Sulfonylurea (24 Weeks)	N=109	-	N=109
Major [n (%)]	0	-	0
Minor [n (%)]	4 (3.7)	-	14 (12.8)
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 OADsi (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 asymptomatic 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 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.

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.

Postmarketing Experience

Additional adverse reactions have been identified during postapproval use of FARXIGA. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Ketoacidosis
• Acute Kidney Injury and Impairment in Renal Function
• Urosepsis and Pyelonephritis
• Rash

Therapeutic indications

FARXIGA (dapagliflozin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Limitation Of Use

FARXIGA is not recommended for patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

Pharmacodynamic properties

General

Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in patients with type 2 diabetes mellitus following the administration of dapagliflozin (see Figure 1). Dapagliflozin doses of 5 or 10 mg per day in patients with type 2 diabetes mellitus for 12 weeks resulted in excretion of approximately 70 grams of glucose in the urine per day at Week 12. A near maximum glucose excretion was observed at the dapagliflozin daily dose of 20 mg. This urinary glucose excretion with dapagliflozin also results in increases in urinary volume.

Figure 1: Scatter Plot and Fitted Line of Change from Baseline in 24-Hour Urinary Glucose Amount versus Dapagliflozin Dose in Healthy Subjects and Subjects with Type 2 Diabetes Mellitus (T2DM) (Semi-Log Plot)

Cardiac Electrophysiology

Dapagliflozin was not associated with clinically meaningful prolongation of QTc interval at daily doses up to 150 mg (15 times the recommended maximum dose) in a study of healthy subjects. In addition, no clinically meaningful effect on QTc interval was observed following single doses of up to 500 mg (50 times the recommended maximum dose) of dapagliflozin in healthy subjects.

Pharmacokinetic properties

Absorption

Following oral administration of dapagliflozin, the maximum plasma concentration (Cmax) is usually attained within 2 hours under fasting state. The Cmax and AUC values increase dose proportionally with increase in dapagliflozin dose in the therapeutic dose range. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Administration of dapagliflozin with a high-fat meal decreases its Cmax by up to 50% and prolongs Tmax by approximately 1 hour, but does not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful and dapagliflozin can be administered with or without food.

Distribution

Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment.

Metabolism

The metabolism of dapagliflozin is primarily mediated by UGT1A9; CYP-mediated metabolism is a minor clearance pathway in humans. Dapagliflozin is extensively metabolized, primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide accounted for 61% of a 50 mg [14C]-dapagliflozin dose and is the predominant drug-related component in human plasma.

Elimination

Dapagliflozin and related metabolites are primarily eliminated via the renal pathway. Following a single 50 mg dose of [14C]-dapagliflozin, 75% and 21% total radioactivity is excreted in urine and feces, respectively. In urine, less than 2% of the dose is excreted as parent drug. In feces, approximately 15% of the dose is excreted as parent drug. The mean plasma terminal half-life (t½) for dapagliflozin is approximately 12.9 hours following a single oral dose of FARXIGA 10 mg.

Date of revision of the text

Oct 2017

Name of the medicinal product

Farxiga

Fertility, pregnancy and lactation

Risk Summary

Based on animal data showing adverse renal effects, FARXIGA is not recommended during the second and third trimesters of pregnancy.

Limited data with FARXIGA in pregnant women are not sufficient to determine drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy.

In animal studies, adverse renal pelvic and tubule dilatations, that were not fully reversible, were observed in rats when dapagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy, at all doses tested; the lowest of which provided an exposure 15-times the 10 mg clinical dose.

The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c greater than 7% and has been reported to be as high as 20 to 25% in women with HbA1c greater than 10%. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal And/Or Embryo-Fetal Risk

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.

Data

Animal Data

Dapagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1, 15, or 75 mg/kg/day, increased kidney weights and increased the incidence of renal pelvic and tubular dilatations at all dose levels. Exposure at the lowest dose tested was 15-times the 10 mg clinical dose (based on AUC). The renal pelvic and tubular dilatations observed in juvenile animals did not fully reverse within a 1-month recovery period.

In a prenatal and postnatal development study, dapagliflozin was administered to maternal rats from gestation day 6 through lactation day 21 at doses of 1, 15, or 75 mg/kg/day, and pups were indirectly exposed in utero and throughout lactation. Increased incidence or severity of renal pelvic dilatation was observed in 21-day-old pups offspring of treated dams at 75 mg/kg/day (maternal and pup dapagliflozin exposures were 1415-times and 137-times, respectively, the human values at the 10 mg clinical dose, based on AUC). Dose-related reductions in pup body weights were observed at greater or equal to 29-times the 10 mg clinical dose (based on AUC). No adverse effects on developmental endpoints were noted at 1 mg/kg/day (19-times the 10 mg clinical dose, based on AUC).

In embryo-fetal development studies in rats and rabbits, dapagliflozin was administered throughout organogenesis, corresponding to the first trimester of human pregnancy. In rats, dapagliflozin was neither embryolethal nor teratogenic at doses greater than 75 mg/kg/day (1441-times the 10 mg clinical dose, based on AUC). Dose-related effects on the rat fetus (structural abnormalities and reduced body weight) occurred only at higher dosages, greater than 150 mg/kg (more than 2344-times the 10 mg clinical dose, based on AUC), which were associated with maternal toxicity. These outcomes occurred with drug exposure during periods of renal development in rats that corresponds to the late second and third trimester of human development. No developmental toxicities were observed in rabbits at doses up to 180 mg/kg/day (1191-times the 10 mg clinical dose, based on AUC).

Qualitative and quantitative composition

Dosage Forms And Strengths

• FARXIGA 5 mg tablets are yellow, biconvex, round, film-coated tablets with “5” engraved on one side and “1427” engraved on the other side.
• FARXIGA 10 mg tablets are yellow, biconvex, diamond-shaped, film-coated tablets with “10” engraved on one side and “1428” engraved on the other side.

FARXIGA (dapagliflozin) tablets have markings on both sides and are available in the strengths and packages listed in Table 15.

Table 14: FARXIGA Tablet Presentations

Tablet Strength	Film-Coated Tablet Color/Shape	Tablet Markings	Package Size	NDC Code
5 mg	yellow, biconvex, round	“5” engraved on one side and “1427” engraved on the other side	Bottles of 30	0310-6205- 30
10 mg	yellow, biconvex, diamond-shaped	“10” engraved on one side and “1428” engraved on the other side	Bottles of 30	0310-6210- 30

Storage And Handling

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F).

Distributed by: Astra Zeneca Pharmaceuticals LP Wilmington, DE 19850. Revised: Oct 2017

Special warnings and precautions for use

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS Hypotension

FARXIGA causes intravascular volume contraction. Symptomatic hypotension can occur after initiating FARXIGA particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m²), 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.

Ketoacidosis

Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus receiving sodium-glucose cotransporter 2 (SGLT2) inhibitors, including FARXIGA. Fatal cases of ketoacidosis have been reported in patients taking FARXIGA. FARXIGA is not indicated for the treatment of patients with type 1 diabetes mellitus.

Patients treated with FARXIGA who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels as ketoacidosis associated with FARXIGA may be present even if blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected, FARXIGA should be discontinued, the patient should be evaluated and prompt treatment should be instituted. Treatment of ketoacidosis may require insulin, fluid and carbohydrate replacement.

In many of the postmarketing reports, and particularly in patients with type 1 diabetes, the presence of ketoacidosis was not immediately recognized and the institution of treatment was delayed because the presenting blood glucose levels were below those typically expected for diabetic ketoacidosis (often less than 250 mg/dL). Signs and symptoms at presentation were consistent with dehydration and severe metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. In some but not all cases, factors predisposing to ketoacidosis such as insulin dose reduction, acute febrile illness, reduced caloric intake due to illness or surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse were identified.

Before initiating FARXIGA, consider factors in the patient history that may predispose to ketoacidosis including pancreatic insulin deficiency from any cause, caloric restriction and alcohol abuse. In patients treated with FARXIGA consider monitoring for ketoacidosis and temporarily discontinuing FARXIGA in clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery).

Acute Kidney Injury And Impairment In Renal Function

FARXIGA causes intravascular volume contraction , and can cause renal impairment. There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients receiving FARXIGA; some reports involved patients younger than 65 years of age.

Before initiating FARXIGA, consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure, and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs). Consider temporarily discontinuing FARXIGA in any setting of reduced oral intake (such as acute illness or fasting) or fluid losses (gastrointestinal illness or excessive heat exposure); monitor patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs, discontinue FARXIGA promptly and institute treatment.

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. Renal function should be evaluated prior to initiation of FARXIGA and monitored periodically thereafter. Use of FARXIGA is not recommended in patients with an eGFR persistently between 30 and less than 60 mL/min/1.73 m² and is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m².

Urosepsis And Pyelonephritis

There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization 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.

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. 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.

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. Monitor and treat appropriately.

Increases In Low-Density Lipoprotein Cholesterol (LDL-C)

Increases in LDL-C occur with FARXIGA. Monitor LDL-C and treat per standard of care after initiating FARXIGA.

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.

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with FARXIGA.

Patient Counseling Information

See FDA-approved patient labeling (Medication Guide).

Instructions

Instruct patients to read the Medication Guide before starting treatment with FARXIGA and to reread it each time the prescription is renewed.

Inform patients of the potential risks and benefits of FARXIGA and of alternative modes of therapy. Also inform patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and HbA1c testing, recognition and management of hypoglycemia and hyperglycemia, and assessment of diabetes complications. Advise patients to seek medical advice promptly during periods of stress such as fever, trauma, infection, or surgery, as medication requirements may change.

Instruct patients to take FARXIGA only as prescribed. If a dose is missed, advise patients to take it as soon as it is remembered unless it is almost time for the next dose, in which case patients should skip the missed dose and take the medicine at the next regularly scheduled time. Advise patients not to take two doses of FARXIGA at the same time.

Inform patients that the most common adverse reactions associated with use of FARXIGA are genital mycotic infections, nasopharyngitis, and urinary tract infections.

Instruct patient to immediately inform her healthcare provider if she is pregnant or plans to become pregnant. Based on animal data, FARXIGA may cause fetal harm in the second and third trimesters of pregnancy.

Instruct patient to immediately inform her healthcare provider if she is breastfeeding or planning to breastfeed. It is not known if FARXIGA is excreted in breast milk; however, based on animal data, FARXIGA may cause harm to nursing infants.

Hypotension

Inform patients that symptomatic hypotension may occur with FARXIGA and advise them to contact their healthcare provider if they experience such symptoms. Inform patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake.

Genital Mycotic Infections In Females (e.g., Vulvovaginitis)

Inform female patients that vaginal yeast infections may occur and provide them with information on the signs and symptoms of vaginal yeast infections. Advise them of treatment options and when to seek medical advice.

Ketoacidosis

Inform patients that ketoacidosis is a serious life-threatening condition. Cases of ketoacidosis have been reported during use of FARXIGA. Instruct patients to check ketones (when possible) if symptoms consistent with ketoacidosis occur even if blood glucose is not elevated. If symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness and labored breathing) occur, instruct patients to discontinue FARXIGA and seek medical advice immediately.

Acute Kidney Injury

Inform patients that acute kidney injury has been reported during use of FARXIGA. Advise patients to seek medical advice immediately if they have reduced oral intake (due to acute illness or fasting) or increased fluid losses (due to vomiting, diarrhea, or excessive heat exposure), as it may be appropriate to temporarily discontinue FARXIGA use in those settings.

Serious Urinary Tract Infections

Inform patients of the potential for urinary tract infections, which may be serious. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice promptly if such symptoms occur.

Genital Mycotic Infections In Males (e.g., Balanitis)

Inform male patients that yeast infections of the penis (e.g., balanitis or balanoposthitis) may occur, especially in patients with prior history. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice.

Hypersensitivity Reactions

Inform patients that serious hypersensitivity reactions (e.g., urticaria and angioedema) have been reported with FARXIGA. Advise patients to immediately report any signs or symptoms suggesting allergic reaction or angioedema, and to take no more of the drug until they have consulted prescribing physicians.

Bladder Cancer

Inform patients to promptly report any signs of macroscopic hematuria or other symptoms potentially related to bladder cancer.

Pregnancy

Advise pregnant patients of the potential risk to a fetus with treatment with FARXIGA. Instruct patients to immediately inform their healthcare provider if pregnant or planning to become pregnant.

Lactation

Advise patients that use of FARXIGA is not recommended while breastfeeding.

Laboratory Tests

Due to its mechanism of action, patients taking FARXIGA will test positive for glucose in their urine.

Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility

Dapagliflozin did not induce tumors in either mice or rats at any of the doses evaluated in 2-year carcinogenicity studies. Oral doses in mice consisted of 5, 15, and 40 mg/kg/day in males and 2, 10, and 20 mg/kg/day in females, and oral doses in rats were 0.5, 2, and 10 mg/kg/day for both males and females. The highest doses evaluated in mice were approximately 72 times (males) and 105 times (females) the clinical dose of 10 mg per day based on AUC exposure. In rats, the highest dose was approximately 131 times (males) and 186 times (females) the clinical dose of 10 mg per day based on AUC exposure.

Dapagliflozin was negative in the Ames mutagenicity assay and was positive in a series of in vitro clastogenicity assays in the presence of S9 activation and at concentrations ≥ 100 μg/mL. Dapagliflozin was negative for clastogenicity in a series of in vivo studies evaluating micronuclei or DNA repair in rats at exposure multiples >2100 times the clinical dose.

There was no carcinogenicity or mutagenicity signal in animal studies, suggesting that dapagliflozin does not represent a genotoxic risk to humans.

Dapagliflozin had no effects on mating, fertility, or early embryonic development in treated male or female rats at exposure multiples ≤ 1708 times and 998 times the maximum recommended human dose in males and females, respectively.

Use In Specific Populations Pregnancy Risk Summary

Based on animal data showing adverse renal effects, FARXIGA is not recommended during the second and third trimesters of pregnancy.

Limited data with FARXIGA in pregnant women are not sufficient to determine drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy.

In animal studies, adverse renal pelvic and tubule dilatations, that were not fully reversible, were observed in rats when dapagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy, at all doses tested; the lowest of which provided an exposure 15-times the 10 mg clinical dose.

The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c greater than 7% and has been reported to be as high as 20 to 25% in women with HbA1c greater than 10%. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal And/Or Embryo-Fetal Risk

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.

Data

Animal Data

Dapagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1, 15, or 75 mg/kg/day, increased kidney weights and increased the incidence of renal pelvic and tubular dilatations at all dose levels. Exposure at the lowest dose tested was 15-times the 10 mg clinical dose (based on AUC). The renal pelvic and tubular dilatations observed in juvenile animals did not fully reverse within a 1-month recovery period.

In a prenatal and postnatal development study, dapagliflozin was administered to maternal rats from gestation day 6 through lactation day 21 at doses of 1, 15, or 75 mg/kg/day, and pups were indirectly exposed in utero and throughout lactation. Increased incidence or severity of renal pelvic dilatation was observed in 21-day-old pups offspring of treated dams at 75 mg/kg/day (maternal and pup dapagliflozin exposures were 1415-times and 137-times, respectively, the human values at the 10 mg clinical dose, based on AUC). Dose-related reductions in pup body weights were observed at greater or equal to 29-times the 10 mg clinical dose (based on AUC). No adverse effects on developmental endpoints were noted at 1 mg/kg/day (19-times the 10 mg clinical dose, based on AUC).

In embryo-fetal development studies in rats and rabbits, dapagliflozin was administered throughout organogenesis, corresponding to the first trimester of human pregnancy. In rats, dapagliflozin was neither embryolethal nor teratogenic at doses greater than 75 mg/kg/day (1441-times the 10 mg clinical dose, based on AUC). Dose-related effects on the rat fetus (structural abnormalities and reduced body weight) occurred only at higher dosages, greater than 150 mg/kg (more than 2344-times the 10 mg clinical dose, based on AUC), which were associated with maternal toxicity. These outcomes occurred with drug exposure during periods of renal development in rats that corresponds to the late second and third trimester of human development. No developmental toxicities were observed in rabbits at doses up to 180 mg/kg/day (1191-times the 10 mg clinical dose, based on AUC).

Lactation Risk Summary

There is no information regarding the presence of dapagliflozin in human milk, the effects on the breastfed infant, or the effects on milk production. Dapagliflozin is present in the milk of lactating rats. However, due to species-specific differences in lactation physiology, the clinical relevance of these data are not clear. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney.

Because of the potential for serious adverse reactions in breastfed infants, advise women that use of FARXIGA is not recommended while breastfeeding.

Data

It is not known whether FARXIGA is excreted in human milk. Dapagliflozin was present in rat milk at a milk/plasma ratio of 0.49 indicating that dapagliflozin and its metabolites are transferred into milk at a concentration that is approximately 50% of that in maternal plasma. Juvenile rats directly exposed to dapagliflozin showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation.

Pediatric Use

Safety and effectiveness of FARXIGA in pediatric patients under 18 years of age have not been established.

Geriatric Use

No FARXIGA dosage change is recommended based on age. A total of 1424 (24%) of the 5936 FARXIGA-treated patients were 65 years and older and 207 (3.5%) patients were 75 years and older in a pool of 21 double-blind, controlled, clinical safety and efficacy studies of FARXIGA. After controlling for level of renal function (eGFR), efficacy was similar for patients under age 65 years and those 65 years and older. In patients ≥ 65 years of age, a higher proportion of patients treated with FARXIGA had adverse reactions related to volume depletion and renal impairment or failure compared to patients treated with placebo.

Renal Impairment

The safety and efficacy of FARXIGA were evaluated in a study that included patients with moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m²). Compared to placebo-treated patients, patients with moderate renal impairment treated with FARXIGA did not have improvement in glycemic control and had more renal-related adverse reactions and more bone fractures ; therefore, FARXIGA initiation is not recommended in this population.

Based on its mechanism of action, FARXIGA is not expected to be effective in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m²) or ESRD.

Hepatic Impairment

No dose adjustment is recommended for patients with mild, moderate, or severe hepatic impairment. However, the benefit-risk for the use of dapagliflozin in patients with severe hepatic impairment should be individually assessed since the safety and efficacy of dapagliflozin have not been specifically studied in this population.

Dosage (Posology) and method of administration

Recommended Dosing

The recommended starting dose of FARXIGA is 5 mg once daily, taken in the morning, with or without food. In patients tolerating FARXIGA 5 mg once daily who require additional glycemic control, the dose can be increased to 10 mg once daily.

In patients with volume depletion, correcting this condition prior to initiation of FARXIGA is recommended.

Patients With Renal Impairment

Assessment of renal function is recommended prior to initiation of FARXIGA therapy and periodically thereafter.

Initiation of FARXIGA is not recommended in patients with an eGFR less than 60 mL/min/1.73 m².

No dose adjustment is needed in patients with mild renal impairment (eGFR of 60 mL/min/1.73 m² or greater).

Use of FARXIGA is not recommended in patients with an eGFR persistently between 30 and less than 60 mL/min/1.73 m².

FARXIGA is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m².

Interaction with other medicinal products and other forms of interaction

In Vitro Assessment Of Drug Interactions

In in vitro studies, dapagliflozin and dapagliflozin 3-O-glucuronide neither inhibited CYP 1A2, 2C9, 2C19, 2D6, or 3A4, nor induced CYP 1A2, 2B6, or 3A4. Dapagliflozin is a weak substrate of the P-glycoprotein (P-gp) active transporter, and dapagliflozin 3-O-glucuronide is a substrate for the OAT3 active transporter. Dapagliflozin or dapagliflozin 3-O­glucuronide did not meaningfully inhibit P-gp, OCT2, OAT1, or OAT3 active transporters. Overall, dapagliflozin is unlikely to affect the pharmacokinetics of concurrently administered medications that are P-gp, OCT2, OAT1, or OAT3 substrates.

Effects Of Other Drugs On Dapagliflozin

Table 6 shows the effect of coadministered drugs on the pharmacokinetics of dapagliflozin. No dose adjustments are recommended for dapagliflozin.

Table 6: Effects of Coadministered Drugs on Dapagliflozin Systemic Exposure

Coadministered Drug (Dose Regimen) *	Dapagliflozin (Dose Regimen)*	Effect on Dapagliflozin Exposure (% Change [90% CI])
Cmax	AUC†
No dosing adjustments required for the following:
Oral Antidiabetic Agents
Metformin (1000 mg)	20 mg	↔	↔
Pioglitazone (45 mg)	50 mg	↔	↔
Sitagliptin (100 mg)	20 mg	↔	↔
Glimepiride (4 mg)	20 mg	↔	↔
Voglibose (0.2 mg three times daily)	10 mg	↔	↔
Other Medications
Hydrochlorothiazide (25 mg)	50 mg	↔	↔
Bumetanide (1 mg)	10 mg once daily for 7 days	↔	↔
Valsartan (320 mg)	20 mg	↓12% [↓3%, ↓20%]	↔
Simvastatin (40 mg)	20 mg	↔	↔
Anti-infective Agent
Rifampin (600 mg once daily for 6 days)	10 mg	↓7% [↓22%, ↑11%]	↓22% [↓27%, ↓17%]
Nonsteroidal Anti-inflammatory Agent
Mefenamic Acid (loading dose of 500 mg followed by 14 doses of 250 mg every 6 hours)	10 mg	↑13% [↑3%, ↑24%]	↑51% [↑44%, ↑58%]
↔ = no change (geometric mean ratio of test: reference within 0.80 to 1.25); ↓ or ↑ = parameter was lower or higher, respectively, with coadministration compared to dapagliflozin administered alone (geometric mean ratio of test: reference was lower than 0.80 or higher than 1.25) * Single dose unless otherwise noted. † AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses.

Effects Of Dapagliflozin On Other Drugs

Table 7 shows the effect of dapagliflozin on other coadministered drugs. Dapagliflozin did not meaningfully affect the pharmacokinetics of the coadministered drugs.

Table 7: Effects of Dapagliflozin on the Systemic Exposures of Coadministered Drugs

Coadministered Drug (Dose Regimen)*	Dapagliflozin (Dose Regimen)*	Effect on Coadministered Drug Exposure (% Change [90% CI])
Cmax	AUC†
No dosing adjustments required for the following:
Oral Antidiabetic Agents
Metformin (1000 mg)	20 mg	↔	↔
Pioglitazone (45 mg)	50 mg	↓7% [↓25%, ↑15%]	↔
Sitagliptin (100 mg)	20 mg	↔	↔
Glimepiride (4 mg)	20 mg	↔	↑13% [0%, ↑29%]
Other Medications
Hydrochlorothiazide (25 mg)	50 mg	↔	↔
Bumetanide (1 mg)	10 mg once daily for 7 days	↑13% [↓2%, ↑31%]	↑13% [↓1%, ↑30%]
Valsartan (320 mg)	20 mg	↓6% [↓24%, ↑16%]	↑5% [↓15%, ↑29%]
Simvastatin (40 mg)	20 mg	↔	|19%
Digoxin (0.25 mg)	20 mg loading dose then 10 mg once daily for 7 days	↔	↔
Warfarin (25 mg)	20 mg loading dose then 10 mg once daily for 7 days	↔	↔
↔ = no change (geometric mean ratio of test: reference within 0.80 to 1.25); ↓ or ↑ = parameter was lower or higher, respectively, with coadministration compared to the other medicine administered alone (geometric mean ratio of test: reference was lower than 0.80 or higher than 1.25). * Single dose unless otherwise noted. † AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses.