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 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.

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 (5.1)].

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).

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 (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 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 (14)] is shown in Table 5. Hypoglycemia was more frequent when FARXIGA was added to sulfonylurea or insulin [see Warnings and Precautions (5.3)].

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

Pregnancy Category C

There are no adequate and well-controlled studies of FARXIGA in pregnant women. Based on results of reproductive and developmental toxicity studies in animals, dapagliflozin may affect renal development and maturation. In a juvenile rat study, increased incidence and/or severity of renal pelvic and tubular dilatations were evident at the lowest tested dose which was approximately 15 times clinical exposure from a 10 mg dose.

These outcomes occurred with drug exposures during periods of animal development that correlate with the late second and third trimesters of human pregnancy. During pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters. FARXIGA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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

In a prenatal and postnatal development study, maternal rats were dosed 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 adult 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 clinical dose). Dose-related reductions in pup body weights were observed at doses ≥1 mg/kg/day (approximately ≥19 times the clinical dose). No adverse effects on developmental endpoints were noted at 1 mg/kg/day, or approximately 19 times the clinical dose.

In embryo-fetal development studies in rats and rabbits, dapagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans. No developmental toxicities were observed in rabbits at any dose tested. In rats, dapagliflozin was neither embryolethal nor teratogenic at doses up to 75 mg/kg/day or 1441 times the maximum clinical dose of 10 mg. At higher doses in rats, malformations of blood vessels, ribs, vertebra, manubria, and skeletal variations in fetuses at ≥150 mg/kg or 2344 times the 10 mg clinical dose were observed.

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 dose of 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 [see Adverse Reactions (6.1)].

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.

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.

Specific Populations

Drug Interactions

Add-On Combination Therapy with a Sulfonylurea

A total of 597 patients with type 2 diabetes and inadequate glycemic control (HbA1c ≥7% and ≤10%) were randomized in this 24-week, placebo-controlled study to evaluate FARXIGA in combination with glimepiride (a sulfonylurea).

Patients on at least half the maximum recommended dose of glimepiride as monotherapy (4 mg) for at least 8 weeks lead-in were randomized to FARXIGA 5 mg, FARXIGA 10 mg, or placebo in addition to glimepiride 4 mg per day. Down-titration of glimepiride to 2 mg or 0 mg was allowed for hypoglycemia during the treatment period; no up-titration of glimepiride was allowed.

In combination with glimepiride, FARXIGA 10 mg provided statistically significant improvement in HbA1c, FPG, and 2-hour PPG, and statistically significant reduction in body weight compared with placebo plus glimepiride at Week 24 (see Table 13). Statistically significant (p<0.05 for both doses) mean changes from baseline in systolic blood pressure relative to placebo plus glimepiride were −2.8 mmHg and −3.8 mmHg with FARXIGA 5 mg and 10 mg plus glimepiride, respectively.

Add-On Combination Therapy with a Thiazolidinedione

A total of 420 patients with type 2 diabetes with inadequate glycemic control (HbA1c ≥7% and ≤10.5%) participated in a 24-week, placebo-controlled study to evaluate FARXIGA in combination with pioglitazone (a thiazolidinedione [TZD]) alone. Patients on a stable dose of pioglitazone of 45 mg per day (or 30 mg per day, if 45 mg per day was not tolerated) for 12 weeks were randomized after a 2-week lead-in period to 5 or 10 mg of FARXIGA or placebo in addition to their current dose of pioglitazone. Dose titration of FARXIGA or pioglitazone was not permitted during the study.

In combination with pioglitazone, treatment with FARXIGA 10 mg provided statistically significant improvements in HbA1c, 2-hour PPG, FPG, the proportion of patients achieving HbA1c <7%, and a statistically significant reduction in body weight compared with the placebo plus pioglitazone treatment groups (see Table 13) at Week 24. A statistically significant (p<0.05) mean change from baseline in systolic blood pressure relative to placebo in combination with pioglitazone was −4.5 mmHg with FARXIGA 10 mg in combination with pioglitazone.

Add-On Combination Therapy with a DPP4 Inhibitor

A total of 452 patients with type 2 diabetes who were drug naive, or who were treated at entry with metformin or a DPP4 inhibitor alone or in combination, and had inadequate glycemic control (HbA1c ≥7.0% and ≤10.0% at randomization), participated in a 24-week, placebo-controlled study to evaluate FARXIGA in combination with sitagliptin (a DPP4 inhibitor) with or without metformin.

Eligible patients were stratified based on the presence or absence of background metformin (≥1500 mg per day), and within each stratum were randomized to either FARXIGA 10 mg plus sitagliptin 100 mg once daily, or placebo plus sitagliptin 100 mg once daily. Endpoints were tested for FARXIGA 10 mg versus placebo for the total study group (sitagliptin with and without metformin) and for each stratum (sitagliptin alone or sitagliptin with metformin). Thirty-seven percent (37%) of patients were drug naive, 32% were on metformin alone, 13% were on a DPP4 inhibitor alone, and 18% were on a DPP4 inhibitor plus metformin. Dose titration of FARXIGA, sitagliptin, or metformin was not permitted during the study.

In combination with sitagliptin (with or without metformin), FARXIGA 10 mg provided statistically significant improvements in HbA1c, FPG, and a statistically significant reduction in body weight compared with the placebo plus sitagliptin (with or without metformin) group at Week 24 (see Table 13). These improvements were also seen in the stratum of patients who received FARXIGA 10 mg plus sitagliptin alone (placebo-corrected mean change for HbA1c −0.56%; n=110) compared with placebo plus sitagliptin alone (n=111), and the stratum of patients who received FARXIGA 10 mg plus sitagliptin and metformin (placebo-corrected mean change for HbA1c −0.40; n=113) compared with placebo plus sitagliptin with metformin (n=113).

Add-On Combination Therapy with Insulin

A total of 808 patients with type 2 diabetes who had inadequate glycemic control (HbA1c ≥7.5% and ≤10.5%) were randomized in a 24-week, placebo-controlled study to evaluate FARXIGA as add-on therapy to insulin. Patients on a stable insulin regimen, with a mean dose of at least 30 IU of injectable insulin per day, for a period of at least 8 weeks prior to enrollment and on a maximum of 2 oral antidiabetic medications (OADs), including metformin, were randomized after completing a 2-week enrollment period to receive either FARXIGA 5 mg, FARXIGA 10 mg, or placebo in addition to their current dose of insulin and other OADs, if applicable. Patients were stratified according to the presence or absence of background OADs. Up- or down-titration of insulin was only permitted during the treatment phase in patients who failed to meet specific glycemic goals. Dose modifications of blinded study medication or OAD(s) were not allowed during the treatment phase, with the exception of decreasing OAD(s) where there were concerns over hypoglycemia after cessation of insulin therapy.

In this study, 50% of patients were on insulin monotherapy at baseline, while 50% were on 1 or 2 OADs in addition to insulin. At Week 24, FARXIGA 10 mg dose provided statistically significant improvement in HbA1c and reduction in mean insulin dose, and a statistically significant reduction in body weight compared with placebo in combination with insulin, with or without up to 2 OADs (see Table 13); the effect of FARXIGA on HbA1c was similar in patients treated with insulin alone and patients treated with insulin plus OAD. Statistically significant (p<0.05) mean change from baseline in systolic blood pressure relative to placebo in combination with insulin was −3.0 mmHg with FARXIGA 10 mg in combination with insulin.

At Week 24, FARXIGA 5 mg (−5.7 IU, difference from placebo) and 10 mg (−6.2 IU, difference from placebo) once daily resulted in a statistically significant reduction in mean daily insulin dose (p<0.0001 for both doses) compared to placebo in combination with insulin, and a statistically significantly higher proportion of patients on FARXIGA 10 mg (19.6%) reduced their insulin dose by at least 10% compared to placebo (11.0%).

How Supplied

FARXIGA (dapagliflozin) tablets have markings on both sides and are available in the strengths and packages listed in Table 14.

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) [see USP Controlled Room Temperature].

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 [see Warnings and Precautions (5.1)]. 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 [see Warnings and Precautions (5.4)].

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 [see Warnings and Precautions (5.4)].

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.

Urinary Tract Infections

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

Bladder Cancer

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

Laboratory Tests

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