Dapagliflozin

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# Overview
Dapagliflozin is an endocrine-metabolic agent that is FDA approved for the treatment of type 2 diabetes mellitus.   Common adverse reactions include female genital mycotic infections, nasopharyngitis, and urinary tract infections.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- 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.
- Dosing Information
- 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.
- FARXIGA should not be initiated 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).
- FARXIGA should be discontinued when eGFR is persistently less than 60 mL/min/1.73 m2.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Dapagliflozin in adult patients.

### NonGuideline-Supported Use
- There is limited information regarding Off-Label NonGuideline-Supported Use of Dapagliflozin in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
- There is limited information regarding FDA-Labeled Use of Dapagliflozin in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Dapagliflozin in pediatric patients.

### NonGuideline-Supported Use
- There is limited information regarding Off-Label NonGuideline-Supported Use of Dapagliflozin in pediatric patients.

# Contraindications
- History of a serious hypersensitivity reaction to FARXIGA.
- Severe renal impairment, end-stage renal disease (ESRD), or patients on dialysis.

# Warnings
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.
Impairment in Renal Function
- FARXIGA increases serum creatinine and decreases eGFR. Elderly patients and patients with impaired renal function may be more susceptible to these changes. Adverse reactions related to renal function can occur after initiating FARXIGA. Renal function should be evaluated prior to initiation of FARXIGA and monitored periodically thereafter.
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 LDLC occur with FARXIGA. Monitor LDLC 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 or any other antidiabetic drug.

# Adverse Reactions

## Clinical Trials Experience
- The following important adverse reactions are described below and elsewhere in the labeling:
- Hypotension
- Impairment in Renal Function
- Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
- Genital Mycotic Infections
- Increases in Low-Density Lipoprotein Cholesterol (LDLC)
- 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.
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.
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). 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.
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 mgtreated 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.

## Postmarketing Experience
There is limited information regarding Dapagliflozin Postmarketing Experience in the drug label.

# Drug Interactions
Positive Urine Glucose Test
- Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors as SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Use alternative methods to monitor glycemic control.
Interference with 1,5-anhydroglucitol (1,5-AG) Assay
- Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 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.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dapagliflozin in women who are pregnant.

### Labor and Delivery
- There is no FDA guidance on use of Dapagliflozin during labor and delivery.

### Nursing Mothers
- It is not known whether FARXIGA is excreted in human milk. Dapagliflozin is excreted in rat milk reaching levels 0.49 times that found in maternal plasma. Data in juvenile rats directly exposed to dapagliflozin showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. 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 many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from FARXIGA, a decision should be made whether to discontinue nursing or to discontinue FARXIGA, taking into account the importance of the drug to the mother.

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

### Geriatic 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.

### Gender
- There is no FDA guidance on the use of Dapagliflozin with respect to specific gender populations.

### Race
- There is no FDA guidance on the use of Dapagliflozin with respect to specific racial populations.

### 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 should not be initiated 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.

### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Dapagliflozin in women of reproductive potentials and males.

### Immunocompromised Patients
- There is no FDA guidance one the use of Dapagliflozin in patients who are immunocompromised.

# Administration and Monitoring

### 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.
- FARXIGA should not be initiated 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).
- FARXIGA should be discontinued when eGFR is persistently less than 60 mL/min/1.73 m2.
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.

### Monitoring
- There is limited information regarding Monitoring of Dapagliflozin in the drug label.

# IV Compatibility
- There is limited information regarding IV Compatibility of Dapagliflozin in the drug label.

# Overdosage
- 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 patients clinical status. The removal of dapagliflozin by hemodialysis has not been studied.

# Pharmacology
There is limited information regarding Dapagliflozin Pharmacology in the drug label.

## Mechanism of Action
- Sodium-glucose cotransporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Dapagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, dapagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.

## Structure
- Dapagliflozin is described chemically as D-glucitol, 1,5-anhydro-1-C-phenyl]-, (1S)-, compounded with (2S)-1,2-propanediol, hydrate (1:1:1). The empirical formula is C21H25ClO6C3H8O2H2O and the molecular weight is 502.98. The structural formula is:
- FARXIGA is available as a film-coated tablet for oral administration containing the equivalent of 5 mg dapagliflozin as dapagliflozin propanediol or the equivalent of 10 mg dapagliflozin as dapagliflozin propanediol, and the following inactive ingredients: microcrystalline cellulose, anhydrous lactose, crospovidone, silicon dioxide, and magnesium stearate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and yellow iron oxide.

## Pharmacodynamics
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.
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.

## Pharmacokinetics
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 -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 -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 (t12) for dapagliflozin is approximately 12.9 hours following a single oral dose of FARXIGA 10 mg.
Specific Populations
Renal Impairment
- At steady state (20 mg once-daily dapagliflozin for 7 days), patients with type 2 diabetes with mild, moderate, or severe renal impairment (as determined by eGFR) had geometric mean systemic exposures of dapagliflozin that were 45%, 2.04-fold, and 3.03-fold higher, respectively, as compared to patients with type 2 diabetes with normal renal function. Higher systemic exposure of dapagliflozin in patients with type 2 diabetes mellitus with renal impairment did not result in a correspondingly higher 24-hour urinary glucose excretion. The steady-state 24-hour urinary glucose excretion in patients with type 2 diabetes and mild, moderate, and severe renal impairment was 42%, 80%, and 90% lower, respectively, than patients with type 2 diabetes with normal renal function. The impact of hemodialysis on dapagliflozin exposure is not known.
Hepatic Impairment
- In subjects with mild and moderate hepatic impairment (Child-Pugh classes A and B), mean Cmax and AUC of dapagliflozin were up to 12% and 36% higher, respectively, as compared to healthy matched control subjects following single-dose administration of 10 mg dapagliflozin. These differences were not considered to be clinically meaningful. In patients with severe hepatic impairment (Child-Pugh class C), mean Cmax and AUC of dapagliflozin were up to 40% and 67% higher, respectively, as compared to healthy matched controls.
Effects of Age, Gender, Race, and Body Weight on Pharmacokinetics
- Based on a population pharmacokinetic analysis, age, gender, race, and body weight do not have a clinically meaningful effect on the pharmacokinetics of dapagliflozin and thus, no dose adjustment is recommended.
Pediatric
- Pharmacokinetics in the pediatric population has not been studied.
Drug Interactions
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-O-glucuronide 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.
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.

## Nonclinical Toxicology
There is limited information regarding Dapagliflozin Nonclinical Toxicology in the drug label.

# Clinical Studies
Overview of Clinical Studies of FARXIGA for Type 2 Diabetes
- FARXIGA has been studied as monotherapy and in combination with metformin, pioglitazone, glimepiride, sitagliptin (with or without metformin), or insulin (with or without other oral antidiabetic therapy). The efficacy of FARXIGA was compared to a sulfonylurea (glipizide) added on to metformin. FARXIGA has also been studied in patients with type 2 diabetes and moderate renal impairment.
- Treatment with FARXIGA as monotherapy and in combination with metformin, glimepiride, pioglitazone, sitagliptin, or insulin produced statistically significant improvements in mean change from baseline at Week 24 in HbA1c compared to control. Reductions in HbA1c were seen across subgroups including gender, age, race, duration of disease, and baseline BMI.
Monotherapy
- A total of 840 treatment-naive patients with inadequately controlled type 2 diabetes participated in 2 placebo-controlled studies to evaluate the safety and efficacy of monotherapy with FARXIGA.
- In 1 monotherapy study, a total of 558 treatment-naive patients with inadequately controlled diabetes participated in a 24-week study. Following a 2-week diet and exercise placebo lead-in period, 485 patients with HbA1c 7% and 10% were randomized to FARXIGA 5 mg or FARXIGA 10 mg once daily in either the morning (QAM, main cohort) or evening (QPM), or placebo.
- At Week 24, treatment with FARXIGA 10 mg QAM provided significant improvements in HbA1c and FPG compared with placebo (see Table 8).
Initial Combination Therapy with Metformin
- A total of 1241 treatment-naive patients with inadequately controlled type 2 diabetes (HbA1c 7.5% and 12%) participated in 2 active-controlled studies of 24-week duration to evaluate the safety and efficacy of initial therapy with FARXIGA 5 mg or 10 mg in combination with metformin extended-release (XR) formulation.
- In 1 study, 638 patients were randomized to 1 of 3 treatment arms following a 1-week lead-in period: FARXIGA 10 mg plus metformin XR (up to 2000 mg per day), FARXIGA 10 mg plus placebo, or metformin XR (up to 2000 mg per day) plus placebo. Metformin XR dose was up-titrated weekly in 500 mg increments, as tolerated, with a median dose achieved of 2000 mg.
- The combination treatment of FARXIGA 10 mg plus metformin XR provided statistically significant improvements in HbA1c and FPG compared with either of the monotherapy treatments and statistically significant reduction in body weight compared with metformin XR alone (see Table 9 and Figure 2). FARXIGA 10 mg as monotherapy also provided statistically significant improvements in FPG and statistically significant reduction in body weight compared with metformin alone and was noninferior to metformin XR monotherapy in lowering HbA1c.
- In a second study, 603 patients were randomized to 1 of 3 treatment arms following a 1-week lead-in period: FARXIGA 5 mg plus metformin XR (up to 2000 mg per day), FARXIGA 5 mg plus placebo, or metformin XR (up to 2000 mg per day) plus placebo. Metformin XR dose was up-titrated weekly in 500 mg increments, as tolerated, with a median dose achieved of 2000 mg.
- The combination treatment of FARXIGA 5 mg plus metformin XR provided statistically significant improvements in HbA1c and FPG compared with either of the monotherapy treatments and statistically significant reduction in body weight compared with metformin XR alone (see Table 10).
Add-On to Metformin
- A total of 546 patients with type 2 diabetes with inadequate glycemic control (HbA1c 7% and 10%) participated in a 24-week, placebo-controlled study to evaluate FARXIGA in combination with metformin. Patients on metformin at a dose of at least 1500 mg per day were randomized after completing a 2-week, single-blind, placebo lead-in period. Following the lead-in period, eligible patients were randomized to FARXIGA 5 mg, FARXIGA 10 mg, or placebo in addition to their current dose of metformin.
- As add-on treatment to metformin, FARXIGA 10 mg provided statistically significant improvements in HbA1c and FPG, and statistically significant reduction in body weight compared with placebo at Week 24 (see Table 11 and Figure 3). Statistically significant (p<0.05 for both doses) mean changes from baseline in systolic blood pressure relative to placebo plus metformin were 4.5 mmHg and 5.3 mmHg with FARXIGA 5 mg and 10 mg plus metformin, respectively.
Active Glipizide-Controlled Study Add-On to Metformin
- A total of 816 patients with type 2 diabetes with inadequate glycemic control (HbA1c >6.5% and 10%) were randomized in a 52-week, glipizide-controlled, noninferiority study to evaluate FARXIGA as add-on therapy to metformin. Patients on metformin at a dose of at least 1500 mg per day were randomized following a 2-week placebo lead-in period to glipizide or dapagliflozin (5 mg or 2.5 mg, respectively) and were up-titrated over 18 weeks to optimal glycemic effect (FPG <110 mg/dL, <6.1 mmol/L) or to the highest dose level (up to glipizide 20 mg and FARXIGA 10 mg) as tolerated by patients. Thereafter, doses were kept constant, except for down-titration to prevent hypoglycemia.
- At the end of the titration period, 87% of patients treated with FARXIGA had been titrated to the maximum study dose (10 mg) versus 73% treated with glipizide (20 mg). FARXIGA led to a similar mean reduction in HbA1c from baseline at Week 52 (LOCF), compared with glipizide, thus demonstrating noninferiority (see Table 12). FARXIGA treatment led to a statistically significant mean reduction in body weight from baseline at Week 52 (LOCF) compared with a mean increase in body weight in the glipizide group. Statistically significant (p<0.0001) mean change from baseline in systolic blood pressure relative to glipizide plus metformin was 5.0 mmHg with FARXIGA plus metformin.
Add-On Combination Therapy with Other Antidiabetic Agents
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 ) 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%).
Use in Patients with Type 2 Diabetes and Renal Impairment
- The efficacy of FARXIGA was assessed in a study of diabetic patients with moderate renal impairment (252 patients with mean eGFR 45 mL/min/1.73 m2). FARXIGA did not show efficacy in this study. The placebo-corrected mean HbA1c change at 24 weeks was 0.1% (95% CI ) for both FARXIGA 5 mg (n=83) and 10 mg (n=82).

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

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

# Images

## Drug Images

## Package and Label Display Panel

# 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.
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.
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.

# Precautions with Alcohol
- Alcohol-Dapagliflozin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
Farxiga

# Look-Alike Drug Names
- A  B

# Drug Shortage Status

# Price