DAPAGLIFLOZIN PROPANEDIOL: 16,873 Adverse Event Reports & Safety Profile

XIGDUO XR tablets contain: dapagliflozin, a SGLT2 inhibitor, and metformin HCl, a biguanide.

Dapagliflozin

Dapagliflozin is described chemically as D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-, (1S)-, compounded with (2S)-1,2-propanediol, hydrate (1:1:1). The empirical formula is C 21 H 25 ClO 6

• C 3 H 8 O 2
• H 2 O and the formula weight is 502.98. The structural formula is: Dapagliflozin chemical structure Metformin HCl Metformin HCl (N,N-dimethylimidodicarbonimidic diamide HCl) is a white to off-white crystalline compound with a molecular formula of C 4 H 11 N 5
• HCl and a molecular weight of 165.63. Metformin HCl is freely soluble in water, slightly soluble in alcohol, and is practically insoluble in acetone, ether, and chloroform. The pK a of metformin is 12.4. The pH of a 1% aqueous solution of metformin HCl is 6.68. The structural formula is: Metformin hydrochloride chemical structure XIGDUO XR XIGDUO XR is available for oral administration as tablets containing the equivalent of 2.5 mg dapagliflozin as dapagliflozin propanediol and 1,000 mg metformin HCl which is equivalent to 779.86 mg metformin base (XIGDUO XR 2.5 mg/1,000 mg), 5 mg dapagliflozin as dapagliflozin propanediol and 500 mg metformin HCl which is equivalent to 389.9 mg metformin base (XIGDUO XR 5 mg/500 mg), the equivalent of 5 mg dapagliflozin as dapagliflozin propanediol and 1,000 mg metformin HCl which is equivalent to 779.86 mg metformin base (XIGDUO XR 5 mg/1,000 mg), the equivalent of 10 mg dapagliflozin as dapagliflozin propanediol and 500 mg metformin HCl which is equivalent to 389.9 mg metformin base (XIGDUO XR 10 mg/500 mg), or the equivalent of 10 mg dapagliflozin as dapagliflozin propanediol and 1,000 mg metformin HCl which is equivalent to 779.86 mg metformin base (XIGDUO XR 10 mg/1,000 mg). Each film-coated tablet of XIGDUO XR contains the following inactive ingredients: anhydrous lactose, carboxymethylcellulose sodium, crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, and silicon dioxide. The film coatings contain the following inactive ingredients: polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Additionally, the film coating for the XIGDUO XR 5 mg/500 mg tablets contains FD&C Yellow No. 6/Sunset Yellow FCF aluminum lake. The film coating for the XIGDUO XR 2.5 mg/1,000 mg, 5 mg/1,000 mg, 10 mg/500 mg, and 10 mg/1,000 mg tablets contains iron oxides.

AND USAGE Dapagliflozin and Metformin HCl extended-release tablets are a combination of dapagliflozin and metformin hydrochloride (HCl) extended-release, indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. Dapagliflozin, when used as a component of Dapagliflozin and Metformin HCl extended-release tablets, is indicated in adults with type 2 diabetes mellitus to reduce the risk of:

• Sustained eGFR decline, end stage kidney disease, cardiovascular death, and hospitalization for heart failure in patients with chronic kidney disease at risk of progression.
• Cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in patients with heart failure.
• Hospitalization for heart failure in patients with type 2 diabetes mellitus and either established cardiovascular disease (CVD) or multiple cardiovascular (CV) risk factors. Limitations of Use
• Dapagliflozin and Metformin HCl extended-release tablets are not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus [see Warnings and Precautions (5.2) ].
• Because of the metformin HCl component, the use of Dapagliflozin and Metformin HCl extended-release tablets are limited to patients with type 2 diabetes mellitus for all indications.
• Dapagliflozin and Metformin HCl extended-release tablets are not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of immunosuppressive therapy for kidney disease. Dapagliflozin and Metformin HCl extended-release tablets are not expected to be effective in these populations. Dapagliflozin and Metformin HCl extended-release tablets are a combination of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and metformin hydrochloride (HCl), a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. (1) Dapagliflozin when used as a component of Dapagliflozin and Metformin HCl extended-release tablets is indicated in adults with type 2 diabetes mellitus to reduce the risk of:
• Sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in patients with chronic kidney disease at risk of progression. (1)
• Cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in patients with heart failure. (1)
• Hospitalization for heart failure in patients with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors. (1) Limitations of use :
• Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. (1)
• Because of the metformin HCI component, the use of Dapagliflozin and Metformin HCl extended-release tablets are limited to patients with type 2 diabetes mellitus for all indications. (1)
• Not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of immunosuppressive therapy for the treatment of kidney disease. Dapagliflozin and Metformin HCl extended-release tablets are not expected to be effective in these populations. (1)

AND ADMINISTRATION

• Assess renal function prior to initiating and then as clinically indicated. ( 2.1 )
• Assess volume status and correct volume depletion before initiating. ( 2.1 )
• Individualize the starting dosage based on the patient’s current treatment. ( 2.3 )
• Administer orally once daily in the morning with food. ( 2.2 )
• To improve glycemic control, for patients aged 10 years and older not already taking dapagliflozin, the recommended starting dosage for dapagliflozin is 5 mg once daily. ( 2.3 )
• For indications in adults related to heart failure and chronic kidney disease the recommended dosage of dapagliflozin is 10 mg once daily. ( 2.3 )
• Do not exceed a daily dosage of 10 mg dapagliflozin/2,000 mg metformin HCl extended-release. ( 2.3 )
• See Full Prescribing Information for dosage recommendations in patients with renal impairment. ( 2.4 )
• Dapagliflozin and Metformin HCl extended-release tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. ( 2.5 )
• Withhold Dapagliflozin and Metformin HCl extended-release tablets for at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. ( 2.6 )

2.1 Testing Prior to Initiation of Dapagliflozin and Metformin HCl Extended-Release Tablets

• Assess renal function prior to initiating Dapagliflozin and Metformin HCl extended-release tablets and then as clinically indicated [see Warnings and Precautions ( 5.1 , 5.3 )] .
• Assess volume status. In patients with volume depletion, correct this condition before initiating Dapagliflozin and Metformin HCl extended-release tablets [see Warnings and Precautions (5.3) and Use in Specific Populations (8.5 , 8.6)].

2.2 Recommended Administration

• Take Dapagliflozin and Metformin HCl extended-release tablets orally once daily in the morning with food.
• Swallow Dapagliflozin and Metformin HCl extended-release tablets whole and never crush, cut, or chew.

2.3 Recommended Dosage

• Individualize the starting dosage of Dapagliflozin and Metformin HCl extended-release tablets based upon the patient’s current regimen. Patients taking an evening dosage of metformin HCl extended-release should skip their last dose before starting Dapagliflozin and Metformin HCl extended-release tablets.
• To improve glycemic control in adults and pediatric patients aged 10 years and older not already taking: ∘ Dapagliflozin: the recommended starting dosage of dapagliflozin in Dapagliflozin and Metformin HCl extended-release tablets is 5 mg orally once daily. ∘ Metformin HCl extended-release: the recommended starting dosage of metformin HCl extended release in Dapagliflozin and Metformin HCl extended-release tablets is 500 mg orally once daily.
• For Dapagliflozin and Metformin HCl extended-release tablets indications in adults related to heart failure and chronic kidney disease, the recommended dosage of dapagliflozin in Dapagliflozin and Metformin HCl extended-release tablets is 10 mg orally once daily.
• For all Dapagliflozin and Metformin HCl extended-release tablets indications, the dosage may be adjusted based on effectiveness and tolerability. The maximum recommended daily dosage of dapagliflozin is 10 mg and 2,000 mg of metformin HCl extended-release, with gradual dosage escalation to reduce gastrointestinal adverse reactions with metformin HCl [see Adverse Reactions (6.1) ].

2.4 Recommended Dosage in Patients with Renal Impairment

• The recommended dosage of Dapagliflozin and Metformin HCl extended-release tablets in patients with an estimated glomerular filtration rate (eGFR) greater than or equal to 45 mL/min/1.73 m 2 is the same as the recommended dosage in patients with normal renal function.
• Initiation of Dapagliflozin and Metformin HCl extended-release tablets is not recommended in patients with an eGFR between 30 and 45 mL/min/1.73 m 2 . Assess the benefit and risk of continuing therapy if eGFR falls persistently below this level. ∘ Dapagliflozin is likely to be ineffective to improve glycemic control in patients with eGFR less than 45 mL/min/1.73 m 2 . ∘ Metformin HCl initiation is not recommended for patients with eGFR less than 45 mL/min/1.73 m 2 .
• Dapagliflozin and Metformin HCl extended-release tablets are contraindicated in patients with an eGFR below 30 mL/min/1.73 m 2 and end-stage renal disease due to the metformin HCl component [see Contraindications (4) , Warnings and Precautions (5.1 , 5.2) , and Use in Specific Populations (8.6) ].

2.5 Discontinuation for Iodinated Contrast Imaging Procedures Discontinue Dapagliflozin and Metformin HCl extended-release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR less than 60 mL/min/1.73 m 2 , in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart Dapagliflozin and Metformin HCl extended-release tablets if renal function is stable <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> .

2.6 Temporary Interruption for Surgery Withhold Dapagliflozin and Metformin HCl extended-release tablets for at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting.

Resume

Dapagliflozin and Metformin HCl extended-release tablets when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2) ] .

Dapagliflozin and Metformin HCl extended-release tablets are contraindicated in patients with:

• Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) or end-stage renal disease [see Warnings and Precautions (5.1) ] .
• History of a serious hypersensitivity reaction to dapagliflozin, metformin HCl, or any of the excipients in Dapagliflozin and Metformin HCl extended-release tablets. Serious hypersensitivity reactions, including anaphylaxis and angioedema have been reported with dapagliflozin [see Adverse Reactions (6.1) ] .
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin [see Warnings and Precautions (5.1) and Warnings and Precautions (5.2) ] .
• Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) or end-stage renal disease. ( 4 )
• History of serious hypersensitivity to dapagliflozin, metformin HCl, or any of the excipients in Dapagliflozin and Metformin HCl extended-release tablets. ( 4 )
• Metabolic acidosis, including diabetic ketoacidosis. ( 4 )

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

• Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1) ]
• Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis [see Warnings and Precautions (5.2) ]
• Volume Depletion [see Warnings and Precautions (5.3) ]
• Urosepsis and Pyelonephritis [see Warnings and Precautions (5.4) ]
• Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions (5.5) ]
• Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) [see Warnings and Precautions (5.6) ]
• Vitamin B 12 Concentrations [see Warnings and Precautions (5.7) ]
• Genital Mycotic Infections [see Warnings and Precautions (5.8) ]
• Adverse reactions reported in >5% of patients treated with Dapagliflozin and Metformin HCl extended-release tablets were female genital mycotic infection, nasopharyngitis, urinary tract infection, diarrhea, and headache. (6.1)
• Adverse reactions reported in >5% of patients treated with metformin extended-release are: diarrhea and nausea/vomiting. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Prasco Laboratories at 1-866-525-0688 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Clinical

Trials with Metformin HCl Extended-Release in Adults with Type 2 Diabetes Mellitus In placebo-controlled monotherapy trials of metformin HCl extended-release, diarrhea and nausea/vomiting were reported in >5% of metformin-treated patients and more commonly than in placebo-treated patients (9.6% versus 2.6% for diarrhea and 6.5% versus 1.5% for nausea/vomiting). Diarrhea led to discontinuation of study medication in 0.6% of the patients treated with metformin HCl extended-release.

Clinical

Trials with Dapagliflozin in Adults Dapagliflozin Dapagliflozin has been evaluated in clinical trials in adult and pediatric patients 10 years of age and older with type 2 diabetes mellitus, in adult patients with heart failure, and in adult patients with chronic kidney disease. The overall safety profile of dapagliflozin was consistent across the studied indications. No new adverse reactions were identified in the DAPA-HF, DELIVER and DAPA-CKD trials. Pools of Placebo-Controlled Clinical Trials for Glycemic Control in Adults Pool of 8 Placebo-Controlled Adult Trials for Dapagliflozin and Metformin HCl for Glycemic Control Data from a prespecified pool of adult patients from 8 short-term, placebo-controlled trials of dapagliflozin coadministered with metformin HCl immediate- or extended-release was used to evaluate safety. This pool included several add-on trials (metformin HCl alone and in combination with a dipeptidyl peptidase-4 [DPP4] inhibitor and metformin HCl, or insulin and metformin HCl, 2 initial combination with metformin HCl trials, and 2 trials of patients with CVD and type 2 diabetes mellitus who received their usual treatment [with metformin HCl as background therapy]). For trials that included background therapy with and without metformin HCl, only patients who received metformin HCl were included in the 8-trial placebo-controlled pool. Across these 8 trials, 983 patients were treated once daily with dapagliflozin 10 mg and metformin HCl, and 1185 were treated with placebo and metformin HCl.

These

8 trials provide a mean duration of exposure of 23 weeks. The mean age of the population was 57 years and 2% were older than 75 years. Fifty-four percent (54%) of the population was male; 88% White, 6% Asian, and 3% Black or African American. At baseline, the population had diabetes for an average of 8 years, mean hemoglobin A1c (HbA1c) was 8.4%, and renal function was normal or mildly impaired in 90% of patients and moderately impaired in 10% of patients. The overall incidence of adverse events for the 8-trial, short-term, placebo-controlled pool in adult patients treated with dapagliflozin 10 mg and metformin HCl was 60.3% compared to 58.2% for the placebo and metformin HCl group. Discontinuation of therapy due to adverse events in patients who received dapagliflozin 10 mg and metformin HCl was 4% compared to 3.3% for the placebo and metformin HCl group. The most commonly reported events leading to discontinuation and reported in at least 3 patients treated with dapagliflozin 10 mg and metformin HCl were renal impairment (0.7%), increased blood creatinine (0.2%), decreased renal creatinine clearance (0.2%), and urinary tract infection (0.2%).

Table

2 shows common adverse reactions in adults associated with the use of dapagliflozin and metformin HCl. These adverse reactions were not present at baseline, occurred more commonly on dapagliflozin and metformin HCl than on placebo, and occurred in at least 2% of patients treated with either dapagliflozin 5 mg or dapagliflozin 10 mg.

Table

2: Adverse Reactions in Placebo-Controlled Trials Reported in ≥2% of Adult Patients Treated with Dapagliflozin and Metformin HCl Adverse Reaction % of Patients Pool of 8 Placebo-Controlled Trials Placebo and Metformin HCl N=1185 Dapagliflozin 5 mg and Metformin HCl N=410 Dapagliflozin 10 mg and Metformin HCl N=983 Female genital mycotic infections Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for females: vulvovaginal mycotic infection, vaginal infection, genital infection, vulvovaginitis, fungal genital infection, vulvovaginal candidiasis, vulval abscess, genital candidiasis, and vaginitis bacterial. (N for females: Placebo and metformin HCl=534, dapagliflozin 5 mg and metformin HCl=223, dapagliflozin 10 mg and metformin HCl=430). 1.5 9.4

9.3 Nasopharyngitis 5.9 6.3

5.2 Urinary tract infections Urinary tract infections include the following adverse reactions, listed in order of frequency reported: urinary tract infection, cystitis, pyelonephritis, urethritis, and prostatitis. 3.6 6.1

5.5 Diarrhea 5.6 5.9

4.2 Headache 2.8 5.4

3.3 Male genital mycotic infections 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, posthitis, and balanoposthitis. (N for males: Placebo and metformin HCl=651, dapagliflozin 5 mg and metformin HCl=187, dapagliflozin 10 mg and metformin HCl=553). 0 4.3

3.6 Influenza 2.4 4.1

2.6 Nausea 2.0 3.9

2.6 Back pain 3.2 3.4

2.5 Dizziness 2.2 3.2

1.8 Cough 1.9 3.2

1.4 Constipation 1.6 2.9

1.9 Dyslipidemia 1.4 2.7

1.5 Pharyngitis 1.1 2.7

1.5 Increased urination Increased urination includes the following adverse reactions, listed in order of frequency reported: pollakiuria, polyuria, and urine output increased. 1.4 2.4

2.6 Discomfort with urination 1.1 2.2

1.6 Pool of 12 Placebo-Controlled Adult Trials for Dapagliflozin 5 and 10 mg for Glycemic Control The data in Table 3 are derived from 12 glycemic control placebo-controlled trials in adults ranging from 12 to 24 weeks.

In

4 trials dapagliflozin was used as monotherapy, and in 8 trials dapagliflozin was used as add-on to background antidiabetic therapy or as combination therapy with metformin HCl [see Clinical Studies (14.1) ] . These data reflect exposure of 2338 adult patients to dapagliflozin with a mean exposure duration of 21 weeks. Patients received placebo (N=1393), dapagliflozin 5 mg (N=1145), or dapagliflozin 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 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 m 2 ).

Table

3 shows common adverse reactions in adults associated with the use of dapagliflozin. These adverse reactions were not present at baseline, occurred more commonly on dapagliflozin than on placebo, and occurred in at least 2% of patients treated with either dapagliflozin 5 mg or dapagliflozin 10 mg.

Table

3: Adverse Reactions in Placebo-Controlled Trials of Glycemic Control Reported in ≥2% of Adults Treated with Dapagliflozin Adverse Reaction % of Patients Pool of 12 Placebo-Controlled Trials Placebo N=1393 Dapagliflozin 5 mg N=1145 Dapagliflozin 10 mg N=1193 Female genital mycotic infections 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, dapagliflozin 5 mg=581, dapagliflozin 10 mg=598). 1.5 8.4

6.9 Nasopharyngitis 6.2 6.6

6.3 Urinary tract infections 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. 3.7 5.7

4.3 Back pain 3.2 3.1

4.2 Increased urination Increased urination includes the following adverse reactions, listed in order of frequency reported: pollakiuria, polyuria, and urine output increased. 1.7 2.9

3.8 Male genital mycotic infections Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for males: balanitis, fungal genital infection, balanitis candida, genital candidiasis, genital infection male, penile infection, balanoposthitis, balanoposthitis infective, genital infection, and posthitis. (N for males: Placebo=716, dapagliflozin 5 mg=564, dapagliflozin 10 mg=595). 0.3 2.8

2.7 Nausea 2.4 2.8

2.5 Influenza 2.3 2.7

2.3 Dyslipidemia 1.5 2.1

2.5 Constipation 1.5 2.2

1.9 Discomfort with urination 0.7 1.6

2.1 Pain in extremity 1.4 2.0

1.7 Pool of 13 Placebo-Controlled Adult Trials for Dapagliflozin 10 mg for Glycemic Control Dapagliflozin 10 mg was also evaluated in a larger glycemic control placebo-controlled trial pool in adult patients. This pool combined 13 placebo-controlled trials, including 3 monotherapy trials, 9 add-on to background antidiabetic therapy trials, and an initial combination with metformin HCl trial. Across these 13 trials, 2360 patients were treated once daily with dapagliflozin 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 m 2 ).

Other Adverse

Reactions with Dapagliflozin in Adults with Type 2 Diabetes Mellitus Volume Depletion Dapagliflozin causes an osmotic diuresis, which may lead to a reduction in intravascular volume. Adverse reactions related to volume depletion (including reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension) for the 12-trial and 13-trial, short-term, placebo-controlled pools and for the DECLARE trial are shown in Table 4 [see Warnings and Precautions (5.3) ] .

Table

4: Adverse Reactions Related to Volume Depletion Volume depletion includes reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension. in Adult Clinical Trials with Dapagliflozin Pool of 12 Placebo-Controlled Trials Pool of 13 Placebo-Controlled Trials DECLARE Trial Placebo Dapagliflozin 5 mg Dapagliflozin 10 mg Placebo Dapagliflozin 10 mg Placebo Dapagliflozin 10 mg Overall population N (%) N=1393 5 (0.4%) N=1145 7 (0.6%) N=1193 9 (0.8%) N=2295 17 (0.7%) N=2360 27 (1.1%) N=8569 207 (2.4%) N=8574 213 (2.5%)

Patient

Subgroup n (%) Patients on loop diuretics n=55 1 (1.8%) n=40 0 n=31 3 (9.7%) n=267 4 (1.5%) n=236 6 (2.5%) n=934 57 (6.1%) n=866 57 (6.6%) Patients with moderate renal impairment with eGFR ≥30 and <60 mL/min/1.73 m 2 n=107 2 (1.9%) n=107 1 (0.9%) n=89 1 (1.1%) n=268 4 (1.5%) n=265 5 (1.9%) n=658 30 (4.6%) n=604 35 (5.8%) Patients ≥65 years of age n=276 1 (0.4%) n=216 1 (0.5%) n=204 3 (1.5%) n=711 6 (0.8%) n=665 11 (1.7%) n=3950 121 (3.1%) n=3948 117 (3.0%)

Hypoglycemia

The frequency of hypoglycemia in adult patients by trial [see Clinical Studies (14.1) ] is shown in Table 5. Hypoglycemia was more frequent when dapagliflozin was added to sulfonylurea or insulin [see Warnings and Precautions (5.5) ] .

Table

5: Incidence of Severe Hypoglycemia Severe episodes of hypoglycemia were defined as episodes of severe impairment in consciousness or behavior, requiring external (third party) assistance, and with prompt recovery after intervention regardless of glucose level. and Hypoglycemia with Glucose < 54 mg/dL Episodes of hypoglycemia with glucose < 54 mg/dL (3 mmol/L) were defined as reported episodes of hypoglycemia meeting the glucose criteria that did not also qualify as a severe episode. in Controlled Glycemic Control Clinical Trials in Adults Placebo Dapagliflozin 5 mg Dapagliflozin 10 mg Add-on to Metformin HCl (24 weeks) N=137 N=137 N=135 Severe [n (%)] 0 0 0 Glucose < 54 mg/dL [n (%)] 0 0 0 Add-on to DPP4 inhibitor (with or without Metformin HCl) (24 weeks) N=226 – N=225 Severe [n (%)] 0 – 1 (0.4) Glucose < 54 mg/dL [n (%)] 1 (0.4) – 1 (0.4) Add-on to Insulin with or without other OADs OAD = oral antidiabetic therapy. (24 weeks) N=197 N=212 N=196 Severe [n (%)] 1 (0.5) 2 (0.9) 2 (1.0) Glucose < 54 mg/dL [n (%)] 43 (21.8) 55 (25.9) 45 (23.0) In the DECLARE trial [see Clinical Studies (14.3) ] , severe events of hypoglycemia were reported in 58 (0.7%) out of 8574 adult patients treated with dapagliflozin 10 mg and 83 (1.0%) out of 8569 adult patients treated with placebo.

Genital Mycotic

Infections In the glycemic control trials in adults, genital mycotic infections were more frequent with dapagliflozin treatment. Genital mycotic infections were reported in 0.9% of patients on placebo, 5.7% on dapagliflozin 5 mg, and 4.8% on dapagliflozin 10 mg, in the 12-trial placebo-controlled pool. Discontinuation from trial due to genital infection occurred in 0% of placebo-treated patients and 0.2% of patients treated with dapagliflozin 10 mg. Infections were more frequently reported in females than in males (see Table 3). 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 trial than those with no prior history (10.0%, 23.1%, and 25.0% versus 0.8%, 5.9%, and 5.0% on placebo, dapagliflozin 5 mg, and dapagliflozin 10 mg, respectively). In the DECLARE trial [see Clinical Studies (14.3) ] , serious genital mycotic infections were reported in <0.1% of patients treated with dapagliflozin 10 mg and <0.1% of patients treated with placebo. Genital mycotic infections that caused trial drug discontinuation were reported in 0.9% of patients treated with dapagliflozin 10 mg and <0.1% of patients treated with placebo.

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., angioedema, urticaria, hypersensitivity) were reported with dapagliflozin treatment. In glycemic control trials in adults, serious anaphylactic reactions and severe cutaneous adverse reactions and angioedema were reported in 0.2% of comparator-treated patients and 0.3% of dapagliflozin-treated patients. If hypersensitivity reactions occur, discontinue use of dapagliflozin; treat per standard of care and monitor until signs and symptoms resolve. Ketoacidosis In the DECLARE trial [see Clinical Studies (14.3) ], events of diabetic ketoacidosis (DKA) were reported in 27 out of 8574 adult patients in the dapagliflozin-treated group and in 12 out of 8569 adult patients in the placebo group. The events were evenly distributed over the trial period.

Laboratory

Tests in Adults with Type 2 Diabetes Mellitus treated with Dapagliflozin or Metformin HCl Dapagliflozin Increases in Serum Creatinine and Decreases in eGFR Initiation of SGLT2 inhibitors, including dapagliflozin, causes a small increase in serum creatinine and decrease in eGFR. These changes in serum creatinine and eGFR generally occur within two weeks of starting therapy and then stabilize regardless of baseline kidney function. Changes that do not fit this pattern should prompt further evaluation to exclude the possibility of acute kidney injury [see Warnings and Precautions (5.3) ] . In two trials that included adult patients with type 2 diabetes mellitus with moderate renal impairment, the acute effect on eGFR reversed after treatment discontinuation, suggesting acute hemodynamic changes may play a role in the renal function changes observed with dapagliflozin. Increase in Hematocrit In the pool of 13 placebo-controlled trials of glycemic control, increases from baseline in mean hematocrit values were observed in dapagliflozin-treated adult 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 dapagliflozin 10 mg group.

By Week

24, hematocrit values >55% were reported in 0.4% of placebo-treated patients and 1.3% of dapagliflozin 10 mg–treated patients. Increase in Low-Density Lipoprotein Cholesterol In the pool of 13 placebo-controlled trials of glycemic control, changes from baseline in mean lipid values were reported in dapagliflozin-treated adult 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 dapagliflozin 10 mg groups, respectively. In the DECLARE trial [see Clinical Studies (14.3)], mean changes from baseline after 4 years were 0.4 mg/dL versus -4.1 mg/dL for total cholesterol, and -2.5 mg/dL versus -4.4 mg/dL for LDL cholesterol, in dapagliflozin 10 mg treated and the placebo groups, respectively. Decrease in Serum Bicarbonate In a trial of concomitant therapy of dapagliflozin 10 mg with exenatide extended-release (on a background of metformin HCl) in adults, 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 dapagliflozin and exenatide extended-release treatment groups [see Warning and Precautions (5.2) ] . Metformin HCl Vitamin B 12 Concentrations In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients.

Clinical

Trials in Pediatric Patients Aged 10 to 17 Years with Type 2 Diabetes Mellitus Dapagliflozin The dapagliflozin safety profile observed in the 26-week placebo-controlled clinical trial with a 26-week extension in 157 pediatric patients aged 10 years and older with type 2 diabetes mellitus was similar to that observed in adults [see Clinical Studies (14.2) ] . Metformin HCl In clinical trials with metformin HCl immediate-release tablets in pediatric patients with type 2 diabetes mellitus, the profile of adverse reactions was similar to that observed in adults.

6.2 Postmarketing Experience Additional adverse reactions have been identified during post-approval use of Dapagliflozin and Metformin HCl extended-release tablets, dapagliflozin or metformin HCl. 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.

Dapagliflozin

Infections: Necrotizing fasciitis of the perineum (Fournier’s Gangrene), urosepsis and pyelonephritis Metabolism and Nutrition Disorders: Ketoacidosis Renal and Urinary Disorders: Acute kidney injury Skin and Subcutaneous Tissue Disorders: Rash Metformin HCl Hepatobiliary Disorders: Cholestatic, hepatocellular, and mixed hepatocellular liver injury

AND PRECAUTIONS

• Lactic Acidosis : See boxed warning. ( 5.1 )
• Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: Consider ketone monitoring in patients at risk for ketoacidosis, as indicated. Assess for ketoacidosis regardless of presenting blood glucose levels and discontinue Dapagliflozin and Metformin HCl extended-release tablets if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting. (5.2)
• Volume Depletion: Before initiating Dapagliflozin and Metformin HCl extended-release tablets, assess and correct volume status in the elderly, patients with renal impairment or low systolic blood pressure, and in patients on diuretics. Monitor for signs and symptoms during therapy. (5.3 )
• Urosepsis and Pyelonephritis : Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated. (5.4)
• Hypoglycemia : Consider a lower dosage of insulin or an insulin secretagogue to reduce the risk of hypoglycemia when used concomitantly with Dapagliflozin and Metformin HCl extended-release tablets. (5.5)
• Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Serious, life-threatening cases have occurred in both females and males. Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment. (5.6)
• Vitamin B 12 Deficiency : Metformin may lower vitamin B 12 levels. Measure hematological parameters annually. ( 5.7 )
• Genital Mycotic Infections : Monitor and treat if indicated. (5.8)

5.1 Lactic Acidosis There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by non-specific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (&gt;5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels generally &gt;5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of Dapagliflozin and Metformin HCl extended-release tablets.

In

Dapagliflozin and Metformin HCl extended-release tablets-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin HCl is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery. Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur, instruct them to discontinue Dapagliflozin and Metformin HCl extended-release tablets and report these symptoms to their healthcare provider. For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: Renal Impairment : The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include [see Dosage and Administration (2.1 , 2.4 ) and Clinical Pharmacology (12.3) ] :

• Before initiating Dapagliflozin and Metformin HCl extended-release tablets, obtain an estimated glomerular filtration rate (eGFR).
• Dapagliflozin and Metformin HCl extended-release tablets are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2 [see Contraindications (4) ] .
• Obtain an eGFR at least annually in all patients taking Dapagliflozin and Metformin HCl extended-release tablets. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.

Drug

Interactions: The concomitant use of Dapagliflozin and Metformin HCl extended-release tablets with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation (e.g., cationic drugs) [see Drug Interactions (7) ] . Therefore, consider more frequent monitoring of patients.

Age

65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5) ] .

Radiological

Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis.

Stop

Dapagliflozin and Metformin HCl extended-release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart Dapagliflozin and Metformin HCl extended-release tablets if renal function is stable. Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. Dapagliflozin and Metformin HCl extended-release tablets should be temporarily discontinued while patients have restricted food and fluid intake.

Hypoxic

States: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue Dapagliflozin and Metformin HCl extended-release tablets.

Excessive Alcohol

Intake: Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving Dapagliflozin and Metformin HCl extended-release tablets.

Hepatic

Impairment: Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of Dapagliflozin and Metformin HCl extended-release tablets in patients with clinical or laboratory evidence of hepatic disease.

5.2 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis In patients with type 1 diabetes mellitus, dapagliflozin, a component of Dapagliflozin and Metformin HCl extended-release tablets, significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received sodium-glucose cotransporter 2 (SGLT2) inhibitors compared to patients who received placebo. Dapagliflozin and Metformin HCl extended-release tablets are not indicated for glycemic control in patients with type 1 diabetes mellitus.

Type

2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are also risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors, including dapagliflozin. Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse. Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 3 days after discontinuing Dapagliflozin and Metformin HCl extended-release tablets [see Clinical Pharmacology (12.2 )] ; however, there have been postmarketing reports of ketoacidosis and/or glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors. Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue Dapagliflozin and Metformin HCl extended-release tablets, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting Dapagliflozin and Metformin HCl extended-release tablets.

Withhold

Dapagliflozin and Metformin HCl extended-release tablets, if possible, in temporary clinical situations that could predispose patients to ketoacidosis.

Resume

Dapagliflozin and Metformin HCl extended-release tablets when the patient is clinically stable and has resumed oral intake [see Dosage and Administration (2.6) ] . Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue Dapagliflozin and Metformin HCl extended-release tablets and seek medical attention immediately if signs and symptoms occur.

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

5.4 Urosepsis and Pyelonephritis Serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization have been reported in patients receiving SGLT2 inhibitors, including dapagliflozin. 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> .

5.5 Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues Insulin and insulin secretagogues (e.g., sulfonylureas) are known to cause hypoglycemia. Dapagliflozin and Metformin HCl extended-release tablets may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.

5.6 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) Reports of necrotizing fasciitis of the perineum (Fournier’s Gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including dapagliflozin. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death. Patients treated with Dapagliflozin and Metformin HCl extended-release tablets presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement.

Discontinue

Dapagliflozin and Metformin HCl extended-release tablets, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.

5.7 Vitamin B 12 Concentrations In controlled clinical trials of metformin of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B 12 supplementation. Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels. Measure hematologic parameters on an annual basis and vitamin B 12 at 2- to 3-year intervals in patients on Dapagliflozin and Metformin HCl extended-release tablets and manage any abnormalities <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> .

5.8 Genital Mycotic Infections Dapagliflozin increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Monitor and treat appropriately.

INTERACTIONS Table 4: Clinically Relevant Interactions with DAPAGLIFLOZIN TABLETS Insulin or Insulin Secretagogues Clinical Impact The risk of hypoglycemia may be increased when DAPAGLIFLOZIN TABLETS are used concomitantly with insulin or insulin secretagogues (e.g., sulfonylurea) [see Warnings and Precautions (5.4) ] .

Intervention

Concomitant use may require lower doses of insulin or the insulin secretagogue to reduce the risk of hypoglycemia.

Lithium Clinical Impact

Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations.

Intervention

Monitor serum lithium concentration more frequently during DAPAGLIFLOZIN TABLETS initiation and dosage changes.

Positive Urine Glucose Test Clinical

Impact SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests.

Intervention

Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control. Interference with 1,5-anhydroglucitol (1,5-AG)

Assay Clinical Impact

Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors.

Intervention

Monitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor glycemic control.

• See full prescribing information for information on drug interactions and interference of DAPAGLIFLOZIN TABLETS with laboratory tests. (7)

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 5 shows the effect of coadministered drugs on the pharmacokinetics of dapagliflozin in adults. No dose adjustments are recommended for dapagliflozin.

Table

5: Effects of Coadministered Drugs on Dapagliflozin Systemic Exposure Coadministered Drug (Dose Regimen) Single dose unless otherwise noted. Dapagliflozin (Dose Regimen) Effect on Dapagliflozin Exposure [% Change (90% CI)] C max AUC AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses. 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). Effects of Dapagliflozin on Other Drugs Table 6 shows the effect of dapagliflozin on other coadministered drugs in adults. Dapagliflozin did not meaningfully affect the pharmacokinetics of the coadministered drugs.

Table

6: Effects of Dapagliflozin on the Systemic Exposures of Coadministered Drugs Coadministered Drug (Dose Regimen) Single dose unless otherwise noted. Dapagliflozin (Dose Regimen) Effect on Coadministered Drug Exposure [% Change (90% CI)] C max AUC AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses. 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).