Dapagliflozin Propanediol 10 mg Tablet

4 CONTRAINDICATIONS

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History of a serious hypersensitivity reaction to dapagliflozin, such as anaphylactic reactions or angioedema [see Adverse Reactions (6.1)].

6 ADVERSE REACTIONS

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

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Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis [see Warnings and Precautions (5.1)]

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Volume Depletion [see Warnings and Precautions (5.2)]

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Urosepsis and Pyelonephritis [see Warnings and Precautions (5.3)]

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Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.4)]

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Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) [see Warnings and Precautions (5.5)]

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Genital Mycotic Infections [see Warnings and Precautions (5.6)]

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.

Dapagliflozin has been evaluated in clinical trials in patients with type 2 diabetes mellitus, in patients with heart failure, and in patients with chronic kidney disease. The overall safety profile of dapagliflozin was consistent across the studied indications. Severe hypoglycemia and diabetic ketoacidosis (DKA) were observed only in patients with diabetes mellitus.

Clinical Trials in Patients with Type 2 Diabetes Mellitus

Pool of 12 Placebo-Controlled Studies for Dapagliflozin 5 and 10 mg for Glycemic Control

The data in Table 2 is derived from 12 glycemic control placebo-controlled studies in patients with type 2 diabetes mellitus ranging from 12 to 24 weeks. In 4 studies dapagliflozin was used as monotherapy, and in 8 studies dapagliflozin was used as add-on to background antidiabetic therapy or as combination therapy with metformin [see Clinical Studies (14.1)].

These data reflect exposure of 2338 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 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 2 shows common adverse reactions 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.

Pool of 13 Placebo-Controlled Studies for Dapagliflozin 10 mg for Glycemic Control

Dapagliflozin 10 mg was also evaluated in a larger glycemic control placebo- controlled study pool in patients with type 2 diabetes mellitus. 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 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 m2).

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) in patients with type 2 diabetes mellitus for the 12-study and 13-study, short-term, placebo-controlled pools and for the DECLARE study are shown in Table 3 [see Warnings and Precautions (5.2)].

Hypoglycemia

The frequency of hypoglycemia by study in patients with type 2 diabetes mellitus [see Clinical Studies (14.1)] is shown in Table 4. Hypoglycemia was more frequent when dapagliflozin was added to sulfonylurea or insulin [see Warnings and Precautions (5.4)].

In the DECLARE study [see Clinical Studies (14.2)], severe events of hypoglycemia were reported in 58 (0.7%) out of 8574 patients treated with dapagliflozin and 83 (1.0%) out of 8569 patients treated with placebo.

Genital Mycotic Infections

In the glycemic control trials, 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-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 dapagliflozin 10 mg. Infections were more frequently reported in females than in males (see Table 2). 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, dapagliflozin 5 mg, and dapagliflozin 10 mg, respectively). In the DECLARE study [see Clinical Studies (14.2)], serious genital mycotic infections were reported in <0.1% of patients treated with dapagliflozin and <0.1% of patients treated with placebo. Genital mycotic infections that caused study drug discontinuation were reported in 0.9% of patients treated with dapagliflozin 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 studies, 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 TABLETS; treat per standard of care and monitor until signs and symptoms resolve.

Ketoacidosis in Patients with Diabetes Mellitus

In the DECLARE study [see Clinical Studies (14.2)], events of diabetic ketoacidosis (DKA) were reported in 27 out of 8574 patients in the dapagliflozin-treated group and 12 out of 8569 patients in the placebo group. The events were evenly distributed over the study period.

Laboratory Tests

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 (5.2)]. In two studies that included 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 studies of glycemic control, increases from baseline in mean hematocrit values were observed in dapagliflozin-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 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 studies of glycemic control, changes from baseline in mean lipid values were reported in dapagliflozin-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 dapagliflozin 10 mg groups, respectively. In the DECLARE study [see Clinical Studies (14.2)], 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-treated and the placebo groups, respectively.

Decrease in Serum Bicarbonate

In a study of concomitant therapy of dapagliflozin 10 mg with exenatide extended-release (on a background of metformin), four patients (1.7%) on concomitant therapy had a serum bicarbonate value of less than or equal to 13 mEq/L compared to one each (0.4%) in the dapagliflozin and exenatide-extended release treatment groups [see Warnings and Precautions (5.1)].

DAPA-HF and DELIVER Heart Failure Studies

No new adverse reactions were identified in the DAPA-HF and DELIVER heart failure studies.

DAPA-CKD Chronic Kidney Disease Study

No new adverse reactions were identified in the DAPA-CKD study in patients with chronic kidney disease.

6.2 Postmarketing Experience

Additional adverse reactions have been identified during post-approval use of dapagliflozin in patients with diabetes mellitus. 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.

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

7 DRUG INTERACTIONS

10 OVERDOSAGE

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

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

2 DOSAGE AND ADMINISTRATION

2.1 Prior to Initiation of DAPAGLIFLOZIN TABLETS

Assess renal function prior to initiation of DAPAGLIFLOZIN TABLETS therapy and then as clinically indicated [see Warnings and Precautions (5.2)].

Assess volume status. In patients with volume depletion, correct this condition before initiating DAPAGLIFLOZIN TABLETS [see Warnings and Precautions (5.2) and Use in Specific Populations (8.5, 8.6)].

2.2 Recommended Dosage

See Table 1 for dosage recommendations based on estimated glomerular filtration rate (eGFR).

2.3 Temporary Interruption for Surgery

Withhold DAPAGLIFLOZIN TABLETS for at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting. Resume DAPAGLIFLOZIN TABLETS when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2)].

RECENT MAJOR CHANGES

Indications and Usage (1) 09/2023

Dosage and Administration (2.3) 09/2023

Warnings and Precautions (5.1) 09/2023

3 DOSAGE FORMS AND STRENGTHS

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DAPAGLIFLOZIN TABLETS 5 mg are yellow, biconvex, round, film-coated tablets with “5” engraved on one side and “1427” engraved on the other side.

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DAPAGLIFLOZIN TABLETS 10 mg are yellow, biconvex, diamond-shaped, film-coated tablets with “10” engraved on one side and “1428” engraved on the other side.

11 DESCRIPTION

Dapagliflozin, an inhibitor of SGLT2, 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 C21H25ClO6•C3H8O2•H2O and the molecular weight is 502.98. The structural formula is:


DAPAGLIFLOZIN TABLETS are available as film-coated tablets 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.

12 CLINICAL PHARMACOLOGY

12.1 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 thereby promotes urinary glucose excretion.

Dapagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. This may influence several physiological functions including, but not restricted to, lowering both pre- and afterload of the heart and downregulation of sympathetic activity, and decreased intraglomerular pressure which is believed to be mediated by increased tubuloglomerular feedback.

12.2 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 doses of 5 or 10 mg per day in patients with type 2 diabetes mellitus for 12 weeks resulted in excretion of approximately 70 grams of glucose in the urine per day at Week 12. A near maximum glucose excretion was observed at the dapagliflozin daily dose of 20 mg. This urinary glucose excretion with dapagliflozin also results in increases in urinary volume [see Adverse Reactions (6.1)]. After discontinuation of dapagliflozin, on average, the elevation in urinary glucose excretion approaches baseline by about 3 days for the 10 mg dose.

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

Cardiac Electrophysiology

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

12.3 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 [14C]-dapagliflozin dose and is the predominant drug-related component in human plasma.

Elimination

Dapagliflozin and related metabolites are primarily eliminated via the renal pathway. Following a single 50 mg dose of [14C]-dapagliflozin, 75% and 21% total radioactivity is excreted in urine and feces, respectively. In urine, less than 2% of the dose is excreted as parent drug. In feces, approximately 15% of the dose is excreted as parent drug. The mean plasma terminal half-life (t½) for dapagliflozin is approximately 12.9 hours following a single oral dose of dapagliflozin 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%, 100%, and 200% higher, respectively, as compared to patients with type 2 diabetes mellitus with normal renal function. There was no meaningful difference in exposure between patients with chronic kidney disease with and without type 2 diabetes. 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 mellitus and mild, moderate, and severe renal impairment was 42%, 80%, and 90% lower, respectively, than in patients with type 2 diabetes mellitus with normal renal function.

The impact of hemodialysis on dapagliflozin exposure is not known [see Dosage and Administration (2.2), Warnings and Precautions (5.2), Use in Specific Populations (8.6), and Clinical Studies (14)].

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 [see Use in Specific Populations (8.7)].

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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

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

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

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

16 HOW SUPPLIED/STORAGE AND HANDLING

DAPAGLIFLOZIN TABLETS have markings on both sides: yellow, biconvex, diamond- shaped and “10” engraved on one side and “1428” engraved on the other side.

NDC: 63629-3253-1: 30 Tablets in a BOTTLE

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].

Repackaged/Relabeled by:
Bryant Ranch Prepack, Inc.
Burbank, CA 91504

Distributed by:
Prasco Laboratories
Mason, OH 45040 USA

**Diabetic ketoacidosis (increased ketones in your blood or urine) in people with type 1 diabetes and other ketoacidosis**. DAPAGLIFLOZIN TABLETS can cause ketoacidosis that can be life-threatening and may lead to death. Ketoacidosis is a serious condition which needs to be treated in a hospital. People with type 1 diabetes have a high risk of getting ketoacidosis. People with type 2 diabetes or pancreas problems also have an increased risk of getting ketoacidosis. Ketoacidosis can also happen in people who: are sick, cannot eat or drink as usual, skip meals, are on a diet high in fat and low in carbohydrates (ketogenic diet), take less than the usual amount of insulin or miss insulin doses, drink too much alcohol, have a loss of too much fluid from the body (volume depletion), or who have surgery. Ketoacidosis can happen even if your blood sugar is less than 250 mg/dL. Your healthcare provider may ask you to periodically check ketones in your urine or blood.   

nausea

vomiting

stomach area (abdominal) pain

tiredness 

trouble breathing

ketones in your urine or blood

**Dehydration. DAPAGLIFLOZIN TABLETS can cause some people to become dehydrated (the loss of body water and salt). Dehydration may cause you to feel dizzy, faint, lightheaded, or weak, especially when you stand up (orthostatic hypotension). There have been reports of sudden kidney injury in people with Type 2 diabetes who are taking DAPAGLIFLOZIN TABLETS.** You may be at a higher risk of dehydration if you:

take medicines to lower your blood pressure, including water pills (diuretics)

are on a low salt diet

have kidney problems 

are 65 years of age or older
Talk to your healthcare provider about what you can do to prevent dehydration including how much fluid you should drink on a daily basis. Call your healthcare provider right away if you reduce the amount of food or liquid you drink, for example if you cannot eat or you start to lose liquids from your body, for example from vomiting, diarrhea, or being in the sun too long.

**Vaginal yeast infection.** Women who take DAPAGLIFLOZIN TABLETS may get vaginal yeast infections. Symptoms of a vaginal yeast infection include:

vaginal odor

white or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese)

vaginal itching

**Yeast infection of the penis (balanitis).** Swelling of an uncircumcised penis may develop that makes it difficult to pull back the skin around the tip of the penis. Other symptoms of yeast infection of the penis include:

redness, itching, or swelling of the penis

foul smelling discharge from the penis

rash of the penis

pain in the skin around the penis
Talk to your healthcare provider about what to do if you get symptoms of a yeast infection of the vagina or penis. Your healthcare provider may suggest you use an over-the-counter antifungal medicine. Talk to your healthcare provider right away if you use an over-the-counter antifungal medication and your symptoms do not go away.

DAPAGLIFLOZIN TABLETS are a prescription medicine used:

to reduce the risk of further worsening of your kidney disease, end-stage kidney disease (ESKD), death due to cardiovascular disease, and hospitalization for heart failure in adults with chronic kidney disease

to reduce the risk of cardiovascular death, hospitalization for heart failure and urgent heart failure visit in adults with heart failure, when the heart cannot pump enough blood to the rest of your body

to reduce the risk of hospitalization for heart failure in adults with type 2 diabetes who also have known cardiovascular disease or multiple cardiovascular risk factors

along with diet and exercise to improve blood sugar (glucose) control in adults with type 2 diabetes.

DAPAGLIFLOZIN TABLETS are not for use to improve blood sugar (glucose) control in people with type 1 diabetes.

DAPAGLIFLOZIN TABLETS are not for use to improve blood sugar (glucose) control in adults with type 2 diabetes who have moderate to severe kidney problems, because it may not work.

DAPAGLIFLOZIN TABLETS are not for people with certain genetic forms of polycystic kidney disease, or who are taking or have recently received immunosuppressive therapy to treat kidney disease. DAPAGLIFLOZIN TABLETS are not expected to work if you have these conditions.

It is not known if DAPAGLIFLOZIN TABLETS are safe and effective in children younger than 18 years of age.

are allergic to dapagliflozin or any of the ingredients in DAPAGLIFLOZIN TABLETS. See the end of this Medication Guide for a list of ingredients in DAPAGLIFLOZIN TABLETS. Symptoms of a**serious** allergic reaction to DAPAGLIFLOZIN TABLETS may include:

rash

raised red patches on your skin (hives)

swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing.
If you have any of these symptoms, stop taking DAPAGLIFLOZIN TABLETS and contact your healthcare provider or go to the nearest hospital emergency room right away.

have type 1 diabetes or have had diabetic ketoacidosis.

have a decrease in your insulin dose.

have a serious infection.

have a history of infection of the vagina or penis.

have liver problems.

have a history of urinary tract infections or problems with urination.

are on a low sodium (salt) diet. Your healthcare provider may ask you to change your diet.

are going to have surgery. Your healthcare provider may stop your DAPAGLIFLOZIN TABLETS before you have surgery. Talk to your healthcare provider if you are having surgery about when to stop taking DAPAGLIFLOZIN TABLETS and when to start it again. 

are eating less or there is a change in your diet.

are dehydrated.

have or have had problems with your pancreas, including pancreatitis or surgery on your pancreas.

drink alcohol very often or drink a lot of alcohol in the short term (“binge” drinking).

are pregnant or plan to become pregnant. DAPAGLIFLOZIN TABLETS may harm your unborn baby. If you become pregnant while taking DAPAGLIFLOZIN TABLETS, your healthcare provider may switch you to a different medicine to control your blood sugar. Talk to your healthcare provider about the best way to control your blood sugar if you plan to become pregnant or while you are pregnant.

are breastfeeding or plan to breastfeed. It is not known if dapagliflozin passes into your breast milk. You should not breastfeed if you take DAPAGLIFLOZIN TABLETS.

Take DAPAGLIFLOZIN TABLETS exactly as your healthcare provider tells you to take it.

Take DAPAGLIFLOZIN TABLETS by mouth 1 time each day, with or without food.

Your healthcare provider will tell you how much DAPAGLIFLOZIN TABLETS to take and when to take it. Your healthcare provider may change your dose if needed.

If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take 2 doses of DAPAGLIFLOZIN TABLETS at the same time. Talk with your healthcare provider if you have questions about a missed dose.

If you take too much DAPAGLIFLOZIN TABLETS, call your healthcare provider or go to the nearest emergency room right away.

If you have diabetes:

When your body is under some types of stress, such as fever, trauma (such as a car accident), infection, or surgery, the amount of diabetes medicine you need may change. Tell your healthcare provider right away if you have any of these conditions and follow your healthcare provider’s instructions.

Your healthcare provider may tell you to take DAPAGLIFLOZIN TABLETS along with other diabetes medicines. Low blood sugar can happen more often when DAPAGLIFLOZIN TABLETS are taken with certain other diabetes medicines. See**“What are the possible side effects of DAPAGLIFLOZIN TABLETS?”**.

DAPAGLIFLOZIN TABLETS will cause your urine to test positive for glucose.

Your healthcare provider may do certain blood tests before you start DAPAGLIFLOZIN TABLETS and during treatment as needed. Your healthcare provider may change your dose of DAPAGLIFLOZIN TABLETS based on the results of your blood tests.

**Serious urinary tract infections.** Serious urinary tract infections that may lead to hospitalization have happened in people who are taking DAPAGLIFLOZIN TABLETS. Tell your healthcare provider if you have any signs or symptoms of a urinary tract infection such as a burning feeling when passing urine, a need to urinate often, the need to urinate right away, pain in the lower part of your stomach (pelvis), or blood in the urine. Sometimes people also may have a fever, back pain, nausea or vomiting.

**Low blood sugar (hypoglycemia****) in patients with diabetes mellitus.** If you take DAPAGLIFLOZIN TABLETS with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take DAPAGLIFLOZIN TABLETS. Signs and symptoms of low blood sugar may include: 

headache

confusion

hunger

shaking or feeling jittery

drowsiness

dizziness

fast heartbeat

weakness

sweating

irritability

**A rare but serious bacterial infection that causes damage to the tissue under the skin (necrotizing fasciitis) in the area between and around the anus and genitals (perineum).** Necrotizing fasciitis of the perineum has happened in women and men with diabetes mellitus who take DAPAGLIFLOZIN TABLETS. Necrotizing fasciitis of the perineum may lead to hospitalization, may require multiple surgeries, and may lead to death**. Seek medical attention right away if you have fever or you are feeling very weak, tired, or uncomfortable (malaise) and you develop any of the following symptoms in the area between and around the anus and genitals:**

pain or tenderness  

swelling  

redness of skin (erythema)  

**Serious allergic reaction.** If you have any symptoms of a serious allergic reaction, stop taking DAPAGLIFLOZIN TABLETS and call your healthcare provider right away or go to the nearest hospital emergency room. See**“Who should not take DAPAGLIFLOZIN TABLETS?”**. Your healthcare provider may give you a medicine for your allergic reaction and prescribe a different medicine for your diabetes.

vaginal yeast infections and yeast infections of the penis 

stuffy or runny nose and sore throat

changes in urination, including urgent need to urinate more often, in larger amounts, or at night

This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised 09/2023

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

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

Limited data with dapagliflozin in pregnant women are not sufficient to determine drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes and untreated heart failure in pregnancy (see Clinical Considerations).

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

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

Clinical Considerations

Disease-associated maternal and/or embryofetal risk

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

Data

Animal Data

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

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

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

8.2 Lactation

Risk Summary

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

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

Data

Dapagliflozin was present in rat milk at a milk/plasma ratio of 0.49, indicating that dapagliflozin and its metabolites are transferred into milk at a concentration that is approximately 50% of that in maternal plasma. Juvenile rats directly exposed to dapagliflozin showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation.

8.4 Pediatric Use

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

8.5 Geriatric Use

No DAPAGLIFLOZIN TABLETS dosage change is recommended based on age.

A total of 1424 (24%) of the 5936 dapagliflozin-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 studies assessing the efficacy of dapagliflozin in improving glycemic control in type 2 diabetes mellitus. 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 dapagliflozin for glycemic control had adverse reactions of hypotension [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

In the DAPA-CKD, DAPA-HF and DELIVER studies, safety and efficacy were similar for patients age 65 years and younger and those older than 65. In the DAPA-HF study, 2714 (57%) out of 4744 patients with HFrEF were older than 65 years. In the DELIVER study, 4759 (76%) out of 6263 patients with heart failure (LVEF

40%) were older than 65 years. In the DAPA-CKD study, 1818 (42%) out of 4304 patients with CKD were older than 65 years.

8.6 Renal Impairment

Dapagliflozin was evaluated in 4304 patients with chronic kidney disease (eGFR 25 to 75 mL/min/1.73 m2) in the DAPA-CKD study. Dapagliflozin was also evaluated in 1926 patients with an eGFR of 30 to 60 mL/min/1.73 m2 in the DAPA-HF study. The safety profile of dapagliflozin across eGFR subgroups in these studies was consistent with the known safety profile [see Adverse Reactions (6.1) and Clinical Studies (14.3 and 14.4)].

Dapagliflozin was evaluated in two glycemic control studies that included patients with type 2 diabetes mellitus with moderate renal impairment (an eGFR of 45 to less than 60 mL/min/1.73 m2 [see Clinical Studies (14.1)], and an eGFR of 30 to less than 60 mL/min/1.73 m2, respectively). Patients with diabetes and renal impairment using dapagliflozin may be more likely to experience hypotension and may be at higher risk for acute kidney injury secondary to volume depletion. In the study of patients with an eGFR 30 to less than 60 mL/min/1.73 m2, 13 patients receiving dapagliflozin experienced bone fractures compared to none receiving placebo. Use of DAPAGLIFLOZIN TABLETS for glycemic control in patients without established CV disease or CV risk factors is not recommended when eGFR is less than 45 mL/min/1.73 m2 [see Dosage and Administration (2.2)].

Efficacy and safety studies with dapagliflozin did not enroll patients with an eGFR less than 25 mL/min/1.73 m2 or on dialysis.

8.7 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 [see Clinical Pharmacology (12.3)].

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis

In patients with type 1 diabetes mellitus, inform them that using DAPAGLIFLOZIN TABLETS can increase their risk of life-threatening diabetic ketoacidosis. For all other patients, inform them that DAPAGLIFLOZIN TABLETS can cause potentially fatal ketoacidosis and that type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are risk factors.

Educate all patients on precipitating factors (such as insulin dose reduction or missed insulin doses, infection, reduced caloric intake, ketogenic diet, surgery, dehydration, and alcohol abuse) and symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing). Inform patients that blood glucose may be normal even in the presence of ketoacidosis.

Advise patients that they may be asked to monitor ketones. If symptoms of ketoacidosis occur, instruct patients to discontinue DAPAGLIFLOZIN TABLETS and seek medical attention immediately [see Warnings and Precautions (5.1)].

Volume Depletion

Inform patients that symptomatic hypotension may occur with DAPAGLIFLOZIN TABLETS and advise them to contact their healthcare provider if they experience such symptoms [see Warnings and Precautions (5.2)]. Inform patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake.

Serious Urinary Tract Infections

Inform patients of the potential for urinary tract infections, which may be serious. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice promptly if such symptoms occur [see Warnings and Precautions (5.3)].

Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

Inform patients that the incidence of hypoglycemia may increase when DAPAGLIFLOZIN TABLETS are added to an insulin secretagogue (e.g., sulfonylurea) and/or insulin. Educate patients on the signs and symptoms of hypoglycemia [see Warnings and Precautions (5.4)].

Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)

Inform patients that necrotizing infections of the perineum (Fournier’s Gangrene) have occurred with dapagliflozin in patients with diabetes mellitus. Counsel patients to promptly seek medical attention if they develop pain or tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, along with a fever above 100.4°F or malaise [see Warnings and Precautions (5.5)].

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

Inform female patients that vaginal yeast infections may occur and provide them with information on the signs and symptoms of vaginal yeast infections. Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.6)].

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

Inform male patients that yeast infections of the penis (e.g., balanitis or balanoposthitis) may occur, especially in patients with prior history. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.6)].

Hypersensitivity Reactions

Inform patients that serious hypersensitivity reactions (e.g., urticaria, anaphylactic reactions, and angioedema) have been reported with dapagliflozin. 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.

Pregnancy

Advise pregnant patients of the potential risk to a fetus with treatment with DAPAGLIFLOZIN TABLETS. Instruct patients to immediately inform their healthcare provider if pregnant or planning to become pregnant [see Use in Specific Populations (8.1)].

Lactation

Advise patients that use of DAPAGLIFLOZIN TABLETS is not recommended while breastfeeding [see Use in Specific Populations (8.2)].

Laboratory Tests

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

Missed Dose

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 DAPAGLIFLOZIN TABLETS at the same time.