Dapagliflozin Tablet, Film Coated
FDA Label NDC 60505-4911

Dapagliflozin tablets are indicated:

• To reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors.
• As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Limitations of Use

• Dapagliflozin tablets are not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus  [see Warnings and Precautions (5.1)].
• Dapagliflozin tablets are not recommended for use to improve glycemic control in patients with type 2 diabetes mellitus with an eGFR less than 45 mL/min/1.73 m ². Dapagliflozin tablets are likely to be ineffective in this setting based upon its mechanism of action.

Pediatric use information is approved for AstraZeneca AB’s Farxiga ^®(dapagliflozin) Tablets. However, due to AstraZeneca AB’s marketing exclusivity rights, this drug product is not labeled with that information.

• Assess renal function prior to initiation of dapagliflozin tablets 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)] .

In adults with type 2 diabetes mellitus, the recommended starting dosage of dapagliflozin tablets is 5 mg orally once daily to improve glycemic control. For additional glycemic control, the dosage can be increased to 10 mg orally once daily.

For Adult Patients with Type 2 Diabetes Mellitus and Renal Impairment:

• The recommended dosage for dapagliflozin tablets in patients with an eGFR greater than or equal to 45 mL/min/1.73 m ²is the same as the recommended dosage in patients with normal renal function.
• Dapagliflozin tablets are not recommended for use to improve glycemic control in patients with type 2 diabetes mellitus with an eGFR less than 45 mL/min/1.73 m ². Dapagliflozin tablets are likely to be ineffective to improve glycemic control in this setting based upon its mechanism of action.

Pediatric use information is approved for AstraZeneca AB’s Farxiga ^®(dapagliflozin) Tablets. However, due to AstraZeneca AB’s marketing exclusivity rights, this drug product is not labeled with that information.

The recommended dosage of dapagliflozin tablets is 10 mg orally once daily in adults for the following indications:

• To reduce the risk of hHF in patients with type 2 diabetes mellitus and either established CV disease or multiple CV risk factors.

For Adults with Renal Impairment Receiving Dapagliflozin Tablets for Indications Other than Glycemic Control:

• The recommended dosage of dapagliflozin tablets in patients with an eGFR greater than or equal to 25 mL/min/1.73 m ²is the same as the recommended dosage in patients with normal renal function.
• Initiation with dapagliflozin tablets is not recommended in patients with an eGFR less than 25 mL/min/1.73 m ².

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)].

Tablets:

• 5 mg, Light yellow to yellow colored round shaped film-coated tablets debossed with “D” on one side and “5” on the other side. Should be free from physical defects.
• 10 mg, Light yellow to yellow colored diamond shaped film-coated tablets debossed with “D” on one side and “10” on the other side. Should be free from physical defects.

Dapagliflozin tablets are contraindicated in patients with a history of a serious hypersensitivity reaction to dapagliflozin or any of the excipients in dapagliflozin tablets. Serious hypersensitivity reactions, including anaphylaxis and angioedema have been reported with dapagliflozin tablets [see Adverse Reactions (6.1)] .

In patients with type 1 diabetes mellitus, dapagliflozin 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 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 tablets.

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 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 with type 1 diabetes mellitus and consider ketone monitoring in others 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 tablets, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting dapagliflozin tablets.

Withhold dapagliflozin tablets, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume dapagliflozin tablets when the patient is clinically stable and has resumed oral intake [see Dosage and Administration (2.4)] .

Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue dapagliflozin tablets and seek medical attention immediately if signs and symptoms occur.

Dapagliflozin tablets 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 tablets. 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 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.

Serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization have been reported in patients receiving SGLT2 inhibitors, including dapagliflozin tablets. 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 [see Adverse Reactions (6)] .

Insulin and insulin secretagogues (e.g., sulfonylureas) are known to cause hypoglycemia. Dapagliflozin tablets may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse Reactions (6.1)] . Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when these agents are used in combination with dapagliflozin tablets [see Drug Interactions (7)] .

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 tablets. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death.

Patients treated with dapagliflozin 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 tablets, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.

Dapagliflozin tablets increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections [see Adverse Reactions (6.1)] . Monitor and treat appropriately.

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

• Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis [see Warnings and Precautions (5.1)]
• Volume Depletion [see Warnings and Precautions (5.2)]
• Urosepsis and Pyelonephritis [see Warnings and Precautions (5.3)]
• Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.4)]
• Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) [see Warnings and Precautions (5.5)]
• Genital Mycotic Infections [see Warnings and Precautions (5.6)]

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 adult patients with type 2 diabetes mellitus. 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 for Glycemic Control in Adult Patients with Type 2 Diabetes Mellitus

Pool of 12 Placebo-Controlled Adult Trials forDapagliflozin Tablets 5 and 10 mg for Glycemic Control

The data in Table 1 is derived from 12 glycemic control placebo-controlled trials in adult patients with type 2 diabetes mellitus ranging from 12 to 24 weeks. In 4 trials dapagliflozin tablets were used as monotherapy, and in 8 trials dapagliflozin tablets were 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 adult patients to dapagliflozin tablets with a mean exposure duration of 21 weeks. Patients received placebo (N=1393), dapagliflozin tablets 5 mg (N=1145), or dapagliflozin tablets 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 m ²).

Table 1 shows common adverse reactions in adults associated with the use of dapagliflozin tablets. These adverse reactions were not present at baseline, occurred more commonly on dapagliflozin tablets than on placebo, and occurred in at least 2% of patients treated with either dapagliflozin tablets 5 mg or dapagliflozin tablets 10 mg.

Additional adverse reactions have been identified during post-approval use of dapagliflozin tablets 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

Table 4: Clinically Relevant Interactions with Dapagliflozin Tablets

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 tablets 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 uteroand 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).

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 uteroand 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 are 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.

The safety and effectiveness of dapagliflozin tablets for glycemic control in type 2 diabetes mellitus have not been established in pediatric patients less than 10 years of age.
The safety and effectiveness of dapagliflozin tablets have not been established in pediatric patients to reduce the risk of [see Indications and Usage (1)]:

• hospitalization for heart failure in patients with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors.

Pediatric use information is approved for AstraZeneca AB’s Farxiga ^®(dapagliflozin) Tablets. However, due to AstraZeneca AB’s marketing exclusivity rights, this drug product is not labeled with that information.

No dapagliflozin tablets dosage change is recommended based on age.

A total of 1424 (24%) of the 5936 dapagliflozin tablets-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 trials assessing the efficacy of dapagliflozin tablets 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 tablets for glycemic control had adverse reactions of hypotension [see Warnings and Precautions (5.2)and Adverse Reactions (6.1)] .

Dapagliflozin tablets were evaluated in two glycemic control adult trials that included patients with type 2 diabetes mellitus with moderate renal impairment (an eGFR of 45 to less than 60 mL/min/1.73 m ²[see Clinical Studies (14.1)] , and an eGFR of 30 to less than 60 mL/min/1.73 m ², respectively). Patients with diabetes and renal impairment using dapagliflozin tablets may be more likely to experience hypotension and
may be at higher risk for acute kidney injury secondary to volume depletion. In the trial of adult patients with an eGFR 30 to less than 60 mL/min/1.73 m ², 13 patients receiving dapagliflozin tablets 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 m ²[see Dosage and Administration (2.1)].

Efficacy and safety trials with dapagliflozin tablets did not enroll patients with an eGFR less than 25 mL/min/1.73 m ²or on dialysis.

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)].

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

In the event of an overdose, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. 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.

Dapagliflozin is described chemically as (1S)-1,5-Anhydro-1-C-[4-chloro-3-[(4ethoxyphenyl)methyl]phenyl]-D-glucitol(2S,3R,4R,5S,6R)-2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol. The empirical formula is C ₂₁H ₂₅ClO ₆and the molecular weight is 408.88. The structural formula is:

Structural (Structure)

Dapagliflozin tablets are available as film-coated tablets for oral administration containing the equivalent of 5 mg dapagliflozin or the equivalent of 10 mg dapagliflozin, and the following inactive ingredients: crospovidone, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. In addition, the film coating contains the following inactive ingredients: glycerol esters of fatty acids, iron oxide yellow, polyvinyl alcohol, sodium lauryl sulfate, talc, and titanium dioxide.

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.

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 vitroclastogenicity 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 vivostudies 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.

Overview of Clinical Trials of Dapagliflozin Tablets in Adults with Type 2 Diabetes Mellitus

Dapagliflozin tablets has been studied in adult patients as monotherapy, in combination with metformin, pioglitazone, sulfonylurea (glimepiride), sitagliptin (with or without metformin), metformin plus a sulfonylurea, or insulin (with or without other oral antidiabetic therapy), compared to a sulfonylurea (glipizide), and in combination with a GLP-1 receptor agonist (exenatide extended-release) added-on to metformin. Dapagliflozin tablets has also been studied in adult patients with type 2 diabetes mellitus and moderate renal impairment.

Treatment with dapagliflozin tablets as monotherapy and in combination with metformin, glimepiride, pioglitazone, sitagliptin, or insulin produced statistically significant improvements in mean change from baseline at Week 24 in HbA1c compared to control. Reductions in HbA1c were seen across subgroups including gender, age, race, duration of disease, and baseline body mass index (BMI).

Monotherapy

A total of 840 treatment-naive adult patients with inadequately controlled type 2 diabetes mellitus participated in 2 placebo-controlled trials to evaluate the safety and efficacy of monotherapy with dapagliflozin tablets.

In one monotherapy trial, a total of 558 treatment-naive patients with inadequately controlled diabetes participated in a 24-week trial ( NCT00528372). Following a 2-week diet and exercise placebo lead-in period, 485 patients with HbA1c ≥7% and ≤10% were randomized to dapagliflozin tablets 5 mg or dapagliflozin tablets 10 mg once daily in either the morning (QAM, main cohort) or evening (QPM), or placebo.

At Week 24, treatment with dapagliflozin tablets 10 mg QAM provided significant improvements in HbA1c and fasting plasma glucose (FPG) compared with placebo (see Table 7).

Add-On to Metformin

A total of 546 adult patients with type 2 diabetes mellitus with inadequate glycemic control (HbA1c ≥7% and ≤10%) participated in a 24-week, placebo-controlled trial to evaluate dapagliflozin tablets in combination with metformin ( NCT00528879). Patients on metformin at a dose of at least 1,500 mg per day were randomized after completing a 2-week, single-blind, placebo lead-in period. Following the lead-in period, eligible patients were randomized to dapagliflozin tablets 5 mg, dapagliflozin tablets 10 mg, or placebo in addition to their current dose of metformin.

As add-on treatment to metformin, dapagliflozin tablets 10 mg provided statistically significant improvements in HbA1c and FPG, and statistically significant reduction in body weight compared with placebo at Week 24 (see Table 10 and Figure 3). Statistically significant (p <0.05 for both doses) mean changes from baseline in systolic blood pressure relative to placebo plus metformin were −4.5 mmHg and −5.3 mmHg with dapagliflozin tablets 5 mg and 10 mg plus metformin, respectively.

Figure 3: Adjusted Mean Change from Baseline Over Time in HbA1c (%) in a 24-Week Placebo-Controlled Trial of Dapagliflozin Tablets in Combination with Metformin

Figure (Figure3)

Pediatric use information is approved for AstraZeneca AB’s Farxiga ^®(dapagliflozin) Tablets. However, due to AstraZeneca AB’s marketing exclusivity rights, this drug product is not labeled with that information.

Dapagliflozin Effect on Cardiovascular Events (DECLARE, NCT01730534) was an international, multicenter, randomized, double-blind, placebo-controlled, clinical trial conducted to determine the effect of dapagliflozin tablets relative to placebo on cardiovascular (CV) outcomes when added to current background therapy. All patients had type 2 diabetes mellitus and either established CV disease or two or more additional CV risk factors (age ≥55 years in men or ≥60 years in women and one or more of dyslipidemia, hypertension, or current tobacco use). Concomitant antidiabetic and atherosclerotic therapies could be adjusted, at the discretion of investigators, to ensure participants were treated according to the standard care for these diseases.

Of 17160 randomized patients, 6974 (40.6%) had established CV disease and 10186 (59.4%) did not have established CV disease. A total of 8582 patients were randomized to dapagliflozin tablets 10 mg, 8578 to placebo, and patients were followed for a median of 4.2 years.

Approximately 80% of the trial population was White, 4% Black or African American, and 13% Asian. The mean age was 64 years, and approximately 63% were male.

Mean duration of diabetes was 11.9 years and 22.4% of patients had diabetes for less than 5 years. Mean eGFR was 85.2 mL/min/1.73 m ². At baseline, 23.5% of patients had microalbuminuria (UACR ≥30 to ≤300 mg/g) and 6.8% had macroalbuminuria (UACR >300 mg/g). Mean HbA1c was 8.3% and mean BMI was 32.1 kg/m ². At baseline, 10% of patients had a history of heart failure.

Most patients (98.1%) used one or more antihyperglycemic medications at baseline. 82.0% of the patients were being treated with metformin, 40.9% with insulin, 42.7% with a sulfonylurea, 16.8% with a DPP4 inhibitor, and 4.4% with a GLP-1 receptor agonist.

Approximately 81.3% of patients were treated with angiotensin converting enzyme inhibitors or angiotensin receptor blockers, 75.0% with statins, 61.1% with antiplatelet therapy, 55.5% with acetylsalicylic acid, 52.6% with beta-blockers, 34.9% with calcium channel blockers, 22.0% with thiazide diuretics, and 10.5% with loop diuretics.

A Cox proportional hazards model was used to test for non-inferiority against the pre-specified risk margin of 1.3 for the hazard ratio (HR) of the composite of CV death, myocardial infarction (MI), or ischemic stroke (MACE) and if non-inferiority was demonstrated, to test for superiority on the two primary endpoints: 1) the composite of hospitalization for heart failure or CV death, and 2) MACE.

The incidence rate of MACE was similar in both treatment arms: 2.30 MACE events per 100 patient-years on dapagliflozin vs 2.46 MACE events per 100 patient-years on placebo. The estimated hazard ratio of MACE associated with dapagliflozin relative to placebo was 0.93 with a 95% CI of (0.84, 1.03). The upper bound of this confidence interval, 1.03, excluded the pre-specified non-inferiority margin of 1.3.

Dapagliflozin tablets were superior to placebo in reducing the incidence of the primary composite endpoint of hospitalization for heart failure or CV death [HR 0.83 (95% CI 0.73, 0.95)].

The treatment effect was due to a significant reduction in the risk of hospitalization for heart failure in subjects randomized to dapagliflozin tablets [HR 0.73 (95% CI 0.61, 0.88)], with no change in the risk of CV death (Table 15 and Figures 4 and 5).

Figure 4: Time to First Occurrence of Hospitalization for Heart Failure or CV Death in the DECLARE Trial

Figure (Figure4)

Figure 5: Time to First Occurrence of Hospitalization for Heart Failure in the DECLARE Trial

Figure (Figure5)

How Supplied

Dapagliflozin tablets have markings on both sides and are available in the strengths and packages listed in Table 18.

Storage and Handling

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

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 tablets 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 tablets. 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 are 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.

Manufactured by :

Aizant Drug Research Solutions Pvt Ltd

Hyderabad, Telangana 500100, India.

Manufactured for:

Apotex Corp.

Weston, Florida 33326 USA.

This Medication Guide has been approved by the U.S. Food and Drug Administration.                                           Revised 03/2026

NDC 60505-4911-3

Dapagliflozin Tablets

5 mg

Dispense the Medication Guide provided separately to each patient

Rx only

30 Tablets

Apotex Corp.

Label (Image01)

NDC 60505-4912-3

Dapagliflozin Tablets

10 mg

Dispense the Medication Guide provided separately to each patient

Rx only

30 Tablets

Apotex Corp.

Image Description (Image02)