DAPAGLIFLOZIN

(N for females: Placebo=677, dapagliflozin 5 mg=581, dapagliflozin 10 mg=598). † 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.

‡ Increased urination includes the following adverse reactions, listed in order of frequency reported: pollakiuria, polyuria, and urine output increased. § 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). 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 with type 2 diabetes mellitus.

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 trial. Across these 13 trials, 2,360 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. 2%, and 30% had established microvascular disease.

73 m 2 ). Other Adverse Reactions in Adult Patients with Type 2 Diabetes Mellitus Volume Depletion Dapagliflozin causes an osmotic diuresis, which may lead to a reduction in intravascular volume. 2 )] . 0%) * Volume depletion includes reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension.

1 )] is shown in Table 3. 4 ) ] . 0) * 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.

† 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. ‡ OAD = oral antidiabetic therapy. 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. 8% on dapagliflozin 10 mg, in the 12-trial placebo-controlled pool. 2% of patients treated with dapagliflozin 10 mg.

Infections were more frequently reported in females than in males (see Table 1). The most frequently reported genital mycotic infections were vulvovaginal mycotic infections in females and balanitis in males. 0% on placebo, dapagliflozin 5 mg, and dapagliflozin 10 mg, respectively).

1% of patients treated with placebo. 1% of patients treated with placebo. , angioedema, urticaria, hypersensitivity) were reported with dapagliflozin treatment. 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.

3)] , events of diabetic ketoacidosis (DKA) were reported in 27 out of 8574 adult patients in the dapagliflozin-treated group and 12 out of 8569 adult patients in the placebo group. The events were evenly distributed over the trial period.

Laboratory Tests in Adult Patients with Type 2 Diabetes Mellitus 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. 2)] . 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.

30% in the dapagliflozin 10 mg group. 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.

9% for LDL cholesterol in the placebo and dapagliflozin 10 mg groups, respectively. 4 mg/dL for LDL cholesterol, in dapagliflozin-treated and the placebo groups, respectively. 1)] . 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. 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

Dapagliflozin is not indicated for glycemic control in patients with type 1 diabetes mellitus. , 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. , less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected.

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, promptly evaluate, and treat ketoacidosis, if confirmed.

Monitor patients for resolution of ketoacidosis before restarting dapagliflozin. Withhold dapagliflozin, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. 4 )] . Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue dapagliflozin and seek medical attention immediately if signs and symptoms occur.

2 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.

73 m 2 ), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating dapagliflozin 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. 3 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 [see Adverse Reactions ( 6 )] . , sulfonylureas) are known to cause hypoglycemia.

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 [see Drug Interactions ( 7 )] . 5 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 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, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.

6 Genital Mycotic Infections Dapagliflozin increases the risk of genital mycotic infections. 1 )] . Monitor and treat appropriately.