dapagliflozin (Rx)

>10%

Renal impairment

• Overall (1.8-6.7%)
• Age ≥65 yr (3.1-14%)
• eGFR 30-60 mL/min (8-28.3%)
• Age ≥65 yr and eGFR 30-60 mL/min (7-35.1%)

1-10%

Female genital mycotic infections (6.9-8.4%)

Nasopharyngitis (6.3-6.6%)

Urinary tract infection (4.3-5.7%)

Back pain (3.1-4.2%)

Increased urination (2.9-3.8%)

Male genital mycotic infections (2.7-2.8%)

Nausea (2.5-2.8%)

Influenza (2.3-2.7%)

Dyslipidemia (2.1-2.5%)

Constipation (1.9-2.2%)

Discomfort with urination (2.1-2.6%)

Extremity pain (1.7-2%)

Volume depletion

• Overall (0.6-1.1%)
• Patients on loop diuretics (0-9.7%; 1.8-2.5%)
• Patients with moderate renal impairment, GFR 30-60 mL/min (0.9-1.9%)
• Age ≥65 yr (0.5-1.7%)

<1%

Hypersensitivity (0.3%)

Postmarketing Reports

Rash

Ketoacidosis

Acute kidney injury and renal impairment

Urosepsis and pyelonephritis

Necrotizing fasciitis of the perineum

Hypoglycemia

Contraindications

Serious hypersensitivity to dapagliflozin (eg, anaphylaxis, angioedema)

Patients who are being treated for glycemic control without established CVD or multiple CV risk factors with severe renal impairment (eGFR <30 mL/min/1.73 m²)

Patients on dialysis

Cautions

Genital mycotic infections may occur; patients with history of genital mycotic infections and uncircumcised males are more susceptible

Serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization reported in patients receiving SGLT2 inhibitors

Necrotizing fasciitis of the perineum (Fournier gangrene) reported with SGLT2 inhibitors; signs and symptoms include tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, and have a fever above 100.4ºF or a general feeling of being unwell; if suspected, discontinue SGLT2 inhibitor and start treatment immediately with broad-spectrum antibiotics and surgical debridement if necessary

An increased risk for lower limb amputation (primarily of the toe) has been observed in clinical studies with another SGLT2 inhibitor; before initiating, consider factors that may predispose patient to increased risk of amputations (eg, history of prior amputation, peripheral vascular disease, neuropathy, diabetic foot ulcers)

Dose-related increases in LDL-C reported

No conclusive evidence of macrovascular risk reduction with empagliflozin or any other antidiabetic agent

Intravascular volume contraction

• Symptomatic hypotension may occur after initiating, particularly in patients with renal impairment (eGFR <60 mL/min/1.73 m²), with low systolic blood pressure, taking loop diuretics, or who are elderly
• Renal impairment may occur owing to intravascular volume contraction; before initiating, consider factors that may predispose patients to acute kidney injury, including hypovolemia, chronic renal insufficiency, CHF, and concomitant medications (eg, diuretics, ACE inhibitors, ARBs, NSAIDs); consider temporarily discontinuing dapagliflozin in any setting of reduced oral intake or fluid loss; monitor for signs and symptoms of acute kidney injury, and, if evident, discontinue drug promptly and institute treatment

Ketoacidosis

• Before initiating therapy, consider factors in patient history that may predispose to ketoacidosis, including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse
• Consider temporarily discontinuing dapagliflozin for at least 3 days before undergoing scheduled surgery to avoid euglycemic ketoacidosis
• Consider monitoring for ketoacidosis and temporarily discontinuing therapy in other clinical situations known to predispose to ketoacidosis (eg, prolonged fasting due to acute illness or post-surgery); ensure risk factors for ketoacidosis are resolved prior to restarting therapy
• Restart once the patient’s oral intake is back to baseline and any other risk factors for ketoacidosis (blood acid buildup) are resolved

Drug interactions overview

• Hypoglycemia risk increased with insulin and insulin secretagogues (eg, sulfonylureas); a lower dose of insulin or insulin secretagogue may be required

Laboratory testing

• Urine glucose tests is not recommended in patients taking SGLT2 inhibitors, as SGLT2 inhibitors, increase urinary glucose excretion and lead to positive urine glucose tests; use alternative methods to monitor glycemic control
• 1,5-AG assay is not recommended, as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors; use alternative methods to monitor glycemic control

Pregnancy

Based on animal data showing adverse renal effects drug is not recommended during second and third trimesters of pregnancy

Limited data in pregnant women are not sufficient to determine drug-associated risk for major birth defects or miscarriage; there are risks to mother and fetus associated with poorly controlled diabetes in pregnancy

In animal studies, adverse renal pelvic and tubule dilatations, that were not fully reversible, were observed in rats when administered during a period of renal development corresponding to late second and third trimesters of human pregnancy, at all doses tested

Clinical considerations

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

Lactation

There is no information regarding presence of dapagliflozin in human milk, effects on breastfed infant, or on milk production; drug is present in milk of lactating rats; however, due to species-specific differences in lactation physiology, clinical relevance of these data are not clear

Since human kidney maturation occurs in utero and during first 2 years of life when lactational exposure may occur, there may be risk to developing human kidney; because of potential for serious adverse reactions in breastfed infants, advise women that therapy is not recommended while breastfeeding

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Selective sodium-glucose transporter-2 (SGLT2) inhibitor

SGLT-2, expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen; SGLT2 inhibitors will reduce glucose reabsorption and lower the renal threshold for glucose, thereby increasing urinary glucose excretion

Absorption

Bioavailability: 78%

Peak plasma time: 2 hr (fasting); ~3 hr (with high fat meal)

High fat meal decreases peak plasma concentration by up to 50%

Distribution

Protein bound: 91%

Metabolism

Metabolism primarily mediated by UGT1A9

CYP-mediated metabolism is a minor clearance pathway in humans

Extensively metabolized, primarily to yield dapagliflozin 3-O-glucuronide (inactive metabolite)

Elimination

Half-life: 12.9 hr

Excretion: 75% urine; 21% feces

Oral Administration

Administer in the morning, with or without food

Storage

Store at room temperature at 20-25°C (68-77°F)