dapagliflozin (Rx)

>10%

1-10%

Female genital mycotic infections (6.9-8.4%)

Urinary tract infection (4.3-5.7%)

Increased urination (2.9-3.8%)

Male genital mycotic infections (2.7-2.8%)

Dyslipidemia (2.1-2.5%)

Constipation (1.9-2.2%)

Discomfort with urination (2.6-2.1%)

Extremity pain (1.7-2%)

<1%

Hypersensitivity (0.3%)

Postmarketing Reports

Rash

Contraindications

Documented hypersensitivity

Severe renal impairment (eGFR <30 mL/min/1.73 m²), end-stage renal disease, or patients on dialysis

Cautions

Hypotension may occur as a result of intravascular volume contraction, particularly in patients with impaired renal function

Before initiating therapy, assess volume status and correct hypovolemia in the elderly, in patients with renal impairment or low systolic blood pressure, and in patients on diuretics; monitor for signs and symptoms during therapy

Consider temporarily discontinuing in settings of reduced oral intake or fluid losses; if acute kidney injury occurs, discontinue and promptly treat; monitor renal function during therapy

Causes intravascular volume contraction and symptomatic hypotension and/or acute kidney injury can occur, particularly if eGFR <60 mL/min/1.73 m²; before initiating therapy, consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure, and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs); consider temporarily discontinuing therapy in any setting of reduced oral intake (such as acute illness or fasting) or fluid losses (gastrointestinal illness or excessive heat exposure); monitor patients for signs and symptoms of acute kidney injury; if acute kidney injury occurs, discontinue therapy promptly and institute treatment;

Not recommended in patients with an eGFR persistently between 30 and less than 60 mL/min/1.73 m² contraindicated if eGFR <30 mL/min/1.73 m²

Monitor renal function prior to initiating therapy and monitored periodically thereafter

Hypoglycemia risk increased with insulin and insulin secretagogues, adjust dose

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

Increases risk of urinary tract infections (UTIs), including life-threatening urosepsis and pyelonephritis that started as UTIs; evaluate for signs and symptoms of urinary tract infections and treat promptly, if indicated

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 100.4 F 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

Ketoacidosis associated with SGLT2 inhibitors reported; monitor for signs of ketoacidosis, even if blood glucose levels are <250 mg/dL, and advise patients to seek immediate medical attention for symptoms (eg, difficulty breathing, nausea, vomiting, abdominal pain, confusion, unusual fatigue or sleepiness); consider risk factors for ketoacidosis prior to initiating therapy; patients may require temporary discontinuation of therapy in clinical situation that may predispose to ketoacidosis

Dose-related increases in LDL-C reported

Across 22 clinical studies, newly diagnosed cases of bladder cancer were reported in 10/6045 patients (0.17%) treated with dapagliflozin and 1/3512 patient (0.03%) treated with placebo/comparator; bladder cancer risk factors and hematuria (a potential indicator of preexisting tumors) were balanced between treatment arms at baseline and there were too few cases to determine whether the emergence of these events is related to dapagliflozin

Therapy should not be administered to patients with active bladder cancer and should be administered with caution in patients with a prior history of bladder cancer

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

GLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests; 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

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

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