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

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

Drug increases serum creatinine and decreases eGFR; elderly patients and patients with impaired renal function may be more susceptible to these changes; renal function should be evaluated prior to initiation of therapy and monitored periodically thereafter

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 for signs and symptoms of acute kidney injury; if acute kidney injury occurs, discontinue therapy promptly and institute treatment;

Bone fractures reported in patients with eGFR 30 to less than 60 mL/min/1.73 m2, for treatment durations up to 104 weeks

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

Fatal cases of ketoacidosis reported in patients taking dapagliflozin; monitor for symptoms (eg, difficulty breathing, nausea, vomiting, abdominal pain, confusion, unusual fatigue or sleepiness); assess patients who present and 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

Newly diagnosed cases of bladder cancer reported in 0.17% treated with dapagliflozin and 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

Do not administer to patients with active bladder cancer and use caution in patients with a prior history of bladder cancer

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

SGLT2 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

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)