Dosing and uses of Farxiga (dapagliflozin)
Adult dosage forms and strengths
tablet
- 5mg
- 10mg
Diabetes Mellitus Type 2
Selective sodium-glucose transporter-2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control with type 2 diabetes mellitus
Initial: 5 mg PO qDay; take in am with or without food
May increase to 10 mg qDay in patients tolerating 5 mg/day who have an eGFR ≥60 mL/min/1.73 m² and require additional glycemic controL
Dosage modifications
Renal impairment
- eGFR ≥60 mL/min/1.73 m²: No dosage adjustment required
- eGFR <60 mL/min/1.73 m²: Do not initiate
- Not recommended with eGFR that declines persistently between 30 to <60 mL/min/1.73 m²
- eGFR <30 mL/min/1.73 m²: Contraindicated
Hepatic impairment
- Mild or moderate: No dosage adjustment required
- Severe: Not studied
Dosing Considerations
Indicated as monotherapy, as initial therapy with metformin, or as an add-on to other oral glucose-lowering agents, including metformin, pioglitazone, glimepiride, sitagliptin, and insulin
Not recommended for treating type 1 diabetes mellitus or diabetic ketoacidosis
Correct volume depletion prior to initiating
Assess renal function before initiating
Pediatric dosage forms and strengths
Safety and efficacy not established
Farxiga (dapagliflozin) adverse (side) effects
>10%
Renal impairment
- Overall (1.8-6.7%; placebo 1.7-4.2%)
- Age ≥65 yr (3.1-14%; placebo 2.1-7.9%)
- eGFR 30-60 mL/min (8-28.3%; placebo 6.5-16.1%)
- Age ≥65 yr and eGFR 30-60 mL/min (7-35.1%; placebo 4.9-19.1%)
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%)
Volume depletion
- Overall (0.6-1.1%; placebo 0.4-0.7%)
- 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%; placebo 1.5-1.9%)
- Age ≥65 yr (0.5-1.7%; placebo 0.4-0.8%)
<1%
Hypersensitivity (0.3%)
Warnings
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
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 and lactation
Pregnancy category: C
Based on results of reproductive and developmental toxicity studies in animals, dapagliflozin may affect renal development and maturation
Lactation: Unknown whether distributed in human breast milk; breast feeding women should discontinue dapagliflozin or nursing taking into account the importance of the drug to the mother
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.
Pharmacology of Farxiga (dapagliflozin)
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
