Farxiga Max-Dose Use and Beyond: Dapagliflozin Titration Guide

What is the maximum dose of dapagliflozin?

The maximum approved dose is 10 mg once daily [1]. The FDA product listing for Farxiga shows two tablet strengths, 5 mg and 10 mg [2].

The route to 10 mg depends on the indication. For glycemic control in adults and children aged 10 and older with type 2 diabetes, the label starts at 5 mg once daily and says the dose can be increased to 10 mg once daily for additional glycemic control [1]. For heart failure, chronic kidney disease, and the type 2 diabetes indication for reducing heart failure hospitalization risk, the recommended dose is 10 mg once daily [1].

Does dapagliflozin need to be titrated?

For type 2 diabetes, the label gives a 5 mg starting dose and says the dose can be increased to 10 mg for additional glycemic control [1].

For heart failure and chronic kidney disease, the label does not use a 5 mg starting step. The recommended dose is 10 mg once daily [1]. DAPA-HF, DELIVER, and DAPA-CKD all used dapagliflozin 10 mg once daily in their randomized comparisons [4][5][6].

What did the 10 mg trials show?

In DAPA-HF, 4,744 adults with heart failure and an ejection fraction of 40% or less received dapagliflozin 10 mg once daily or placebo [4]. Worsening heart failure or cardiovascular death occurred in 16.3% versus 21.2% over a median of 18.2 months (hazard ratio 0.74; 95% CI 0.65 to 0.85) [4].

In DELIVER, 6,263 adults with heart failure and an ejection fraction above 40% received dapagliflozin 10 mg once daily or placebo [5]. Worsening heart failure or cardiovascular death occurred in 16.4% versus 19.5% over a median of 2.3 years (hazard ratio 0.82; 95% CI 0.73 to 0.92) [5].

In DAPA-CKD, 4,304 adults with chronic kidney disease and an eGFR of 25 to 75 received dapagliflozin 10 mg once daily or placebo [6]. The primary kidney and cardiovascular composite occurred in 9.2% versus 14.5% over a median of 2.4 years (hazard ratio 0.61; 95% CI 0.51 to 0.72) [6].

In DECLARE-TIMI 58, 17,160 adults with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease received dapagliflozin 10 mg once daily or placebo [3]. The trial did not show a lower rate of major adverse cardiovascular events (8.8% versus 9.4%; hazard ratio 0.93; 95% CI 0.84 to 1.03). The composite of cardiovascular death or heart failure hospitalization was lower (4.9% versus 5.8%; hazard ratio 0.83; 95% CI 0.73 to 0.95), driven by heart failure hospitalization (hazard ratio 0.73), while cardiovascular death alone was unchanged (hazard ratio 0.98) [3].

How is the dose adjusted for kidney function?

The label separates glycemic use from heart and kidney use.

For glycemic control, dapagliflozin is not recommended in type 2 diabetes when eGFR is below 45 mL/min/1.73 m2 [1]. The label says it is likely to be ineffective in that setting based on its mechanism [1].

For heart failure and chronic kidney disease, the 10 mg dose can be started at an eGFR of 25 or higher [1]. The label does not recommend starting below eGFR 25 [1]. If eGFR falls below 25 while a patient is already taking dapagliflozin, the label says patients may continue 10 mg once daily to reduce the risk of eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure [1].

DAPA-CKD enrolled adults with eGFR 25 to 75 and used 10 mg once daily throughout; it was stopped early for efficacy [6].

What should be checked when starting or increasing the dose?

The label gives two pre-treatment checks: assess renal function, and assess volume status and correct volume depletion before starting [1]. It also says to monitor for signs and symptoms of hypotension and renal function after starting in patients at higher risk, including those with eGFR below 60, older adults, and patients on loop diuretics [1].

The label's warnings that matter during treatment are ketoacidosis, volume depletion and acute kidney injury, genitourinary infections including Fournier's gangrene, and hypoglycemia when dapagliflozin is used with insulin or an insulin secretagogue [1].

Ketoacidosis can occur with blood glucose below 250 mg/dL [1]. The label says to assess for ketoacidosis regardless of presenting glucose, discontinue Farxiga if ketoacidosis is suspected, and monitor for resolution before restarting [1]. In DECLARE-TIMI 58, diabetic ketoacidosis occurred in 0.3% of the dapagliflozin group versus 0.1% of the placebo group [3].

For hypoglycemia, the label says a lower dose of insulin or the insulin secretagogue may be required when used with dapagliflozin [1].

What side effects were reported at the 10 mg dose?

In a pooled analysis of 12 placebo-controlled trials in adults with type 2 diabetes, female genital mycotic infections occurred in 6.9% with dapagliflozin 10 mg versus 1.5% with placebo, and male genital mycotic infections occurred in 2.7% versus 0.3% [1]. Urinary tract infections occurred in 4.3% versus 3.7%, and increased urination in 3.8% versus 1.7% [1]. The most common adverse reactions at 5% or more were female genital mycotic infections, nasopharyngitis, and urinary tract infections [1].

Volume depletion events in that 12-trial pool were 0.8% with 10 mg versus 0.4% with placebo; in DECLARE-TIMI 58 they were 2.5% versus 2.4% [1].

Can a dose above 10 mg be used?

The label's recommended dosages are 5 mg and 10 mg once daily, and 10 mg is the highest [1]. The outcome trials above also tested 10 mg once daily [3][4][5][6].