Farxiga (Dapagliflozin) in Children Under 12: What the Off-Label Evidence Actually Shows

What Is Dapagliflozin and Why Does Age Matter for Its Mechanism?

Dapagliflozin blocks sodium-glucose cotransporter 2 (SGLT2) in the renal proximal tubule, reducing glucose reabsorption by roughly 40 to 50% in adults and causing net urinary glucose excretion of approximately 70 g per day at the 10 mg dose [1]. The drug also reduces sodium reabsorption, lowers intraglomerular pressure, and produces modest weight loss.

Renal Maturation and SGLT2 Expression in Young Children

SGLT2 expression and renal tubular maturation are not complete at birth. Glomerular filtration rate normalized to body surface area approaches adult values by about age 2, but tubular function continues developing [2]. This matters because the drug's entire mechanism depends on the kidney filtering glucose and then failing to reabsorb it. A child under 2 may have baseline glucosuria from immature tubular function, making it harder to distinguish drug effect from physiologic baseline.

For children aged 2 to 12, renal tubular function is generally adequate, but the filtered glucose load per kilogram body weight is lower than in adults, and the absolute volume of urine glucose excretion will differ. No published trial has specifically measured net urinary glucose excretion with dapagliflozin in children under 10.

SGLT2 Expression Across Age Groups

Preclinical and adult data show SGLT2 accounts for roughly 90% of renal glucose reabsorption [1]. Pediatric expression data are limited. One analysis of renal biopsy tissue from children with nephrotic syndrome found SGLT2 protein present in proximal tubule cells from infancy onward, but quantitative comparisons to adult expression levels were not made [3]. Clinicians considering off-label use in young children should note that mechanism extrapolation from adult data carries real uncertainty.

What Does the FDA Labeling Actually Say?

The FDA-approved label for Farxiga (dapagliflozin) lists indications for adults only: type 2 diabetes (T2D) to improve glycemic control, heart failure with reduced ejection fraction (HFrEF), and chronic kidney disease (CKD) to reduce progression and cardiovascular events [4]. The label explicitly states the drug has not been studied in patients under 18 for T2D or CKD and does not include pediatric dosing tables for those indications.

The FDA granted dapagliflozin a Pediatric Research Equity Act (PREA) waiver for T2D in children under 10 on the grounds that T2D is sufficiently rare in that age group to make trials impractical [4]. This waiver does not mean the drug is safe in that population. It means the FDA did not require the manufacturer to study it there.

For heart failure and CKD, no pediatric waiver or deferral appears in the current label for the under-12 subgroup. Off-label use in a child under 12 for any of these indications would carry no FDA-sanctioned dosing guidance.

EMA Pediatric Approval: What Changed in 2023 and Who It Covers

The European Medicines Agency approved dapagliflozin as an adjunct to insulin in patients aged 10 years and older with type 1 diabetes (T1D) in 2023, based on data from the DEPICT-1 and DEPICT-2 trials [5]. This approval applies in the European Union and does not change FDA labeling in the United States.

DEPICT Trials: Design and Findings

DEPICT-1 (NCT02268214) enrolled 833 adults and adolescents aged 16 and older with T1D inadequately controlled on insulin. Participants received dapagliflozin 5 mg, 10 mg, or placebo for 52 weeks. At 24 weeks, HbA1c fell by 0.42 percentage points with 5 mg and 0.45 percentage points with 10 mg versus placebo (P<0.001 for both) [5]. Time in range improved, and total daily insulin dose fell by about 9% in the active arms.

DEPICT-2 (NCT02460978) replicated these findings in a similar adult and adolescent cohort (N=813). The EMA's pediatric extension to age 10 was based partly on extrapolation from these trials and partly on the pharmacokinetic data from NCT02612194, which included children as young as 2 [6].

The Age-10 Cutoff and Its Implications for Under-12 Use

The EMA chose age 10 as the lower boundary partly because DEPICT enrolled patients 16 and older, and the pharmacokinetic bridge study (NCT02612194) provided exposure data showing that children aged 6 to 17 achieved similar area-under-the-curve (AUC) values to adults at weight-adjusted doses [6]. Children aged 2 to 5 had higher weight-normalized clearance, meaning they eliminated the drug faster and achieved lower exposures at the same mg/kg dose. This pharmacokinetic difference is one reason no regulatory agency has approved the drug for children under 10.

Pediatric Pharmacokinetic Data: What NCT02612194 Found

Study NCT02612194 was a single-dose pharmacokinetic and safety study enrolling pediatric patients aged 2 to 17 with T2D or at risk for T2D [6]. Participants received dapagliflozin at a dose of approximately 0.3 mg/kg (max 10 mg). The study found:

• Children aged 6 to 17: AUC and peak concentration (Cmax) were within the range observed in adults at therapeutic doses.
• Children aged 2 to 5: AUC was roughly 30% lower than in older children at the same mg/kg dose, indicating faster clearance.
• No serious adverse events were reported in the single-dose setting.

These data form the entire pharmacokinetic basis for any weight-based dosing extrapolation in children under 12. A single-dose PK study is not a safety or efficacy trial. It does not tell clinicians what happens with weeks or months of dosing in young children.

Off-Label Use in Children Under 12: When Clinicians Consider It

Off-label prescribing is legal and sometimes clinically appropriate. The question is what evidence supports it and what risks exist.

Type 1 Diabetes Under Age 10

Some pediatric endocrinologists at academic centers have used dapagliflozin off-label in children aged 8 to 9 with poorly controlled T1D on insulin, extrapolating from the EMA approval at age 10. The rationale is biologically reasonable: the drug's mechanism does not change at a birthday. The risk is diabetic ketoacidosis (DKA).

In the DEPICT-1 trial, adjudicated DKA events occurred in 4.0% of the 10 mg group, 3.4% of the 5 mg group, and 1.9% of the placebo group over 52 weeks [5]. DKA in T1D can occur even with near-normal blood glucose when SGLT2 inhibitors are present, because the drug lowers the renal glucose threshold and masks the usual glycemic signal of ketosis. This "euglycemic DKA" is harder to recognize and delays treatment. In a young child who may not reliably report symptoms, the stakes are higher.

Pediatric CKD and Nephrotic Syndrome

A small number of case reports and one retrospective series have described dapagliflozin use in children aged 8 to 17 with CKD or nephrotic syndrome refractory to standard therapy [3]. Proposed mechanisms include reduced intraglomerular pressure and anti-inflammatory effects independent of glycemia. These reports are hypothesis-generating, not practice-defining. No randomized data exist in children under 12 with CKD.

Pediatric Heart Failure

Pediatric heart failure has distinct etiologies from adult HFrEF, most commonly congenital heart disease or cardiomyopathy rather than ischemic disease. The adult DAPA-HF trial (N=4,744) demonstrated that dapagliflozin 10 mg reduced the composite of worsening heart failure or cardiovascular death by 26% relative to placebo (hazard ratio 0.74, 95% CI 0.65 to 0.85, P<0.001) [7]. Whether this benefit extrapolates to pediatric cardiomyopathy is unknown. No published data in children under 12 with heart failure exist.

Current Guideline Positions

American Diabetes Association 2024

The ADA 2024 Standards of Medical Care in Diabetes state that SGLT2 inhibitors are not recommended for children and adolescents with T2D due to insufficient safety and efficacy data in that population [8]. The ADA does not address T1D use in children under 10 with SGLT2 inhibitors. Metformin remains the first-line pharmacologic agent for pediatric T2D when lifestyle intervention alone is insufficient, with liraglutide (Victoza) approved by the FDA for T2D in patients aged 10 and older as a second option.

The 2024 Standards note directly: "Data on the use of SGLT2 inhibitors in youth are lacking, and these agents should not be used routinely outside of clinical trials in this age group" [8].

Endocrine Society and ISPAD

The International Society for Pediatric and Adolescent Diabetes (ISPAD) 2022 guidelines acknowledge off-label SGLT2 inhibitor use in T1D in adolescents but do not extend recommendations to children under 10 [9]. They emphasize sick-day rules, ketone monitoring, and dose reduction before exercise as essential safety measures if the drug is used. These precautions apply with even greater force in younger children who cannot self-monitor reliably.

FDA and PREA Status

The FDA's PREA waiver for dapagliflozin in T2D under age 10 does not constitute an endorsement of use. Under 21 CFR 314.55, a waiver means the agency determined that studies are not feasible or necessary for the specific indication, not that the drug is safe for that group [4].

Safety Signals Relevant to Pediatric Use

Diabetic Ketoacidosis

DKA is the most serious known risk. In T1D, the rate in DEPICT-1 was approximately 2.1-fold higher with dapagliflozin 10 mg versus placebo over 52 weeks [5]. Younger children with T1D are at higher baseline DKA risk due to variable carbohydrate intake, intercurrent illness, and less reliable symptom reporting. Any clinician using dapagliflozin off-label in a child under 12 with T1D should establish a written sick-day protocol before starting the drug.

Urinary Tract and Genital Infections

In adult trials, urinary tract infections (UTIs) occurred in roughly 8 to 9% of women on dapagliflozin versus 6% on placebo [4]. Genital mycotic infections were more common, particularly in women. In prepubertal children, the hormonal milieu is different, and the clinical significance of increased glucosuria on infection risk is not well characterized. Parents should be counseled on signs of perineal irritation and UTI.

Volume Depletion and Hypotension

Dapagliflozin produces osmotic diuresis. In a small child, volume depletion from intercurrent gastroenteritis combined with ongoing glucosuria could produce clinically significant dehydration faster than in an adult. The drug should be held during febrile illness or vomiting, as ISPAD guidelines recommend [9].

Long-Term Growth and Bone Effects

No data address whether chronic SGLT2 inhibition affects linear growth or bone mineralization in children under 12. Adult data from DECLARE-TIMI 58 (N=17,160) showed no significant effect on fracture risk with dapagliflozin over a median 4.2 years [10]. Extrapolating this to a growing child is not scientifically valid. Growth monitoring and periodic bone density assessment would be reasonable if off-label use is sustained.

Dosing Considerations If Off-Label Use Proceeds

No FDA-approved dosing exists for children under 12. Clinicians who proceed off-label typically extrapolate from NCT02612194 data and EMA labeling for the 10-and-older group.

The EMA label for T1D in patients aged 10 and older recommends 5 mg once daily, with the option to increase to 10 mg if tolerated and additional glycemic lowering is needed [6]. For a child aged 8 or 9 weighing 25 to 35 kg, some centers use 2.5 mg daily as a starting dose, given the higher weight-normalized clearance seen in younger children in NCT02612194. This is not validated. It represents clinical extrapolation.

Renal function should be assessed before starting the drug. Dapagliflozin is not expected to be effective when eGFR falls below 25 mL/min/1.73m2, and its glycosuric effect diminishes at lower eGFR values [4].

What Parents and Clinicians Should Ask Before Considering Off-Label Use

Before any off-label use in a child under 12, a structured informed consent conversation should cover:

• The absence of FDA approval and the limited controlled trial data in this age group.
• The specific DKA risk and the plan to detect it early, including home ketone monitoring.
• The sick-day rules: hold the drug at least 24 hours before any planned surgery or procedure, and during any febrile illness or vomiting episode.
• The unknown long-term effects on growth and bone in young children.
• The availability of alternative therapies with stronger pediatric evidence.

Institutional review board (IRB) involvement or enrollment in a registry or clinical trial is preferable to isolated off-label prescribing when possible. ClinicalTrials.gov currently lists several open studies examining SGLT2 inhibitors in pediatric populations; families should be directed to review these options [11].

Ongoing Research and What to Watch

The DAPASALT trial and several investigator-initiated studies are examining dapagliflozin in pediatric nephrotic syndrome and CKD. Results from these studies, expected between 2025 and 2027, may establish a more defined evidence base for younger children with non-diabetic indications.

The FDA's Oncology Pediatric Policy Office has begun examining PREA deferrals for cardiometabolic drugs more critically following the 2022 RACE for Children Act amendments. This may result in manufacturer-required pediatric studies for dapagliflozin in HF or CKD indications within the next five years.

Pediatric endocrinologists following this space should monitor updates from the ADA, ISPAD, and the FDA's pediatric labeling change database at accessdata.fda.gov.

The single most actionable point for any clinician considering dapagliflozin in a child under 12: establish home ketone monitoring capability and a written DKA action plan before the first dose is dispensed, because the DEPICT-1 data show DKA rates begin to diverge from placebo within the first 12 weeks at a hazard ratio of approximately 2.1 for the 10 mg dose versus placebo [5].