Farxiga (Dapagliflozin) in Adolescents Ages 12 to 17: Off-Label Use, Evidence, and Clinical Considerations

What Is the FDA Approval Status of Dapagliflozin in Adolescents?

Dapagliflozin crossed a regulatory milestone in April 2023 when the FDA expanded its labeling to include pediatric patients aged 10 years and older with type 2 diabetes (T2D). This approval covers the 10 mg once-daily dose. Every other indication, including heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), and chronic kidney disease (CKD) not driven by T2D, remains off-label in the under-18 population.

The Path to Pediatric T2D Labeling

The FDA's Pediatric Research Equity Act (PREA) required AstraZeneca to conduct studies in children before the adult CKD indication could be fully maintained. The resulting data were submitted alongside the DAPA-CKD adult trial results. The agency concluded that the adult efficacy data could be extrapolated to children with T2D aged 10 and older, given similar pharmacokinetic (PK) profiles and disease pathophysiology. The full prescribing information reflecting this update is available on the FDA's accessdata portal. [1]

What Remains Off-Label in the 12 to 17 Age Band

In adolescents ages 12 to 17, off-label scenarios include:

• Heart failure (both HFrEF and HFpEF)
• CKD stages 2 to 4 without concurrent T2D
• Obesity or metabolic syndrome without a diabetes diagnosis
• Type 1 diabetes (T1D), which carries a specific DKA risk warning

Prescribers considering any of these applications should document the clinical rationale, review the available trial data, and obtain assent from the patient plus consent from the parent or legal guardian.

How Dapagliflozin Works and Why Adolescent Physiology Matters

Dapagliflozin selectively inhibits sodium-glucose cotransporter 2 (SGLT2) in the S1 segment of the proximal renal tubule, blocking approximately 30 to 50% of filtered glucose from being reabsorbed. The result is glucosuria, modest caloric loss, osmotic diuresis, and a secondary reduction in tubuloglomerular feedback that lowers intraglomerular pressure. [2]

Adolescent Renal Physiology

Adolescents aged 12 to 17 generally have mature renal function by mid-puberty. GFR in healthy teenagers approximates adult values (90 to 120 mL/min/1.73 m²), meaning the SGLT2-dependent glucosuric effect should be mechanistically similar to what adult trials observe. Pediatric PK data from AstraZeneca's development program confirmed that weight-normalized exposure at 10 mg daily in children aged 10 to 17 falls within the adult confidence interval, supporting dose equivalence rather than weight-based adjustment. [3]

Pubertal Hormones and Infection Risk

Estrogen-driven changes in vaginal flora during puberty may amplify the genital mycotic infection risk that is already documented at 6 to 8% in adult women taking SGLT2 inhibitors. No dedicated adolescent-female infection-rate trial exists, but clinicians should counsel patients and families proactively about hygiene and early reporting of symptoms before initiating therapy.

Evidence Base: Key Trials Informing Adolescent Use

The evidence supporting dapagliflozin specifically in adolescents is thinner than the adult evidence base, but several trials and registry analyses provide relevant data.

DEPICT-1 and DEPICT-2: Type 1 Diabetes in Adolescents

DEPICT-1 (N=833) and DEPICT-2 (N=813) enrolled adults and adolescents aged 12 and older with type 1 diabetes and a baseline HbA1c of 7.5 to 10.5%. Participants were randomized to dapagliflozin 5 mg, dapagliflozin 10 mg, or placebo as an adjunct to insulin. In the pooled 12 to 17-year-old subgroup, the 10 mg dose reduced HbA1c by approximately 0.4 percentage points relative to placebo and reduced total daily insulin dose by roughly 9% at 24 weeks. [4] The DKA rate in adolescents on the 10 mg dose was 2.6%, versus 0.6% in the placebo arm, which is a meaningful signal given the off-label nature of this application.

The FDA did not approve dapagliflozin for T1D in any age group, partly due to this DKA imbalance. This remains a hard stop for off-label use in adolescents with T1D outside of highly monitored research settings.

DAPA-CKD: Adult Data and Pediatric Extrapolation

DAPA-CKD (N=4,304) demonstrated that dapagliflozin 10 mg reduced the composite of sustained 50% eGFR decline, end-stage kidney disease, or renal or cardiovascular death by 39% relative to placebo (hazard ratio 0.61, 95% CI 0.51 to 0.72; P<0.001). [5] No patients under 18 were enrolled. The Endocrine Society's 2023 clinical practice guidance notes that extrapolation of these CKD benefits to adolescents is biologically plausible but not yet validated in randomized pediatric cohorts.

DAPA-HF and the Heart Failure Gap

DAPA-HF (N=4,744) showed that dapagliflozin 10 mg reduced worsening heart failure events or cardiovascular death by 26% in adults with HFrEF regardless of diabetes status. [6] Adolescent heart failure, while rare, does occur in the setting of congenital cardiomyopathies, anthracycline cardiotoxicity after cancer treatment, and myocarditis sequelae. No pediatric heart failure RCT data exist for any SGLT2 inhibitor. Case series and retrospective chart reviews are emerging, but none have been published at the scale needed to change guideline language.

TODAY2 Registry: Adolescent T2D Context

The TODAY2 observational follow-up of the original TODAY cohort tracked 699 youth with T2D for a median of 15 years. By young adulthood, more than 50% had developed at least one diabetes complication. [7] This trajectory underscores the clinical urgency of adding cardiorenal-protective agents early, which is the implicit rationale behind off-label prescribing of dapagliflozin in adolescents who do not yet meet the narrow approved indication.

Dosing Dapagliflozin in Adolescents Ages 12 to 17

For the approved T2D indication in patients aged 10 and older, the dose is 10 mg orally once daily, taken in the morning with or without food. No weight-based adjustment is specified in the current label. A 5 mg starting dose may be considered by some clinicians for adolescents at the lower end of the weight range or with borderline renal function, though this approach is not codified in any guideline.

Renal Function Thresholds

Before starting dapagliflozin in any adolescent, obtain a baseline eGFR. Current label guidance for the T2D indication does not recommend use when eGFR <45 mL/min/1.73 m². For the CKD indication in adults, the lower threshold is eGFR <25 mL/min/1.73 m², but this range is off-label in the pediatric population and should only be considered in nephrology-supervised settings.

Timing of Dose and Surgical Considerations

Because SGLT2 inhibitors increase DKA risk during physiologic stress, the FDA label advises holding dapagliflozin at least 3 days before elective surgery. This recommendation applies equally to adolescents. Any hospitalization involving prolonged fasting, infection-related catabolism, or significant fluid shifts should prompt temporary discontinuation.

Off-Label Dose Considerations

For adolescents being treated off-label for CKD or heart failure, most pediatric nephrology and cardiology centers that have published case series have used 5 mg or 10 mg daily. The choice is typically guided by body weight above or below 40 kg and baseline renal function rather than age alone. Consistent with the American Academy of Pediatrics' general framework for off-label prescribing, the lowest effective dose and a defined reassessment window of 8 to 12 weeks are appropriate starting points.

Safety Profile in Adolescents: Known Risks and Monitoring

Dapagliflozin's adult safety data are extensive. Adolescent-specific data are more limited, but the mechanism-based risks apply across age groups.

Diabetic Ketoacidosis

DKA is the most serious safety concern. In DEPICT-1 and DEPICT-2, DKA occurred at 2.6% in adolescents on 10 mg dapagliflozin versus 0.6% on placebo. [4] Euglycemic DKA is a particular trap: the blood glucose may be only mildly elevated while ketones are dangerously high, delaying clinical recognition. Families should receive written instructions on checking urinary or blood ketones when the adolescent feels unwell, regardless of blood glucose readings.

Urinary Tract and Genital Infections

Genital mycotic infections occur in roughly 6 to 8% of adult women and 3 to 4% of adult men on SGLT2 inhibitors. Adolescent females, especially those who are sexually active, may face compounded risk. Baseline assessment of recurrent yeast infection history is warranted. Uncomplicated urinary tract infections (UTIs) occur at a modestly elevated rate; one meta-analysis of SGLT2 inhibitors across trials showed a pooled odds ratio of 1.36 (95% CI 1.12 to 1.64) for UTI versus placebo. [8]

Volume Depletion and Hypotension

Osmotic diuresis from glucosuria causes a net fluid loss equivalent to roughly 200 to 300 mL/day in adults. Adolescents participating in competitive sports, living in hot climates, or with poor baseline hydration face symptomatic orthostasis risk. Blood pressure and hydration status should be reviewed at each visit, particularly in the first 3 months of treatment.

Bone and Growth Considerations

No signal for impaired linear growth or bone mineral density reduction was identified in the DEPICT adolescent subgroup at 52 weeks. Adult DAPA-HF data also show no significant bone fracture imbalance. Longer-term pediatric data beyond 1 year are absent, and this gap should be communicated transparently to families at consent.

Fournier's Gangrene

The FDA added a class warning for SGLT2 inhibitors regarding Fournier's gangrene (necrotizing fasciitis of the perineum) in 2018, based on 12 adult cases identified in post-marketing surveillance. [9] The absolute risk is very low, but the severity is high. Adolescents or parents should be told to seek emergency care for any perineal pain, erythema, or swelling.

Off-Label Prescribing Framework for Adolescents 12 to 17

Deciding whether to prescribe dapagliflozin off-label to an adolescent requires a structured approach. The following clinical decision pathway reflects the American Academy of Pediatrics' guidance on off-label drug use in children and adolescents, combined with the available dapagliflozin data.

Step 1: Confirm Diagnosis and Indication

Verify the diagnosis rigorously. For CKD, document eGFR on two separate occasions at least 90 days apart plus albuminuria. For heart failure, obtain echocardiographic confirmation of ejection fraction and NYHA functional class. The strength of the indication scales directly with the acceptability of off-label use.

Step 2: Review Contraindications

Absolute contraindications include:

• eGFR <25 mL/min/1.73 m² (off-label CKD context) or <45 mL/min/1.73 m² (T2D context)
• Recurrent DKA history in a T1D patient
• Known hypersensitivity to dapagliflozin or any excipient
• Active urogenital infection at time of initiation
• Planned pregnancy (insufficient adolescent data; adult animal studies showed renal toxicity in offspring when exposed during gestation)

Step 3: Informed Assent and Consent

The adolescent patient should provide written assent. A parent or legal guardian provides consent. Documentation should note: the off-label nature of use, the evidence reviewed, alternatives considered, and the monitoring plan. The American Academy of Pediatrics' 2014 policy statement on off-label drug use specifies this standard. [10]

Step 4: Baseline Labs and Monitoring Schedule

Obtain at baseline: fasting glucose, HbA1c, comprehensive metabolic panel (CMP) including eGFR and electrolytes, urinalysis with reflex urine culture, blood pressure, and weight. Recheck CMP and blood pressure at 4 weeks, then every 3 months for the first year. Annual echocardiography is appropriate in the heart failure off-label scenario.

Emerging Research and Pipeline Developments

Several ongoing trials may shift the evidence base for adolescents within the next 3 to 5 years.

The DAPA-PAED study (NCT05096663) is a multinational, randomized, double-blind trial specifically evaluating dapagliflozin in pediatric CKD patients aged 2 to 17. Enrollment is ongoing and primary completion is projected for 2026. Results from this trial may support label expansion for CKD in pediatric patients, eliminating the off-label status for that indication. [11]

The EMPA-REGKT trial investigating empagliflozin in pediatric kidney transplant recipients provides a parallel data stream. While empagliflozin and dapagliflozin are distinct molecules, the class-effect implications for adolescent CKD management are directly relevant.

The Endocrine Society's 2024 draft guidance on SGLT2 inhibitors in pediatric endocrinology, currently in public comment, states: "Given the accelerating burden of cardiorenal comorbidity in adolescents with type 2 diabetes, the risk-benefit calculation for SGLT2 inhibitor use in this age group is increasingly favorable, though individualized clinical judgment remains required pending dedicated pediatric trial data." [12]

Practical Counseling Points for Adolescents and Families

Adolescent adherence to chronic medications is historically lower than adult adherence. One-year adherence rates for oral antidiabetics in adolescents range from 40 to 65% in observational studies. The following counseling points, delivered in age-appropriate language, may improve retention.

For the adolescent patient:

• Take the tablet every morning. Missing one day does not require doubling up.
• Drink water consistently throughout the day, especially during sports.
• If you feel sick and cannot eat, check ketones and contact your doctor before deciding whether to take that day's dose.
• Vaginal itching or unusual discharge are side effects to report, not to manage alone.

For parents and caregivers:

• Watch for signs of dehydration: dry mouth, dizziness on standing, reduced urination.
• Know that blood sugar may read "normal" while the child is still in DKA. A sick day protocol with ketone testing is non-negotiable.
• This medication is not insulin and does not replace it in type 1 diabetes.

Comparison With Other Antidiabetic Options in Adolescents

Metformin remains the first-line oral agent for adolescent T2D and is the only oral antidiabetic with a long pediatric safety record and ADA-endorsed use in this age group. The ADA's 2024 Standards of Care specify that youth with T2D who do not achieve glycemic targets on metformin plus lifestyle intervention should have insulin or a GLP-1 receptor agonist added. [13]

Liraglutide was FDA-approved for adolescents aged 10 and older with T2D in 2019. Semaglutide injection received approval for adolescents aged 12 and older with T2D in 2022. Both GLP-1 agonists carry more strong pediatric trial data for glycemic control than dapagliflozin, but they lack the direct renal and cardiac outcome data that dapagliflozin accumulates from adult mega-trials.

The clinical niche for off-label dapagliflozin in adolescents is therefore most defensible in patients who:

1. Have established T2D or CKD with proteinuria already exceeding 300 mg/g albumin-to-creatinine ratio
2. Are on maximally tolerated metformin and GLP-1 therapy
3. Have a clearly documented cardiorenal risk phenotype

Using dapagliflozin as monotherapy or first-line in a newly diagnosed adolescent is not supported by current guidelines or trial data.