Improving propranolol adherence and tolerability with a generic strawberry flavor in patients with infantile hemangiomas

Introduction

Infantile hemangiomas (IHs) are the most common vascular tumors of infancy, affecting 3–10% of children (1). Treatment is typically reserved for high-risk IHs, including those with life-threatening complications, functional impairment, ulceration, disfigurement, or syndromic associations [PHACE (Posterior fossa malformations, Hemangioma, Arterial anomalies, Cardiac defects, Eye abnormalities), LUMBAR (Lower body hemangioma, Urogenital anomalies, Myelopathy, Bony deformities, Anorectal malformations, Renal anomalies)] (2). Early treatment, ideally by 1 month of age, is recommended to reduce complications and improve outcomes (2).

Treatment options include topical and oral beta-blockers, corticosteroids, laser, surgery, and, in refractory cases, sirolimus or vincristine (3). Hemangeol^® (propranolol hydrochloride oral solution, 4.28 mg/mL; Pierre Fabre Pharmaceuticals, Lavour, France), the only Food and Drug Administration (FDA)-approved therapy, is strawberry-flavored and well tolerated. Hemangeol^® contains propranolol hydrochloride as the active ingredient along with inactive ingredients including artificial strawberry flavor, citric acid, purified water, sodium benzoate, and sucrose. However, Hemangeol^® is not always covered by insurance and may be excluded by commercial plans. Copay assistance is available but limited to a per-bottle basis, leading to out-of-pocket costs as treatment often extends until age 12–18 months (2,4).

Alternatively, generic propranolol can be used and is typically covered by insurance. Generic propranolol formulation includes 20 mg/5 mL (pre-flavored as mint or cherry) and 40 mg/5 mL (unflavored). Tolerability remains a concern as infants prefer sweet tastes (e.g, breastmilk) and may reject sour or bitter tastes (5,6).

At the University of Florida (UF), we see many high-risk IHs. To address cost and tolerability, we flavored generic unflavored 40 mg/5 mL propranolol with strawberry to approximate Hemangeol^® and evaluated caregiver-reported tolerability and adherence compared to the mint/cherry 20 mg/5 mL formulation. To our knowledge, no prior report has evaluated the systematic addition of strawberry flavoring to generic high-concentration propranolol as a practical strategy to address tolerability concerns when Hemangeol^® is financially inaccessible.

Methods

Medical records of infants with IHs treated with oral propranolol between August 2022 and November 2025 at the UF Department of Dermatology were obtained. This study specifically included a subset of 13 patients who were transitioned from the standard 20 mg/5 mL propranolol formulation to a strawberry-flavored 40 mg/5 mL formulation due to tolerability concerns. It does not represent all patients treated with propranolol at our institution during the study period and was not designed to estimate the prevalence of intolerance or compare tolerability across formulations. All patients were initially prescribed propranolol 20 mg/5 mL (pre-flavored as mint or cherry) and transitioned to a strawberry-flavored 40 mg/5 mL formulation prepared by the UF Specialty Pharmacy using FLAVORx, a commercially available standardized medication flavoring platform [generic propranolol oral solution, national drug code (NDC) 00054-3730-63]. Per FLAVORx guidelines, the addition of flavoring does not alter the expiration date, storage requirements, or drug concentration established by the manufacturer, and this approach does not constitute traditional pharmaceutical compounding (7).

We collected data on demographics, hemangioma characteristics (location, size, subtype, ulceration), and treatment details (initial dose, age at initiation and switch, reason for switching, and duration on the strawberry-flavored formulation). Propranolol was initiated at 1 mg/kg/day and increased to the standard maintenance dose of 2 mg/kg/day after one week (2). Starting dose was individualized based on clinical context. Younger or premature infants were started at 0.5 mg/kg/day, while term infants were often initiated directly at 2 mg/kg/day. Escalation to 3 mg/kg/day was used for hemangiomas at higher-risk anatomical sites, including the head and neck, genitalia, and hands (2). Escalation occurred either after an insufficient response at 2 mg/kg/day or was planned based on lesion location.

The primary outcome was tolerability of the 40 mg/5 mL strawberry-flavored formulation, defined as the absence of caregiver-reported medication refusal, regurgitation attributed to palatability (not gastroesophageal reflux), or clinician-documented intolerance necessitating a formulation change. Poor tolerability was defined as the presence of one or more of these documented events prompting clinical action. Secondary outcomes included adherence, treatment duration, dose adjustments, and treatment completion.

Adherence was measured by continued prescription fills and absence of documented treatment interruptions. Treatment duration was calculated from propranolol initiation to documented discontinuation. Treatment completion was defined as discontinuation at or after 12 months of age per clinical judgment. Because data were extracted retrospectively without a standardized template, all outcomes reflect clinician- and caregiver-reported documentation rather than objective measurement.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the University of Florida Institutional Review Board (No. IRB00000335) and individual consent for this retrospective analysis was waived.

Results

Thirteen patients with a total of 20 IHs were included in the study (Tables 1,2). Among the 20 IHs, 77% were mixed-type, 15% were superficial, and 10% were deep. Most lesions (52%) involved the head/neck; other sites included the trunk, extremities, and genitals. Only two hemangiomas were ulcerated. All 13 patients began 20 mg/5 mL propranolol (46% at 1 mg/kg/day, 31% at 0.5 mg/kg/day, 23% at 2 mg/kg/day). Mean age at propranolol initiation was 2.5 months (Table 1).

Twelve of 13 patients were switched to the strawberry-flavored 40 mg/5 mL formulation due to regurgitation not attributable to gastrointestinal reflux, confirmed by medical record review and discussion with parents. One patient was switched at the parents’ request to reduce medication volume. Average switching age was 7.1 months. Post-switch doses were 2 mg/kg/day (38.5%) and 3 mg/kg/day (61.5%). Twelve of 13 patients had no further documented tolerability concerns after the switch and completed treatment. Among the 13 patients, the average discontinuation age was 17.8 months, and the mean duration on the strawberry-flavored formulation was 10.7 months (Table 1).

The one patient who did not tolerate the strawberry-flavored formulation presented with an ulcerated mixed-type IH of the right cheek. Propranolol was initiated at 0.5 mg/kg/day and uptitrated to 3 mg/kg/day by 5 months of age, coinciding with the transition to the strawberry-flavored formulation given the head and neck location. Despite the flavor change, persistent regurgitation and caregiver-reported refusal continued throughout treatment, and propranolol was discontinued at 16 months in favor of atenolol. No adverse events were documented in the medical records during the follow-up period.

Discussion

Propranolol remains the gold standard for IH treatment, and early initiation is essential, particularly for lesions on the face, airway, or other high-risk sites. Strawberry-flavored generic propranolol (40 mg/5 mL) was associated with caregiver-reported improved tolerability in nearly all patients who transitioned. The most common reason for switching from pre-flavored 20 mg/5 mL generic propranolol to the strawberry-flavored 40 mg/5 mL formulation was regurgitation, which often appeared to compromise adherence. After transitioning, most patients appeared to maintain therapy without interruption, which is critical for achieving optimal outcomes. It is important to note that the observed improvement in tolerability cannot be attributed to strawberry flavor alone. The transition also involved a doubling of drug concentration (from 4 to 8 mg/mL), which reduced the administration volume per dose, a factor that may have independently contributed to better tolerability. The relative contributions of flavor, concentration, and volume reduction cannot be elucidated in this retrospective series and should be addressed in future prospective studies.

Cost and access remain challenges with Hemangeol^®. Although strawberry-flavored and well tolerated, Hemangeol^® costs over $662 per 120 mL bottle (4,8). A copay card reduces this to $55 per bottle but excludes Medicaid, Tricare, or Indian Health Service patients (4,8). In contrast, generic propranolol 40 mg/5 mL costs approximately $18 per 120 mL, and strawberry flavoring was provided at no additional charge at our institution’s specialty pharmacy using FLAVORx, a commercially available platform. While FLAVORx is available beyond our institution, the cost of flavoring services may vary by practice setting, and this cost comparison should be considered illustrative rather than a formal pharmacoeconomic analysis. Nonetheless, the approach suggests a potential cost advantage and warrants formal pharmacoeconomic evaluation. The higher concentration of generic propranolol 40 mg/5 mL (8 mg/mL versus Hemangeol^®’s 4.28 mg/mL) reduces volume required per dose, reducing refills and easing logistical and financial burden for families. Insurance coverage for Hemangeol^® varies by plan type, region, and individual policy; clinicians should verify local formulary coverage and copay assistance program availability.

To our knowledge, this is the first report of adding strawberry flavoring to generic 40 mg/5 mL propranolol as a strategy to address caregiver-reported tolerability concerns in IH treatment. In our retrospective cohort, patients were transitioned from generic 20 mg/5 mL propranolol due to tolerability concerns, so a direct comparison with the innovator product was not available. Future prospective comparative studies should include a Hemangeol^® comparator arm and incorporate systematic tracking of discontinuation reasons, standardized tolerability and efficacy endpoints, and objective adherence measures to rigorously evaluate this approach. Notably, the clinical efficacy of the strawberry-flavored formulation, including hemangioma involution and treatment response, was not formally compared to other propranolol formulations in this series, and future prospective studies should incorporate standardized efficacy endpoints alongside tolerability measures.

While our findings are observational, the study is limited by several important factors: (I) retrospective design and chart-based outcome collection; (II) lack of standardized or validated outcome measures for tolerability and adherence; (III) absence of a comparator group, including Hemangeol^®; (IV) reliance on caregiver-reported rather than objectively measured tolerability; (V) possible confounding by the simultaneous change in drug concentration (from 4 mg/mL to 8 mg/mL) and consequent reduction in administration volume, which cannot be disentangled from the effect of strawberry flavor alone; (VI) limited generalizability due to single-center design; (VII) the absence of formal efficacy assessment (size reduction, color change, involution); and (VIII) non-systematic adverse event surveillance, such that the absence of documented events should not be interpreted as confirmed absence of occurrence. The availability and cost of FLAVORx flavoring services may also vary across practice settings. Future multi-center prospective studies are needed to evaluate long-term outcomes, formal efficacy endpoints, and the cost-saving potential of this approach.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://pm.amegroups.com/article/view/10.21037/pm-26-0049/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://pm.amegroups.com/article/view/10.21037/pm-26-0049/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the University of Florida Institutional Review Board (No. IRB00000335) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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