Sorilla Prey, Jean-Jacques Voisard, Alain Delarue, Geneviève Lebbe, Alain Taïeb, Christine Leaute-Labreze, Khaled Ezzedine. Safety of Propranolol Therapy for Severe Infantile Hemangioma. JAMA. 2016;315(4):413–415. doi:10.1001/jama.2015.13969
Infantile hemangioma is a vascular tumor characterized by rapid growth during the first weeks of life and spontaneous involution over a few years.1 Severe forms require systemic therapy. Propranolol induces regression, but safety data are lacking in children.2,3
The French Health Products Agency (ANSM) allows compassionate use of promising off-label drugs without available therapeutic alternatives. Children throughout France with proliferative infantile hemangioma requiring systemic therapy for life-threatening (ie, potential airway obstruction) or functional risks (ie, amblyopia) or severe ulceration were referred to specialist centers for compassionate use of pediatric oral propranolol.4 Analyses involved data collected between April 2010 and April 2013 of consecutive children enrolled during this period after ANSM institutional board approval and parents’ verbal consent.
Demographic and clinical data were collected at inclusion. Adverse drug reactions (ADRs) were collected by questioning parents and reviewing the child health record at each monthly visit for up to 2 years. Causality was established by the pharmaceutical company providing propranolol using the standard method in France, confirmed by ANSM and the first author, and based on chronological, clinical, and pharmacological criteria on a scale from 0 (unlikely) to 5 (very likely) with 2 or greater considered possibly related to propranolol.5
Of 922 patients referred, 906 were treated with propranolol and had a median age of 114 days (interquartile range [IQR], 1-2282 days; mean, 185 days). Indications for treatment included functional impairment in 72.4%, severe ulceration in 40.0%, and life-threatening conditions in 16.2% (Table 1). Before inclusion, 43 patients had received systemic therapies, mainly corticosteroids (n = 34). Propranolol was administered at a median dose of 2.0 mg/kg/d (IQR, 0.4-4.0 mg/kg/d) for a median duration of 198 days (IQR, 3-929 days). Median duration of follow-up was 396 days (IQR, 18-730 days). Of 313 children who stopped propranolol by April 2013, 83.7% stopped for satisfactory efficacy and 5.8% for ADRs.
Of 922 patients, 81 (8.8%) had 133 ADRs, including 24 (2.6%) with 36 serious ADRs (Table 2). The most commonly reported ADRs were respiratory disorders (mostly infections), which were reported in 31 patients (serious ADRs related to propranolol in 6 patients). The most serious ADRs were cardiac and metabolic disorders.
Four patients had cardiac ADRs, 2 of which were serious ADRs related to propranolol. One death occurred in a 5-month-old child with biliary atresia and portal hypertension, with satisfactory cardiac monitoring, after 14 days of propranolol treatment (dose: 2 mg/kg/d) for hemangioma. Fatal atrioventricular block occurred 15 minutes after sclerotherapy with lauromacrogol for esophageal varices. Causality with propranolol was considered doubtful. In the second case, bradycardia was detected on cardiac monitoring 9 days after initiation of propranolol in a 4-month-old child with metabolic disease; the holter electrocardiogram improved after discontinuation.
Four patients experienced serious hypoglycemia, including 2 children aged 8 and 9 months with hypoglycemic seizures 5.5 and 7 months after propranolol introduction, respectively. One hypoglycemic seizure occurred due to viral gastroenteritis (after fasting and vomiting) and 1 after poor food intake; both recovered after glucose perfusion.
Other common ADRs included sleep disturbances, primarily nightmares (12/20 cases); benign vascular disorders (7 acrocyanosis and 2 asymptomatic hypotension); and digestive disorders, primarily benign diarrhea (5 cases). These ADRs often resolved when treatment administration was altered (ie, earlier evening dose or decreasing daily dose).
Propranolol was stopped for 45/88 (51%) of patients and successfully restarted in 18 (40%).
This large prospective cohort study found that serious ADRs were rare when propranolol was used to treat severe infantile hemangiomas, confirming 2 smaller studies.3,6 The most serious ADR was bradycardia, which occurred in children with severe comorbidities despite monitoring at initiation. Also worrisome were bronchoreactivity and hypoglycemia, aggravated by the β-adrenergic antagonist properties of propranolol, and worsening conditions of children who also had other concomitant diseases.
Limitations include that off-label prescription of propranolol could have been missed, and there was no control group. Attribution of causality may not be accurate, but the criteria used are well established.
Prescribers must counsel parents at each follow-up visit to discontinue propranolol during fasting and intercurrent illness, especially in the setting of restricted oral intake and respiratory symptoms.
Corresponding Author: Sorilla Prey, MD, Service de Dermatologie Pédiatrique et Centre de Référence des Maladies Rares de la Peau, Hôpital des Enfants Pellegrin, Place Amélie Raba Léon, 33 076 Bordeaux, France (email@example.com).
Author Contributions: Dr Prey had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Leaute-Labreze and Ezzedine contributed equally to this work.
Study concept and design: Prey, Voisard, Léauté-Labrèze.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Prey, Taïeb, Léauté-Labrèze, Ezzedine.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Prey, Ezzedine.
Administrative, technical, or material support: Prey, Voisard, Delarue, Lebbe, Taïeb, Léauté-Labrèze.
Study supervision: Prey, Voisard, Taïeb, Léauté-Labrèze, Ezzedine.
Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Drs Prey and Leaute-Labreze reported being investigators in clinical trials evaluating propranolol in infantile hemangioma promoted by Pierre Fabre Dermatologie pharmaceutical company. No other disclosures were reported.
Funding/Support: This study was supported by Pierre Fabre Dermatologie pharmaceutical company and the French Health Products Agency. The pharmaceutical company developed and provided the oral pediatric specific formulation of propranolol chlorhydrate.
Role of the Funder/Sponsor: Pierre Fabre Dermatologie pharmaceutical company and the French Health Products Agency had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We thank Valérie Ortis, MD (Laboratoire Pierre Fabre Dermatologie, Lavaur, France), for coordinating the French Compassionate Use Program, in particular checking inclusion criteria and collection of vigilance data, and Sarah Tilly, MS (Scinopsis, Frejus, France), for reviewing the manuscript. Both were compensated.