Infantile Hemangioma: A Review of Current Pharmacotherapy Treatment and Practice Pearls

Abstract

Infantile hemangioma (IH) is the most common vascular tumor of infancy, affecting as many as 5% to 10% of all infants. The exact cause is unclear, but specific risk factors, such as low birth weight, prematurity, female sex, white race, and family history are associated with IH development. Most IHs are benign and self-resolving, but a small subset of patients with IHs are at risk of severe or life-threatening outcomes. Systemic and topical β-blockers are effective and safe for use in pediatric patients and considered first-line treatment for both complicated and uncomplicated IHs. Recently published guidelines provide a thorough review of IH and management. This article focuses on IH pharmacotherapy and provides practice pearls to support health care providers in IH medication management.

Introduction

Infantile hemangioma (IH) is the most common tumor of infancy, affecting as many as 5% to 10% of infants within the first year of life.^1–3 Infantile hemangiomas characteristically present within the first few weeks of life, proliferate rapidly during infancy, and spontaneously resolve in early childhood without significant consequences in the majority of cases. Most IHs are benign, but a small subset of IH patients are at risk for complicaions and poor outcomes without prompt intervention. Early identification and intervention in patients with high-risk IHs improves patient outcomes. Infantile hemangioma classification and severity scoring tools have been developed to assist in risk stratification and treatment decisions.^1–7

Pharmacotherapy, specifically β-adrenergic blockers, are the mainstay of IH treatment. Corticosteroids formed the backbone of IH pharmacotherapy prior to the discovery of β-blocker effectiveness in IH treatment, but use in pediatric patients is limited by short- and long-term adverse effects.^1,3 Both oral and topical β-blockers are effective in IH treatment. Oral propranolol is widely available, effective, and safe for use in pediatric patients, making it the agent of choice for systemic IH therapy. Timolol maleate ophthalmic formulation is recommended for topical IH therapy. Treatment decisions, product selection, and route of administration is individualized for each patient based on IH properties, patient risk factors, and family preferences. Early intervention and longer therapy durations improve successful long-term outcomes in IH.^1–3,5

The American Academy of Pediatrics developed and revised clinical practice guidelines for the management of IHs that provide a robust disease state review and outline treatment recommendations for providers.^1,3 This article details IH pharmacotherapy provides practice pearls to support IH pharmacotherapy management.

Background

Presentation. Infantile hemangiomas are differentiated from other childhood tumors by their distinctive bright-red skin lesions and characteristic life cycle. IHs may present at birth as subtle telangiectasias or reddened macules, but more often become visible by 2 to 3 weeks of age once proliferation begins.^8–10 Deep IHs involve subcutaneous tissues, exhibit a blueish coloration, and have delayed presentation compared with superficial lesions. Infantile hemangiomas have a biphasic lifecycle consisting of proliferation and involution. Growth occurs rapidly in the proliferation phase starting in the first weeks of life and continues until 4 to 6 months of age. Up to 80% of growth occurs between Pharmacotherapy Treatment Options in Infantile Hemangioma 3 weeks and 3 months of age.^3,8,9,11,12 Involution occurs following proliferation and is characterized by growth cessation and gradual IH resolution throughout early childhood. The timing and extent of IH regression is variable and ranges from partial to complete resolution over 1 to 10 years. Pharmacotherapy can hasten IH growth cessation and resolution.^1–3,12

Classification. Infantile hemangiomas are broadly classified as superficial, deep, or mixed based on the extent of soft tissue involvement. Deep IHs extend into the subcutaneous tissue, superficial IHs involve the skin surface, and mixed IHs exhibit qualities of superficial and deep IHs. Infantile hemangiomas are classified more specifically based on anatomic arrangement as focal, multifocal, segmental, or indeterminate.^3,8,9 Focal IHs are well-defined lesions that appear to originate from a central focal point. Focal IHs are the most common type and make up 68% of IHs. Multifocal IHs are focal lesions that involve more than one anatomic site. Segmental IHs involve large areas of skin in a plaque-like manner and occur in patterns thought to result from embryonal developmental units. Segmental IHs are the least common type, comprising 13% of IHs; IHs that are neither focal nor segmental are classified as indeterminate and make up 17% of IHs.^3,9,11–13

Pathophysiology. Several theories exist describing IH pathophysiology. The most likely theory is the placental origin theory. This theory proposes that disruption of the placenta prior to or during birth gives rise to placental-derived endothelial progenitor cells (EPCs) that migrate and proliferate under the influence of both intrinsic and extrinsic factors and circulate until favorable growth conditions are encountered. Intrinsic factors include dysregulation of angiogenesis and vasculogenesis. Extrinsic factors include tissue hypoxia and developmental field disturbances.^3,14 The placental origin theory is supported by the presence of molecular markers characteristic of placental tissue, such as glucose transport protein-1 (GLUT-1) within IHs.³

Intrinsic factors participate in various pathways ultimately resulting in IH formation from EPCs through angiogenesis or vasculogenesis. This is supported by the presence of angiogenic growth factors within IHs during proliferation and subsequent downregulation during involution.³ Extrinsic factors are thought to promote favorable conditions for IH formation. Prenatal, postnatal, and intrapartum hypoxia contribute to IH formation through the activation of angiogenic factors. The increased IH prevalence in low–birth weight and preterm infants and the presence of hypoxia-induced intrinsic factors, such as GLUT-1, support this hypothesis. GLUT-1 is expressed throughout the IH life cycle and can be used to differentiate IHs from other vascular malformations.^1–3,15,16

Epidemiology. Known risk factors for infantile hemangioima development include female sex, white race, prematurity, low birth weight, and family history of IH.^3,11,15–18 Infantile hemangioma risk increases 25% for every 500-g reduction in birth weight and affects 25% to 30% of infants <1000-g.^3,11 Two syndromes are associated with an increased frequency of IHs: PHACE syndrome (posterior fossa defects, hemangiomas, cerebrovascular arterial anomalies, cardiovascular anomalies and eye anomalies) and LUMBAR syndrome (lower-body hemangiomas, urogenital anomalies, ulceration, myelopathy, body deformities, anorectal malformations, arterial and renal anomalies). PHACE syndrome is characterized by large segmental hemangiomas of the upper body and can include hepatic hemangiomas.^15–17 LUMBAR syndrome is associated with lower-body hemangiomas often involving the lumbosacral area.^3,11,15–18

Complications. Life-threatening infantile hemangioma complications make up 20% to 40% of IH complications.^3,7,8 Risk factors associated with IH complications are classified as patient related or lesion related (Table 1). Patient-specific risk factors include prematurity, low birth weight, and presence of an associated syndrome. Lesion-specific factors include IH size and location, subtype, and specific growth characteristics. Infantile hemangioma size and subtype impart the greatest complication risk, with large segmental IHs carrying the highest likelihood of complications.^4,7,11,18 In a retrospective study by Akcay et al,⁴ patients with hemangiomas ≥5 cm were 32 times more likely to experience complications than those with lesions <5 cm. Hepatic IHs associated with PHACE syndrome can result in hepatomegaly, congestive heart failure, or severe consumptive hypothyroidism.^3,4,7

Table 1.

Risk Factors for Infantile Hemangioma Complications^3,4,7

Component	Affect on Complication Risk
Anatomic Location	Perineal > Facial > Extremities > Trunk
Lesion size	Every 10 cm2 increase in lesion size associated with 5%–9% increase in complications Increased risk of ulceration in lesions >25 cm2
Morphologic subtype	Greatest predictor of complications Segmental > indeterminate > focal = multifocal
Patient factors	Prematurity, low birth weight PHACE or LUMBAR syndrome

LUMBAR, lower-body hemangiomas, urogenital anomalies, ulceration, myelopathy, body deformities, anorectal malformations, arterial and renal anomalies; PHACE, posterior fossa defects, hemangiomas, cerebrovascular arterial anomalies, cardiovascular anomalies and eye anomalies

In a large prospective study of 1058 children with IH, the most frequent complication was ulceration, affecting 23.2% of children.¹¹ Ulceration is more common in mixed-type hemangiomas (20%) than focal (7%) and is commonly associated with hemangiomas of the lower lip (30%) and perianal region (50%). Almost 95% of ulcerations occur during the proliferation phase.^7,11 Ulceration is common in areas prone to mechanical friction, such as the perianal region, and these areas are susceptible to bleeding, pain, and local infections. Ulcerated hemangiomas require wound care treatment with topical products and occlusive dressings to avoid secondary infections and wound progression. Oral and perianal areas can be difficult to clean and are subject to primary and secondary infections. Systemic antibiotics may be necessary. Pain resulting from ulceration can be treated with acetaminophen. Opioids are rarely necessary and should be avoided in most patients. Ulceration and bleeding are often highly concerning for patients and families but are typically not life-threatening.^3,4,10,11

Severe, life-threatening IH complications are uncommon but can result in poor outcomes. Severe complications include visual impairment, airway obstruction, auditory canal obstruction, and cardiac compromise.^3,6,7 Visual impairment can occur in up to 41% of periorbital IHs due to increases in pressure, visual axis occlusion, or strabismus. Permanent visual changes have been reported in patients with periorbital IHs left untreated for as little as 1 week.^13,18 Hepatic IHs can result in congestive heart failure and consumptive hypothyroidism without treatment (Table 2).^3,6,11,13

Table 2.

Complications of Infantile Hemangiomas^3,4–7

Complication	Incidence	Management*
Ulceration Bleeding Pain Infections	10%–30% Up to 50% in the perianal region	Wound care Occlusive dressings Topical antithrombolytics Acetaminophen Topical antibiotics Systemic antibiotics
Disfigurement	55%–65% permanent skin changes in untreated IH	Pulsed-dye laser therapy Surgical intervention
Airway obstruction	1.8%	Surgical intervention
Visual impairment	6.9%	Surgical intervention
Others: heart failure, consumptive hypothyroidism	<0.5%	Heart failure management Thyroid hormone replacement

^* In addition to IH treatment.

Severity Scoring. Subjective assessments are the mainstay of infantile hemangioma evaluation. Objective scoring tools have been developed to facilitate standardized IH assessments (Table 3).^19–23 There are three IH scoring tools: the Hemangioma Severity Scale (HSS), the Hemangioma Activity Score (HAS), and the Hemangioma Activity and Severity Index (HASI). The HSS is used to determine initial IH severity and the need for treatment; the HAS is used to monitor IH progression and response to treatment; and the HASI evaluates severity and response to treatment. The scoring tools assess and assign numeric values to IH features, such as size and color that are totaled to generate an overall score. The resultant score is used to determine the course of treatment or response to treatment. The HSS and HAS have been validated and exhibit high intrarater and interrater reliability. The available scoring tools require less than 2 minutes to complete.^19–25 Use of objective IH scoring tools is not widespread in clinical practice.

Table 3.

Validated Infantile Hemangioma Assessment Tools^19–24

	Assessment Items	Score	Comments
Hemangioma Severity Scale (HSS)	Initial size Location Risk for associated structural anomalies Complications at first visit Pain* Risk of disfigurement*	0–33 points ≤6: monitor only or topical timolol ≥11: oral propranolol	Does not account for patient age, IH morphology, or caregiver preference. Assigns higher scores to patients with associated syndromes. Not used for monitoring response to treatment
Hemangioma Activity Score (HAS)	“Activity” Swelling Change in swelling at follow-up* Color Coloration after activity Ulcer size (if present)	0–12 points	Used to monitor IH progression and response to treatment.
			Can be used on patients or photographs.

^* Subjective measures.

Management

The goals of IH treatment are to prevent life-threatening complications and permanent disfigurement, decrease psychosocial stress for the patient and family, and avoid unnecessary interventions.^25–27 Indications for IH treatment include risk of life-threatening complications, ulceration, and permanent scarring. Potential disfigurement and permanent scarring are the most frequent reason for treatment.¹ Early expert consultation should be considered for patients with complicated, high-risk IHs or associated syndromes. Early intervention, between 4 and 6 weeks of age, can reduce or prevent IH complications.¹

Conservative, non-pharmacologic management with active monitoring is appropriate for most simple, uncomplicated lesions.¹ Infantile hemangiomas typically begin to spontaneously involute by 12 months of age without intervention. Pharmacotherapy hastens IH proliferation and reduces time to complete involution.^1–4 Surgical intervention and laser therapy are reserved for pharmacologic treatment failures or to treat residual effects after involution (Figure 1).^1,6,20

Figure 1.

Infantile hemangioma (IH) intervention algorithm.^{1–3,5,6,37,38}

Prognosis for uncomplicated IHs is very good. Most IHs cause minor cosmetic effects and resolve without intervention by 4 years of age.^3,18,20 Permanent skin changes, such as telangiectasias and scarring, are more likely to occur in IHs that are untreated, persist beyond 6 years of age, or occur at high-risk anatomic sites.^3,18,20 Permanent skin changes are observed in 55% to 69% of untreated IHs.¹ Once pharmacotherapy is discontinued, IHs may reoccur in up to 20% to 40% of patients. Infantile hemangioma reoccurrence is managed with therapy reinitiation and lengthening treatment duration.^18,20

Pharmacotherapy is the mainstay of IH treatment. Local, systemic, or combination treatment is used in IH management. β-Blockers are very effective for IH treatment and are recommended first-line agents (Table 4).³ Oral propranolol is the recommended agent for most patients because of its safety and effectiveness. Topical β-blockers are effective for IH and are used alone and in combination with systemic therapy. Traditional IH pharmacotherapy options, such as systemic and intralesional steroids are no longer first-line for most IH patients (Table 5).^3,28–30

Table 4.

Pharmacotherapy With β-Blocking Agents^37,38

Agent	Indications (Contraindications)	Adverse Effects	Dose	How Supplied and Cost	Other Considerations
Propranolol oral solution	Off-label for IH treatment (cardiogenic shock; bradycardia; hypotension; heart block >first degree; bronchial asthma)	Hypotension Bradycardia Bronchospasm Hypoglycemia Sleep disturbances Diarrhea Increased risk of stroke in PHACE syndrome	Initial dose: 0.5–1 mg/kg/dose twice daily* Target dose: 1–2 mg/kg/dose twice daily*	4 mg/mL and 8 mg/mL Dye-, sugar-free Store at room temperature and discard 1 yr after opening AWP: $65.89/500 mL ($0.03/mg)	>1 concentration; Caution with prescribing, dispensing errors, transitions of care Avoid abrupt discontinuation
Propranolol oral solution	FDA approved for IH in patients >5 wk of age and >2 kg (infants weighing <2 kg; asthma or history of bronchospasm; bradycardia (HR <80 bpm), heart block >first degree; decompensated heart failure; hypotension (BP <50/30 mm Hg); pheochromocytoma)	Hypotension Bradycardia Bronchospasm Hypoglycemia Sleep disturbances Diarrhea Increased risk of stroke in PHACE syndrome	Initial dose: 0.6 mg/kg/dose twice daily Week 2: 1.1 mg/kg/dose twice daily Week 3: 1.7 mg/kg/dose twice daily	4.28 mg/mL Alcohol-, dye-, sugar-free Store at room temperature and discard 60 days after opening. Do not shake. AWP: $694.87/120 mL ($1.35/mg)	Availability through a single, specialty pharmacy; access to patient support center 120-mL bottle with dosing syringe, bottle adapter; product information includes pediatric administration instructions Avoid abrupt discontinuation
Atenolol	Off-label for IH treatment	Hypotension; bradycardia; bronchospasm; hypoglycemia	0.5–1 mg/kg/day once daily for 6 mo Adjust dose for patient weight change ≥10%	Compounded oral suspension: 2 mg/mL Shake before use	Avoid abrupt discontinuation
Timolol maleate ophthalmic	Off-label for IH treatment	Local irritation; ulceration; alopecia at application site; bronchospasm; bradycardia; hypoglycemia with significant systemic absorption	1–2 drops once to twice daily May increase dosage or frequency for deep lesions Prior to applying caregiver should wash hands; apply medication and spread to cover the entire hemangioma surface	Ophthalmic GFS: 0.25%, 0.5% Ophthalmic solution: 0.25%, 0.5% Invert bottle and shake once prior to administration Once opened, discard after 28 days	Studies performed with the gel product Gel product adheres better to the specific location because of viscosity; less systemic absorption

GFS, gel-forming solution; IH, infantile hemangioma; PHACE, posterior fossa defects, hemangiomas, cerebrovascular arterial anomalies, cardiovascular anomalies, and eye anomalies

^*Dose can be divided 3 times daily to increase tolerability.

Table 5.

Pharmacotherapy With Other Medications ^*

Agent	Adverse Effects	Dose	Other Information
Prednisolone	Cushingoid appearance; infection; growth suppression; hypertension; mood changes; adrenal suppression	2–3 mg/kg/day; up to 5 mg/kg/day	Prednisolone oral solution 3 mg/mL
Intralesional triamcinolone or betamethasone	Skin atrophy; necrosis; depigmentation; bleeding; ulceration; postinjection flare	Dependent on hemangioma size. Maximum: 3 mg/kg/dose or 30 mg/dose.	Administered by health care provider. Injection: 10 mg/mL and 40 mg/mL (10 mg/mL concentration used for IH) Administer using 1-mL syringe and 23- to 25-gauge needles. Single-use vial. Discard unused product immediately after use.
Bleomycin	Ulceration; soft tissue atrophy; skin rash; alopecia; hyperpigmentation; pain at injection site	0.3–0.5 mg/kg/dose	Administered monthly by health care provider. Injection: 15 mg/mL Single-use vial. Discard unused product immediately after use. Can be diluted to 3 mg/mL with sterile water or normal saline for small doses. NIOSH hazardous Medication subject to USP800; requirements.
Bevacizumab	Skin atrophy, necrosis, depigmentation, ulceration	0.625 mg	Injection: 100 mg/4 mL. Use a small syringe with the smallest needle to administer; Inject around the hemangioma site.

IH, infantile hemangioma; NIOSH, National Institute of Occupational Safety and Health

^* Off-label use for IH treatment.

Propranolol. Oral propranolol is first-line therapy for systemic treatment of proliferating IHs in patients >5 weeks of age.^3,5 The effectiveness of propranolol for IH treatment was first reported in 2008 by Leaute-Labreze et al² when a 1-month-old infant treated with propranolol for obstructive hypertrophic cardiomyopathy simultaneously experienced IH resolution. Additional case reports, clinical reviews, and placebo-controlled trials further support the effectiveness of propranolol in IH treatment.^32–36 The mechanism of propranolol in IH resolution is not completely understood but is theorized to result from propranolol-induced IH growth arrest. Proposed mechanisms of action for IH growth arrest include vasoconstriction, blockade of vascular endothelial growth factor and basic fibroblast growth factor signaling, inhibition of nitric oxide production, regulation of the renin-angiotensin system, and direct cellular apoptosis.^14,32 Propranolol is thought to exhibit different mechanisms based on IH phase. Propranolol may act via vasoconstriction in the proliferation phase and antiangiogenesis and apoptosis during the involution phase.^3,14,37–40

Propranolol has a long history of safe use in pediatric patients. Adverse effects during propranolol therapy are typically mild and severe adverse effects are uncommon.^3,29,30 Propranolol is a lipophilic, non-specific β₁, β₂, and β₃ receptor antagonist and can have cardiac, respiratory, and CNS adverse effects, such as bradycardia, wheezing, and drowsiness. Other CNS adverse effects include agitation and sleep disturbances. The CNS effects are usually temporary and rarely require intervention. Propranolol can cause varying degrees of airway hyperactivity and should not be used in patients with a history of asthma or bronchospasms. Transient airway hyperactivity and wheezing can occur in patients without previous airway concerns during concurrent respiratory tract illness.^3,34,37,38

Potentially severe adverse effects of propranolol therapy include hypoglycemia, bradycardia, and hypotension.^3,31–38 Hypoglycemia occurs primarily in patients age <1 year of age during periods of fasting or poor oral intake and is not dose related. The signs and symptoms of hypoglycemia can be masked by β-blocker therapy. Sweating may be the only outward symptom prior to the onset of severe hypoglycemia. Propranolol is administered during or following feedings and not given during times of decreased oral intake to avoid hypoglycemia. Infantile hemangioma guidelines do not recommend routine glucose monitoring following therapy intiation.^3,37,38

Propranolol cardiac β-adrenergic blockade results in decreased HR and BP. Peak effects occur 2 hours after an oral dose.^34,35,37,38 Prior to starting propranolol, a cardiac exam or ECG should be performed. Routine cardiovascular monitoring is not recommended once normal baseline measurements are obtained.^1,33–34

The FDA-approved dosing of propranolol for IH is a starting dose of 0.6 mg/kg/dose twice daily, increased on week 2 and week 3 to 1.1 mg/kg/dose twice daily and 1.7 mg/kg/dose twice daily, respectively.³⁸ The total daily dose can be divided 3 times daily to increase tolerance.^37,38 The dose should be adjusted for patient weight gain during treatment to maintain the target dose.^1,38 The propranolol dose for IH treatment is based on a randomized, placebo-controlled trial conducted by Leaute-Labreze et al³² in which 460 infants were treated with either placebo or 1 of 2 different propranolol dosing regimens. This study randomized patients into 1 of 4 treatment regimens, propranolol 1 mg/kg/day or 3 mg/kg/day for 3 and 6 months.³²

The groups were compared at months 6 and 12 of treatment. The 6-month treatment regimens were included in the final efficacy analysis. Complete or nearly complete IH resolution was observed in 8% of patients in the placebo group, 38% of patients receiving propranolol 1 mg/kg/day for 6 months (p = 0.004), and 63% of patients receiving propranolol 3 mg/kg/day for 6 months (p < 0.001). Thirty-three serious adverse events occurred in the propranolol treatment groups, with no difference demonstrated compared with the placebo groups. Transient decreases in HR and BP occurred in the propranolol treatment groups. These effects did not require intervention and resolved by 8 weeks of therapy without dose reductions.³² This study determined propranolol dosed at 3 mg/kg/day for 6 months was effective in decreasing IH size by 60%, with minimal adverse effects.

Duration of propranolol therapy is associated with IH resolution. An open-label, phase 3 study evaluating the effect of treatment duration on resolution of high-risk IHs demonstrated safety and effectiveness of propranolol up to 12 months.³⁶ Patients were treated with propranolol 3 mg/kg/day for 6 months. The effect of treatment was evaluated at 6 months. Patients with incomplete IH resolution continued therapy for an additional 6 months before reevaluation. Higher IH resolution rate was observed with 12 months of therapy compared with 6 months (76% vs 47%). Both treatment groups maintained IH resolution during the 3-month follow-up period. A total of 80% of patients experienced mild to moderate adverse effects during treatment. Adverse effects did not result in therapy discontinuation.³⁶

Pharmacotherapy intervention early in the IH proliferative phase results in improved outcomes compared with late-therapy initiation. Kim et al⁴¹ retrospectively evaluated infants with IH treated with propranolol 3 mg/kg/day between 2015 and 2017. Twenty-three patients were photographed prior to and serially during propranolol therapy. Patients were categorized into 2 groups: propranolol therapy initiation before 6 months of age and propranolol therapy started after 6 months of age. Median reduction in IH size was 32% during the study period (range, 1.1%–92.6%). Patients starting treatment prior to 6 months of age demonstrated a greater reduction in lesion size compared with those starting therapy after 6 months (62.3% vs 15.8%, p = 0.001). No severe side effects were reported in either treatment group.⁴¹

Propranolol is approved for outpatient initiation in healthy infants >5 weeks corrected gestational age.³⁸ Infantile hemangioma guidelines recommend inpatient propranolol initiation for patients ages <8 weeks of age (Figure 2).¹ All patients should receive a baseline cardiac exam prior to starting propranolol therapy for IH.^1,37,38 Pretreatment ECG is recommended for patients with comorbidities, including HR lower than normal for age, history of or current arrhythmia, family history of congenital heart conditions, maternal history of connective tissue disease, an associated syndrome, and large or bulky hemangiomas. Routine ECG monitoring is not recommended.^1,37,38

Figure 2.

Inpatient propranolol initiation.^{3,32–38,52,61}

In-office propranolol initiation is recommended for all patients who do not meet requirements for in-patient intiation (Figure 3). Patients should have HR, BP, and glucose monitored in the physician's office at 1 and 2 hours following the first dose and with each dose increase. Infants who are born premature, are age <8 weeks, or who have a history of hypoglycemia, cardiovascular, or respiratory conditions should start propranolol therapy in an inpatient setting where close monitoring and immediate access to emergency care are available.^{1,35,37,38,43,44}

Figure 3.

Outpatient propranolol initiation.^{3,32–38,52,61}

Abrupt propranolol discontinuation should be avoided. The dose should be weaned slowly to avoid rebound tachycardia and hypertension. Propranolol can be discontinued during the course of a month by halving the dose for 2 weeks, halving the dose again for another 2 weeks, then discontinuing.^1,37,38

Propranolol oral solution is commercially available in 3 strengths: 4, 4.28, and 8 mg/mL.^37,38 Propranolol oral solution 4.28 mg/mL (Hemangeol, Pierre-Fabre Dermo-Cosmetique, Brossard, QC, Canada) received FDA approval in 2014 for the treatment of IH in patients >5 weeks of age and >2 kg. This product is available through a single, specialty pharmacy.³⁸ Restricted access is intended to increase dispensing safety and patient support during therapy.^35,37,38,52 Propranolol 4 mg/mL oral solution is commonly used off-label for IH treatment and may provide cost savings.^1,37

Atenolol. Atenolol is an alternative therapy for patients who have intolerable adverse effects or contraindications to propranolol. Atenolol is a β₁-selective, hydrophilic β-receptor antagonist.^3,45 Atenolol does not cross the blood-brain barrier and is expected to cause fewer CNS adverse effects than propranolol. Evidence shows equivalent efficacy for atenolol and propranolol. Between the years 2013 and 2018, a total of 341 IH cases were published in which patients were treated with β-blockers. Of these 341 patients, 44 patients were transitioned from propranolol to atenolol because of adverse effects. Atenolol dosing ranged from 1 to 2 mg/kg/day, and treatment duration was at least 6 months. Patients previously treated with propranolol exhibited a response rate to atenolol therapy of 90.4% (40 of 44). Patients experienced an improvement in the adverse effects that occurred during propranolol therapy (95.5%). Minor side effects of atenolol therapy included β-blocker–related side effects of hypoglycemia, bronchospasm, bradycardia, and hypotension.⁴⁵ Data available comparing the effectiveness of propranolol and atenolol show insignificant differences in efficacy.^3,45 Infantile hemangioma guidelines suggest an atenolol trial in patients who are unable to tolerate propranolol due to side effects or contraindications to propranolol.^3,5

Topical Timolol. Topical therapy is recommended for patients with thin, superficial focal IHs and for patients with contraindications to systemic therapy. Topical therapy can be used in combination therapy regimens and to minimize systemic adverse effects.^3,5,46 Timolol maleate is the topical agent of choice. Timolol is a non-selective β-antagonist whose mechanism of action is similar to those of propranolol and atenolol. Topical β-blockers act locally via the renin-angiotensin system to reduce angiotensin II levels on the surface of the hemangioma to cause IH regression and eventual resolution.^46–51 In 2009, Pope and Chakkittakandiyil⁴⁹ first described the successful use of timolol maleate ophthalmic formulation for the treatment of superficial IH. Yu et al⁴⁷ compared 101 IH patients treated with topical timolol to 23 patients who received no intervention. This study showed a statistically significant difference in IH growth cessation, size reduction, color lightening, and softening with the treatment group compared with the observation group.⁴⁷ In a large case series by Wu et al,⁴⁸ 724 children with superficial IHs were treated with topical timolol or oral propranolol (362 patients in each group). Propranolol (97%) and timolol (96.4%) had excellent response rates (p = 0.2). The incidence of adverse effects differed between the 2 treatment groups, with 3.9% of propranolol-treated patients experiencing an adverse effect compared with 0% in the topical timolol group (p < 0.001).⁴⁷ Topical agents are often combined with systemic therapy in clinical practice. In a survey of pediatric dermatologists, 91% stated they use topical timolol and 66% acknowledged using topical timolol in combination with oral propranolol.^29,46,50

Timolol maleate is commercially available as 0.25% and 0.5% ophthalmic solutions and gel-forming solutions (GFS) FDA approved for the treatment of elevated intraocular pressure in adult and pediatric patients. These formulations are used off-label for topical IH treatment. Timolol GFS is the preferred formulation of topical timolol for treatment.^46,50,51 The viscosity of the gel eases application and increases the amount of medication remaining at the site after application. Timolol GFS is dosed 1 to 2 drops of the 0.5% solution applied once to twice daily (total of 1–4 drops per day). The solution should be applied to the area, gently spread to cover the entire lesion, and then massaged into the IH. Caregivers should wash their hands with soap and water after application and avoid contact with mucous membranes. Topical timolol should not be applied to mucous membranes or ulcerated areas because of the potential for systemic absorption.^46–51 FDA labeling for timolol maleate topical includes contraindications in patients with asthma, bradycardia, second- or third-degree heart block, and cardiogenic shock. Systemic absorption can occur with topical administration, but adverse effects are uncommon.⁵¹ Timolol topical therapy is well tolerated, and no specific monitoring is recommended. Transition to systemic IH therapy may be necessary if timolol topical is ineffective. Topical propranolol ointment has been investigated for IH treatment. When compared to timolol topical therapy, topical propranolol is about 90% effective compared with 99% for timolol.^46,51 Propranolol ointment is not available commercially, but it can be compounded.

Corticosteroids. Systemic and intralesional corticosteroids were the mainstay of IH therapy prior to β-blocker use. Corticosteroids act through non-specific, anti-inflammatory mechanisms to induce IH resolution.³ In a randomized controlled trial, corticosteroids demonstrated >98% effectiveness in IH resolution compared with 31% in placebo-treated patients (p < 0.05).^3,41 Corticosteroids have significant short- and long-term adverse effects, including hyperglycemia, weight gain, behavior disturbances, adrenal and immunosuppression, hypertension, and growth suppression. Corticosteroids should be reserved for patients who experience intolerable adverse effects or lack of response with β-blocker therapy.^41,53 Treatment durations >2 weeks increase the risk of corticosteroid-related morbidity. Corticosteroids should be discontinued slowly at the end of therapy to avoid adverse effects.^3,41,53,54

A meta-analysis conducted in 2013 evaluated oral corticosteroid and propranolol therapies. This study included 1162 studies with 2629 steroid patients and 795 propranolol patients. Propranolol-treated patients demonstrated a 97.3% (p < 0.001) response rate compared with 69.1% (p < 0.001) for intralesional or systemic corticosteroids. Treatment duration ranged from 1 to 3 months for steroids and 1 to 12 months for propranolol. Adverse effects were observed in 17.6% of steroid-treated patients and 9.6% of propranolol-treated patients. The study concluded propranolol is more effective and has fewer adverse effects than steroid therapy.⁵⁴ Longer durations of therapy in propranolol-treated patients compared with steroid-treated patients (1–3 months vs 1–12 months) may attribute to the higher response rates observed with propranolol. The authors emphasized the need for well-designed randomized controlled trials comparing oral corticosteroids and propranolol therapies.⁵⁴

A 2017 non-inferiority trial of corticosteroids and propranolol⁴¹ included 34 patients and concluded that corticosteroids have an efficacy similar to that of propranolol (decrease in IH volume 46.5% vs 55.8%, respectively; p = 0.27). Safety analysis demonstrated significantly lower HRs (p = 0.003), body temperature (p = 0.002), and glucose levels (p = 0.002) in the propranolol group compared with the steroid group. Clinically significant adverse events (i.e., bradycardia, hypotension, hypoglycemia, respiratory concerns, hypertension, and growth disability) were not significantly different between groups.⁴¹ The study was limited by small sample sizes.

Combination oral corticosteroid and propranolol IH treatment regimens have been investigated. Aly et al⁵⁵ studied the effectiveness of a combination regimen. Patients received 2 weeks of combination therapy with corticosteroids and propranolol (steroid “priming”) or a propranolol-only treatment regimen. The authors noted statistically significant improved response with the combination treatment regimen early in therapy at 2, 4, and 8 weeks, but the superior response was no longer evident at 6 months.⁵⁵

Intralesional Therapies. Intralesional steroids, bleomycin, vincristine, bevacizumab, and interferon-α have been studied alone and in combination for IH treatment. Intralesional steroids have the most robust evidence for use and were considered first-line IH therapy prior to β-blocker use.^3,5,28–30

Oral propranolol is superior in efficacy and safety compared with intralesional corticosteroids. In a retrospective analysis of patients with periorbital hemangioma, patients (N = 25) were treated with intralesional betamethasone, oral propranolol, or both agents. All patients in the propranolol group (8 of 8) experienced complete IH resolution compared with 13 of 16 in the intralesional betamethasone group. Patients receiving propranolol experienced minimal adverse effects compared with those receiving intralesional betamethasone.⁵⁶ In a study by Hoornweg et al,57 IH patients treated with intralesional corticosteroids (n = 8) experienced bleeding and ulceration. Patients treated with oral propranolol (n = 21) reported no side effects.⁵⁷

Intralesional bleomycin has been used for IHs unresponsive or incompletely responsive to propranolol therapy.^3,58 In a retrospective study by Kar et al,59 patients (n = 104) who previously failed low-dose propranolol therapy were treated with intralesional bleomycin. Patients received a relatively low dose of 1 mg/kg/day propranolol for 6 to 12 months and were reassessed for IH regression. If lesion regression was <25%, intralesional bleomycin was initiated at a dose of 0.3 to 0.5 mg/kg per injection. Patients requiring intralesional bleomycin (n = 5) demonstrated an improvement in IH regression (56.2% to 93.3%).⁵⁹ Intralesional bevacizumab has been investigated for use in localized IH because of its antiangiogenic properties via vascular endothelial growth factor inhibition, but sufficient data are lacking and use remains experimental.⁶⁰ Recommendations regarding timing of intralesional therapy, product selection, and appropriate dosing are not available in current IH guidelines.^1,5,57–60

Surgical and Laser Therapy. Surgical and laser treatments are commonly withheld until 3 to 5 years of age. Anesthesia adverse effects and the risk of blood loss makes surgical intervention unfavorable for most patients. Significant bleeding can occur during IH surgical procedures due to the vascularity of IHs. Surgical intervention may be necessary in patients with impending life-threatening obstructive IHs or certain IHs unresponsive to pharmacologic therapy. Surgical inteventions are used in conjunction with pharmacotherapy unless contraindicated.^1,5,62 Laser therapy is not recommended for IH treatment in infants because of ulceration risk, but is used for treating residual skin changes and scarring following IH resolution.^3,6,20,62

Practitioner Considerations

Propranolol prescriptions must indicate the product strength and the prescribed dose in milligrams with the corresponding volume in milliliters (mL) to reduce the risk of medication errors that can occur due to the availability of three propranolol oral solution concentrations. A recent patient weight in kilograms should be included with the prescription to allow for dose verification. Thorough parent and caregiver counseling should include medication administration instructions, expected adverse effects, signs and symptoms of hypoglycemia and bradycardia, and a sick-day plan for withholding doses when the child is ill (Table 6). β-blockers and corticosteroids require dose weaning at the end of therapy to avoid associated adverse effects.^{3,32–35,52,61}

Table 6.

Propranolol Medication Counseling^{3,32–38,52,61}

General counseling

Administer during or after feeds

Administer during daytime hours

Administer directly into the infant’s mouth or mix with small amount of milk, formula, or juice

Provide frequent feeds (every 3–4 hr in infants <6 wk, every 5 hr for infants 6 wk to 4 mo, and every 6–8 hr for infants > 4 mo)

Omit dose(s) if infant is refusing feeds or feeding less frequently

Omit dose(s) if infant is ill or experiencing respiratory symptoms

Administer doses at least 8 hr apart

If a dose is missed, give the dose as soon as remembered as long as it is after a feed and the next scheduled dose is at least 8 hr away

Do not double up or increase doses to make up for missed doses

If the infant spits out the dose, do not repeat it; give the next dose at the scheduled time

Propranolol 4.28 mg/mL oral solution: date the box when the bottle is first opened and discard after 60 days; do not shake before use

Do not abruptly discontinue therapy without physician advice; medication should be decreased slowly to avoid adverse effects

Common adverse effects

Sleep disturbances (falling asleep, staying asleep)

Gastrointestinal problems (diarrhea, vomiting)

Irritability, agitation, nightmares

Seek immediate medical attention for any of the below serious adverse reactions

Low blood sugar (hypoglycemia): sweating, shakiness, increased drowsiness or irritability, poor feeding, pale skin color, low body temperature, seizures

Low HR (bradycardia) or low BP (hypotension): pale skin color, slow or uneven heartbeats, cool or cold extremities, blue skin color, or fainting

Breathing problems (bronchospasms): breathing difficulties or wheezing

Conclusion

Early recognition, risk assessment, and intervention improve patient outcomes in IH. Pharmacotherapy management for IH has changed since the discovery of β-blocker effectiveness in IH treatment. When selected, initiated, and monitored appropriately, systemic and topical β-blockers are effective for IH resolution in the majority of cases. Product selection and treatment plans are formulated based on patient- and IH-specific factors. Caregiver medication counseling and support are essential components of pharmacotherapy management. Alternative therapies are available for patients with IHs unresponsive or incompletely responsive to β-blockers, or patients with contraindications to β-blocker therapy.

ABBREVIATIONS

BP

blood pressure

CNS

central nervous system

ECG

electrocardiogram

GFS

gel-forming solution

EPC

endothelial progenitor cells

FDA

US Food and Drug Administration

GLUT-1

glucose transport protein-1

HR

heart rate

HAS

hemangioma activity score

HASI

hemangioma activity and severity index

HSS

hemangioma severity scale

IH

infantile hemangioma

LUMBAR

lower-body hemangiomas, urogenital anomalies, ulceration, myelopathy, body deformities, anorectal malformations, arterial and renal anomalies

PHACE

posterior fossa defects, hemangiomas, cerebrovascular arterial anomalies, cardiovascular anomalies and eye anomalies