Medication Summary
The goals of pharmacotherapy for infantile hemangiomas are to reduce morbidity and mortality and to prevent complications. Note that only propranolol oral solution (Hemangeol) is approved for treatment of infantile hemangiomas by the FDA, and all other therapies should be considered off-label usage.
Propranolol
Propranolol oral solution (Hemangeol) was approved by the FDA in March 2014. Approval was based on the results from a dose-ranging study of 460 infants aged 35 days to 5 months with proliferating hemangiomas (excluding life-threatening, ulcerated, or function-threatening infantile hemangiomas). Overall, 2 (4%) of 55 patients in the placebo arm and 61 (60%) of 101 patients taking propranolol 3.4 mg/kg/day for 6 months had complete or nearly complete resolution of their hemangioma at week 24 (P< .0001). [69, 79] Beta-blockers, most specifically propranolol and more recently topical timolol, have been in use since mid 2008 for infants with severe or disfiguring hemangiomas. [80, 81] Several reports in the literature describe efficacy for life- and sight-threatening airway and retro-orbital hemangiomas, respectively. [65, 82, 83] Some have been treated with the beta-1 selective blockers acebutolol and atenolol. However, most infants reported have been treated with the nonselective beta-blocker, propranolol, at a dose of 2-3mg/kg/day in 2-3 divided doses. Duration of therapy varies from 2-12 months. As early as 24 hours after the initiation of therapy, many infantile hemangiomas have begun to change from intense red to purple, with evidence of softening. Most continue to improve until nearly flat and with significantly diminished color.
Treatment of nasal infantile hemangioma with propranolol reduced the need for invasive treatment in a retrospective cohort study of 58 children (mean age, 5 months). [84, 85] The researchers divided the study participants into a prepropranolol group, a propranolol group, and a nonpropranolol group. Infants treated with propranolol for a mean of 7.6 months at a total dosage of 2 mg/kg/day were 56% less likely than infants in the prepropranolol group to undergo any invasive treatment, 61% less likely to undergo surgical treatment, and 25% less likely to receive laser treatment.
The mechanism of action of propranolol in these patients is unknown; however, some hypothesize that local vasoconstriction may be a factor, which is based on the early color change and softening of the lesion. One study has demonstrated that nonspecific and beta 2-selective blockers (eg, propranolol) triggered apoptosis of capillary endothelial cells in adult rat lung tissue, suggesting a similar mechanism may be plausible for hemangioma endothelial cells. [86] Propranolol has also been shown to inhibit signaling from the renin-angiotensin system. See Causes.
One published consensus protocol from 2013 describes initiating propranolol therapy in infants with hemangiomas. [11] Therapy should be approached with extreme caution in neonates and infants who generally do not have preexisting venous hypertension or any other hemodynamic disorder. Of particular note, infants with hemangiomas associated with PHACE syndrome with cerebrovascular anomalies are at higher risk for cerebral vascular accidents and therefore should not receive beta-blockers unless the benefits outweigh the risks.
Provisional guidelines for initiation of treatment are described below.
Pretreatment
Exclude infants with evidence of the following:
-
Bronchospasm
-
Cardiac disease
-
CNS vascular anomalies (suspected PHACE syndrome, large cervicofacial hemangiomas [see Mortality/Morbidity for PHACE syndrome definition])
Baseline laboratory tests and evaluation may include the following:
-
Physical examination of the heart, lungs and peripheral vascular system
-
Heart rate
-
Blood pressure
-
Electrocardiography (variable)
-
Echocardiogram (if considering PHACE syndrome or other clinical indications)
-
Pediatric cardiology consultation for evaluation and dosing recommendations (if any concerning findings)
Dosing
Initial dosing is as follows:
-
Inpatient: Suggested for infants younger than 8 weeks of gestationally corrected age or with co-morbidconditions, starting dose at 1 mg/kg/day or 0.33 mg/kg/dose q8hr and check heart rate and blood pressure 1 and 2 hours after first 1-3 doses; if tolerated, increase to 2 mg/kg/day or 0.66 mg/kg/dose q8hr and if tolerated discharge to home on this regimen
-
Outpatient: Suggested for infants older than 8 weeks of gestationally corrected age and adequate social support, starting dose at 1 mg/kg/day or 0.33 mg/kg/dose q8hr and check heart rate and blood pressure 1 and 2 hours after first dose; if tolerated, patient is sent home and continues this dose for 3-7 days then returns and increases to 0.5 mg/kg/dose q8hr (1.5 mg/kg/day) and if tolerated is discharged to home on that dose; again, if tolerated for 3-7 days, then increase dose to 0.66 mg/kg q8hr (2 mg/kg/day)
Monitoring
Monitoring 1 and 2 hours after administration (dosing) includes the following:
-
Blood pressure check
-
Heart rate check (hold dose for heart rate at < 100 beats/min)
-
Blood glucose level (because of the potential for blocking of liver glycogen phosphorylase) only for inpatients; recommended that young infants feed every 3-4 hours to decrease risk of hypoglycemia
-
Temperature determination to evaluate for hypothermia
-
Observation for bronchospasm
At home, parents should observe for signs of lethargy, poor feeding, and/or bronchospasm.
Blood pressure and heart rate should be evaluated intermittently at the pediatrician's office.
Note that practices vary considerably.
Discontinuation
Consider a gradual taper over 2 weeks, rather than abrupt discontinuation. Cardiac hypersensitivity may occur 24-48 hours after propranolol is discontinued (peaks at 4-8 d).
Timolol ophthalmic
Timolol eye drops have become a widely used off-label medication for the treatment of infantile hemangiomas. Most experience exists with timolol 0.5% gel or solution; however, other concentrations and vehicles appear effective. Use is primarily limited to superficial hemangiomas, and several studies have found it to be safe and effective for these lesions. [87] It should be used with caution when treating ulcerated infantile hemangiomas, because timolol is a more potent beta-blocker than propranolol and systemic absorption may result in adverse reactions.
Corticosteroids
Oral and intralesional corticosteroids are effective at slowing the growth and decreasing the size of proliferating infantile hemangiomas. The mechanism of action has not been elucidated completely; however, corticosteroids have been shown to inhibit VEGF-A expression and subsequent proliferation in hemangioma stem cells in a murine hemangioma model. [88] Evidence indicates that corticosteroids block estradiol receptors in hemangiomas in vitro. Responses vary widely, from less than 40% to greater than 90%, depending on dose, duration of treatment, and age at which corticosteroid therapy is initiated. [89] Corticosteroid therapy should be administered during the proliferative phase because it has a negligible effect on involuting and otherwise stable infantile hemangiomas. The oral route generally is preferred over intralesional therapy; however, the location, size, patient age, and physician experience factor into the decision-making process.
Interferons
Initially used as an antiviral agent in HIV-infected patients, interferon alfa was found to induce regression of Kaposi sarcoma. This led to its use in treating other vascular lesions (eg, hemangiomas). Interferon alfa inhibits endothelial cell migration and proliferation and specific growth factors (eg, endothelial growth factor, fibroblast growth factor). Studies have demonstrated the efficacy of interferon alfa-2b in treating infantile hemangiomas. [90]
Because interferon alfa works by a different mechanism, it can be used in lesions that are unresponsive to steroids. [91] In fact, unlike steroids, it does not require that administration occur during the proliferation phase to be effective. The onset of action is slower than that of corticosteroids, usually requiring several weeks; this makes it less attractive for use in acute life- or sight-threatening situations. Interferon alfa should be used only if steroid, beta-blocker, and other potentially toxic therapies fail.
The most significant adverse event limiting its use in hemangiomas is potentially irreversible spastic diplegia; while most infants have displayed significant recovery of spasticity of lower extremities, it appeared permanent in other infants. [92, 93] A meta-analysis of interferon use in children revealed all cases of neurological dysfunction occurred when interferon was used prior to the patient’s first birthday. [94]
Biologic immune response modifiers
Imiquimod
Only a few case reports and two small, open-label, uncontrolled trials suggest some minimal efficacy for the treatment of infantile hemangiomas. [95, 96, 97] This treatment should be considered experimental until placebo-controlled trials are performed and therapy is determined safe for infants. Imiquimod cream is the only medication in this new class. It purportedly works by stimulation of toll-like receptor 7 (TLR-7) and increases local interferon-alpha and interferon-gamma, through which it may exert antiangiogenic effects. In a mouse model, imiquimod-treated vascular tumors showed decreased tumor cell proliferation, increased tumor apoptosis, and increased expression of tissue inhibitor of matrix metalloproteinase-1, with decreased activity of matrix metalloproteinase-9, both of which are observed in the natural involution of infantile hemangiomas.
Becaplermin
A few reports in the literature suggest that becaplermin is helpful for ulcerated infantile hemangiomas, especially those in the diaper area. [50] Data are limited and no placebo-controlled trial have been published to date. Seven infants with refractory ulcerated infantile hemangiomas experienced healing 3-21 days after initiating therapy.
Beta-adrenergic Blocker
Class Summary
Selective beta-blockers specifically block beta-1 receptors alone, although they can be nonselective at higher doses.
Caution should be used in administering these agents in the setting of asthma or severe chronic obstructive pulmonary disease (COPD), regardless of beta-selectivity profile. In addition, exacerbations of angina and, in some cases, myocardial infarction have been reported following abrupt discontinuance of beta-blocker therapy. The doses should be gradually reduced over at least a few weeks.
Propranolol (Hemangeol)
The mechanism of propranolol's effects on infantile hemangiomas is not well understood. Propranolol is a nonselective beta-adrenergic receptor blocking agent possessing no other autonomic nervous system activity. It is indicated for treatment of proliferating hemangioma requiring systemic therapy. It is available as an oral solution (4.28 mg/mL).
Antiglaucoma, Beta-Blockers
Class Summary
These agents decrease aqueous production, possibly by blocking adrenergic beta receptors present in the ciliary body. The nonselective medications in this class can also interact with the beta-receptors in the heart and lungs, causing significant adverse effects.
Timolol ophthalmic (Betimol, Istalol, Tim Ak)
Timolol may reduce elevated and normal intraocular pressure, with or without glaucoma, by reducing the production of aqueous humor.
Corticosteroids
Class Summary
These agents have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli and inhibit the synthesis of tumor necrosis factor (TNF)–alpha, interleukin (IL)–2, IL-6, and interferon (IFN)–gamma. In addition, glucocorticoids modulate serum and leukocyte-bound levels of cell adhesion molecules.
Prednisolone (Prelone Syrup, Pediapred Oral Solution, Delta-Cortef, OraPred)
Prednisolone decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reducing capillary permeability.
Interferons
Class Summary
Interferons are naturally produced proteins with antitumor and immunomodulatory effects.
Interferon alfa-2b (Intron A)
Interferon alfa-2b is a protein product manufactured by recombinant DNA technology. Indications are adult hairy cell leukemia, malignant melanoma, condyloma acuminata, AIDS-related Kaposi sarcoma, and certain forms of chronic viral hepatitis. Interferon alfa-2b has also used to treat children with these conditions and, most recently, infants with life-threatening hemangiomas.
Interferon alfa 2b (Interferon alfa-2b, Intron A)
Interferon alfa-2b is a protein product manufactured by recombinant DNA technology. Indications are adult hairy cell leukemia, malignant melanoma, condyloma acuminata, AIDS-related Kaposi sarcoma, and certain forms of chronic viral hepatitis. Interferon alfa-2b has also been used to treat children with these conditions and, most recently, infants with life-threatening hemangiomas.
Biologic immune response modifiers
Class Summary
These agents induces the secretion of interferon alpha and other cytokines; the mechanisms of action are unknown.
Imiquimod (Aldara cream)
Imiquimod is an immune response modifier indicated for condyloma acuminata, actinic keratoses, and superficial basal cell carcinoma in adults. It is not approved by the FDA for use in children.
Becaplermin 0.01% gel (Regranex Gel)
Becaplermin gel 0.01% (Regranex) is a recombinant human platelet-derived growth factor that is produced through genetic engineering.
-
Histopathology of a proliferating infantile hemangioma with plump endothelial cells in the dermis.
-
This proliferating superficial infantile hemangioma on the trunk required no therapy.
-
Exquisitely painful ulcerated mixed hemangioma (superficial and deep) of the left deltoid in a 6-month-old female infant. This lesion was treated successfully with pulsed dye laser.
-
This superficial and deep infantile hemangioma resulted in astigmatism of the left eye, requiring spectacles to correct the refractive error and to prevent amblyopia. Further growth of this hemangioma necessitated a course of oral prednisolone. The hemangioma shrunk rapidly, and the patient's astigmatism decreased such that the spectacles were unnecessary 1 month after beginning steroids.
-
Segmental infantile hemangioma in a female infant with PHACE syndrome involving the posterior neck and right forehead associated with an absent right vertebral artery and a laryngeal hemangioma.
-
Segmental infantile hemangioma with minimal or arrested growth of the bilateral buttocks and posterior thigh in this male infant with PELVIS syndrome (complicated by cutaneous ulceration, hypospadias, anal stenosis, intraspinal lipoma with tethered cord). The white material is a barrier diaper cream.
-
Superficial proliferating infantile hemangioma on the lower extremity
