Infantile Hemangioma Medication
- Author: Richard J Antaya, MD; Chief Editor: William D James, MD more...
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.
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. Evidence indicates that corticosteroids block estradiol receptors in hemangiomas in vitro. Response vary widely, from less than 40% to greater than 90%, depending on dose, duration of treatment, and age at which corticosteroid therapy is initiated. 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.
Prednisolone decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reducing capillary permeability.
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 IH). Overall, 2 of 55 patients (4%) in the placebo arm and 61 of 101 patients (60%) taking propranolol 3.4 mg/kg/day for 6 months had complete or nearly complete resolution of their hemangioma at week 24 (p < 0.0001). Beta-blockers, most specifically propranolol and more recently topical timolol, have been in use since mid 2008 for infants with severe or disfiguring hemangiomas.[60, 61] Several reports in the literature describe efficacy for life- and sight-threatening airway and retro-orbital hemangiomas, respectively.[47, 62, 63] Some have been treated with the beta-1 selective blocker, acebutolol. However, most infants reported have been treated with the nonselective blocker, propranolol, at a dose of 2-3mg/kg/d in 2-3 divided doses. Duration of therapy varies from 2-10 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.
A retrospective study of 39 children in France with infantile hemangiomas of the head and neck concluded that propranolol treatment effectively lightened and reduced hemangiomas, especially as first-line treatment started during proliferative growth (mean age, 4.1 m; mean duration, 8.5 m). Of 37 hemangiomas successfully treated with propranolol, 26 were in locations (parotid area, lips, or nose) where the authors would not have initiated corticosteroid therapy.
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). The researchers divided the study participants into a pre-propranolol group, a propranolol group, and a non-propranolol 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 pre-propranolol group to undergo any invasive treatment, 61% less likely to undergo surgical treatment, and 25% less likely to receive laser treatment.[65, 66]
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 beta2-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.
No protocol for initiating propranolol therapy in infants with hemangiomas is universally accepted. 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.
Provisional guidelines for initiation
Exclude infants with evidence of the following:
- Cardiac disease
- CNS vascular anomalies (suspected PHACE syndrome, large cervicofacial hemangiomas [see Mortality/Morbidity for PHACE syndrome definition]
Baseline laboratory tests and evaluation include the following:
- Blood glucose level
- Blood pressure check
- Electrocardiography (variable)
- Echocardiogram (if considering PHACE syndrome or other clinical indications)
- Pediatric cardiology consultation for evaluation and dosing recommendations (if any concerning findings)
Dosing - See below
Initially in the hospital (whether in or out of intensive care unit, cardiac care unit, or monitored bed), monitor for 24-72 hours; practices vary considerably.
Monitoring 1 hour after administration (dosing) includes the following:
- Blood pressure check
- Heart rate check (hold dose for heart rate at < 100 beats per min)
- Blood glucose level (due to potential blocking of liver glycogen phosphorylase): 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.
Consider 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).
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. Available as an oral solution (4.28 mg/mL).
Initially used as an antiviral agent in HIV-infected patients, interferon alfa-2a 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). Numerous studies have demonstrated the efficacy of interferon alfa-2a and interferon alfa-2b in treating infantile hemangiomas.[69, 70]
Because interferon alfa-2a works by a different mechanism, it can be used in lesions that are unresponsive to steroids. 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-2a 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.[72, 73] 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.
Interferon alfa-2a (Roferon-A)
Interferon alfa-2a is a protein product manufactured by recombinant DNA technology. Its mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles. Interferon alfa-2a may be given topically, systemically, and intralesionally.
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.
Biologic immune response modifiers
Only a few case reports and two small open-label uncontrolled trials suggest some minimal efficacy for the treatment of infantile hemangiomas.[75, 76, 77] 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 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.
Imiquimod is an immune response modifier indicated condyloma acuminata, actinic keratoses, and superficial basal cell carcinoma in adults. It is not approved by FDA for use in children.
A few reports in the literature (Metz, 2004) suggest this is helpful for ulcerated infantile hemangiomas, especially those in the diaper area. 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.
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