Variability of Delivery of Timolol for the Treatment of Infantile Hemangiomas.

BACKGROUND/OBJECTIVES: Topical timolol maleate solution or gel-forming solution is used alone or in conjunction with oral propranolol for the treatment of infantile hemangiomas. The consistency of the amount of timolol dispensed has never been evaluated. We evaluated the variability of drug delivery between different brands and formulations of timolol solution and gel-forming solution. METHODS: Five blinded volunteers sequentially dispensed five drops from each of the eight bottles containing timolol 0.5% solution or gel-forming solution. This was repeated three times per user for each bottle. The average amount of timolol dispensed was analyzed according to brand, formulation, and user for variability. The intra- and interuser variability of dispensing both formulations of timolol was also measured. RESULTS: Our study demonstrates statistically significant differences in the amount of timolol dispensed between timolol solution and gel-forming solution, with the latter closer to manufacturer estimates. Significant differences in the amount of timolol dispensed were noted between users regardless of the formulation or brand. Variability in the amount of timolol dispensed was greater for gel-forming solution than 0.5% solution. Inter- and intrauser variability in the amount of timolol dispensed was greater for gel-forming solution than 0.5% solution. CONCLUSION: Statistically significant differences were noted in the amount of timolol dispensed according to formulation, brand, and user. Whether this is clinically significant is unknown given the lack of pharmacokinetic data available for timolol.

Adverse Events in Young and Preterm Infants Receiving Topical Timolol for Infantile Hemangioma.

BACKGROUND: The success of oral propranolol for treatment of infantile hemangiomas (IHs) has led practitioners to use topical ß-blockers. In preterm infants, clinicians frequently turn to topical timolol, with the presumption that topical application will result in less systemic absorption. We used Holter monitoring to assess for drug-induced bradycardia in high-risk infants. METHODS: We retrospectively reviewed the charts of 22 at-risk infants who received a Holter monitor to assess for association between timolol administration and development of significant bradycardia. RESULTS: Four infants had episodic bradycardia detected by Holter monitoring. Two of these infants were full term; weighed more than 3,000 g; and had rare, brief, asymptomatic episodes unrelated to the timing of the timolol application. The other two infants had symptomatic bradycardia while on timolol and were the only two babies that weighed less than 2,500 g at initiation of therapy. Both were young (postmenstrual age [PMA] 34 and 37 wks) at initiation and had a timolol dose above the average exposure for the cohort. CONCLUSION: In this cohort of at-risk infants, topical timolol appeared to provide safe treatment for IHs in full-term infants receiving a dose of less than 0.2 mg/kg/day, but infants with a PMA of less than 44 weeks and weight at treatment initiation of less than 2,500 g may be at risk of adverse events, including bradycardia, hypotension, apnea, and hypothermia. We recommend close monitoring of temperature, blood pressure, and heart rate in premature and low-birthweight infants with IHs at initiation of and during therapy with topical timolol.

Infantile hemangiomas: an update.

Infantile hemangioma (IH) is a common vascular tumor of infancy. Although benign, infants with IH can experience complications including ulceration, visual and airway impairment, and residual scarring and disfigurement. It is often challenging for clinicians to predict which tumors are in need of systemic treatment. However, data from various demographic and other studies have revealed further insights into this tumor. This article reviews the identification, evaluation, and management of high-risk IHs, including the indications for treatment and the use of systemic treatments such as corticosteroids, ß-blockers, and vincristine.

Propranolol treatment of infantile hemangiomas: anticipatory guidance for parents and caretakers.

Infantile hemangiomas (IH) are benign tumors of endothelial-like cells. Occurring in 4.5% of children, they are the most common tumor of childhood. The great majority of patients with IH will not need treatment, but 10% require systemic treatment. Many treatments have been described for the treatment of IH, but the Food and Drug Administration has not approved any. Over the last decade, numerous reports of successful treatment of IH with propranolol have been published. Despite its widespread use, little is known regarding the proper dosing, safety monitoring, and during of treatment or long-term outcomes for propranolol treatment of IH. Given its potential side effects, detailed education regarding proper administration of the medication as well as warning signs to watch for is necessary for parents and caretakers. Herein, we provide a parental handout that practitioners can individually tailor for use in their clinics when educating parents and caretakers about the use of propranolol for IH. Updates will also need to be made as more is learned regarding the optimal dosing and safety monitoring when using propranolol for this indication.

Initiation and use of propranolol for infantile hemangioma: report of a consensus conference.

Infantile hemangiomas (IHs) are common neoplasms composed of proliferating endothelial-like cells. Despite the relative frequency of IH and the potential severity of complications, there are currently no uniform guidelines for treatment. Although propranolol has rapidly been adopted, there is significant uncertainty and divergence of opinion regarding safety monitoring, dose escalation, and its use in PHACE syndrome (PHACE = posterior fossa, hemangioma, arterial lesions, cardiac abnormalities, eye abnormalities; a cutaneous neurovascular syndrome characterized by large, segmental hemangiomas of the head and neck along with congenital anomalies of the brain, heart, eyes and/or chest wall). A consensus conference was held on December 9, 2011. The multidisciplinary team reviewed existing data on the pharmacologic properties of propranolol and all published reports pertaining to the use of propranolol in pediatric patients. Workgroups were assigned specific topics to propose protocols on the following subjects: contraindications, special populations, pretreatment evaluation, dose escalation, and monitoring. Consensus protocols were recorded during the meeting and refined after the meeting. When appropriate, protocol clarifications and revision were made and agreed upon by the group via teleconference. Because of the absence of high-quality clinical research data, evidence-based recommendations are not possible at present. However, the team agreed on a number of recommendations that arose from a review of existing evidence, including when to treat complicated IH; contraindications and pretreatment evaluation protocols; propranolol use in PHACE syndrome; formulation, target dose, and frequency of propranolol; initiation of propranolol in infants; cardiovascular monitoring; ongoing monitoring; and prevention of hypoglycemia. Where there was considerable controversy, the more conservative approach was selected. We acknowledge that the recommendations are conservative in nature and anticipate that they will be revised as more data are made available.