Adverse Events in Infants Treated With Topical Timolol for Infantile Hemangioma | PracticeUpdate
Adverse Events in Infants Treated With Topical Timolol for Infantile Hemangioma
This retrospective study evaluated 22 infants with infantile hemangiomas treated with topical timolol who were assessed for bradycardia using Holter monitoring. For this study, infants were classified as high risk if they received more than 2 drops of timolol per day, began therapy before 44 weeks' postmenstrual age, or received therapy applied to a site with a relatively high risk of systemic absorption. Episodic, asymptomatic bradycardia (heart rate <80 beats per minute) was detected by the Holter monitor in 2 infants and was unrelated to the timing of the timolol doses. These episodes are commonly seen in infants and are considered normal. Another 2 infants had symptomatic bradycardia; these infants both weighted less than 2500 g, were young at initiation of therapy, were preterm, had eyelid hemangiomas, and had a timolol dose above the median exposure for the cohort.
Topical timolol was safe for the treatment of infantile hemangiomas in this at-risk group. Infants weighing less than 2500 g or aged less than 44 weeks' postmenstrual age may be at risk for symptomatic bradycardia, including hypotension, apnea, and hypothermia, and should be monitored closely if timolol therapy is initiated.
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Since the first report of the efficacy of propranolol for infantile hemangioma (IH) treatment, the literature has exploded with case series of oral and topical beta-blocker use for this indication. Off-label use of topical maleate solution and gel-forming solution (GFS; 0.25% or 0.5%) has become commonplace for IH, with little or no available prospective pharmacokinetic or toxicity data. Timolol maleate GFS was approved in 2007 for pediatric glaucoma therapy, and systemic effects of bradycardia, hypotension, apnea, hypoglycemia, and bronchial reactivity are observed with pediatric intraocular use. In this study, Holter monitoring was performed in 22 infants at high risk for complications (ie, young infants, those using more than 2 drops, those with IH on mucosal sites, ulcerated IH, or IH under occlusion).
Dosing of timolol ranged from 2 to 6 drops per 24 hours divided into 2 doses. In total, 4 infants were noted to have bradycardia, and 2 of these were asymptomatic; the bradycardia seemed unrelated to the timing of application. The 2 infants who experienced symptomatic bradycardia were preterm, young, and had application doses higher than the median exposure. Of note, these infants had eyelid IH and bradycardia before timolol exposure and with later propranolol administration.
While topical timolol is a great option for small and non–function threatening IH, caution should be used in very young, small, and premature infants. No adverse events were noted in this study in infants receiving less than 0.2 mg/kg/day, and it would be worthwhile and reassuring to calculate dosing in infants prior to use. The timolol 0.5% GFS bottle dispenses 0.05 mL/drop and each drop contains 0.25 mg of timolol.
- For a 3-kg infant: 1 drops twice daily = 0.17 mg/kg/day.
- For a 4-kg infant: 1 drop three times daily = 0.19 mg/kg/day.
- For a 5-kg infant: 2 drops twice daily = 0.20 mg/kg/day.
Of note, in my practice, I use timolol in a 1 drop twice daily or 1 drop three times daily routine, with efficacy noted after several weeks of use. Efficacy often includes lack of continued hemangioma growth and decreased redness and thickness.
Abstract
BACKGROUND
The success of oral propranolol for treatment of infantile hemangiomas (IHs) has led practitioners to use topical β-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.
Adverse Events in Young and Preterm Infants Receiving Topical Timolol for Infantile Hemangioma
Pediatr Dermatol 2016 May 31;[EPub Ahead of Print], P Frommelt, A Juern, D Siegel, K Holland, M Seefeldt, J Yu, M Uhing, K Wade, B DroletSent from my iPad
posted by dermatica at
July 16, 2016
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