Safety and efficacy of topical timolol treatment of infantile haemangioma: a prospective trial

DEAR EDITOR, Topical timolol therapy is considered a relatively ‘safer’ alternative for the treatment of infantile haemangiomas (IH); however, sufficient supportive pharmacokinetic data does not exist. Most efficacy studies have not evaluated systemic absorption. To our knowledge, this is the first prospective trial (trial registration: NCT02145884) to assess the clinical response of proliferating IH to topical timolol maleate 0 5% gel-forming solution and to determine if systemic absorption occurred. The study was approved by the University of California San Diego institutional review board and 26 infants with IH were enrolled. These infants, aged 5–24 weeks, did not require systemic treatment and received timolol for 4 months. IH ≤ 2 cm in diameter received one drop twice daily; larger lesions received two drops twice daily. The patients were assessed at baseline, 2 and 4 weeks, and every 4 weeks thereafter; vital signs were obtained and IH size and colour were assessed. Standardized front, oblique and side view photographs were taken. A blood sample was obtained at week 2 to assess for systemic absorption. Significant response was defined as a smaller and lighter coloured haemangioma; minimal response as either a smaller or lighter haemangioma; and lack of response as either no change or an increase in height or colour. Logistic regression was used to calculate odds ratios for significant vs. minimal response. To assess timolol blood level, we used two-sample t-tests and Fisher’s exact tests. With blood level as a continuous variable, we used Spearman correlations. Facial location (42%) was most common, and there was an equal distribution at other sites (limb, scalp and trunk, 19% each). Size ranged from 0 02 to 10 5 cm. (A table of patient characteristics is available on request from the authors). The average time of timolol application before the blood draw was 3 45 h. Each drop (0 05 mL) of drug contained 0 25 mg of timolol. The mean dose of timolol was therefore 0 12 mg kg 1 daily. Six infants withdrew from the study before completion for reasons of convenience. In total, 20 patients were assessed for response at 16 weeks; 40% had a significant response to treatment, 95% (95% confidence interval 75 1–99 8%, P < 0 001) had at least a minimal response and one child did not respond. Of the infants, 24 underwent blood level analysis; 38% had detectable levels ranging from 0 3 to 1 6 ng mL . A significant relationship was found between blood level and dose (mg kg 1 daily) (Fig. 1). Infants with a detectable level had an average dose twice as high (0 18 mg kg 1 daily) as those without a detectable level (0 09 mg kg 1 daily) (P = 0 003). Per-protocol analysis did not reveal a significant relationship between the likelihood of a significant response to treatment and ascertainable blood level, chronological or gestational age, prematurity, sex, birth weight, ethnicity, dose, time from application or location. No relationship was noted between the risk factors (e.g. prematurity) evaluated and timolol blood levels. Ascertainable blood levels were noted in 44% of patients with treated scalp lesions, as compared with 0% on the face, 33% on the limbs and 22% on the trunk. A Kruskal–Wallis test showed significant differences between the locations after the level was normalized by dose, to account for the different size of IH (P = 0 034). A comparison between locations demonstrated that the plasma level on the face was different from the scalp (P = 0 003). No adverse effects were noted in our patients. Two other studies have investigated systemic absorption of topical timolol in infants with IH. One utilized abnormal Holter-monitoring findings as a surrogate marker for absorption and found a higher risk in patients treated with > 0 2 mg kg 1 daily. The other study evaluated urine timolol levels in treated patients, but neither prospectively evaluated plasma timolol levels in all patients. Most data on systemic absorption comes from ophthalmic or cardiology investigations. In one of the few studies that included children, five received one drop of timolol 0 25% solution twice daily in each eye 0·0 0·5 1·0 1·5 0· 00 0· 10 0· 20 0· 30