Infantile haemangioma: topical timolol

If the haemangioma is particularly large or affects areas where resolution may be incomplete such as around the nose, lips or ears.

If the haemangioma is ulcerating.

If the haemangioma is interfering with important functions or development of the senses, such as feeding, breathing, hearing or vision.

A systematic review and meta‑analysis of the efficacy and adverse effects of locally administered beta‑blockers for treating mainly superficial infantile haemangiomas included 9 studies of topical timolol (1 RCT and 8 observational studies, total n=279; Ovadia et al. 2015). The included studies varied in their treatment protocols (concentration of timolol, frequency of application and duration of treatment) and in how they measured response to treatment. The authors of the systematic review calculated response rates for each of the included studies and combined these using random effects models. Response was defined as a clinically significant change in the haemangioma after treatment, which represented at least a 20% decrease in size, a 5% decrease in volume, or a significant improvement as visually assessed by heath care providers or care givers. Response rates in the individual studies ranged from 47% (95% CI 24% to 71%) to 100% (95% CI 59% to 100%), with the meta‑estimate being 83% (95% CI 65% to 93%).

In the RCT included in the meta‑analysis (Chan et al 2013), 41 infants with small, focal superficial haemangiomas that did not require systemic therapy, were not ulcerated and were not near mucosal surfaces were randomised to 1 drop of topical timolol 0.5% (n=19) or placebo gel (n=22) applied twice daily. Response to treatment was assessed by estimating the volume of the haemangioma (based on measurements of its circumference) and scoring photographs of the haemangioma for redness (blinded to treatment allocation). There was no statistically significant difference in the volume of haemangiomas between the timolol group and the placebo group at any time point. In terms of relative reduction of size, at week 24, statistically significantly more haemangiomas had reduced in volume by at least 5% in the timolol group compared with the placebo group (60% compared with 11%, p≤0.04). However, specialists involved in the production of this evidence summary have suggested that a 5% reduction in volume is unlikely to be clinically significant. No statistically significant difference in photograph score distribution was seen at baseline or 12 weeks, but there was a difference at 24 weeks (p=0.003). At week 24 the proportion of scores of 0 (no redness) was 47% in the timolol group and 6% in the placebo group; and the proportion of scores of 2 (completely red) was 6% in the timolol group and 55% in the placebo group.

An RCT of 60 children with superficial or mixed infantile haemangiomas (Tawfik et al. 2015) compared between 1 and 3 drops of topical timolol 0.5% ophthalmic solution applied twice daily (n=30) with 595‑nm pulsed dye and 1064‑nm Nd:YAG laser treatment given monthly (n=30). Response, defined as regression or cessation of growth, shrinkage or flattening of the lesion, or lightening of surface colour, was assessed by the blinded evaluation of photographs and a skin analysis camera system to measure average haemoglobin levels of lesions. The authors report that 'excellent improvement' of between 76% and 100% in the parameters studied was seen in 40% of the timolol group compared with 20% of the laser group (no statistical analysis). For superficial haemangiomas, they report that earlier regression was seen with timolol compared with laser treatment and the timolol group had a shorter treatment duration. However, the degree of improvement of mixed haemangiomas was greater in the laser group.

The largest prospective study of topical timolol for the treatment of infantile haemangiomas (Yu et al 2013) included 124 infants with cutaneous superficial haemangiomas. Of these, 101 received topical 0.5% timolol drops applied 3 times a day, with erythromycin ointment applied around the lesion to stop the drops from leaking. The other 23 infants underwent observation only. Response was evaluated from photographs with changes in colour, size and texture recorded. At 4 months, timolol was ineffective in 8 patients (8%), controlled the growth of the haemangioma in 36 patients (36%) and promoted regression in 57 patients (56%). Complete regression was seen in 12 patients who stopped receiving the drug and showed no relapse during the next 3 to 5 months follow‑up. In the observation group, the lesion continued to grow in 15 patients (65%), 7 patients (30%) had controlled growth and 1 patient (4%) had regression.

The largest retrospective cohort study of topical timolol for the treatment of infantile haemangiomas (Chakkittakandiyil et al. 2012) included 73 infants treated with timolol 0.1% (11/73) or 0.5% (62/73) gel‑forming solution applied twice daily for a mean of 3.4±2.7 months. Of the 62 patients for whom data were available, 46 (74%) had superficial haemangiomas, 14 (23%) had mixed haemangiomas and 2 (3%) had deep haemangiomas. None of the haemangiomas were ulcerated. Results were evaluated by rating photographs using a visual analogue scale (VAS). The VAS used a 100 mm scale on which −100 mm represented a doubling in the size and extent of the lesion, 0 represented no change and +100 mm represented complete shrinkage, with 5 mm reflecting a 10% change. At the last follow‑up visit, the mean improvement in the appearance of the haemangioma from baseline was 45±29.5%.

If absorbed systemically, timolol can cause the same types of cardiovascular, pulmonary and other adverse reactions seen with other beta‑blockers. Systemic absorption has been shown with timolol used topically to treat infantile haemangiomas. However, the actual number of adverse events seen in studies of topical timolol for the treatment of infantile haemangiomas is low. In the systematic review and meta‑analysis (Ovadia et al. 2015), 1 adverse effect was reported across the 9 studies of topical timolol (total n=279). This was sleep disturbance in 1 infant in the retrospective study by Chakkittakandiyil et al. 2012. The other studies reported no local or systemic adverse effects. In the placebo‑controlled RCT by Chan et al. 2013, mean heart rate, systolic blood pressure and diastolic blood pressure did not differ between treatment with topical timolol or placebo and no cases of bradycardia or hypotension were reported. In the RCT comparing topical timolol with laser treatment (Tawfik et al. 2015), shortness of breath and insomnia were reported in 1 patient in the timolol group. In both RCTs, infants or children with wheezing or asthma, cardiac rhythm disturbances or heart disease were excluded.

Overall, limited high‑quality evidence was found that investigated how effective topical timolol is for the treatment of infantile haemangiomas. Only 2 small RCTs were identified (n=41 and n=60) along with observational studies. The systematic review and meta‑analysis (Ovadia et al. 2015) provides a useful summary of the efficacy and safety of topical timolol for treating mainly superficial infantile haemangiomas. However, it has several limitations inherent in the methodology which combines results from 1 RCT and 8 observational studies (n=7 to 101) which varied in their treatment protocols and in how they measured response to treatment. There is no validated assessment for treatment response in infantile haemangiomas, and it is difficult to evaluate whether the responses seen in the studies are clinically significant. All the studies included in this evidence summary used different scoring systems to measure response. The studies are also too small to analyse any rare adverse events.

Most of the evidence for using topical timolol is in the treatment of small, superficial infantile haemangiomas. Specialists have suggested that topical timolol may offer an alternative to using oral propranolol in these cases, if the clinician and the parents choose to treat the haemangioma. However, it may also be appropriate to choose not to treat such haemangiomas. Neither topical timolol nor most oral propranolol preparations are licensed for treating infantile haemangiomas.