Key points from the evidence

Summary

Limited evidence from 2 small randomised controlled trials (RCTs) and several observational studies suggests that topical timolol reduces the redness of superficial haemangiomas and may reduce their size or volume, but the clinical significance of these changes is unclear. The number of adverse events seen in the studies was low. However, systemic absorption has been shown with timolol used topically to treat infantile haemangiomas and larger studies would be useful to provide more safety data.

Regulatory status: off‑label. This topic was prioritised because there was a high volume of requests from the NHS.

Effectiveness

  • In a systematic review and meta‑analysis of 9 studies of topical timolol for mainly superficial infantile haemangiomas (1 RCT and 8 observational studies, total n=279), response rates ranged from 47% (95% confidence interval [CI] 24% to 71%) to 100% (95% CI 59% to 100%) in the individual studies, with a meta‑estimate of 83% (95% CI 65% to 93%). Response was defined as at least a 20% decrease in size, a 5% decrease in volume, or a significant improvement assessed visually by heath care providers or care givers.

  • In a placebo‑controlled RCT (n=41), there was no statistically significant difference in the volume of superficial haemangiomas with timolol at week 24, but scores for redness were different (p=0.003). The proportion of scores of 0 (no redness) was 47% with timolol and 6% with placebo. The proportion of scores of 2 (completely red) was 6% with timolol and 55% with placebo.

  • In a RCT comparing topical timolol with laser treatment (n=60), there was greater improvement in lesion growth or colour, and shorter treatment duration with timolol compared with laser treatment for superficial haemangiomas, but the degree of improvement of mixed haemangiomas was greater in the laser group.

Safety

  • Adverse effects that could occur from systemic absorption of timolol include bradycardia, hypotension, bronchospasm, peripheral vasoconstriction, weakness and fatigue, sleep disturbance and hypoglycaemia. However, the number of adverse events seen in studies of topical timolol for infantile haemangiomas is low.

  • In a systematic review and meta‑analysis of 9 studies of topical timolol (total n=279) there was 1 adverse event of sleep disturbance.

  • In a placebo‑controlled RCT (n=41) mean heart rate and blood pressure did not differ between topical timolol and placebo and no cases of bradycardia or hypotension were seen.

  • In a RCT comparing topical timolol with laser treatment (n=60) shortness of breath and insomnia were reported in 1 child in the timolol group.

  • The RCTs excluded infants or children with wheezing or asthma, cardiac rhythm disturbances or heart disease.

Patient factors

  • Topical timolol is available in a variety of formulations, mainly as eye drops or gels, which are applied directly to the surface of the haemangioma.

  • In the studies included in this review, topical timolol was applied between 1 and 5 times a day. Great Ormond Street Hospital use the gel‑forming eye drops solution, Timoptol‑LA 0.5%, applied at a dose of 1 drop 3 times a day.

  • Topical timolol is generally well tolerated.

  • Most of the evidence for using topical timolol is for treating often small, superficial infantile haemangiomas.

Resource implications

  • Timolol 0.5% eye drops solution is £1.30 for 1×5 ml and Timoptol‑LA 0.5% gel‑forming eye drops solution is £3.12 for 1×2.5 ml (Drug Tariff, July 2015).

Introduction and current guidance

Infantile haemangiomas (commonly known as strawberry marks or naevi) are benign vascular lesions that typically appear during the first 4 to 6 weeks of life. They have a characteristic evolution with early rapid growth (proliferation), followed by a stabilisation period and a slow spontaneous involution. Infantile haemangiomas differ greatly in terms of size, location, risk of complication, rate of proliferation and involution, and results after involution, and treatment is therefore individualised. The British Association of Dermatologists haemangioma of infancy information leaflet states that most haemangiomas do not require treatment except in the following situations:

  • 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.

Treatments, which are generally off‑label, can include topical, oral, intravenous or intralesional corticosteroids, topical timolol, oral propranolol, laser treatment or surgery. Emollients, non‑adherent dressings, pain relief and antibiotics may also be required.

In April 2014, an oral propranolol product, Hemangiol 3.75 mg/ml oral solution, received a Europe‑wide marketing authorisation for the treatment of proliferating infantile haemangioma requiring systemic therapy. Hemangiol has not been launched in the UK.

Full text of introduction and current guidance.

Product overview

Timolol is a beta‑blocker, which is used topically in eye drops to reduce raised intra‑ocular pressure. In 2008, the beta‑blocker propranolol was found to be effective at treating infantile haemangiomas, when taken orally. Since then topical treatment with propranolol or timolol has been investigated. There are no topical timolol preparations licensed for treating infantile haemangiomas, and the use of any topical timolol preparation for this condition would be off‑label.

The product currently used off‑label at Great Ormond Street Hospital to treat infantile haemangiomas is the gel‑forming eye drops solution, Timoptol-LA 0.5%, applied at a dose of 1 drop 3 times a day (Great Ormond Street Hospital: treating small infantile haemangiomas with topical timolol).

Full text of product overview.

Evidence review

  • 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.

Full text of evidence review.

Context and estimated impact for the NHS

Timolol 0.5% eye drops solution is £1.30 for 1×5 ml. Timoptol‑LA 0.5% gel‑forming eye drops solution is £3.12 for 1×2.5 ml (Drug Tariff, July 2015).

No estimate of the current use of off‑label topical timolol for treating infantile haemangioma is available.

Full text of context and estimated impact for the NHS.

Information for the public

A plain English summary is available on the NICE website. This sets out the main points from the evidence summary in non‑technical language and may be especially helpful for parents or carers of infants with haemangiomas who are thinking about trying topical timolol treatment.

About this evidence summary

'Evidence summaries: unlicensed or off‑label medicines' summarise the published evidence for selected unlicensed or off‑label medicines that are considered to be of significance to the NHS, where there are no clinically appropriate licensed alternatives. The summaries provide information for clinicians and patients to inform their decision‑making and support the construction and updating of local formularies.

The summaries support decision‑making on the use of an unlicensed or off‑label medicine for an individual patient, where there are good clinical reasons for its use, usually when there is no licensed medicine for the condition requiring treatment, or the licensed medicine is not appropriate for that individual.

The strengths and weaknesses of the relevant evidence are critically reviewed within this summary, but this summary is not NICE guidance.