NIHR Signal Propranolol generally safe in treating childhood haemangioma birthmarks

Published on 17 January 2017

Treating ‘infantile haemangioma’ strawberry birthmarks with oral propranolol is known to be effective and in this review was associated with low levels of adverse events. The most common adverse events included coldness in the hands and feet, diarrhoea, sleep disorders and upper respiratory infections.

More serious problems such as low blood pressure, slow heart rate, over-reactivity of the airways and low blood sugar were also reported. Though rare, parents and prescribers need to be aware of these side effects.

There is currently no UK guidance on treating haemangioma. The beta-blocker propranolol is usually used to treat heart conditions. Although commonly used, UK preparations of this drug are not specifically licensed to be marketed to treat haemangioma.

This systematic review gathered safety data from 83 studies, along with additional non-published data collected by manufacturers of the brand licensed in Europe (Hemangiol).

The findings indicates that propranolol is generally safe to use, but reinforce the need to assess children for risk factors before prescribing, and monitor for adverse events.

Why was this study needed?

Infantile haemangiomas, or strawberry birthmarks, are a cluster of abnormal blood vessels under the skin which form a red to purple lump. They affect around 5% of children, most commonly girls, and about 60% are on the head or neck, although they can occur anywhere on the body.

Strawberry birthmarks tend to grow rapidly for the first six months of life, before gradually shrinking and disappearing by around the age of seven. A small number, around 10-15%, require treatment due to their size or position, for example if they interfere with the child’s airway or are close to the eye.

Since 2008 it has been recognised that propranolol (a drug from the beta blocker group) may have benefits. Studies have shown propranolol to be more effective than other options such as steroids or creams and it is now considered the treatment of choice with response rates of up to 98%. This review is the first to focus specifically on the safety of propranolol.

What did this study do?

This systematic review investigated the number and type of adverse events that have resulted from propranolol treatment of strawberry birthmarks.

The authors identified 83 relevant publications by searching two literature databases for studies of any design reporting side effects from this use. From the manufacturer they accessed pooled data from three unpublished clinical trials, along with safety data from a “compassionate use programme” (CUP) for people not eligible for trials. Together these sources provided data for 5,862 children.

Propranolol doses ranged from 1mg to 3mg per kilogram body weight daily. Children were treated for an average six months.

The study designs varied (only four from the literature were randomised trials). As a result quality and potential for bias was not assessed, which reduces confidence in the findings. Nevertheless the review of observational data provides a useful overview of the safety data available.

What did it find?

  • A low proportion of children experienced adverse events thought related to propranolol in studies from the literature (15.3%) and CUP (9.7%). The manufacturer’s studies reported a much higher rate at 38.2%, but there was also an unexplained high rate of treatment-related adverse effects reported for children receiving placebo (15.3%). Across all three data sources, 2.5% of children withdrew treatment as a result of side effects.
  • The most common adverse events were slow heart rate (4.4%) and low blood pressure (3 to 4%).There were a further five cases of slow heart rate and seven of low blood pressure, and two serious cardiovascular effects (atrioventricular heart block). All of these adverse effects resolved after stopping treatment.
  • Bronchitis (inflammation of the main airways) was reported in 9.4% in the manufacturer’s trials. Bronchiolitis (infection and inflammation of the small airways within the lungs) was reported in 6.2% and was also the most common adverse effect reported in CUP data (2.3%).
  • Across all three data sources there were also 33 cases of low blood sugar, and four cases of fit (seizure) reported as a result.
  • Other common non-serious adverse events reported across all three sources included coldness in the hands and feet, diarrhoea and sleep disorders. High temperature, coughs, colds and sore throats were also reported by up to a quarter of people in the manufacturer’s trials.
  • Five children across all three data sources died, but no deaths were related to treatment.

What does current guidance say on this issue?

There is currently no UK guidance on this topic. NICE has published an evidence summary to provide advice on the use of another beta-blocker (timolol) applied as a cream to the haemangioma.

These authors do point to other reviews that say that propranolol is now considered first-line therapy for those haemangiomas requiring systemic therapy. They quote a response rate of up to 98% for propranolol compared with other therapies with lower rates, such as corticosteroids.

Currently timolol and propranolol are marketed for treating other conditions but are not specifically approved for use in treating haemangioma.  

A specific propranolol product, Hemangiol, is licensed for sale across Europe for treating haemangioma, but it is not available in the UK.

What are the implications?

Propranolol is widely used for treating haemangioma and the evidence indicates that it is effective. This review further suggests that propranolol is generally safe, though the rare reports of serious cardiovascular, respiratory and metabolic side effects will need monitoring.

Direct comparison of rates across studies is challenging as the studies varied in how they reported and monitored adverse events.

The adverse events observed were all already known to be associated with propranolol, but are now quantified. This will allow a more informed decision by parents and their paediatrician. There remains a need to assess the risk of propranolol on an individual basis (for example if the child has asthma), and provide appropriate monitoring to detect adverse events.

Citation and Funding

Léaute-Labrèze C, Boccara O, Degrugillier-Chopinet C, et al. Safety of Oral Propranolol for the Treatment of Infantile Hemangioma: A Systematic Review. Pediatrics. 2016;138(4). pii: e20160353.

All phases of this study were funded by Pierre Fabre Dermatologie.

Bibliography

BAD. Haemangioma of infancy. London: British Association of Dermatologists; 2016.

BNFC. Propranolol. London: National Institute for Health and Care Excellence; 2016.

BNFC. Propranolol hydrochloride. London: National Institute for Health and Care Excellence; 2016.

EMA. Hemoangiol. London: European Medicines Agency; 2014.

EMC. Propranolol Rosemont 5mg/5ml Oral Solution. European Medicines Consortium; 2016.

NICE. Infantile haemangioma: topical timolol. ESUOM47. London: National Institute for Health and Care Excellence; 2015.

NHS Choices. Birthmarks. London: Department of Health; 2016.

NHS Choices. Treating birthmarks. London: Department of Health; 2016.

Why was this study needed?

Infantile haemangiomas, or strawberry birthmarks, are a cluster of abnormal blood vessels under the skin which form a red to purple lump. They affect around 5% of children, most commonly girls, and about 60% are on the head or neck, although they can occur anywhere on the body.

Strawberry birthmarks tend to grow rapidly for the first six months of life, before gradually shrinking and disappearing by around the age of seven. A small number, around 10-15%, require treatment due to their size or position, for example if they interfere with the child’s airway or are close to the eye.

Since 2008 it has been recognised that propranolol (a drug from the beta blocker group) may have benefits. Studies have shown propranolol to be more effective than other options such as steroids or creams and it is now considered the treatment of choice with response rates of up to 98%. This review is the first to focus specifically on the safety of propranolol.

What did this study do?

This systematic review investigated the number and type of adverse events that have resulted from propranolol treatment of strawberry birthmarks.

The authors identified 83 relevant publications by searching two literature databases for studies of any design reporting side effects from this use. From the manufacturer they accessed pooled data from three unpublished clinical trials, along with safety data from a “compassionate use programme” (CUP) for people not eligible for trials. Together these sources provided data for 5,862 children.

Propranolol doses ranged from 1mg to 3mg per kilogram body weight daily. Children were treated for an average six months.

The study designs varied (only four from the literature were randomised trials). As a result quality and potential for bias was not assessed, which reduces confidence in the findings. Nevertheless the review of observational data provides a useful overview of the safety data available.

What did it find?

  • A low proportion of children experienced adverse events thought related to propranolol in studies from the literature (15.3%) and CUP (9.7%). The manufacturer’s studies reported a much higher rate at 38.2%, but there was also an unexplained high rate of treatment-related adverse effects reported for children receiving placebo (15.3%). Across all three data sources, 2.5% of children withdrew treatment as a result of side effects.
  • The most common adverse events were slow heart rate (4.4%) and low blood pressure (3 to 4%).There were a further five cases of slow heart rate and seven of low blood pressure, and two serious cardiovascular effects (atrioventricular heart block). All of these adverse effects resolved after stopping treatment.
  • Bronchitis (inflammation of the main airways) was reported in 9.4% in the manufacturer’s trials. Bronchiolitis (infection and inflammation of the small airways within the lungs) was reported in 6.2% and was also the most common adverse effect reported in CUP data (2.3%).
  • Across all three data sources there were also 33 cases of low blood sugar, and four cases of fit (seizure) reported as a result.
  • Other common non-serious adverse events reported across all three sources included coldness in the hands and feet, diarrhoea and sleep disorders. High temperature, coughs, colds and sore throats were also reported by up to a quarter of people in the manufacturer’s trials.
  • Five children across all three data sources died, but no deaths were related to treatment.

What does current guidance say on this issue?

There is currently no UK guidance on this topic. NICE has published an evidence summary to provide advice on the use of another beta-blocker (timolol) applied as a cream to the haemangioma.

These authors do point to other reviews that say that propranolol is now considered first-line therapy for those haemangiomas requiring systemic therapy. They quote a response rate of up to 98% for propranolol compared with other therapies with lower rates, such as corticosteroids.

Currently timolol and propranolol are marketed for treating other conditions but are not specifically approved for use in treating haemangioma.  

A specific propranolol product, Hemangiol, is licensed for sale across Europe for treating haemangioma, but it is not available in the UK.

What are the implications?

Propranolol is widely used for treating haemangioma and the evidence indicates that it is effective. This review further suggests that propranolol is generally safe, though the rare reports of serious cardiovascular, respiratory and metabolic side effects will need monitoring.

Direct comparison of rates across studies is challenging as the studies varied in how they reported and monitored adverse events.

The adverse events observed were all already known to be associated with propranolol, but are now quantified. This will allow a more informed decision by parents and their paediatrician. There remains a need to assess the risk of propranolol on an individual basis (for example if the child has asthma), and provide appropriate monitoring to detect adverse events.

Citation and Funding

Léaute-Labrèze C, Boccara O, Degrugillier-Chopinet C, et al. Safety of Oral Propranolol for the Treatment of Infantile Hemangioma: A Systematic Review. Pediatrics. 2016;138(4). pii: e20160353.

All phases of this study were funded by Pierre Fabre Dermatologie.

Bibliography

BAD. Haemangioma of infancy. London: British Association of Dermatologists; 2016.

BNFC. Propranolol. London: National Institute for Health and Care Excellence; 2016.

BNFC. Propranolol hydrochloride. London: National Institute for Health and Care Excellence; 2016.

EMA. Hemoangiol. London: European Medicines Agency; 2014.

EMC. Propranolol Rosemont 5mg/5ml Oral Solution. European Medicines Consortium; 2016.

NICE. Infantile haemangioma: topical timolol. ESUOM47. London: National Institute for Health and Care Excellence; 2015.

NHS Choices. Birthmarks. London: Department of Health; 2016.

NHS Choices. Treating birthmarks. London: Department of Health; 2016.

Safety of Oral Propranolol for the Treatment of Infantile Hemangioma: A Systematic Review

Published on 1 October 2016

Leaute-Labreze, C.,Boccara, O.,Degrugillier-Chopinet, C.,Mazereeuw-Hautier, J.,Prey, S.,Lebbe, G.,Gautier, S.,Ortis, V.,Lafon, M.,Montagne, A.,Delarue, A.,Voisard, J. J.

Pediatrics , 2016

BACKGROUND AND OBJECTIVES: Given the widespread use of propranolol in infantile hemangioma (IH) it was considered essential to perform a systematic review of its safety. The objectives of this review were to evaluate the safety profile of oral propranolol in the treatment of IH. METHODS: We searched Embase and Medline databases (2007-July 2014) and unpublished data from the manufacturer of Hemangiol/Hemangeol (marketed pediatric formulation of oral propranolol; Pierre Fabre Dermatologie, Lavaur, France). Selected studies included >/=10 patients treated with oral propranolol for IH and that either reported >/=1 adverse event or effect (AE) or planned to capture AEs. Data capture was standardized and extracted study design, demographic characteristics, IH characteristics, intervention, and safety outcomes. AEs were assigned a system organ class and preferred term. RESULTS: A total of 83 of 398 identified literature records met the inclusion criteria, covering 3766 propranolol-treated patients. The manufacturer's data for 3 pooled clinical trials (435 propranolol-treated patients) and 1 Compassionate Use Program (1661 patients) were included. AE data were reported for 1945 of 5862 propranolol-treated patients. The most frequently reported AEs included a range of sleep disturbances, peripheral coldness, and agitation. The most serious AEs (atrioventricular block, bradycardia, hypotension, bronchospasm/bronchial hyperreactivity, and hypoglycemia-related seizures) were managed by decreasing doses or temporary/permanent discontinuation of propranolol. Limitations included the variety of included study designs; monitoring, collection, and reporting of AE data; small sample sizes for some articles; and the wide scope of review. CONCLUSIONS: Oral propranolol is well tolerated if appropriate pretreatment assessments and within-treatment monitoring are performed to exclude patients with contraindications and to minimize serious side effects during treatment.

Expert commentary

This paper provides a very useful summary of the current data regarding the use of propranolol for the treatment of infantile haemangiomas (strawberry naevi). Propranolol (average 2.1 mg/kg/day for 7.7 months) was generally well tolerated; severe side effects of propranolol were identified in a small number of cases (bradycardia, hypotension, bronchospasm, hypoglycaemia). Although these were mostly detected within the first week, some cases presented after many weeks of treatment. These findings justify the need for pre-treatment screening and post-treatment safety monitoring when prescribing propranolol for the treatment of infantile haemangiomas.

Dr Michael Ardern-Jones, Consultant Dermatologist, University Hospital Southampton

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