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Eur. J. Pediat. Dermatol.23, 93-104, 2013

Evaluation of safety and efficacy of a galenic preparation of 1%propranolol in 89 cases of cutaneous infantile hemangioma.

Bonifazi E., Milano A., Colonna V.Dermatologia Pediatrica, Bari, Italy

Summary Once discovered the effectiveness of oral propranolol on hemangioma, it was natural for the dermatologist to test its topical activity. Topical therapy of infantile hemangioma is indi-cated for hemangiomas with prevailing superficial component, when it is useful to accelera-te their regression. Before the discovery of propranolol topical therapy of hemangioma was based on corticosteroids and more recently on imiquimod, neither devoid of side effects. After the discovery of propranolol topical therapy was based mainly on beta-blockers, in particular on timolol already commercially available for the therapy of glaucoma and pro-pranolol. 89 children with infantile hemangioma were treated with topical 1% propranolol in this study that highlights the safety and efficacy of the treatment. Topical propranolol, for its lower systemic absorption, is to be preferred to timolol.

Key words Topical propranolol, hemangioma.

The majority of cases of infantile hemangioma (IH) does not need any treatment having regard to its spontaneous regression. However a low per-centage of IH estimated at around 10% of cases needs a treatment, which will be systemic in ca-ses that threaten the patient’s life or the function of an important organ (larynx, eye, liver), syste-mic or topical in case of compromise of a less important organ (for example in cases disturbing the support or prehensile function for an IH of the palmar-plantar region) or when a significant es-thetic damage is expected may persist as the child enters alone in a group of peers (kindergarten): you will choose the topical or systemic treatment based on the existence of a deep component, ul-ceration, extension of HI and according to the site of the same.

As regards topical treatment, to the oldest cor-ticosteroids and more recent imiquimod, neither devoid of important side effects (8, 14), since 2008 has been added propranolol (3) and further

timolol for the pharmacological similarity in ad-dition to the commercial availability (22). Below are the figures of a prospective study of 89 cases of IH treated with 1% topical propranolol.

Material and methods

From July 2008 to November 2012, we propo-sed a topical treatment with propranolol to 112 children consecutively observed in the clinic pre-senting hemangioma with exclusive or predomi-nant superficial component and with a maximum diameter of 6 cm. 89 children (62 females and 27 males) aged between 3 and 52 weeks (mean age at onset of therapy 10 weeks and 3 days) entered the study. Particularly, the age of onset of topical treatment was 3-9 weeks in 38 cases (low initial age), 10-20 weeks in 39 cases (intermediate ini-tial age) and 22-52 weeks in 12 cases (high initial age).

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Fig. 1 Fig. 2Fig. 1, 2: The topical treatment is indicated in hemangiomas with prevailing superficial component when it is useful to ac-celerate their regression.

Regarding the affected site were treated 46 he-mangiomas of the head and neck, 18 of the up-per limbs (mainly hands-wrists), 14 of the trunk (mainly neckline and mammary region), 4 of the lower limbs (mostly surfaces of support); 7 chil-dren had multiple hemangiomas in different loca-tions and in this case only the hemangioma of the most visible site was treated.

Each hemangioma was photographed at the moment of entering the study. Parents applied on hemangioma 2 times a day a galenic preparation of 1% propranolol hydrochloride in fat base cre-am for a maximum daily quantity not more than 2 mg/kg of weight: for example, in a child wei-ghing 5 kg the jar containing 10 g of cream, and then 100 mg of propranolol, had to last at least 10 days.

The parents were informed that the galenic preparation was not yet officially on the market and gave their consent to treatment. They were also informed that any activity of propranolol

would be carried out only on the superficial com-ponent so that its use would not have prevented the possible growth of a deep component of he-mangioma.

In the first month was treated only a portion of hemangioma representative of the entire le-sion and not more than 50% of the same. After 1 month, during the first control visit, when the treated portion of IH was less congested and/or less infiltrated compared with the untreated, the-rapy was extended to the whole hemangioma and continued for 4-6 months.

In 9 cases the treatment was withdrawn for lack of improvement in the treated portion. The control examinations were carried once a month up to 3 months after the withdrawal of treatment. In each visit hemangioma was photographed and evaluated comparatively with the previous photo. At the last check-up the evaluation was expres-sed in 3 grades: excellent, for a regression greater than 60% (Fig. 3-8), poor, for a regression less

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than 20% (Fig.13-16), fair in the other cases (Fig. 9-12).

In order to put in evidence a possible contact sensitization at the end of treatment a patch test with propranolol 1% aqueous solution was per-formed in 36 children and 40 parents who had applied the topical preparation. The test was read after 48 hours.

Results

59 children followed the treatment protocol until the end and are therefore evaluable; 9 cases (4 of high initial age, 3 of intermediate initial age and 2 of low initial age) dropped out for a lack of improvement of the treated portion after the first month of treatment. 21 cases dropped out from

1% topical propranolol in superficial hemangioma

Fig. 3 Fig. 4

Fig. 5 Fig. 6

Fig. 7 Fig. 8Fig. 3, 4, 5, 6, 7, 8: Examples of excellent result before (Fig. 3, 5, 7) and after 1% topical propranolol (Fig. 4, 6, 8).

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the study for the appearance of a deep compo-nent (8 cases) or did not return at two consecutive control visits (13 cases): 4/21 cases were of high initial age, 11 of low initial age and 6 of interme-diate initial age. Of the 59 evaluable cases, 26 cases (20 localized on the face, 3 on the trunk and 3 on the upper limbs) had an excellent result, 22 cases (16 localized on the face, 2 on the trunk, 1 on the upper limbs and 1 on the lower limbs) a fair result and 11 (7 localized on the face, 2 on the upper limbs, 1 on the trunk and 1 on the lower limbs) a poor result.

As regards the age of onset of topical therapy of 25 evaluable cases with low initial age 13 had an excellent result, 8 fair and 4 poor; of 30 eva-luable cases with intermediate initial age 10 had an excellent result, 16 fair and 4 poor. Finally, of 4 evaluable cases with high initial age 1 had a fair result and 3 poor.

The patch test was negative in 36 children tre-ated with topical propranolol and in 40 parents. We never observed side effects neither local of irritant type nor systemic.

Discussion

Until 2008 the topical therapy of hemangioma had few indications, because the drugs most of-ten used, i.e. corticosteroids and imiquimod, al-though effective, were not without side effects, especially ulceration. The latter, which is not exceptional even without the use of any drug, is favored by thinning of the skin in the case of cor-ticosteroids, and significant irritating ability in the case of imiquimod.

The discovery of propranolol actvity on he-mangioma (13) had as a logical consequence

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Fig. 9 Fig. 10

Fig. 11 Fig. 12Fig. 9, 10, 11, 12: Examples of fair result before treatment (Fig. 9, 11) and after treatment with 1% topical propranolol (Fig. 10, 12).

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verification of its safety and efficacy for topical administration (3), similarly to what had already happened in the past for many drugs that showed activity on skin and hair disorders, from cortico-

steroids to tacrolimus, from minoxidil to finaste-ride.

Safety control of topical propranolol. The per-cutaneous absorption of propranolol has been in-

1% topical propranolol in superficial hemangioma

Fig. 13 Fig. 14

Fig. 13, 14, 15, 16: Examples of poor result before treatment (Fig. 13, 15) and after 1% topical propranolol (Fig. 14, 16).Fig. 15 Fig. 16

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vestigated both in experimental animal (10) and in human skin in vitro (1) in the context of studies designed to test the possibility of percutaneous administration of the drug, in order to avoid the liver inactivation. The latter is very different from individual to individual and also influenced by the concomitant food intake, the duration of the administration, the presence or less of hepa-tic dysfunction and possible intake of other drugs that can affect hepatic metabolism. These studies were also aimed at avoiding the repeated oral administration related to the low half-life of the drug (4 hours).

As propranolol hydrochloride is hydrophilic its systemic absorption is poor, so that to ensu-re a transdermal absorption it needs to be incor-porated it into liposomal vesicles (16). A study of human skin in vitro (1) showed that most of the propranolol applied to the skin remains in the skin and that only an amount ranging between 4.1 and 16.1% enters the bloodstream.

These studies, although making unviable per-cutaneous administration in replacement of the oral one, represented an “assist” for the topical use of propranolol in the treatment of hemangio-ma.

On the other hand, the data sheet of another beta-blocker such as timolol gel, which is used in glaucoma, indicates the need for cardiovascular monitoring.

A comparative study of bioavailability and plasma concentration of propranolol and timolol administered by general route showed that the ti-molol reaches a higher plasma concentration also due to a slower clearance (27).

For these reasons, while not lacking in literatu-re reports on the use of topical timolol in heman-gioma (6, 7, 9, 17, 19, 20, 22, 24, 26) we believe that currently the only advantage of timolol is re-presented by its commercial availability; the low systemic absorption of propranolol and its short plasma half-life represent a strength of proprano-lol in the topical treatment of hemangioma.

For added security and to avoid monitoring with cardiovascular and laboratory examinations we also believe, however, that the administration of topical propranolol should follow some rules, such as not to exceed the dose (2mg/kg per day) that is usually used for oral administration of the

drug. Given that percutaneous absorption of pro-pranolol is less than 20% of the amount admini-stered (1) it seems highly unlikely that a systemic absorption of 0.4 mg/kg per day may cause seve-re side effects, when we know that in heart and psychiatric disease propranolol is orally admini-stered also at the dose of 15mg/kg per day.

To comply with this rule, we prefer not to use topical propranolol in the diaper area or in he-mangiomas whose greatest diameter exceeds 6 cm. For the same reason we do not believe pru-dent increase to 2% or 3% the concentration of the drug (18, 28), nor to resort to practices that increase the absorption of the drug as the occlu-sion (11). Rather, in these cases we prefer to use the oral standardized administration with all the controls that such administration requires.

A second concern has been addressed to the possible irritating and sensitizing capacity of pro-pranolol for percutaneous application. Although propranolol is used in medicine from 1964 (2) orally and parenterally, there are no reports in the literature of irritant or allergic contact dermati-tis in patients or nursing staff came in prolonged contact with the drug.

There are only 3 studies in literature (21, 23, 25) reporting allergic contact dermatitis in indu-strial workers involved in the production of the drug. Irritant contact dermatitis has been reported only in experimental animals and it was related to the concentration of propranolol applied to the skin (10).

With regard to the irritant capacity we have not observed so far irritant dermatitis attributable to propranolol, both in cases of topical application and in those where the drug was administered orally, both in patients and their relatives invol-ved in the administration of the drug.

With regard to the sensitizing capacity we have not observed so far skin disorders reminiscent of allergic contact dermatitis. Moreover, the patch test performed in patients and in family members involved in the administration of the drug has been so far always negative.

Control of the effectiveness of topical pro-pranolol. All studies with topical propranolol in superficial cutaneous hemangioma speak in favor of its efficacy. However, assessing the effective-ness of a therapeutic intervention in infantile he-

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1% topical propranolol in superficial hemangioma

Fig. 17 Fig. 18

Fig. 19 Fig. 20Fig. 17, 18, 19, 20: After 5 months of treatment with topical propranolol this hemangioma improved significantly. However, it is not possible to attribute this result to the drug in the absence of adequate controls.

mangioma (IH) is not simple. The expert knows that the natural history of hemangioma is charac-terized by an initial growth phase followed by a very slower regression, but even the expert does not know how long will last the growth phase in the individual case or what will be its intensity, especially when are not available at least two ob-servations spaced over 1-2 weeks, nor the expert knows when the involution phase will start and what will be accurately its speed in the individual case.

Therefore to say that an intervention was ef-fective in a single case of hemangioma (Fig. 17-20), or in a few cases without adequate controls is not sufficient to prove the effectiveness of this intervention.

Initially we studied the effectiveness of topi-cal propranolol in multiple hemangiomas (Fig. 21, 22), applying it only in one and assessing it

comparatively with the other not treated heman-giomas, but we realized that not all hemangiomas of the same subject had superimposable stages of growth and regression.

Then we examined series of hemangiomas matched for clinical characteristics by applying propranolol topical only on one hemangioma and evaluating it comparatively with a not treated si-milar one, but we realized that it was not easy to find hemangiomas matched for clinical characte-ristics (Fig. 23-30) and then the study would have been too long (4).

Finally we decided to initially treat only a re-presentative portion of hemangioma (Fig. 31, 32), to observe after a month any difference between the treated area and the untreated and to extend the topical treatment throughout the hemangioma in the case where the treated area was improved compared with the untreated.

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Fig. 21

Fig. 22Fig. 21, 22: In this 2-month-old little girl with vulvar and knee hemangiomas (Fig. 21) we treated with topical propranolol only the knee hemangioma. After 5 months the latter significantly regressed unlike the vulvar one (Fig. 22). However, it is not sure that the different behavior of the two hemangiomas was related to our treatment, because not all hemangiomas of the same patient run a similar biological behavior.

Fig. 27 Fig. 28 Fig. 29 Fig. 30

Fig. 23 Fig. 24 Fig. 25 Fig. 26

Fig. 23, 24, 25, 26, 27, 28, 29, 30: Spontaneous clinical course (Fig. 23-26) and under topical propranolol (Fig. 27-30) of two superficial hemangiomas matched for age (the pictures were taken every month starting from the first week of age) and site (abdomen). We should have many similar cases to be sure that the regression was due to the treatment.

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1% topical propranolol in superficial hemangioma

Fig. 31 Fig. 32Fig. 31, 32: Superficial hemangioma at the age of 7 (Fig. 31) and 37 (Fig. 32) days. Since the 7th day topical propranolol was applied only on the upper left inset, where 30 days later hemangioma grew less than the upper right portion which was not treated.

As regards the evaluation of the results unfor-tunately we lost more than a third of cases (30 out of 89): 9 cases dropped out after 1 month becau-se the portion of hemangioma treated showed no improvement compared with the untreated. Note that we are dealing with 4/12 cases in which the topical therapy had been started late, 3/39 cases in which the age of onset of therapy was between 10 and 20 weeks and finally 2/38 cases in which topical propranolol was started from 3 to 9 weeks of age.

In other 21 cases the treatment was withdrawn for poor adherence to the protocol. The latter was caused by the appearance of a deep component (8 cases) or because parents had not brought the child to control for 2 subsequent control visits (13 cases).

4/21 cases had high initial age, 11 low initial age (and in 8 of these 11 cases was the onset of the deep component to motivate the withdraval of the topical therapy) and 6 of intermediate initial age.

Regarding the site of hemangioma we did not notice a difference correlated to its skin localiza-tion.

On the other hand, the relationship between outcome and time of onset of treatment seems important. An excellent result was really found in more than the half (13/25) of cases with early onset of treatment, in a third (10 of 30) of cases with intermediate onset and in none of the 4 cases with late onset. A fair result was found in a little less than a third (8/25) of cases with early onset of therapy, in little more than half (16/30) of ca-ses with intermediate onset and in 1/4 cases with a late start. Finally a poor result was attributed to 4/25 cases with early start, 4/30 cases with inter-mediate onset and 3/4 cases with late onset.

So an overall assessment of the results stresses the importance of early onset of topical therapy with propranolol. The only negative point of ear-ly onset of treatment is that the deep component of hemangioma often manifests itself later in life than the superficial component, decreasing espe-cially in the parents the importance of the topical therapy.

Once completed the study and verified the ef-fectiveness of topical propranolol, we abandoned the method of the initial partial treatment because we noticed (15) that the area treated just a month

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Fig. 33 Fig. 34

Fig. 35 Fig. 36Fig. 33, 34, 35, 36: This hemangioma started topical propranolol at the age of 2 months (Fig. 33) only on the right half. One month later (Fig. 34) the right half showed grey areas and minor evidence of the peripheral satellites, leading to treat the entire hemangioma. At the 7th month when the topical treatment was withdrawn (Fig. 35) the right half showed a persistent more significant regression and the latter can be seen even at the age of 18 months (Fig. 36).

earlier had a better evolution even at a distance of 6 months after the application over the enti-re surface of hemangioma (Fig. 33-36), bringing further evidence of the importance to start early topical treatment.

Therefore, currently when facing a superficial hemangioma especially when it is located in vi-sible sites, we start as early as possible the treat-ment on the whole hemangioma, withdrawing it after 1 month in those rare cases in which we see no improvement at the comparative photographic evaluation.

The effectiveness of topical treatment is howe-ver variable due both to expected factors such as earliness of treatment, the thickness hemangioma and to completely unpredictable factors, related with the intensity and duration of the growth pha-

se and the speed and intensity of the regression phase.

In this regard it should kept in mind that the rebound effect after the suspension of proprano-lol was observed not only for the oral treatment (12) but also for the topical one (5). In this study we observed 2 times the rebound effect, in a case where we had started late (sixth month) topical propranolol and in another case where we started topical treatment at the age of 40 days and con-tinued it up the end of the seventh month (Fig. 37-40).

In conclusion, topical propranolol is a safe and effective treatment for the superficial component of hemangioma. In order to avoid unnecessary checks it is good to use a 1% concentration and reserve it for hemangiomas outside the area of

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Fig. 37 Fig. 38

Fig. 39 Fig. 40Fig. 37, 38, 39, 40: Rebound effect after withdrawing topical propranolol. In Fig. 37 a little girl aged 40 days when she started topical propranolol due to a metameric superficial hemangioma of the right frontal-ocular area. When aged 7 months (Fig. 38) hemangioma was no more visible and she withdrew the treatment. One month later (Fig. 39) hemangioma returned visible and it was more visible 12 months later (Fig. 40).

1% topical propranolol in superficial hemangioma

the diaper, avoiding expedients that increase the systemic absorption of the drug. In order to ob-tain the best results it is particularly important to start early topical treatment, advising however,

the parents that the drug is not able to prevent or treat a deep component. Topical propranolol is preferable to timolol due to its lower systemic absorption and more rapid clearance.

Address to:Prof Ernesto BonifaziDermatologia Pediatrica BariVia Bitritto 131 - 70124 Bari, Italyejpd@dermatologiapediatrica.com

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