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DOI: 10.1542/peds.2012-3828; originally published online May 6,
2013;Pediatrics
Hsien Chan, Catherine McKay, Susan Adams and Orli
Wargon24-Week-Olds
RCT of Timolol Maleate Gel for Superficial Infantile Hemangiomas
in 5- to
http://pediatrics.aappublications.org/content/early/2013/04/30/peds.2012-3828
located on the World Wide Web at: The online version of this
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of Pediatrics. All rights reserved. Print ISSN: 0031-4005.
Online ISSN: 1098-4275.Boulevard, Elk Grove Village, Illinois,
60007. Copyright © 2013 by the American Academy published, and
trademarked by the American Academy of Pediatrics, 141 Northwest
Pointpublication, it has been published continuously since 1948.
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RCT of Timolol Maleate Gel for Superficial InfantileHemangiomas
in 5- to 24-Week-Olds
WHAT’S KNOWN ON THIS SUBJECT: The systemic nonselectiveb-blocker
propranolol hydrochloride is increasingly used as first-line
management for infantile hemangiomas. Superficialnonulcerating
lesions do not require systemic medications. Caseseries have
suggested the efficacy of timolol; however, its safetyhas been
questioned.
WHAT THIS STUDY ADDS: This randomized controlled trialindicates
that timolol maleate 0.5% gel is a well-tolerated, safe,and
effective treatment of superficial infantile hemangiomas.
abstractOBJECTIVE: Timolol maleate 0.5% gel is a safe and
effective medica-tion for treating superficial infantile
hemangiomas (IHs) in infantswith a median age of 9 weeks.
METHODS: Forty-one infants who had superficial IHs without
ulcerationand not near mucosal surfaces were recruited and randomly
assignedto placebo and treatment (timolol maleate 0.5% gel) groups.
Efficacywas assessed by performing blinded volume measurements at
weeks0, 1, 2, 3, 4, 8, 12, 16, 20, and 24 and blinded investigator
photographscoring at weeks 0, 12, and 24. Safety was assessed by
measuringheart rate and systolic and diastolic blood pressure at
weeks 0, 1,2, 3, 4, 8, 12, 16, 20, and 24.
RESULTS: Fifteen of the 19 infants receiving treatment and 17 of
the 22infants receiving placebo completed the study. Significant
color changeon the blinded photographic scores was noted at week 24
of the study(P = .003). There was a significantly higher proportion
of treated IHsthat reduced in size by .5% at weeks 20 and 24 (P ,
.02). Thepredicted proportion of IH volume change was also
significantly lessfor treated IHs from week 16 onward when compared
with placebo(P , .05). There was no significant variation in blood
pressure andheart rate between the groups.
CONCLUSIONS: Topical timolol maleate 0.5% gel with a maximum
doseof 0.5 mg per day is a safe and effective option for small
superficial IHsthat have not ulcerated and are not on mucosal
surfaces. Pediatrics2013;131:1–9
AUTHORS: Hsien Chan, MBBS,a Catherine McKay, MBBS,a
Susan Adams, FRACS,b and Orli Wargon, FACDa
Departments of aPediatric Dermatology and bPediatric
Surgery,Sydney Children’s Hospital, Randwick, Australia
KEY WORDSinfantile hemangioma, timolol/adverse effects,
randomizedcontrolled trial
ABBREVIATIONSCI—confidence intervalDBP—diastolic blood
pressureIH—infantile hemangiomaSBP—systolic blood pressure
Drs Chan and McKay participated in the acquisition of
data,analysis and interpretation of data, drafting and revising
thearticle for important intellectual content, and approval ofthe
final manuscript as submitted; Dr Adams participated in thestudy
concept and design, critical revision of the article, andapproval
of the final manuscript as submitted; and Dr Wargonparticipated in
the study concept and design, analysis andinterpretation of data,
critical revision of the article forimportant intellectual content,
and final approval of the finalmanuscript as submitted.
This trial has been registered with the Australian and
NewZealand Clinical Trials Registry at www.anzctr.org.au
(identifierACTRN12610001069044).
www.pediatrics.org/cgi/doi/10.1542/peds.2012-3828
doi:10.1542/peds.2012-3828
Accepted for publication Feb 6, 2013
Address correspondence to Hsien Chan, MBBS, Sydney
Children’sHospital, High St, Randwick, New South Wales 2031,
Australia.E-mail: [email protected]
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,
1098-4275).
Copyright © 2013 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they haveno
financial relationships relevant to this article to disclose.
FUNDING: A Sydney Children’s Hospital Foundation grantprovided
support for statistical analysis of the results. TheTouched by
Olivia Foundation funded the Vascular BirthmarkResearch Fellowship
position.
PEDIATRICS Volume 131, Number 6, June 2013 1
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Infantile hemangiomas (IHs) are amongthe most common tumors of
infancy,with ∼4% of infants affected.1–3 Khanet al4 reported that
IHs arise fromCD133+ stem cells, which can differenti-ate into
several cell lineages includingadipocytes. The mechanisms that
con-trol the proliferation and involution ofthese lesions are not
as yet fully un-derstood. Focal IHs are rarely presentat birth and
exhibit a characteristicgrowth phase typically up to the age of
9months.5 A gradual involution phasetakes place over the subsequent
2 to 10years1,5; however, recently, Couto et al6
suggested that most IHs do not sub-stantially further improve
after 3.5years of age. Increasingly, nonselectiveb-blockers,
including propranolol hy-drochloride, have replaced or been usedin
conjunction with previously recom-mended treatments such as
systemiccorticosteroids and vincristine for thetreatment of IHs to
prevent ulcerationand disfigurement and for systemic
in-volvement.7,8 The mechanism via whichb-adrenergic receptor
antagonists in-hibit the growth of IHs remains tobe fully
elucidated. Whereas the side-effect profile of propranolol
hydrochlo-ride is favorable,8,9 the potential forhypoglycemia,
bronchial hyperactivity,and hypotension makes it difficult
tojustify its use for less severe IHs.
For small, superficial focal lesions with-out features
necessitating propranololor other systemic agents, the use
oftopical imiquimod 0.5%10 and potenttopical corticosteroids11 has
also beenreported. Topical timolol solution isa nonselective
b-adrenergic receptorinhibitor that was approved in 1978 forthe
treatment of glaucoma and has beensafely used as first-line therapy
for pe-diatric glaucoma for .30 years.12,14 Anumber of case reports
and case serieshave observed the efficacy of timololmaleate 0.5%
gel for the treatment ofIHs15–22; however, concern has beenraised
regarding its safety.12
This blinded, randomized, placebo-controlledstudy aims to begin
to answer thesequestions relating to the safety andefficacy of
topical timolol maleate 0.5%gel in the setting of small,
superficialfocal IHs in infants aged 5 to 24 weeks.
METHODS
A randomized, double-blind, placebo-controlled, parallel-group
trial wasconducted in a single institution
be-tweenMarch2011andSeptember2012.Approval was obtained from the
insti-tutional review board of the South East-ern Sydney and
Illawarra Area HealthService, Northern Hospital Network Hu-man
Research Ethics Committee. Writteninformed consentwas obtained from
thechildren’s parents after a discussion ofthe risks and benefits
of participating.
Eligibility of Patients
Patients were recruited at a single ter-tiary center from
neonatal, pediatricophthalmology, general pediatric, andpediatric
surgery clinics from March2011 to April 2012 (Fig 1).
Participationwas offered to infants between the age
5 and 24 weeks with small, focal super-ficial IHs not requiring
systemic therapy.Exclusion criteria included hypersensi-tivity to
timolol maleate, wheezing, car-diac rhythm disturbances or
congenitalheart disease, or large, ulcerated, mu-cosal, or
subcutaneous IHs. During thetrial, proliferation of the lesion,
ulcera-tion, or parental desire to commencesystemic therapy
resulted inwithdrawalfrom the trial and institution of
systemicmedications.
Study Design
Patients were enrolled in the trial by 1of 2 study physicians
and randomlyassigned (by using a method of mini-mization)23 by the
clinical trials phar-macist into 4 groups: age between 5and 15
weeks or between 16 and 24weeks and size of lesion,
or.25mm.Participants, caregivers, and physicianswere blinded to
group status. Baselinescreening comprised a cardiovascu-lar
examination, including blood pres-sure and heart rate, as well as
clinicalphotography and 2 hemicircumferencemeasurements of the IH,
90° apart. The
FIGURE 1Flow diagram of trial participants.
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study medication was dispensed in a ra-tio of 1:1 as placebo or
timolol maleate0.5% gel (5.0 mg of timolol/6.8 mg oftimolol maleate
in 1 mL; gellan gum,trometamol, mannitol, and water for in-jection;
0.0012% benzododecinium bro-mide added as a preservative.)13
Theparents were instructed to apply witha fingertip part of 1 drop
of the gel ontothe surface of the IH (enough to just coatthe
lesion) twice a day, and to gentlyrub it in. One drop of timolol
maleate0.5% gel has been estimated to contain0.25 mg of timolol.12
The first applica-tion was conducted in the outpatientdepartment,
and blood pressure andheart rate were measured just
beforeapplication and 1 hour after applica-tion of placebo or
timolol maleate 0.5%gel. Heart rate and blood pressuremeasurements
were compared withage-related reference ranges.24
Twohemicircumference measurements 90°apart were taken of the IH in
questionbefore the first application of placebo ortimolol maleate
0.5% gel. Repeat hemi-circumference measurements, as wellas blood
pressure and heart rate, weretaken at weeks 0, 1, 2, 3, 4, 8, 12,
16, 20,and 24 after commencement of studyparticipation. In
addition, photographswere taken by a clinical
photographeratbaseline, week 12, and week 24. After 24weeks,
participation in the trial ceasedand subjects were given the option
ofoff-label use of timolol maleate 0.5% gelfor ongoing treatment of
the IH. Interimblinded statistical analysis was carriedout at the
study midpoint to confirmwhether the trial should be continuedor
ceased.
Outcome Measures
Response to therapy was measured by(1) blinded predicted volume
estima-tion25 at weeks 0, 1, 2, 3, 4, 8, 12, 16, 20,and 24 and (2)
blinded scoring of clinicalphotographs at 0, 12, and 24 weeks.
Forvolume estimation, 2 measurements ofthe IH hemispheric diameter
were taken90° apart and the estimated hemispheric
volume was calculated by the formula0.073m3 wherem is the mean
of the 2hemispheric measurements.25 The pho-tographs at 0, 12, and
24 weeks werescored by 1 blinded investigatoras 0 if noredness was
observable, 1 if the lesionwas ∼50% red, or 2 if the lesion
wascompletely red.
With regard to safety data, heart rate,systolic blood pressure
(SBP), and di-astolic blood pressure (DBP) were mea-suredbefore
administering thefirst doseof placeboordrug, aswell as 1
hourafterthe initial dose, and then at every visit.
Statistical Analysis
The datawere analyzed by a statisticianblinded to group status.
Descriptivestatistics arepresentedaspercentages(%) of the group,
means and SD, ormedians and interquartile range.
The number of children with redness asindicated by the photo
score at visits 1,12, and 24 and the percentage witha categorized
lesion size at each timepoint were investigated by using
conti-nuity corrected x2 or Pearson’s x2 test.
A linear mixed model with an autore-gressive covariance
structure wasused to examine whether there weresignificant
differences in volume andpercentage change in volume, heartrate,
SBP, or DBP between the groupsover time. The autoregressive
covari-ance structure was used to allow vol-umes close together in
time to bemore correlated than those fartherapart. A time-by-group
interaction wasincluded to allow the groups to varydifferently by
time. Post hoc compar-isonswith a least significant differencewere
used to determine whether therewas a significant difference
betweengroups at each visit.
RESULTS
A total of 41 children were enrolled inthe study; 19 were
randomly assignedto treatment and 22 were randomly
assigned to placebo. There were nosignificant differences in
gender ratios,age, and site of lesion between thegroups (Table 1).
Although we plannedto recruit and analyze subjects in 2 agegroups
(5–15 weeks and 16–24 weeksold), only 3 of 41 individuals were in
theolder age group category and subjectswere consequently not
stratified on thebasis of age in the results analysis.Similarly,
subjects were also initiallystratified on the basis of an IH
meandiameter being , or .25 mm (vol =1094 mm3). However, only 4 of
41 sub-jects had IH lesions with a mean di-ameter .25 mm. Thus, in
the resultsanalysis all subjects were consideredin 1 group
regardless of lesion size.Whereas all IH lesions analyzed
com-menced asmacular lesions, volumetricapproximation and analysis
were re-quired because a significant number oflesions developed a
height of at least 5mm, thusmakingmean diameter a lessaccurate
measure of IH lesion size.Comparisons of predicted absolutevolume
of IH lesions between treatmentand placebo groups were made at
eachtime point (Table 2). To gauge whetherthere was a significant
reduction inpredicted absolute volume between
TABLE 1 Baseline Characteristics ofSubjects
Treatment Placebo
n 19 22Gender, %Male 26 33Female 74 67
Age, mean (SD), mo 2.1 (0.8) 3 (0.9)Site of lesion, %Face 47
50Neck 16 14Torso 11 —Thigh 11 5Upper limb 11 9Back 5 14Hand —
9
Volume, median (IQR),mm2
60 (180.4) 26.8(179.5)
,10 mm2, % 21 3210–50 mm2, % 21 3250–1000, % 53 32.1000 mm2, % 5
5
IQR, interquartile range; —, indicates 0%.
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treatment and placebo, a comparisonwasmadewith regard to the
number ofIH lesions that decreased in predictedabsolute volume by
$5% in the treat-ment and placebo groups (Table 3).Because 5- to
24-week-old infants growrapidly, most IH lesions also
correspond-ingly increased in size. A comparisonwas thusmade
between relative changein predicted absolute volume of IH le-sions
between treatment and placebo(Fig 2). This comparison was
addition-ally stratified on the basis of initialpredicted absolute
volume of IH lesions(Fig 3).
There was no significant difference inpredicted absolute volume
size be-tween the treatment and placebogroups at baseline or at any
of the in-dividual time points. There was a mar-ginally significant
difference in the sizeof the IH lesions atweeks 12and16,withthe
lesions being smaller in the treat-ment group (Table 2; P = .05).
In termsof relative reduction in size of IHs (Ta-ble 3), there was
a significantly higherproportion of IH lesions with at leasta 5%
volume reduction in the treat-ment group compared with placebo
atweek 8 (P = .04), week 20 (P = .02), andweek 24 (P = .01; Table
3). Because 5- to24-week-old infants grow rapidly andhence their
nonproliferating IHs in-crease in size relatively, a measure-ment
of the proportional change ingrowth compared between groups wasalso
analyzed (Fig 2). Before week 12
there was no significant differencebetween predicted percentage
changein volume between treatment and pla-cebo (P. .05). Subsequent
to week 16,there was a significantly lower pre-dicted percentage
volume increase inthe treatment group compared withthe placebo
group (P , .01).
With regard to which IHs may be moreamenable to topical timolol
maleate0.5% gel treatment, the impact of IHvolume on treatment
efficacy wasconsidered. Therewere 12 IHs thatwere,100mm3 (mean
diameter = 11.3mm)in volume at baseline in the treatmentgroup and
16 in the placebo group. ForIHs with a baseline volume of ,100mm3
(Fig 3), the predicted percentageincrease in mean IH volume was
sig-nificantly less in the treatment groupfromweek 8 onward (P,
.003). For IHswith a baseline volume.100mm3, therewas no
significant difference in pre-dicted percentage change in IH
volumebetween treatment and placebo at anytime point (weeks 1–16,
P. .2; week 20,P = .09; week 24, P = .06). In addition,a receiver
operating characteristic curveplotted for IH lesions in the
treatmentgroup indicated that a cutoff of 65 mm3
for baseline volume predicts whethervolume will decrease by$5%
(area un-der the curve = 0.88, P = .02).
The clinical appearance of IH lesions asdetermined by blinded
photo scorewasalso compared between treatment andplacebo groups at
baseline, week 12,
and week 24. Representative photos ofIHs treated successfully
with topicaltimolol maleate 0.5% gel are shownalong with images of
IHs in the placebogroup in Fig 4. A score of 0 indicated noredness,
a score of 1 indicated the le-sion was 50% red, and a score of
2indicated the lesion was completelyred. As shown in Table 4, no
significantdifference in score distribution was seenat baseline or
at 12 weeks. At 24 weeks,there was a significant difference
inblinded photo score distribution betweentreatment and placebo
groups. The pro-portion of photo scores of 0 (no redness)was
significantly greater in the treatmentgroup (47%) than in the
placebo group(6%). Conversely, the proportion of photoscores of 2
(completely red) was signifi-cantly less in the treatment group
(6%)compared with the placebo group (55%;Pearson’s x2, P =
.003).
With regard to side effects of topicaltimolol maleate gel, there
were nocases of bradycardia or hypotensiveepisodes. Comparisons of
mean heartrate (treatment mean heart rate = 147beats per minute;
95% confidence in-terval [CI]: 140–154; placebo meanheart rate =
147 beats per minute; 95%CI: 140–154; P = .81), mean SBP
(treat-ment mean SBP = 89 mm Hg; 95% CI:86–93; placebo mean SBP =
84 mm Hg;95% CI: 80–89; P = .28), and mean DBP(treatment mean DBP =
43 mm Hg; 95%CI: 36–51; placebomeanDBP=38mmHg;95% CI: 33–43; P =
.40) indicated no
TABLE 2 Volume in Categories by Time
Week Treatment Placebo P
n ,10 mm2 10–50 mm2 50–1000 mm2 .1000 mm2 n ,10 mm2 10–50 mm2
50–1000 mm2 .1000 mm2
1 19 21 21 53 5 22 32 32 32 5 .582 17 24 18 53 6 22 32 32 32 5
.563 17 18 18 59 6 22 36 27 32 5 .364 19 21 21 53 5 21 33 24 38 5
.798 19 37 5 53 5 19 21 32 42 5 .2012 18 33 11 50 6 18 11 50 28 11
.0516 15 40 7 47 7 18 11 44 33 11 .0520 14 36 7 50 7 18 11 39 39 11
.1324 15 33 7 53 7 18 17 33 39 11 .24
Data are percentages (%) of the group or n. There was a
borderline significant difference at weeks 12 and 16 with more
small lesions in the treatment group.
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significant difference between treatmentand placebo groups
(Table 5).
In total, there were 9 dropouts from thestudy (4 in the
treatment group and 5 inthe placebo group) (Fig 1). Reasons
forwithdrawal are summarized in Table 6.
DISCUSSION
Efficacy
IH growth cessation occurring as earlyas 48 hours after
commencement oforal propranolol hydrochloride has
been described previously.7,26–29 Thisrelatively rapid onset of
action forsystemic therapy most likely encour-ages compliance.30 In
comparison,topical timolol maleate gel has beenassociated with
growth arrest anda slower reduction in redness andthickness within
the first 2 to 4 weeksof use as seen in 2 noncontrolledstudies of
the use of topical timololmaleate gel for IHs.20,21 Chamberset al22
reported a significant improve-ment with topical 0.25% timolol
male-ate gel compared with placebo forperiocular IHs after 8 weeks
of treat-ment. The results presented from thisstudy indicate a
therapeutic onset ofaction after 12 to 16 weeks of therapy,with a
significant increase in thenumber of IH lesions decreasing insize
by.5% and a significant decreasein proportional growth rate noted
inthe treatment group compared withthe placebo group. This later
onset ofaction compared with oral proprano-lol hydrochloride may be
related toa lower dose being used in this study
and may explain withdrawals due tosubject-observed lack of
efficacy. With-drawal may also be attributed to pa-rental anxiety
as well as the inability topredict the appropriateness of the
le-sion to topical treatment and the riskof ulceration. Despite the
withdrawal of9 subjects from a relatively small sam-ple size,
intention-to-treat analysis stillrevealed a significant difference
in mea-sured outcomes as described above.From a practical
perspective, it wouldbe suggested that any lesion consideredbeing
at risk of ulceration or developingsigns of early ulceration would
be moresuitable for systemic therapy.
Previous studies have suggested thatsuperficial19,22 and
plaque-like IHs aremore amenable than nodular and deeplesions20 to
topical timolol maleate geltreatment; hence, this study
excludeddeep lesions. By using a receiver op-erating characteristic
analysis andstratifying the data on the basis of IHvolume, a
significant difference wasnoted in drug efficacy for lesions,100mm3
in volume (mean hemisphericdiameter ,11.3 mm) from week 8 on-ward.
Lesions .100 mm3 treated withtopical timolol maleate gel appeared
tohave no significant difference in growthcompared with lesions of
a similar vol-ume in the placebo group at any timepoint. Because a
fixed dose of topicaltimolol maleate gel (1 drop twice a
day)regardless of lesion size was applied,one might predict that
smaller lesions,due to their higher surface area to vol-ume ratio,
aremore amenable to topicaltherapies. The lack of different
dosagesused and the small number of largelesions in the present
study make itdifficult to predict the optimal manage-ment of large
IH lesions with topical ti-molol maleate gel. With regard to
theinfluence of site of IH lesion on topicaltimolol maleate gel
efficacy, whereas itis predicted that IHs in areas in whichthe
epidermis is thinner (eg, the eye-lids) would be more responsive
to
TABLE 3 Infants With IH Volume Reduced by$5%
Week Treatment Placebo P
n Percentage ofGroup
n Percentage ofGroup
2 19 32 22 18 .533 19 26 22 5 .134 19 26 21 5 .148 19 37 20 5
.04*12 18 39 19 16 .2316 16 38 18 22 .5520 15 47 18 6 .02*24 15 60
18 11 .01*
* Significant difference at weeks 8, 20, and 24 with morelesions
reduced by $5% in the treatment group.
FIGURE 2Percentage change in predicted volume for all IHs in
treatment and placebo groups. P for group = .050.Post hoc group
comparisons at each time point: weeks 0–4, P. .20; week 8, P = .07;
week 12, P = .05;week 16, P = .01; week 20, P = .002; week 24, P =
.002.
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topical timolol maleate gel, the safetyconcern and paucity of
existing dataof systemic absorption at these sitesprevented a
direct analysis of thisprediction.
Although it was anticipated that sub-jects in 2 age groups (5–15
weeks and16–24 weeks old) would be recruited,only 3 individuals
were in the 16- to24-week-old age group category. Theoverall mean
age of participants was 9to 10 weeks. Other studies of
topicaltimolol maleate gel for the treatment ofIH have involved
subjects between theages of 5 and 30 weeks21 and 12 and 68weeks20
and cohorts with mean ages of19 weeks22 and 32 weeks.19 The
efficacyof topical timolol maleate gel in therelatively young age
group of the pres-ent study supports previously notedobservations
that timolol maleate gelmay be more effective during the
earlyproliferation stage.20 The safety datafrom this study indicate
that even in thisyounger cohort, a limited volume oftopical timolol
maleate gel has a favor-able side-effect profile.
The sustained effect of the 24-weekcourse of topical timolol
maleate gelhas not directly been considered inthis study. Posttrial
follow-up of themajority of study candidates, however,has provided
the investigators with theimpression that no significant reboundof
IHs occurred in those successfullytreated with topical timolol
maleate gelonce the medication ceased. This find-ing is supported
in other studies inwhich no significant IH rebound at 4weeks after
8 to 30 weeks of treat-ment,21 at 4 months after 6 months
oftreatment,20 and at 3 to 6 months aftera mean treatment duration
of 3.46 2.7months19 was described.
Safety
The specific pharmacokinetics of ti-molol maleate gel are not
well defined;however, 1 study of the systemic ab-sorption of
topically applied 5% timololvia 0.2-mg/cm2 transdermal
patchesindicated that plasma concentrationswere undetectable in 3
of 4 patients 48hours after application.31 This finding
is mirrored by the fact that safety datafrom studies of the use
of topical ti-molol maleate to treat IH have gener-ally been
favorable.19,20,22 However,concern has been voiced regardingthe
potential systemic absorption andside effects that may arise from
topicaltimolol maleate gel and what specificmonitoring requirements
are neededwhile receiving therapy. McMahon et al12
estimated that 1 drop of 0.5% timololgel-forming solution may
equate to 2 to8 mg of oral propranolol hydrochloride.As a
comparison, oral propranolol hy-drochloride is generally used at a
doseof 1 mg/kg 2 to 3 times a day. In thepediatric ophthalmology
literature,systemic bioavailability of timolol so-lution applied to
mucosal surfaces hasbeen estimated to be as high as 60% to80%32 and
has been attributed to casesof apnea, asthma, bradycardia,
dizzi-ness, and dissociated behavior.12 Inthe studies of timolol
maleate solutionfor the treatment of IHs, a case reportof a
4-month-old girl developing ble-pharoptosis after treatment of a
thin-plaque IH on the upper eyelid with 0.5%timolol solution has
been described.16
The systemic absorption of timololmaleate gel formulation is
consideredto be significantly less than that of ti-molol maleate
solution and hence hasbeen favored in more recent studies.33
With regard to the gel formulation, ina study in 73 individuals
treated withtimolol maleate 0.1% or 0.5% gel, 1case of significant
sleep disturbancenecessitating treatment cessation hasbeen reported
as well as local site-of-application side effects such as burn-ing,
stinging, and irritant reactions.19
In a study in 25 individuals aged 12 to68 weeks using topical
timolol 1%gel, no adverse events were noted.20
Similarly, no adverse effects were de-scribed in a
retrospective, consecutive,nonrandomized cohort study of
twice-daily timolol maleate 0.25% gel forthe treatment of
periocular IHs.22 Inthe present study, which used timolol
FIGURE 3Percentage change in predicted volume for small lesions
only (,100 mm3 at baseline). P for group =.003. Post hoc group
comparisons at each time point: weeks 0–4, P. .20; week 8, P =
.003; week 12, P =.001; weeks 16–24, P , .0001.
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FIGURE 4Clinical photos of IHs at baseline (left), 12 weeks
(middle), and 24 weeks (right) after commencement of placebo or
treatment. A, subject no. 131 (treatment);B, subject no. 104
(treatment); C, subject no. 111 (treatment); D, subject no. 202
(placebo); E, subject no. 125 (placebo); F, subject no. 102
(placebo).
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maleate 0.5% gel on intact skin, no ad-verse eventswere noted
and there wereno significant differences in mean heartrate and mean
SBP and DBP. Review ofthe use of topical timolol maleate
forophthalmologic purposes also indicatesno significant differences
in heart rateand blood pressure; however a redu-ction in
exercise-induced increases inheart rate during the daytime has
been
reported.34,35 Similarly, we would sug-gest that the likelihood
of bradycardiaand hypotension due to the use of topi-cal timolol
maleate gel for intact IHs isvery low. Exercise-induced
differenceswould be less pronounced in the youn-ger age
distribution of our presentstudy due to relatively low levels of
ex-ercise, although continuous measure-ment of blood pressure and
heart ratewould provide a more accurate as-sessment of this
possibility. The safetyof topical timolol maleate gel for
ulcer-ated, mucosal, or periorbital IHs alsorequires additional
study.
Limitations
Although numbers were sufficient tocomparebloodpressure andheart
ratebetween the groups, there were in-sufficient numbers to exclude
rare andidiosyncratic adverse events. Continualblood pressure and
heart rate moni-toring would provide additional insightswith regard
to safety. Neither this study
nor previous studies showed significantcomparisons of efficacy
on the basis ofthe IH site.19 A more sensitive scoringsystem
incorporating other variablessuch as height/depth of IH with
orwithout ultrasound imaging and a morecomprehensive photographic
scalewouldhave improved the study.
CONCLUSIONS
This randomized placebo-controlled tri-al in infants aged5 to
24weeks indicatesthat up to 2 drops per day of topicaltimolol
maleate 0.5% gel for 24 weeks’duration is a safe and effective
therapyfor the treatment of IH not requiringsystemic treatment. The
onset of ac-tion appears to be slower than oralpropranolol chloride
with significantimprovements in absolute volume re-duction,
proportional growth, andclinical appearance noted after only12 to
16 weeks. The efficacy of topicaltimolol maleate 0.5% gel appears
tobe more pronounced for lesions witha mean diameter of ,11.3 mm
(ie,,100mm3 in vol). The side-effect profileof topical
timololmaleate 0.5% gel in the5- to 24-week age group is
favorable,with no significant differences in heartrate, SBP, or
DBP. Larger multicentertrials may provide insight into factorssuch
as site-dependent efficacy as wellas additional safety, monitoring,
dosing,duration-of-treatment, and age-group–specific data.
ACKNOWLEDGMENTSThe Vascular Birthmark Research
Fellow-shipisfundedbytheTouchedbyOliviaFoun-dation. We thank Dr
Jenny Peat, HonoraryProfessor of Statistics, Australian
CatholicUniversity, for her assistance in the statis-tical analysis
of the data; Ms Sarah Hill,Clinical Nurse Consultant, Department
ofDermatology, Sydney Children’s Hospital,for assistance in the
collection of subjectdata; and Ms Shelley Wang, University ofNew
South Wales medical student, for herassistance in collection of
subject data.
TABLE 4 Redness as Indicated by BlindedPhoto Score
Time andGroup
n Score0
Score1
Score2
P
Week 1Treatment 19 — 21 79 .17Placebo 21 — 41 59
Week 12Treatment 16 13 56 31 .49Placebo 17 6 44 50
Week 24Treatment 15 47 47 6 .003*Placebo 18 6 39 55
Data are percentages (%) or n of the group with photoscore as
indicated. 2, completely red; 1, half red; 0, noredness. P values
were determined by Pearson’s x2 test.—, indicates 0%.* P , .05.
TABLE 5 Safety Data for Comparison of Mean Heart Rate, SBP, and
DBP Between Treatment andPlacebo Groups
Treatment (95% CI) Placebo (95% CI) P
Mean heart rate, beats per minute 147 (140–154) 147 (140–154)
.81Mean SBP, mm Hg 89 (86–93) 84 (80–89) .28Mean DBP, mm Hg 43
(36–51) 38 (33–43) .40
TABLE 6 Subjects Withdrawn From the Study
SubjectNumber
Treatment orPlacebo
Study WeekWithdrawn
Reason for Withdrawal From Trial
109 Placebo 4 Development of new subcutaneous periorbital
IH;commenced receiving propranolol
115 Placebo 4 At risk of ulceration; commenced
receivingpropranolol
121 Placebo 8 Withdrawn because of transfer to another
tertiarycenter
128 Placebo 12 At risk of ulceration; commenced
receivingpropranolol
135 Placebo 16 Voluntarily withdrawn124 Treatment 8 Voluntarily
withdrawn; subsequently commenced
receiving propranolol201 Treatment 12 Developed small ulcer;
commenced receiving
propranolol108 Treatment 16 At risk of ulceration; commenced
receiving
propranolol119 Treatment 16 Small nonproliferating lesion;
strong parental desire
to commence propranolol
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ARTICLE
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DOI: 10.1542/peds.2012-3828; originally published online May 6,
2013;Pediatrics
Hsien Chan, Catherine McKay, Susan Adams and Orli
Wargon24-Week-Olds
RCT of Timolol Maleate Gel for Superficial Infantile Hemangiomas
in 5- to
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