Pediatr Drugs 2003; 5 (7): 481-504REVIEW ARTICLE 1174-5878/03/0007-0481/$30.00/0

© Adis Data Information BV 2003. All rights reserved.

Safety of the Newer Inhaled Corticosteroids inChildhood AsthmaTabitha L. Randell,1 Kim C. Donaghue,1,2 Geoffrey R. Ambler,1 Christopher T. Cowell,1,2

Dominic A. Fitzgerald2,3,4 and Peter P. Van Asperen2,3

1 Institute of Endocrinology and Diabetes, The Children’s Hospital at Westmead, Sydney, New South Wales, Australia

2 Discipline of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales, Australia

3 Department of Respiratory Medicine, The Children’s Hospital at Westmead, Sydney, New South Wales, Australia

4 Division of Academic and General Medicine, The Children’s Hospital at Westmead, Sydney, New South Wales, Australia

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482

1. Pathophysiology of Asthma and Pharmacokinetics of Inhaled Corticosteroids (ICS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483

1.1 Pathophysiology of Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483

1.2 Mechanism of Action of ICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483

1.3 Pharmacokinetics of ICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483

1.3.1 Oral Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483

1.3.2 Mode of Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484

1.3.3 Systemic Bioavailability of the Newer ICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484

1.3.4 Comparing ICS Systemic Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485

2. Potential Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485

2.1 Topical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485

2.1.1 Dysphonia and Oral Candidiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485

2.1.2 Dental Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485

2.2 Adrenal Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486

2.2.1 Assessment of Adrenal Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486

2.2.2 Biochemical Suppression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486

2.2.3 Clinical Adrenal Suppression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490

2.2.4 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492

2.3 Growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492

2.3.1 Normal Growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492

2.3.2 Effect of ICS and Asthma on Growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492

2.3.3 Short-Term Growth (Knemometry) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493

2.3.4 Linear Growth (Intermediate and Long Term) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494

2.3.5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497

2.4 Bones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497

2.4.1 Normal Bone Mineralization and the Effect of ICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497

2.4.2 Assessing Bone Mineralization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497

2.4.3 Effect of ICS on BMD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498

2.4.4 ICS and Fractures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500

2.4.5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501

482 Randell et al.

2.5 Cataracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501

3. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501

Inhaled corticosteroids (ICS) remain a vital part of the management of persistent asthma, but concerns haveAbstractbeen raised about their potential adverse effects in children. This review examines the safety data on three new

ICS – fluticasone propionate, mometasone, and extrafine beclomethasone in hydrofluoroalkane (HFA-134a)

propellant (QVAR®1 formulation) in relation to the older corticosteroids.

Topical adverse effects such as thrush and dysphonia are rare, but dental erosion is a possibility with powder

forms of ICS because of their low pH. Thus, it is important to stress mouth rinsing after administration and

maintaining good dental hygiene to minimize this risk.

Biochemical adrenal suppression can be readily demonstrated, particularly with high doses of all ICS. The

clinical relevance of this was uncertain in the past, but there have now been >50 reported cases of acute adrenal

crises in children receiving ICS, most of whom were on fluticasone propionate. In order to minimize the risk of

symptomatic adrenal suppression, it is important to back-titrate the ICS dose and alert families of children

receiving high-dose ICS of this potential adverse effect. A pediatric endocrine opinion should be sought if

adrenal suppression is suspected. The older ICS cause temporary slowing of growth velocity, but the limited data

available do not show any significant compromise of final adult height. The effect on growth of fluticasone

propionate may not be as great as with the older ICS, but the studies have been short term and only used low

doses of fluticasone propionate. There have been case reports of growth suppression in children receiving high

doses of fluticasone propionate. The limited studies performed on the effect of ICS on bone mineral density in

children did not show any adverse effects, but there may be an increased risk of fractures.

Hydrofluoroalkane beclomethasone (QVAR) is essentially the same drug as chlorofluorocarbon beclometha-

sone, but with double the lung deposition owing to the smaller particle size. Thus, it could be expected that any

adverse effects seen with chlorofluorocarbon beclomethasone would be the same with hydrofluoroalkane

beclomethasone. However, some of the published data, particularly in adults, suggest that hydrofluoroalkane

beclomethasone may be less systemically active than chlorofluorocarbon beclomethasone, even at equipotent

doses. As yet, there are no long-term data on mometasone, but initial studies in adults suggest there may be less

suppression of the hypothalamic-pituitary-adrenal axis, although further studies are required, particularly in

children.

ICS will remain a cornerstone in the management of persistent pediatric asthma, provided that the diagnosis

of asthma is secure. It is very important to use ICS appropriately and to ensure the lowest possible doses are used

to achieve symptom control, thus minimizing the risk of serious adverse effects.

Inhaled corticosteroid (ICS) therapy has become the corner- safety, particularly when used in high doses.[5] The main concerns

in children have focused on suppression of the hypothalamic-pitui-stone of the preventive management of childhood asthma and is

tary-adrenal (HPA) axis, growth, and potential for decreased bonecurrently recommended as an alternative first-line preventive ther-

mineral density (BMD).apy in frequent episodic or mild persistent asthma, and first-line

therapy in moderate and severe persistent asthma, in children.[1-3] In the past 10 years, newer ICS such as fluticasone propionate,

The efficacy of ICS at controlling symptoms and maintaining mometasone, and extrafine beclomethasone in hydrofluoroalkane

good health in children with asthma is well proven,[4] but more (HFA-134a) propellant (QVAR® formulation, 3M Pharmaceuti-

recently there have been increasing concerns about their overall cals) have been introduced. Fluticasone propionate in particular

1 The use of tradenames is for product identification purposes only and does not imply endorsement.

© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)

Safety of the Newer Inhaled Corticosteroids in Childhood Asthma 483

was hailed as having fewer adverse effects than the previous inflammatory effects include increasing the expression of β2-adre-

generation of ICS.[6,7] Mometasone has mainly been used as an noceptors and increasing anti-inflammatory mediators such as

intranasal preparation, although it is now being prepared for IL-10 (inhibits transcription of inflammatory cytokines), and li-

licensing as an ICS for patients with asthma. Hydrofluoroalkane pocortin-1 (inhibits production of lipid mediators). They also

beclomethasone was introduced to replace the previously used decrease the transcription of inflammatory proteins such as TNF-

chlorofluorocarbon propellant, to alleviate environmental con- α, GM-CSF, IL-2, IL-3, IL-4, IL-5, IL-6, IL-11, and chemokines.

cerns. Thus, mast cell and eosinophil numbers are decreased and T-

lymphocyte activity inhibited, plus mucus secretion is inhibited.[9]This review examines the safety data on these three new ICS in

relation to the older corticosteroids – beclomethasone with chloro-

fluorocarbon propellant, and budesonide. 1.3 Pharmacokinetics of ICS

1. Pathophysiology of Asthma andICS are designed to have a local, topical effect. Thus, the aim is

Pharmacokinetics of Inhaled Corticosteroids (ICS)to minimize potential systemic effects, such as suppression of the

HPA axis, adverse effects on growth, and decreased bone mineral-1.1 Pathophysiology of Asthma ization. Systemic bioavailability is related to both oral and pul-

monary absorption and subsequent metabolism of the compound.Asthma is now defined as a chronic inflammatory disorder of

the airways in which many cells and cellular elements play a role,1.3.1 Oral Absorption

particularly mast cells, eosinophils, T lymphocytes, macrophages,Most of the dose of ICS leaving an inhaler device (about 80%)

neutrophils, and epithelial cells.[1] This inflammatory response iswill be deposited in the oropharynx and then swallowed. The oral

mediated by numerous cytokines, including interleukins (IL),systemic bioavailability of the drug will then depend on the

granulocyte-macrophage colony-stimulating factor (GM-CSF), tu-amount that undergoes first-pass hepatic metabolism. The older

mor necrosis factor (TNF)-α, and growth factors.[8] This inflam-compounds such as chlorofluorocarbon beclomethasone and

mation leads to a susceptibility to recurrent episodes of variablebudesonide are said to undergo 80% and 89% first-pass metabol-

airway obstruction, characterized by contraction of the airwayism, respectively, when absorbed orally, still leaving a significant

smooth muscle, mucosal edema, and mucus hypersecretion. Theseamount of the drug to have a systemic effect (table I).[10] Beclo-

episodes are usually reversible, either spontaneously or withmethasone also undergoes biotransformation to its active metabo-

bronchodilator medication. The inflammation may also contributelite, 17-beclomethasone monopropionate, which undergoes first-

to the underlying bronchial hyper-responsiveness to a variety ofpass inactivation whether it enters via the gut or the lung.[11] In

stimuli, e.g. histamine, methacholine, and exercise. It is now alsofact, a recent study on the biovailability of beclomethasone in

clear that this inflammatory process can lead to airway fibrosis andhealthy volunteers,[12] demonstrated that unchanged beclometha-

remodeling, which results in irreversible airway obstruction.[8]

sone is not absorbed orally and that 17-beclomethasone monopro-Therefore, the rationale for ICS therapy is to reduce this airway

pionate accounts for all the oral bioavailability of the drug. Fur-inflammation by providing both symptom control and a reduction

thermore, the study demonstrated that the total systemic bioavaila-in bronchial hyper-responsiveness. This will hopefully also pre-

bility of 17-beclomethasone monopropionate from an inhaled dosevent permanent airway fibrosis and remodeling.

was 62%, with the lung and the gut thought to contribute 36% and

26%, respectively, to systemic exposure.[12] This may also explain1.2 Mechanism of Action of ICS

why the systemic bioactivity of hydrofluoroalkane beclometha-

Corticosteroids are thought to diffuse across the membrane into sone is comparable to chlorofluorocarbon beclomethasone, despite

cells and then bind to receptors in the cytoplasm.[9] Intracellularly, the greater lung deposition of the hydrofluoroalkane formulation

they act by increasing the transcription of anti-inflammatory genes (which relates to smaller particle size, as discussed in section

and decreasing the transcription of inflammatory genes. Cortico- 1.3.2).[11] In contrast, both fluticasone propionate and mometasone

steroids then act either directly on the primary cell or indirectly on have <1% oral bioavailability, meaning that the majority of sys-

a secondary cell by modifying the release of mediators. The anti- temic bioavailability is via pulmonary absorption.[11]

© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)

484 Randell et al.

Table I. Clinical pharmacology of inhaled corticosteroids[10-14]

Corticosteroid Recommended dosage range in Hepatic first-pass elimination Plasma half-life

children (μg/day) (%) (h)

Chlorofluorocarbon beclomethasone 100–500 80 6.5a

Hydrofluoroalkane beclomethasone 50–200 80 6.5a

Budesonide 100–500 89 2.3–2.8

Fluticasone propionate 50–200 >99 3.7–14.4

Mometasone 100–400b >99 4.45

a Beclomethasone is converted in vivo to beclomethasone monopropionate, which has a half-life of 6.5h.

b Not yet licensed.

1.3.2 Mode of Delivery recent study comparing chlorofluorocarbon beclomethasoneThe method of delivery will affect how much ICS is deposited 200–400 μg/day delivered via MDI + spacer with hydrofluoro-

in the lungs, compared with how much is ingested. There is alkane beclomethasone 100–200 μg/day via Autohaler® (smallerconsiderable variability in the amount of drug delivered to the particle size) in 300 children with asthma aged between 5 and 11lungs when different dry powder devices are used. Undoubtedly, years, showed similar efficacy, growth, and systemic safety over asome of this is attributable to the way in which a patient uses the 12-month period when one-half the dose of hydrofluoroalkanedevice, the current state of their asthma (ability to generate ade- beclomethasone compared with chlorofluorocarbon beclometha-quate inspiratory flow rates), and familiarity with the device. In a sone was used.[20]

study comparing fluticasone propionate with budesonide delivered Overall, when considering different ICS and delivery systems,via dry powder inhalers (DPIs), similar amounts of ICS reached it is important to be mindful of four factors that will significantlythe airways.[7] The choice of device, essentially between metered influence the efficacy of treatment:dose inhaler (MDI) + spacer and dry powder devices, is important

• the drugin children. The age of the child/adolescent and the individual’s

• the delivery deviceability to use a device will directly influence the likely adherence• the age of the patientwith therapy,[15,16] and may well be the predominant arbiter of drug

• the preference of the patient (for older children).effect. Generally speaking, an MDI + spacer is the preferred

delivery method for young children, switching to dry powder1.3.3 Systemic Bioavailability of the Newer ICSdelivery devices during the school years (table II).[3]

Interestingly, the amount of ICS or bronchodilator delivered to The systemic bioavailability of hydrofluoroalkane beclometha-

the lungs by MDI may be increased by as much as 50–100% when sone depends on both the oral deposition of beclomethasone (with

a spacer device is used.[17] Again, patient factors, as well as 80% first-pass metabolism) and its pulmonary deposition. How-

differences between devices, will influence this result. Moreover, ever, as highlighted previously, beclomethasone undergoes con-

the particle size of the delivered medication is also important in version to its active metabolite, 17-beclomethasone monopropion-

dose responsiveness. This is often described in terms of the ate, and beclomethasone itself contributes only about 2% to sys-

‘respirable dose’, derived from the proportion of smaller sized temic bioavailability through pulmonary absorption.[12] In

particles delivered to the distal airways.[18] Hydrofluoroalkane addition, the total systemic bioavailability of 17-beclomethasone

beclomethasone, which was introduced because of environmental monopropionate from an inhaled dose has been estimated to be

concerns of chlorofluorocarbons, is a solution which results in 62%, with the lung and the gut thought to contribute 36% and

smaller particle size. This has clinical correlates in that the smaller 26%, respectively, to systemic exposure.[12] This may help to

particle size in hydrofluoroalkane beclomethasone, compared with explain why there does not appear to be increased systemic ac-

its predecessor chlorofluorocarbon beclomethasone, will allow tivity with hydrofluoroalkane beclomethasone compared with

more drug to be deposited into the lung periphery, and presumably chlorofluorocarbon beclomethasone, despite the increased lung

allow for a reduced dose of ICS to maintain symptom control.[19] A deposition.[11]

© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)

Safety of the Newer Inhaled Corticosteroids in Childhood Asthma 485

In contrast, the other newer ICS, such fluticasone propionate in assessing the significance of studies comparing different ICS,

we have chosen to include comparative data, particularly for theand mometasone, have <1% bioavailability when taken orally as

newer ICS, where pediatric data is limited. At the same time wethey are eliminated by first-pass metabolism (fluticasone propion-

have attempted to point out the limitations of these studies, as wellate)[13] or minimally absorbed from the gut (mometasone).[14]

as highlight the need for further well-designed comparative studiesThus, the main determinant of systemic bioavailability is direct

in children.absorption from the lungs, where there is no first-pass inactivation.

Fluticasone propionate and mometasone are highly lipophilic and2. Potential Adverse Effectswill preferentially partition into the systemic tissue compartment.

At steady state, there is consequently a large volume of distribu-

tion, acting as a reservoir to be slowly released.[11] This may 2.1 Topicalaccount for the greater adverse effects on growth and adrenal

function seen when fluticasone propionate has been given to 2.1.1 Dysphonia and Oral Candidiasispeople with mild or no asthma.[21,22] If the airways are less con- There have previously been concerns about dysphonia and oralstricted or inflamed, more of the drug may be absorbed from the thrush developing in people using ICS. These symptoms havelungs, and thus be systemically available. Initially, a high dose of been described in adults,[24] but subsequent systematic reviews onICS may be needed to control the asthma. If the drug is effective, their use in children have shown these to be uncommon prob-local inflammation will be reduced and airway obstruction will lems.[4,25] The reasons for this are unclear, but may in part beimprove so the amount of drug absorbed through the lungs may because of the greater use of spacer devices in children. There areincrease. This emphasizes the importance of using the lowest no specific data on topical adverse effects with the newer ICS suchpossible dose of ICS for symptom control. as fluticasone propionate or mometasone.

2.1.2 Dental Health1.3.4 Comparing ICS Systemic Activity

ICS may also have an adverse effect on dental health. ChildrenThe difficulties of comparing both the efficacy and safety ofwith asthma have been shown to have a higher incidence of toothICS in asthma have been discussed in detail elsewhere.[23] In brief,decay and dental erosion of both deciduous and permanent teethsystemic activity of ICS will depend on both the potency of thethan those who have never had asthma.[26,27] One possible reasonparticular ICS, and, perhaps more importantly, the pulmonaryfor this is a reported higher prevalence of gastro-esophageal refluxdeposition of the ICS. Pulmonary deposition is still the majorin the children with asthma.[26] However, the pH of the asthmadeterminant of systemic bioavailability, even when there is somemedication could be contributory. Powdered forms of many of theoral bioavailability, as this is usually minimized by using a spacercommon asthma drugs, including bronchodilators and ICS, have aor having the patient rinse and spit after use. In turn, pulmonarypH of <5.5, and tooth substance is known to begin to dissolve atdeposition will depend on factors related to the individual ICS, aspH 5.5.[28] This may be a potential complication with mometasone,well as patient-related factors. As already discussed, factors suchas a dry powder form is being introduced for lung deliveryas the delivery device and the particle size will have a significant

influence on pulmonary drug deposition. In addition patient fac-

tors, particularly inhaler technique and degree of airway obstruc-

tion, will also affect pulmonary deposition. The latter issue is

highlighted by the recent observation that systemic availability of

fluticasone propionate was significantly less in patients with asth-

ma compared with healthy volunteers,[21,22] although interestingly,

systemic availability of budesonide was similar in patients with

asthma and in healthy volunteers.[22] Given the above issues, it is

obviously difficult to compare the relative systemic activity of

different ICS or to determine a ‘threshold’ dose above which

systemic activity is apparent. While these issues are also important

Table II. Choice of inhaler device in children according to age[3]

Route of Age

administration <2y 2–5y 5–8y ≥8y

MDI + small volume spacer + Yes Yes No No

mask

MDI + spacer No Yes Yes Yes

Dry powder device No No Possible Yes

Breath activated device No No Possible Yes

MDI (alone) No No No Yes

MDI = metered dose inhaler.

© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)

486 Randell et al.

(Twisthaler®), and the dry powder form of fluticasone propionate cemia, in particular, can be hazardous, with two fatalities in

(Accuhaler™). Aerosol forms have a pH of between 7 and 9.3, children in the UK in the 1980s[35] (resulting from inappropriate

therefore hydrofluoroalkane beclomethasone and fluticasone pro- treatment of the hypoglycemia), although a more recent paper

pionate pressurized MDI should not have the same adverse effect describes its safe use in more than 500 children.[36] The short

on dental enamel, particularly if spacers are used to ensure the synthetic corticotropin stimulation test is usually the investigation

dose is delivered to the back of the mouth. of choice, but debate even surrounds how best to perform this. The

standard test uses supraphysiological doses (250μg intramuscular-2.2 Adrenal Function ly) of synthetic corticotropin (Synacthen®), and thus it has been

argued that this could give false normal results when secondary2.2.1 Assessment of Adrenal Function adrenal failure is suspected. A low dose, i.e. 10μg or even 0.5 μg/

1.73m2, of Synacthen® may be more sensitive.[37] Others haveSuppression of the Hypothalamic-Pituitary-Adrenal Axiscontradicted this finding[38] and, in the case reports of adrenalSuppression of the HPA axis and the risk of adrenal crises areinsufficiency, standard-dose Synacthen® tests have demonstratedpotentially the most serious adverse effects of exogenous cortico-inadequate cortisol responses whenever they were performed.[31-33]

steroid use. Synthetic glucocorticoids down-regulate corticotropin

(adrenocorticotropic hormone; ACTH) production by the same 2.2.2 Biochemical Suppressionfeedback-inhibition loops that control endogenous glucocorticoid

General Effects of ICSproduction, thus causing adrenal suppression. It is well recognizedMost studies have used early morning blood cortisol levels as athat oral glucocorticoids can cause this,[29] hence the recommenda-

measure of HPA function and, generally, suppression was not seention that any patient on long-term treatment with oral corticoster-until high doses of ICS were used (table III). A recent systematicoids carry a corticosteroid alert card. ICS have been known toreview of the systemic adverse effects of ICS therapy concludedcause biochemical HPA suppression for many years, even at dosesthat marked adrenal suppression occurs with high dosages of ICSconsidered to be moderate or low.[30] The effects of ICS on theabove 1500 μg/day (750 μg/day for fluticasone propionate), al-HPA axis can be assessed by various means, with some debatethough there was a considerable degree of interindividual suscepti-regarding the best method of doing so. Since effects of ICS on thebility.[39] The measurements used as an assessment of adrenalHPA axis are generally mild, sensitive methods are required tofunction were 24-hour or overnight urinary cortisol levels, ordetect suppression.8.00am plasma cortisol levels. Studies included healthy adult

Screening for Adrenal Insufficiencyvolunteers, and both children and adults with asthma.

Clinical indicators of systemic effects, such as poor growth orA further study examined the effects of ICS by dose, rather than

Cushingoid features, are not always present in children withtype of ICS.[40] Forty-five children with asthma who were taking

documented biochemical adrenal insufficiency secondary toregular ICS were investigated and analyzed according to whether

ICS.[31-33] As a basic screening tool, early morning serum orthey were receiving <600 μg/m2/day (n = 23, group 1) or >600 μg/

salivary cortisol concentrations can be reassuring if they are highm2/day (n = 22, group 2). Thirteen children were taking beclo-

normal, but lower levels can be indeterminate.[29] In a study on themethasone, 27 budesonide, and 5 had very recently changed to

effects of high-dosage inhaled chlorofluorocarbon beclometha-fluticasone propionate. In those children receiving fluticasone

sone (2 mg/day) in healthy adult volunteers, 24-hour urinarypropionate, the previous dose of beclomethasone or budesonide

cortisol levels were reduced after only 4 days of treatment.[34]

was used to calculate the amount of ICS administered. The chil-However, this may simply be a result of negative feedback, which

dren were aged between 5 and 15 years and had been taking ICSdoes not indicate significant adrenal suppression. Also, collecting

for a mean of 5.59 (range 1.59–10.18) years. They were at various24-hour urine samples from children is frequently impractical.

stages of puberty. An ultra-low-dose short Synacthen® test (SST)Dynamic Testing was performed (0.5 μg/1.73m2): 48% of group 1 and 68% of group

Dynamic testing is used to formally assess adrenal function, 2 had abnormal responses (60-minute cortisol value <500 nmol/

with the ‘gold-standards’ being the metyrapone suppression or L), with no significant difference between the groups. However,

insulin-induced hypoglycemia tests.[29] Insulin-induced hypogly- the 5 children receiving >900 μg/m2/day all had peak cortisol

© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)

Safety of the New

er Inhaled C

orticosteroids in C

hildhood

Asthm

a487

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Table III. Summary of studies examining biochemical adrenal suppression with inhaled corticosteroids

Study Population studied Drug and dosage Investigation used Results

Clavano et al.[40] 45 children with asthma Beclomethasone/budesonide Ultra-low-dose SST (0.5 μg/ Maximum cortisol <500 nmol/L in

<600 μg/m2/day (I) or >600 μg/ 1.73m2) 48% (I), 68% (II) [no significant

m2/day (II) difference]

Fitzgerald et al.[41] 34 children with asthma Fluticasone propionate 750 μg/ Ultra-low-dose SST (0.5 μg/ Maximum cortisol <500 nmol/L in

day or beclomethasone 1500 μg/ 1.73m2) 70% of children in both groups

day, for 12 weeks each

Kannisto et al.[42] 75 children with asthma Fluticasone propionate 500 μg/ Ultra-low-dose SST (0.5 μg/ 23% abnormal SST, more children

day then 200 μg/day vs 1.73m2) receiving budesonide than

budesonide 800 μg/day then 400 fluticasone propionate affected at

μg/day vs cromones lower dosages

Lipworth et al.[43] 8 children with asthma Fluticasone propionate 200 and Overnight urinary cortisol No suppression of cortisol in any

400 μg/day, or budesonide 200 of the groups

and 400 μg/day, for 4 days each

Lipworth[39] Meta-analysis of 27 studies of Fluticasone propionate 500–2000 24h or overnight urinary cortisol Greater suppression of cortisol

healthy adults, and adults and μg/day; beclomethasone and/or morning plasma cortisol with fluticasone propionate than

children with asthmaa 200–2000 μg/day; budesonide others (exact values not given)

400–2000 μg/day; flunisolide

1000–4000 μg/day; triamcinolone

400–1600 μg/day

Barnes et al.[44] Meta-analysis of 14 studies, two Fluticasone propionate 200–1000 Morning plasma cortisol At presumed equipotent doses

in children μg/day; budesonide 400–1600 less suppression with fluticasone

μg/day; beclomethasone propionate than with budesonide;

400–2000 μg/day similar suppression with fluticasone

propionate and beclomethasone

Continued next page

488R

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Table III. Contd

Study Population studied Drug and dosage Investigation used Results

Fowler et al.[45] 16 healthy adults Hydrofluoroalkane fluticasone Overnight urinary cortisol and Dose-related suppression, more

propionate 500–2000 μg/day and morning serum cortisol with hydrofluoroalkane

hydrofluoroalkane beclomethasone than

beclomethasone 500–2000 μg/ hydrofluoroalkane fluticasone

day propionate

Pedersen et al.[20] 35 children with asthma (out of Hydrofluoroalkane Low-dose Synacthen® test (1 μg/ 4/24 hydrofluoroalkane

300 enrolled) beclomethasone 100–200 μg/day 1.73m2) beclomethasone recipients and 1/

or chlorofluorocarbon 11 chlorofluorocarbon

beclomethasone + spacer beclomethasone recipients had

200–400 μg/day cortisol <500 nmol/L

Davies et al.[46] 233 adults with asthma Hydrofluoroalkane Morning plasma cortisol Less suppression with

beclomethasone 800 μg/day or hydrofluoroalkane beclomethasone

chlorofluorocarbon (cortisol <193 nmol/L)

beclomethasone 1500 μg/day

Gross et al.[47] 347 adults with asthma Hydrofluoroalkane Morning plasma cortisol >96% of patients in both groups

beclomethasone 400 μg/day or had normal cortisol (193–690

chlorofluorocarbon nmol/L)

beclomethasone 800 μg/day

Fireman et al.[48] 354 adults with asthma Hydrofluoroalkane Morning plasma cortisol No suppression with

beclomethasone 200–800 μg/day hydrofluoroalkane

or chlorofluorocarbon beclomethasone, even at 800 μg/

beclomethasone 400-1600 μg/ day

day

Affrime et al.[49] 3 groups, 60–64 adults with Mometasone 400–1600 μg/day Standard-dose Synacthen® test No suppression seen until

asthma in each vs prednisone 10 mg/day, (250μg) mometasone dosage of 1600 μg/

fluticasone propionate 1760 μg/ day (peak cortisol <500 nmol/L)

day or placebo

a Studies involving children used only beclomethasone or budesonide as inhaled corticosteroids.

SST = short Synacthen® test.

Safety of the Newer Inhaled Corticosteroids in Childhood Asthma 489

levels of <500 nmol/L. Urine specimens for 24-hour urinary free = 12) or changed to cromones (n = 18). The third group of 15

cortisol (UFC) were collected prior to the SST, and early morning received cromones for 4 months, and then either continued with

serum cortisol and corticotropin levels were also checked. The them (n = 9) or changed to ICS (budesonide or fluticasone pro-24-hour UFC did not predict those children who had an abnormal pionate [n = 6]). An ultra-low-dose SST was performed at thelow-dose SST. beginning of the study, and at 2, 4, and 6 months. The authors

defined an abnormal result as a stimulated cortisol level of more

than 2 standard deviations below the mean baseline measurement,Fluticasone Propionate

which was calculated before starting treatment (<330 nmol/L).The above-mentioned systematic review concluded that thereUsing this criterion, 23% of children receiving ICS had an abnor-was a significantly steeper dose-related adrenal suppression slopemal SST response at 2 months (no difference between fluticasonewith fluticasone propionate compared with beclomethasone orpropionate or budesonide), with a similar percentage at 4 months,budesonide, even allowing for its greater potency.[39] However, abut with more children receiving budesonide (n = 9) than receivingmeta-analysis of systemic activity of fluticasone propionate at

fluticasone propionate (n = 5) affected (p < 0.05). At 6 months, 4presumed equipotent doses compared with beclomethasone and

children receiving ICS still had an abnormal response but allbudesonide in both children and adults with asthma concluded

there was no greater adrenal suppression with fluticasone propion- cromone users (including those previously on ICS) had a normal

ate.[44] These apparently opposing conclusions may relate to differ- SST.

ent patient groups (healthy individuals or patients with asthma of Fitzgerald et al.[41] studied 34 children who had been on high-different severity),[21,22] differing individual susceptibility, differ-

dosage ICS (budesonide 1200–1600 μg/day or chlorofluorocarbonent ways of measuring HPA suppression, and/or measurements

beclomethasone 1000–2000 μg/day) for at least 12 months andmade at different parts of the adrenal suppression dose-response

were switched to either fluticasone propionate 750 μg/day orcurve.

chlorofluorocarbon beclomethasone 1500 μg/day, via a large vol-There have been limited comparative studies of biochemical

ume spacer. They spent 12 weeks taking the first ICS and thenadrenal suppression in children. Lipworth et al.[43] measured over-

switched to the second ICS for 12 weeks, with both patients andnight urinary cortisol, as a measure of adrenal suppression, in a

observers blinded to the order in which they were given. Twenty-crossover study in 8 children with asthma, comparing fluticasone

four-hour UFC levels did not change during the study period,propionate and budesonide at dosages of 200 and 400 μg/day

regardless of whether the patients were taking fluticasone propion-given over a 4-day period. There was no evidence of significant

ate or beclomethasone. Ultra-low-dose Synacthen® tests wereadrenal suppression with either fluticasone propionate or budeso-

performed at the end of each treatment phase and in both groups;nide at the dosages studied, and the investigators concluded that

>60% of patients showed biochemical evidence of adrenal sup-the results emphasized the good safety profile of these ICS at

pression. Thus, these data suggest that high dosages of fluticasoneconventional dosage levels. These results should be interpreted

propionate do cause biochemical adrenal suppression which is nowith caution as the study was performed over a very short period

greater than equipotent dosages of chlorofluorocarbon beclo-of time and the relevance of overnight urinary cortisol measure-

methasone, supporting the conclusions of the Barnes meta-ana-ments is uncertain.

lysis.[44]

A Finnish study compared 75 children with asthma in whomFigure 1 summarizes the dose effect of fluticasone propionatethe diagnosis had been newly made (n = 62), or who had only

on biochemical adrenal suppression, with the effects of differingpreviously received bronchodilators (n = 9) or cromone medica-doses of fluticasone propionate on the ultra-low-dose SST (com-tions (n = 4).[42] The children were divided into three groups. Thepared with clinical efficacy of the same doses of fluticasonefirst group of 30 children received fluticasone propionate 500 μg/propionate). This figure serves to highlight that increasing theday for 2 months, then 200 μg/day for 2 months, and then eitherdosage of fluticasone propionate above 200 μg/day results in acontinued with that dosage of fluticasone propionate (n = 11) or

significant increase in biochemical adrenal suppression, withoutchanged to cromones (n = 19). The second group of 30 received

any significant increase in clinical benefit. While the clinicalbudesonide 800 μg/day for 2 months, then 400 μg/day for 2

months, and then either continued on that dosage of budesonide (n relevance of this biochemical suppression was uncertain, there are

© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)

490 Randell et al.

included in the analysis. No differences between the 24-hour UFC

levels in the two groups was found, and 4 out of 24 children in the

hydrofluoroalkane beclomethasone group had subnormal

Synacthen® responses, compared with 1 out of 11 in the chloro-

fluorocarbon beclomethasone group.

Studies in adults comparing equipotent doses of hydrofluoro-

alkane beclomethasone and chlorofluorocarbon beclomethasone

have demonstrated no difference in HPA axis suppression,[46-48]

with one showing less suppression of morning plasma cortisol

levels on high-dosage hydrofluoroalkane beclomethasone (800

μg/day) than on high-dosage chlorofluorocarbon beclomethasone

(1500 μg/day).[11,46]

Mometasone

Mometasone is in the process of being introduced for the

treatment of asthma in adolescents and adults. There have been no

studies of its safety or efficacy in children younger than 12 years of

age, although its pharmacokinetics appear to be similar to those of

0

20

40

60

80

100

120

Daily dose of inhaled fluticasone propionate (μg)

Per

cent

age

affe

cted

Asthma controlledAbnormal LDSST

0 100 200 500 750

aa

b

Fig. 1. Schematic diagram comparing the efficacy of fluticasone propionateat different doses (clinical benefit based on percentage of children control-led on varying doses of fluticasone propionate)[42,50] with the effect of differ-ent doses of fluticasone propionate on the low-dose short Synacthen® test(LDSST). Data from Kannisto et al.[42] (a) and Fitzgerald et al.[41] (b).

fluticasone propionate.[14] The effect of mometasone on the HPA

axis has only been evaluated in adults with mild to moderatenow more than 50 case reports of adrenal crises with high-dose

asthma.[49] The authors claimed that there were no adverse effectsfluticasone propionate (see section 2.2.3).

seen until dosages of 1600 μg/day (double the highest recommen-

ded clinical dosage) were used.[49] However, others have criticizedHydrofluoroalkane Beclomethasone

the interpretation of these data, suggesting that suppression wasThe effect of hydrofluoroalkane beclomethasone on adrenal

demonstrable at most time points with both the 800 and 1600 μg/function was compared with identical doses of hydrofluoroalkane

day dosages, when compared with placebo, and questioning thefluticasone propionate in 16 healthy adult volunteers by measuring

authors’ conclusions that the systemic bioavailability of mometa-early morning cortisol and urinary cortisol/creatinine excretion.

sone was negligible.[11] No data are currently available on theHydrofluoroalkane beclomethasone caused significantly greater

effects on children and, clearly, more studies are required to assesssuppression of the overnight urinary cortisol/creatinine ratio than

the potential of mometasone for adrenal suppression, particularlyfluticasone propionate at dosages ≥1000 μg/day.[45] This was felt

given its high lipophilicity.to be a result of the greater lung deposition of hydrofluoroalkane

Clinical Relevancebeclomethasone offsetting the greater glucocorticoid potency of

The clinical relevance of this degree of adrenal suppression isfluticasone propionate.

uncertain, and until recently it was felt that the risk of symptomaticHydrofluoroalkane beclomethasone has also been comparedacute adrenal insufficiency from the use of ICS alone was verydirectly with chlorofluorocarbon beclomethasone with regard tosmall.its effect on the HPA axis.[20] In a multicenter, international, open-

label comparison, children were randomized to either hydrofluoro-2.2.3 Clinical Adrenal Suppression

alkane beclomethasone 100–200 μg/day or chlorofluorocarbonAdrenal Crisesbeclomethasone 200–400 μg/day. At 12 months, the children had

24-hour UFC assessments and/or a low-dose (1 μg/1.73m2) Acute adrenal insufficiency has been rarely reported as a com-

Synacthen® test performed to assess suppression of the HPA axis. plication of ICS therapy until recently. In 1992, Wong and

Children who had been taking dosages higher than those detailed Black[51] reported an adult on high-dosage budesonide (1.6–6.4

above (hydrofluoroalkane beclomethasone up to 400 μg/day or mg/day) who developed acute adrenal insufficiency following

chlorofluorocarbon beclomethasone up to 800 μg/day) were not dosage reduction. In the same year, Zwaan et al.[52] reported a child

© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)

Safety of the Newer Inhaled Corticosteroids in Childhood Asthma 491

on low-dosage budesonide (500 μg/day, inhaled and nasal), who

presented with an adrenal crisis following sudden cessation of ICS

because of concern about systemic adverse effects. Over the past

few years, there have been increasing numbers of case reports of

children receiving ICS who have presented with adrenal crises

(table IV). In 1999, a 9-year-old girl who had been receiving

fluticasone propionate 550 μg/day for severe labile asthma was

described. She was clinically Cushingoid and developed orthosta-

tic hypotension and moderate dehydration following a mild viral

illness. Hypoglycemia was not mentioned. Her 8.00am cortisol

was undetectable and her corticotropin level was inappropriately

low at 21 ng/L (4.62 pmol/L, normal 2.0–10.0 pmol/L).[53] No

other cause for her adrenal insufficiency was found.

A series of eight children with symptomatic adrenal insuffi-

ciency was published in November 2001.[31] Two of these children

presented with altered consciousness as a result of hypoglycemia,

consistent with an adrenal crisis. The rest had a more insidious

course, with poor growth being the main symptom.[31] The two

children with adrenal crises had been on high-dosage fluticasone

propionate (500 μg/day) for at least 4 months before presentation;

however, the dosages did not exceed the recommended dosages

detailed in the British Thoracic Society guidelines.[56,57] Further-

more, four other children who presented with hypoglycemia and

altered consciousness (one of whom had had recurrent hypoglyce-

mic seizures during intercurrent illnesses) were all receiving high-

dosage fluticasone propionate (500–1500 μg/day).[32] None were

Cushingoid, and two of the four had normal growth velocities. All

had inappropriately low cortisol levels on testing with standard

SST.

Three other case series have reported similar presenta-

tions,[33,54,55] the largest being a national survey in the UK in which

33 cases of acute adrenal insufficiency were reported.[54] Twenty-

eight of the 33 were children, and in 28 patients, fluticasone

propionate in dosages of 500–2000 μg/day was the only ICS used.

Of the 33 patients, three were felt not to have asthma. Five were

described as having probable asthma that was being overtreated

with ICS because of concurrent lung diseases simulating asthma

symptoms. Six had moderate asthma as per the British Thoracic

Society guidelines,[56,57] and no information was available on 5

patients. The remainder (1 adult, 13 children) were described as

having severe asthma.[54] In all reported case series, no other

causes of adrenal insufficiency were found. In the UK, fluticasone

propionate accounts for only 15% of all ICS prescriptions and yet

in this case series, 31 out of 33 patients (94%) were taking it.

© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)

Tab

le I

V.

Sum

mar

y of

rep

orts

of

adre

nal c

rises

in p

atie

nts

rece

ivin

g in

hale

d co

rtic

oste

roid

s

Rep

ort

Age

(no

. of

pat

ient

s)D

rug

and

dosa

geP

rese

ntin

g sy

mpt

oms

Cor

tisol

leve

l

Tay

lor

et a

l.[53]

9y (

1)F

lutic

ason

e pr

opio

nate

550

μg/

Cus

hing

oid,

hyp

oten

sion

Und

etec

tabl

e at

8.0

0am

day

Pat

el e

t al

.[31]

4.5–

10y

(2/8

a )F

lutic

ason

e pr

opio

nate

500

μg/

Hyp

ogly

cem

ia,

impa

ired

cons

ciou

snes

s<

500

nmol

/L p

ost-

Syn

acth

en®

or

mor

ning

day

(in t

he c

hild

ren

with

cort

isol

<20

0 nm

ol/L

adre

nal c

rises

)

Dra

ke e

t al

.[32]

4–8y

(4)

Flu

ticas

one

prop

iona

teH

ypog

lyce

mia

, un

cons

ciou

snes

s<

500

nmol

/L p

ost-

Syn

acth

en®

500–

1500

μg/

day

Tod

d et

al.[3

3]7–

9y (

3)F

lutic

ason

e pr

opio

nate

Hyp

ogly

cem

ic s

eizu

res

<50

0 nm

ol/L

pos

t-S

ynac

then

®

500–

2000

μg/

day

Tod

d et

al.[5

4]C

hild

ren

3.3–

10y

(28)

Flu

ticas

one

prop

iona

teH

ypog

lyce

mic

sei

zure

s or

com

a (2

3/33

);<

500

nmol

/L p

ost-

Syn

acth

en®

, co

rtis

olA

dults

(5)

500–

2000

μg/

day

(30/

33);

hypo

tens

ion,

fat

igue

, na

usea

(9/

33);

fat

al<

500

nmol

/L a

t tim

e of

acu

te il

lnes

s, o

rbe

clom

etha

sone

dos

age

NR

(2/

seps

is w

ith h

ypog

lyce

mia

(1/

33)

cort

isol

<50

0 nm

ol/L

pos

t-gl

ucag

on33

); f

lutic

ason

e pr

opio

nate

+st

imul

atio

nbu

deso

nide

, do

sage

NR

(1/

33)

Mac

dess

i et

al.[5

5]4–

11y

(3)

Flu

ticas

one

prop

iona

teH

ypog

lyce

mia

, se

izur

es<

500

nmol

/L p

ost-

Syn

acth

en®

, or

<20

010

00–1

500

μg/d

aynm

ol/L

at

time

of h

ypog

lyce

mia

aN

umbe

r of

pat

ient

s w

ith a

cute

adr

enal

cris

es w

as 2

out

of

8 pa

tient

s in

tot

al r

epor

ted

with

any

end

ocrin

e ad

vers

e ef

fect

s of

IC

S.

NR

= n

ot r

epor

ted.

492 Randell et al.

While there have been suggestions that adrenal suppression is absorbed through the lungs, or whether it is a reflection of

more likely to occur with fluticasone propionate,[32,54] perhaps prescribing practices. However, in the UK survey where 94%

because of its greater lipophilicity,[54] it is clear that other ICS can of patients with adrenal crises were taking fluticasone propion-

also be responsible. It is also apparent that individual susceptibility ate, it accounted for only 15% of all ICS prescriptions.[54]

plays a significant role. The other explanation for the preponder- • It is important to be aware of this potentially very seriousance of fluticasone propionate-related cases is the generally very adverse effect in children who require high doses of ICS, andhigh dosages of fluticasone propionate that have been used in the ‘back-titrate’ doses as soon as adequate control is achieved.patients described. Parents of these children should also be counseled regarding

There have, as yet, been no reports of symptomatic adrenal this risk.

insufficiency with hydrofluoroalkane beclomethasone or mometa- • If an adrenal crisis is suspected, the blood sugar and cortisolsone. level should be checked. If abnormal, the child should be

referred to a pediatric endocrinologist for formal adrenal func-Preventing Adrenal Crises

tion testing.An adrenal crisis can be a life-threatening event, therefore it is

very important to warn parents of children receiving high-dose 2.3 GrowthICS of this potential risk. Any doctor who sees a child in whom an

adrenal crisis is suspected should check the blood glucose and 2.3.1 Normal Growthcollect blood to determine the cortisol level at the same time. It is Growth rate varies considerably during childhood. It can bealso crucial to administer parenteral hydrocortisone (intravenously typically characterized by a rapid growth velocity during infancy,or intramuscularly) as soon as possible if adrenal crisis is suspect- slow deceleration during the prepubertal years to reach a nadired. If the blood glucose level or cortisol level is abnormal, the prior to the onset of puberty, followed by the growth spurt andchild should be urgently referred to a pediatric endocrinologist for attainment of final height. Catch-up and catch-down growth mayformal assessment of adrenal function. As it is difficult to be sure also be seen in infants, and occasionally in children, as program-of the clinical relevance of biochemical evidence of adrenal sup- med by their genetic potential. A potential problem exists whenpression, it may be more appropriate to advise the parents of interpreting the growth data of children receiving ICS as the meanchildren receiving high-dose ICS to seek urgent medical advice ages in many of the studies often overlap with the natural decelera-should their child become significantly unwell. This is particularly tion in growth velocity prior to the onset of puberty.[58]

important with vomiting or diarrheal illnesses, or with high fever2.3.2 Effect of ICS and Asthma on Growth

(temperature >39ºC).[55]

It is postulated that the adverse effects of ICS on growth areIt should also be noted that in several of the case reports, the

caused by potential suppression of growth hormone secretion andchildren were subsequently found not to have asthma or to have

decreasing circulating insulin-like growth factor-1 levels.[59] Corti-asthma of a significantly milder degree than previously as-

costeroids may also have a direct effect on the growth plate,sessed.[54,55] It is recommended that a pediatric respiratory physi-

restricting growth by their effects on the hypertrophic chondro-cian should review any child thought to have asthma who does not

cytes within the cartilage.[60]respond to conventional doses of ICS before increasing the dose

Untreated asthma itself has an adverse effect on growth, espe-further.[2,55]

cially if it is severe.[61,62] Asthma has also been shown to delay2.2.4 Summary puberty, and hence the growth spurt.[63] The effects of ICS on

• Biochemical evidence of adrenal suppression can be commonly growth in children have been of concern for some time. It has,found in children receiving ICS, particularly on high doses. The however, been difficult to ascertain their precise effects. The firstclinical relevance of such adrenal suppression is uncertain. evidence suggesting that ICS could cause growth attenuation was

• While uncommon, there are now reports of adrenal crises in based on retrospective studies, with wide variations in ages of the

children. The majority of these have been on high-dose fluti- children and doses of corticosteroids.[64] Later studies tried to

casone propionate, but it is not clear whether this relates to the control for these factors. While these studies confirmed a slowing

greater potency of fluticasone propionate, particularly when of growth in some children with asthma receiving ICS therapy,[64]

© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)

Safety of the Newer Inhaled Corticosteroids in Childhood Asthma 493

the authors indicated that no firm conclusion could be reached on

final adult height. However, a subsequent study has suggested that

ICS therapy does not reduce final adult height[65] and this issue

will be discussed in more detail in section 2.3.4.

2.3.3 Short-Term Growth (Knemometry)

Growth has been evaluated in two different ways. Knemometry

measures changes in lower leg length as an index for short-term

growth and is generally used in studies to measure growth over a

2–4 week period, with washout periods employed between differ-

ing dose or drug comparisons. However, as has already been

stated, growth in children is not a constant progression, but rather

occurs episodically. Short-term changes in lower leg length veloc-

ity are not predictive of long-term growth,[66] but rather appear to

reflect short-term suppressive effects on collagen turnover.[67]

Other studies have followed children for longer periods of time

and measured their linear growth, comparing it with either healthy

children without asthma, or children with asthma not using ICS, as

controls.

Much of the research using knemometry as a measurement of

growth velocity has been on the older ICS, in particular budeso-

nide. A few have compared fluticasone propionate with either

budesonide or chlorofluorocarbon beclomethasone.[23]

Fluticasone Propionate

In one randomized, crossover, double-blind study, 17 children

were treated with fluticasone propionate and beclomethasone in

three active treatment periods of 15 days, with a washout period in

between each one (table V).[67] Each child acted as his or her own

control and was given either fluticasone propionate 200 μg/day, or

beclomethasone 400 or 800 μg/day via Diskhaler® as a dry pow-

der. Knemometry and other markers of growth were measured

regularly throughout and a greater effect on growth suppression

with beclomethasone than with fluticasone propionate was

found.[67]

Fluticasone propionate was compared with budesonide in an-

other study in which 48 children were assigned to either low-

dosage (200 μg/day) fluticasone propionate or budesonide or

placebo (24 children), or higher-dosage (400 μg/day) fluticasone

propionate or budesonide or placebo (24 children).[68] Each child

again acted as his or her own control and was randomized in a

double-blind fashion to either active drug or placebo given via a

DPI for 15–18 days. There was a 2-week washout period between

each treatment arm, and the same observer performed knemometry

twice weekly throughout. Again fluticasone propionate was shown

© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)

Tab

le V

. S

umm

ary

of e

ffect

s of

inha

led

cort

icos

tero

ids

on k

nem

omet

ry

Stu

dyA

geD

rug

and

dosa

geP

uber

tal s

tatu

sLe

ngth

of

stud

yF

inal

res

ult

(no.

of

child

ren)

Wol

ther

s et

al.[6

7]7–

14y

(17)

Flu

ticas

one

prop

iona

te 2

00 μ

g/da

y vs

16 p

repu

bert

al,

112

wks

(2w

ks o

nB

eclo

met

haso

ne,

but

not

flutic

ason

e

becl

omet

haso

ne 4

00 μ

g/da

y vs

Tan

ner

IIea

ch d

osag

e)pr

opio

nate

, af

fect

ed k

nem

omet

ry

becl

omet

haso

ne 8

00 μ

g/da

y

Age

rtof

t an

d6–

12y

(48)

Flu

ticas

one

prop

iona

te 2

00 μ

g/da

y vs

Pre

pube

rtal

12w

ks (

15–1

8B

udes

onid

e, b

ut n

ot f

lutic

ason

e

Ped

erse

n[68]

bude

soni

de 2

00 μ

g/da

y vs

bud

eson

ide

days

on

each

prop

iona

te,

affe

cted

kne

mom

etry

400

μg/d

aydo

sage

)

Vis

ser

et a

l.[69]

6–10

y (2

1)F

lutic

ason

e pr

opio

nate

200

μg/

day

vsP

repu

bert

al6w

ks f

lutic

ason

eF

lutic

ason

e pr

opio

nate

had

no

effe

ct o

n

bron

chod

ilato

rpr

opio

nate

, 2w

kskn

emom

etry

bron

chod

ilato

r

Anh

oj e

t al

.[70]

1–3y

(25

)F

lutic

ason

e pr

opio

nate

400

μg/

day

vsP

repu

bert

al4w

ks c

ross

over

Flu

ticas

one

prop

iona

te a

nd b

udes

onid

e

bude

soni

de 4

00 μ

g/da

y vs

pla

cebo

affe

cted

kne

mom

etry

to

a si

mila

r

degr

ee

Age

rtof

t an

d7–

12y

(22)

Intr

anas

al m

omet

ason

e 10

0 or

200

μg/

Var

iabl

e pu

bert

y14

wks

(2w

ks o

nM

omet

ason

e an

d bu

deso

nide

had

no

Ped

erse

n[71]

day

vs b

udes

onid

e 40

0 μg

/day

vs

each

dos

age)

adve

rse

effe

ct o

n kn

emom

etry

plac

ebo

494 Randell et al.

to have no adverse effect on short-term growth compared with was used, and confirmed an overall decrease in linear growth

placebo, but high-dosage (400 μg/day) budesonide attenuated velocity of 1.51 cm/year (95% CI 1.15–1.87).[73]

growth. This is despite the fact that fluticasone propionate may Subsequently, a Cochrane review has looked specifically at thehave up to double the potency of budesonide.[68] effect of beclomethasone (given by dry powder Diskhaler® or

A further study examined the effect of fluticasone propionate MDI) on growth. Three randomized, controlled, double-blindalone on knemometry.[69] Twenty-one prepubertal boys with asth- trials examining children aged <18 years of age who were notma were given fluticasone propionate 200 μg/day for 6 weeks, taking any corticosteroids for a minimum of 3 months prior to thefollowed by a 2-week period on bronchodilators alone (washout study were included. The control groups were children with asth-period). Prior to starting fluticasone propionate, the boys had been ma matched for age, pubertal status, and gender, and receivedtaking between 100 and 400 μg/day of ICS (type not specified). either salmeterol or placebo as medication. It was found that inKnemometry was measured at 2-weekly intervals and no differ- children with mild to moderate asthma, a dosage of 400 μg/dayence was found between growth while on fluticasone propionate caused a decrease in linear growth of –1.54 cm/year. However, theor on bronchodilators alone.[69] authors point out that none of the analyzed studies lasted beyond

A recently published study compared the effect of fluticasone 54 weeks, therefore it was not possible to comment on whether this

propionate and budesonide on knemometry in children aged be- decrease in growth was sustained.[74]

tween 1 and 3 years with mild asthma.[70] The study compared The Childhood Asthma Management Program (CAMP) study,fluticasone propionate 400 μg/day, budesonide 400 μg/day, and comparing budesonide 400 μg/day with nedocromil 16 mg/day orplacebo given via an MDI and spacer over a 4-week period, in a placebo, showed a slowing of growth rate by 1cm in the first yearrandomized, double-blind, double-dummy, three-way, crossover in patients receiving budesonide compared with those receivingdesign. They enrolled 40 children, and 25 completed all three nedocromil or placebo. There was no difference in growth rate intreatments. Both fluticasone propionate 400 μg/day and budeso- subsequent years, but the lost 1cm was not regained at the end ofnide 400 μg/day caused a significant slowing of lower leg length the study (mean duration 4.3 years). In spite of this, the predictedgrowth compared with placebo (fluticasone propionate 34 μm/day, final adult height (based on bone age) was within the target geneticbudesonide 45 μm/day, placebo 85 μm/day). predicted height. Also, this study did not comment on pubertal

status of children prior to commencement of treatment, althoughMometasone and Hydrofluoroalkane Beclomethasonepubertal staging at the end of the study was not different betweenThere are no published data on the effect of inhaled mometa-the three groups. Again, asthma control was significantly better insone on knemometry, but no adverse effect was found on short-the budesonide-treated group, compared with patients receivingterm growth when intranasal mometasone was compared withnedocromil or placebo (see figure 2).[75]

intranasal budesonide and placebo.[71] The effect of hydrofluoro-One study followed a cohort of children treated with budeso-alkane beclomethasone on knemometry has not been evaluated.

nide, 142 of whom had reached adult height at follow-up.[76] The2.3.4 Linear Growth (Intermediate and Long Term)

mean duration of asthma was 14 (range 5–23) years, and the mean

Beclomethasone and Budesonide duration of budesonide treatment was 9.2 (range 3–13) years.

These children were compared with their healthy siblings and aA number of studies examining the effects of beclomethasone

control group of children with asthma who did not use ICS. Theiron linear growth have found it was decreased in those children

target adult height was estimated from parental height data. Nousing ICS (table VI).[72-74] In a Canadian study, those children

difference in final adult height was found between any of thereceiving beclomethasone showed a reduction of growth of around

groups, with over 95% of children in each group achieving an1.5 cm/year when treated with 400 μg/day, compared with those

adult height within 9cm of their target height.receiving either salmeterol or placebo. However, they also had

significantly decreased airway hyper-responsiveness and the needHydrofluoroalkane Beclomethasonefor salbutamol (albuterol) rescue therapy.[72] The beclomethasone

preparation used in this study was dry powder via Diskhaler®. A Only one study has so far been published looking specifically at

meta-analysis of the effect of ICS on growth in children found four the effects of hydrofluoroalkane beclomethasone on growth. This

studies in which beclomethasone (dosage range 328–440 μg/day) compared hydrofluoroalkane beclomethasone (100–200 μg/day,

© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)

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Table VI. Summary of linear growth studies in patients receiving inhaled corticosteroids

Study Age Drug and dosage Pubertal status Length of study Final result

(no. of children)

Sharek et al.[74] 6–16y (633) Beclomethasone 400 μg/day via All stages of 7–12mo Overall loss of 1.54cm height compared

Diskhaler® (three study analysis) puberty with controls

CAMP study[75] 7–11y (941) Budesonide 400 μg/day vs nedocromil Prepubertal (at 4.3 (±0.7)y 1cm height loss in first year with

16 mg/day vs placebo start of study) budesonide, not regained

Agertoft and 3–13y (142) Budesonide, mean dosage 412 (range NR at start of Until adulthood (up Slowed growth rate initially, normal

Pedersen[76] 110–877) μg/day vs no ICS study, post- to 12y) adult height

pubertal at end

Pedersen et al.[20] 5–11y (247) Chlorofluorocarbon beclomethasone Prepubertal (at 12mo Growth velocity the same in both

200–400 μg/day vs hydrofluoroalkane start of study) groups at 12mo

beclomethasone 100–200 μg/day

de Benedictis et al.[65] 4–11y (277) Fluticasone propionate 400 μg/day vs Prepubertal 12mo Growth velocity with fluticasone

beclomethasone 400 μg/day propionate better than with

beclomethasone

Allen et al.[50] 4–11y (325) Fluticasone propionate 100 or 200 μg/ Prepubertal 12mo Growth velocity the same in all three

day vs placebo groups

Todd et al.[77]a 7–10y (6) Fluticasone propionate 1000–2250 μg/ NR 1–3y Poor growth in all six patients

day

Patel et al.[31]a 8y (2) Fluticasone propionate 500–1000 μg/ NR 12mo and 4.5y Poor growth for 1 and 2y

day

Schenkel et al.[78] 3–9y (82) Intranasal mometasone 100 μg/day vs Prepubertal 12mo Growth velocity the same in both

placebo groups

a Case reports.

ICS = inhaled corticosteroids; NR = not reported.

496 Randell et al.

0

1

2

3

4

5

6

7

CAMP

Study

Gro

wth

vel

ocity

(cm

/yea

r)

Allen et al. Pedersen et al. de Benedictis et al.Sharek et al.

p < 0.01 p < 0.005 NS NS p < 0.01

Treated with ICSControl groups or lower dose/less potent ICS

Fig. 2. Comparison of different dosages of ICS on growth velocity. Sharek et al.:[74] beclomethasone 400 μg/day vs no ICS; Childhood AsthmaManagement Program (CAMP) study:[75] budesonide 400 μg/day vs no ICS; Allen et al.:[50] fluticasone propionate 100–200 μg/day vs no ICS; Pedersen etal.:[20] chlorofluorocarbon beclomethasone 200–400 μg/day vs hydrofluoroalkane beclomethasone 100–200 μg/day; de Benedictis et al.:[65] chlorofluorocar-bon beclomethasone 400 μg/day vs fluticasone propionate 400 μg/day. ICS = inhaled corticosteroids; NS = not significant.

Fluticasone Propionateusing up to 400 μg/day) with chlorofluorocarbon beclomethasone

+ spacer (200–400 μg/day, using up to 800 μg/day) in an open- Fluticasone propionate appears to cause less effect on growth,

although only low doses have been used in controlled studies. Alabel study in prepubescent children with stable, mild to moderatemulticenter, randomized, blinded, controlled trial compared fluti-asthma.[20] The children were enrolled from 56 multinational sitescasone propionate 200μg twice daily with beclomethasone 200μgand were followed for 6–12 months. It was found that at 6 months,twice daily, both given via DPI.[65] The children enrolled in the

growth velocity was significantly greater in the chlorofluorocar-study were all prepubertal and were treated for 1 year – only those

bon beclomethasone group than in the hydrofluoroalkane beclo- children who were still prepubertal at the end of the study, did notmethasone group, but by 12 months there was no difference. In the require oral corticosteroids, and who were compliant with thehydrofluoroalkane beclomethasone group at month 12, the mean medication, were included in the final analysis (n = 277). The

growth rate in the fluticasone propionate group was 0.7 cm/yearincrease in height from baseline was 5.67cm in the 100 μg/day(95% CI 0.13–1.26 cm/year) greater than in the beclomethasonegroup, compared with only 4.45cm in the 400 μg/day group. Agroup. This was despite fluticasone propionate theoretically hav-similar pattern was seen in the children receiving chlorofluorocar-ing double the potency of beclomethasone.

bon beclomethasone + spacer group: there was an increase inAnother study compared fluticasone propionate at dosages ofheight of 6.13cm in those receiving 200 μg/day versus 5.05cm in

50 or 100μg given twice daily for 1 year by breath-actuated drythose receiving 800 μg/day. However, children receiving the

powder device with placebo in prepubescent children with persis-higher dosages of ICS (hydrofluoroalkane beclomethasone

tent asthma.[50] The final height data showed no difference be-300–400 μg/day or chlorofluorocarbon beclomethasone 600–800 tween the three groups, although only 66% of children in theμg/day) were not included in the statistical analysis (as there were placebo group completed the study compared with more than 80%

in the two fluticasone propionate-treated groups. While theseonly small numbers in each group).

© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)

Safety of the Newer Inhaled Corticosteroids in Childhood Asthma 497

studies are reassuring, low dosages of fluticasone propionate were • Fluticasone propionate appears to have less of an effect on

height than the older ICS, when used in low doses, but there areused and there are now several case reports of marked growth

reports of marked growth suppression at high doses.retardation and adrenal suppression with fluticasone propionate,

particularly when used at higher than recommended dosages.[31,77] • There are, as yet, no data on mometasone in an ICS preparation,

but the intranasal preparation at recommended doses does notMometasone have any adverse effect on growth.

The only data available on the effect of mometasone on growth2.4 Bonesis that which assesses the intranasal preparation. Prepubertal chil-

dren were randomized to either mometasone 100 μg/day or place-2.4.1 Normal Bone Mineralization and the Effect of ICSbo to treat allergic rhinitis for 1 year. There were no differencesThe mineralization of bone in children occurs in three phases,between the two groups in either height at the end of the trial, or in

paralleling linear growth rate. Rapid accretion of bone mass hap-growth velocity.[78] Whether this data can be extrapolated to thepens over the first few years, slows during childhood, and thenpulmonary version of mometasone remains to be seen.accelerates again during puberty and early adulthood. Environ-

mental factors such as diet, exposure to sunlight, and exercise areCompliance Effects

very important in ensuring optimal mineralization, with inade-A final factor which needs to be taken into consideration whenquate bone accretion potentially having lifelong consequences.evaluating the effects of ICS on long-term growth is complianceExcess exogenous corticosteroids are known to disrupt normalwith treatment, something which none of the studies on the newerbone metabolism and their long-term use is well known to causeICS have addressed. The few long-term studies on the effects ofosteoporosis. Glucocorticoids reduce bone formation and increaseICS and growth show a decrease in growth rate during the firstbone resorption by their direct action on osteoblasts and osteo-year of treatment, which is not sustained in the long term.[75,76] Itclasts. They can also lead to increased urinary calcium losses andhas been shown that adherence to treatment inevitably decreasesdecreased gut vitamin D-mediated calcium absorption, resulting inwith time,[79] therefore it has been suggested that the normalizationdecreased total body stores of calcium and secondary hyperpara-

of growth seen after the initial slowing may simply reflect reduc-thyroidism.[5,81] Thus, it could be postulated that ICS use during

tion of the dose of ICS to below growth-suppressive amounts.[80]

these vital periods of bone mineralization could have adverseAn alternative possibility is that some adaptive mechanism devel-

effects on bone mass, and potentially lead to osteoporosis in theops over time to overcome the growth-suppressive effects of the

future.ICS therapy.

2.4.2 Assessing Bone Mineralization2.3.5 Summary

Areal Bone Mineral Density (BMD) and Dual-Energy• The older ICS (budesonide and chlorofluorocarbon beclo-

X-Ray Absorptiometrymethasone) have been shown to cause a reduction in short-term

One of the big problems in assessing the effects of ICS on BMDgrowth velocity that does not appear to be sustained in the long

is the difficulty in accurately measuring BMD in children. Theterm, as final adult height appears to be preserved. The reasons

most commonly used method is dual-energy x-ray absorptiometryfor this are unclear, but may be a reflection of adherence issues (DXA). This measures areal BMD (aBMD [mg/cm2]), which isor adaptive mechanisms. calculated by dividing the total (cortical and trabecular) bone

• Hydrofluoroalkane beclomethasone, when compared with mineral content by the projected area (not volume) of the part ofequipotent doses of chlorofluorocarbon beclomethasone, does the skeleton scanned. aBMD is highly dependent on growth andnot have any additional adverse effects on growth. However, cannot distinguish between changes in the mineral density and sizewhen chlorofluorocarbon beclomethasone was compared with of the bone in growing children.[82,83] This is important as chronicplacebo, it was found to cause a significant decrease in growth severe asthma itself may cause pubertal and growth delay,[63] andvelocity, therefore hydrofluoroalkane beclomethasone may be high doses of ICS have been definitely shown to impair

found to have a similar effect. growth.[31,72,73,77] DXA measures the whole bone mineral content

© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)

498 Randell et al.

Volumetric BMDand does not allow selective measurement of the trabecular bone,

which is more likely to be adversely affected by corticosteroid In one study, 20 prepubertal children with asthma on moderate

excess than cortical bone. If DXA is to be used as a method of to high doses of ICS (as defined by current British Thoracic

assessment of BMD in children, it is important that results are Society guidelines[56,57]) had the volumetric trabecular BMD

compared with height-matched normative data to minimize the (vTBMD) of their lumbar spine, and distal radial trabecular BMD

confounding effects of possible short stature. (rTBMD) measured.[62] The children were taking either beclo-

methasone, budesonide, or fluticasone propionate in dosages >400Volumetric BMD

μg/day (beclomethasone or budesonide) or >200 μg/day (fluti-It has been argued that a more appropriate method of assessing

casone propionate) for at least 1 year. All but 4 children had alsothe mineral content of bone is to use volumetric BMD (vBMD).

had at least one course of oral corticosteroids in the previous year.vBMD can be measured directly using quantitative computed

The BMD results were compared with in-house data on healthytomography (QCT), a technique that is able to distinguish between

White children and with published values from the US, matchingthe cortical and trabecular component of bone. Studies have dem-

for age and gender. It was found that the vTBMD and rTBMD inonstrated that QCT measurement of vBMD at the mid-femur of

all three groups were within the normal range, although thehealthy children is independent of age and height, but that a

standard deviation scores between the budesonide- and fluticasonemodest increase is observed at the lumbar spine at puberty.[84]

propionate-treated groups were significantly different, suggestingPeripheral QCT is a relatively new technique that measures vBMD

that fluticasone propionate had a lesser effect on TBMD thanat peripheral sites in the upper and lower limbs. It has the advan-

budesonide. It should be noted, however, that the numbers in eachtages of precision, relatively low radiation, and excellent norma-

group were very small.[82]tive data.[85]

In another study, 45 children with asthma had their BMD (bothVolume assumptions have been applied to calculate a vBMDareal and volumetric) evaluated, along with adrenal function and(g/cm3) for regional DXA techniques at the spine, hip, and mid-serum markers of bone metabolism.[40] The children were dividedfemur.[86-89] Calculated vBMD is not altered by bone size andinto two groups according to dosage, as previously described (seeremains more or less constant with age in prepubertal chil-section 2.2.2). The mean standard deviation scores for aBMD indren.[82,86] Because of these potential differences, studies usingboth groups were significantly lower than the population means ofvBMD and aBMD DXA are discussed separately in section 2.4.3.zero (p < 0.01), whereas vBMD values were normal. There were

Biochemical Markers no differences in aBMD and vBMD between the two groupsSome other studies on the effect of ICS on bone metabolism in (figure 3). The authors noted that their population was shorter than

children have looked at biochemical markers of bone turnover.[90]normal and they concluded that this would explain the lower

These include urinary hydroxyproline, creatinine and calcium, aBMD values.creatinine ratios, serum osteocalcin, and serum alkaline phospha-

tase levels.[90] However, these markers can be affected by numer- Areal BMDous variables, including recent physical activity, current growth

Chlorofluorocarbon beclomethasone and budesonide: Onevelocity, intercurrent illness, and even the assay used to measure

study compared 14 children with asthma who had taken chloro-them. There is also a paucity of data on normal age- and gender-

fluorocarbon beclomethasone at dosages of 300–400 μg/day forspecific values. Finally, there is a lack of data to validate the

the previous 6 months, with 16 age-, height-, and gender-matchedconnection between bone marker levels and subsequent growth

control individuals with asthma who were not treated with ICS.[93]

and eventual osteoporosis risk.[66] These issues limit our ability toThree children in each group (one girl and two boys) were clinical-

draw useful conclusions on the effects of ICS on bone in childrenly in early puberty. All the others were prepubertal. DXA was used

from studies using these markers.to assess BMD and the results were compared with age-matched

2.4.3 Effect of ICS on BMD (but not height-matched) reference values. The children were

ICS dose-related reduction of BMD has been well established reassessed 6 months after the initial measurements were taken and

in adult patients with asthma,[91,92] but there is limited pediatric there were no differences in BMD between the two groups. During

literature available, particularly on vBMD (table VII). the period of the study, the BMD in the control group increased by

© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)

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Table VII. Summary of studies on effects of inhaled corticosteroids on bone mineral density and fractures

Study Population studied Drug and dosage Outcome measured Result

Reilly et al.[82] 20 prepubertal children Beclomethasone/budesonide >400 μg/day vBMD No difference from healthy

or fluticasone propionate >200 μg/day controls

Clavano et al.[40] 23 (group I), 22 (group II), all Beclomethasone/budesonide <600 μg/m2/ vBMD and aBMD Decreased aBMD, normal vBMD

stages of puberty day (I) or >600 μg/m2/day (II) in both

Pedersen et al.[20] 19 children (prepubertal at Chlorofluorocarbon beclomethasone aBMD (DXA scan) No change from baseline

start of study) 200–400 μg/day vs hydrofluoroalkane

beclomethasone 100–200 μg/day

Baraldi et al.[93] 30 children, variable puberty Chlorofluorocarbon beclomethasone aBMD (DXA scan) No difference between groups

300–400 μg/day vs no ICS

Harris et al.[94] 76 prepubertal children No ICS vs MIC, HIC, or HIC + O aBMD (DXA scan) Lower BMD in HIC + O than MIC

or no ICS groups

Gregson et al.[95] 23 prepubertal children Fluticasone propionate 200 μg/day vs aBMD (DXA scan) No difference from healthy

chlorofluorocarbon beclomethasone 400 μg/ controls

day

van Staa et al.[96] >500 000 adults on ICS, Fluticasone propionate, beclomethasone or Incidence of fractures Increased risk of fractures with

bronchodilators only, or no budesonide, varying dosages ICS, especially high dosages

chest disease

Ma and Jones[97] 324 prepubertal children ICS vs no ICS (drug and dosage not Incidence of fractures Increased risk of fractures with

identified) and BMD ICS, BMD normal

aBMD = areal bone mineral density; BMD = bone mineral density; DXA = dual-energy x-ray absorptiometry; HIC = high-dosage ICS; ICS = inhaled corticosteroids; MIC = moderate-

dosage ICS; O = oral corticosteroids; vBMD = volumetric bone mineral density.

500 Randell et al.

Hydrofluoroalkane beclomethasone: In a multicenter, random-

ized, open-label study, chlorofluorocarbon beclomethasone (via

spacer) and hydrofluoroalkane beclomethasone (administered by

Autohaler®) were directly compared.[20] 256 prepubertal children

with well-controlled asthma were changed from their usual ICS to

equivalent dosages of either chlorofluorocarbon beclomethasone

via spacer (dosage range 200–800 μg/day) or hydrofluoroalkane

beclomethasone (100–400 μg/day). Bone markers (serum osteo-

calcin, carboxy propeptide of procollagen type 1, 1-collagen

telopeptide, and urine deoxypyridinoline) and BMD using DXA

were assessed at the beginning and end of the study (12 months

later) in a subgroup of patients. There were no differences in either

bone markers or BMD on completion of the study compared with

baseline values. However, no comparisons were made with normal

values for children without asthma, and only 19 children out of the

initial 256 enrolled had BMD measured. These only included

children taking either a maximum of hydrofluoroalkane beclo-

methasone 200 μg/day or chlorofluorocarbon beclomethasone 400

μg/day; children receiving higher dosages did not have their BMD

Z s

core

s w

ith 9

5% c

onfid

ence

inte

rval

s

−1.5

−1.0

−0.5

0.0

0.5

1.0

Right femoral neck aBMD Right femoral neck vBMD

Group 1 Group 2

Fig. 3. Comparison of aBMD and vBMD in children receiving <600 μg/m2/day (group 1; n = 23) or >600 μg/m2/day (group 2; n = 22) of ICS.[40] aBMDwas significantly lower than normal in both groups, but vBMD was normalin both groups. There was no significant difference in the aBMD betweengroup 1 and group 2, or in vBMD between the two groups. aBMD = arealbone mineral density; ICS = inhaled corticosteroids; vBMD = volumetricbone mineral density.

reported. In addition, although the children had to be prepubertal at

the start of the study, there is no comment as to whether they were4%, compared with only 2.3% in the beclomethasone group, butexcluded from the final analysis if they started puberty during theanalysis of variance did not show any significant difference be-study.[20]

tween the groups.Fluticasone propionate and mometasone: One study has direct-

Another study examined the effects of different dosages of ICSly compared aBMD in children taking fluticasone propionate or

on the BMD of prepubertal children with asthma. Seventy-sixchlorofluorocarbon beclomethasone.[95] Twenty-three corticoster-

children with asthma who had had no changes to their treatment inoid-naive, prepubertal children were randomized to either fluti-

the previous 6 months were enrolled, all of whom were prepubert-casone propionate 200 μg/day or chlorofluorocarbon beclometha-

al. They were then divided according to whether they had received sone 400 μg/day, and followed for 20 months with regular DXAno ICS, moderate-dosage ICS (400–800 μg/day), high-dosage ICS scans. BMD increased over time, following normal patterns of(>800 μg/day), or high-dosage ICS (>800 μg/day) plus at least one growth, with no difference between the two groups.course of oral corticosteroids. Children were either taking fluti- There are as yet no published data on the effects of mometasonecasone propionate, budesonide, or chlorofluorocarbon beclo- on BMD.methasone, but were allocated to groups according to the dosage

2.4.4 ICS and Fracturesof corticosteroid taken rather than the type. Their lumbar spine

BMD was then assessed using DXA and it was found that, when Fractures in Adultsadjusted for weight, it was lower in those children who had If there are adverse effects on bone mineralization, a potentialreceived high-dosage ICS + oral corticosteroids, compared with adverse effect could be an increased risk of fractures. A recentthose who were in the moderate-dosage ICS, or no ICS groups. very large epidemiological study from the UK looked at theWhen the high-dosage ICS and high-dosage ICS + oral cortico- incidence of fractures in adults (children excluded) who used ICS,steroids groups were combined, the lumbar spine BMD was still compared with two control groups – a matched control group and alower than the moderate-dosage ICS group and it was postulated group of non-corticosteroid bronchodilator users. Patients usingthat long-term high dosages of ICS alone could be associated with oral corticosteroids were excluded from the analysis.[96] It was

reduced bone mass.[94] found that in the ICS-treated group, the relative risks of

© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)

Safety of the Newer Inhaled Corticosteroids in Childhood Asthma 501

nonvertebral, hip, and vertebral fractures were 1.15 (95% CI • Taking into consideration the above limitations, studies to date

1.10–1.20), 1.22 (95% CI 1.04–1.43), and 1.51 (95% CI have not suggested a significant effect of ICS on aBMD or

1.22–1.85) respectively, when compared with control individuals vBMD.

without respiratory disease. There were no differences between the • There does appear to be an increased risk of fractures inICS- and bronchodilator-treated groups. When the types of ICS children who use ICS, although the numbers reported so far arewere analyzed separately (fluticasone propionate, beclometha- small.sone, or budesonide) there were no differences between them.

2.5 CataractsHowever, there was an increased risk of hip and vertebral fracture

in the group treated with high-dosage ICS (>700 μg/day), com-There have been no reported cases of cataracts in children

pared with those treated with medium to low dosages or broncho-receiving ICS alone. One child in the CAMP study was found to

dilators only. This risk disappeared on cessation of treatment. Thehave a questionable posterior subcapsular cataract on slit-lamp

authors conclude that ICS use may increase the risk of fractures,examination, 5 months after initially being assessed as having no

but that the underlying respiratory disease may also have a part toproblems. Vision in that eye was normal and he had been on high

play.doses of budesonide and beclomethasone, oral corticosteroids, and

Fractures in Children also intranasal corticosteroids.[75] There appears to be no risk of

A recent Australian study has looked at the clinical risk factors cataracts in children from ICS alone.

and BMD in children with fractures.[97] A cohort of children has3. Conclusionsbeen followed since birth, and 324 of the original 696 volunteers

were reassessed at the age of 8 years. Thirty-two children had• ICS remain a vital part of the management of persistent asthma,

sustained a fracture (23 boys, 9 girls), and it was found that theybut concerns have been raised about their potential adverse

were older, were less likely to have been breast-fed, had highereffects in children.

levels of sports participation, and higher ICS use in the previous• Topical adverse effects such as thrush and dysphonia are rare,

year than those children who had not had a fracture. Nineteen of 32but dental erosion with powder forms of ICS is a possibility

children with a fracture had used ICS versus 9 out of 292 who hadbecause of their low pH. It is, thus, important to stress mouth

had no fracture. There were no differences in BMD between thoserinsing after administration and maintaining good dental hy-

children with or without fractures. The type and doses of ICS weregiene to minimize this risk.

not specified.• Adverse systemic effects have been recognized for many years

2.4.5 Summary and the newer ICS, particularly fluticasone propionate, were

• The effect of the newer ICS on BMD is difficult to assess initially introduced as being safer than the older ICS. Theoreti-because of the technical problems in measuring it. cally, there would be less systemic availability, as any drug that

• Biochemical markers of bone turnover cannot be recommended was swallowed would be eliminated by the first-pass mecha-

as a measure of bone physiology in children as they are subject nism. However, time has shown this not to be the case, because

to too much day-to-day variability, based on activity levels, of direct absorption from the lungs, particularly in the context

growth rate, etc. of mild asthma.

• aBMD measured using DXA scans is the most commonly used • Biochemical adrenal suppression can be readily demonstrated,

method of assessing BMD, but is highly dependent on the particularly with high doses of ICS. The clinical relevance of

growth of children and does not assess trabecular bone, which this was uncertain in the past, but there have now been >50

is more likely to be affected by ICS. It is important that if it is reported cases of acute adrenal crises in children receiving ICS,

used as an assessment tool, values are matched for height and most of whom were on fluticasone propionate.

not just age. • Screening all children who are on ICS for adrenal insufficiency

• vBMD may be a more accurate way of assessing the actual would be impractical, and while many of the children who

mineral content of bone in children, but very few studies have experienced adrenal crises were on high doses of corticoster-

used it as a tool. oids, others were on doses within the recommended treatment

© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (7)

502 Randell et al.

References of relevant studies were sought from the manufacturers of therange. This suggests that the risk of adrenal crisis is idiosyn-ICS. No sources of funding were used to assist in the preparation of thiscratic and not necessarily possible to predict.manuscript. The authors believe that there are no potential conflicts of interest

• In order to minimize the risk of symptomatic adrenal suppres- that are directly relevant to the content of this manuscript.sion, it is very important to back-titrate the ICS dose once

symptom control is achieved, and alert families of childrenReferencesreceiving high-dose ICS of this potential adverse effect. A

1. National Institutes of Health. National asthma education and prevention programpediatric endocrine opinion should be sought if adrenal sup-

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2. Van Asperen PP, Mellis CM, Sly PD. The role of corticosteroids in the manage-• The older ICS cause temporary slowing of growth velocity, butment of childhood asthma. The Thoracic Society of Australia and New Zealand.

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3. National Asthma Council. Asthma management handbook [online]. Availablemise on final adult height. The effect on growth of fluticasonefrom URL: www.NationalAsthma.org.au [Accessed 2003 Jun 11]

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