Balancing Safety and Efficacy in Pediatric Asthma Management

David P. Skoner, MD

ABSTRACT. In the treatment of childhood asthma, bal- or most children, the onset of asthma occurs ancing safety and efficacy is key to achieving optimal before the age of 2 years, underscoring the need therapeutic benefit. Inhaled corticosteroids (ICS), be- for early treatment not only to control the de- cause of their efficacy, remain a cornerstone in managing F bilitating effects of asthma symptomatology but also persistent pediatric asthma, but also are associated with to prevent irreversible structural changes that can significant adverse effects, including growth suppres- lead to permanent airway obstruction.1 Because sion. Consequently, careful attention must be given to balancing their safety and efficacy, which should include asthma requires chronic—often lifelong—treatment, an understanding of airway patency and systemic ab- a critical issue in the management of pediatric sorption (dose, disease severity, propellant and lipophi- asthma is balancing the safety and efficacy of asthma licity of inhalant), bioavailability (inhalation technique, interventions to achieve optimal long-term results. propellant, delivery devices, and hepatic first-pass me- This review will examine some of the challenges to tabolism), techniques for using minimum effective doses balancing safety and efficacy associated with inhaled (dosing time, add-on therapy), and reduction of other corticosteroid (ICS) therapy and explore the potential exacerbating conditions (allergens, influenza, upper-res- benefits of other available alternative therapies for piratory diseases). The growth-suppressive effects of ICS managing persistent mild-to-moderate pediatric may be most evident in children with: 1) mild asthma asthma. because the relatively high airway patency may facilitate increased levels of deposition and steroid absorption in more distal airways, and 2) evening dosing that may ICS reduce nocturnal growth hormone activity. A step-down As the gold standard for the long-term manage- approach targeting a minimum effective dose and once- ment of asthma in adults and children, ICS reduce daily morning dosing is suggested for achieving the both asthma symptomatology and the markers of most acceptable safety/efficacy balance with ICS. The airway inflammation.2–4 Early intervention with ICS achievement of regular, safe, and correct ICS use requires may preserve pulmonary function and prevent irre- significant knowledge and time for both caregiver and ␤ versible airway obstruction, remodeling, and hyper- patient. Chromones, methylxanthines, long-acting -ago- 4–8 nists, and leukotriene receptor antagonists are currently responsiveness. Nevertheless, important chal- available alternatives to ICS for the control of persistent lenges present themselves with the use of ICS in childhood asthma. Chromones are safe but, like methyl- young children, particularly with the potential for xanthines, are difficult to use and frequently result in systemic adverse effects, including growth suppres- compromised effectiveness. Long-acting ␤-agonists are sion. not recommended as monotherapy for persistent asthma. Several factors that support leukotriene receptor antago- SOURCES AND DETERMINANTS OF SYSTEMIC nists as a therapeutic option for mild-to-moderate per- BIOAVAILABILITY OF ICS sistent pediatric asthma include established efficacy, Although ICS were developed to replace effica- good safety profiles, and simple, oral dosing. Physicians must evaluate and compare the balance of safety and cious, but more highly bioavailable oral glucocorti- efficacy for each agent to determine the appropriate costeroids, they can nonetheless manifest detectable asthma therapy for individual patients. Pediatrics 2002; systemic bioavailability. ICS can be absorbed from 109:381–392; pediatric asthma, inhaled corticosteroids, both the gastrointestinal (GI) system and the airway airway deposition, bioavailability, leukotriene receptor mucosa. Thus, factors that increase the degree of antagonists. airway delivery generally increase the systemic bioavailability of a drug. If sufficient drug enters the ABBREVIATIONS. ICS, inhaled corticosteroids; GI, gastrointesti- blood, effects can be detected using sensitive assays nal; CS, corticosteroids; BDP, beclomethasone diproprionate; of the hypothalamic-pituitary axis or methods to pMDI, pressurized metered-dose inhaler; CFC, chlorofluorocar- measure childhood growth. bon; DPI, dry powder inhalers; HFA, hydrofluoroalkane; FEV1, forced expiratory volume in 1 second; CAMP, Childhood Asthma Individual ICS and Delivery Devices Management Program; PEFR, peak expiratory flow rate. Systemic bioavailability of ICS occurs either through the inhaled fraction of corticosteroids (CS) From the Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania. that makes it into the airways (ϳ20%) or by swal- Received for publication May 4, 2001; accepted Oct 22, 2001. lowing ϳ80% of the delivered CS that makes it no Reprint requests to (D.P.S.) Section of Allergy and Immunology, Children’s further into the airway than the back of the throat. Hospital of Pittsburgh, 3705 Fifth Ave, Rm 4B320, Pittsburgh, PA 15213. E-mail: [email protected] The swallowed CS is subject to hepatic first-pass PEDIATRICS (ISSN 0031 4005). Copyright © 2002 by the American Acad- inactivation after it is absorbed from the gut. For emy of Pediatrics. fluticasone and mometasone, approximately 99% is

Downloaded from www.aappublications.org/news byPEDIATRICS guest on September Vol. 30, 109 2021 No. 2 February 2002 381 inactivated in the liver, and for budesonide and tri- unique safety and efficacy profiles. For example, the amcinolone, 90% and 80% to 90%, respectively, are older pMDI formulation of budesonide delivered inactivated.9 Beclomethasone diproprionate (BDP), much less drug to the airways than the newer Tur- however, is not entirely inactivated in the hepatic buhaler DPI formulation (AstraZeneca, So¨dertalje, first pass (60% to 70%), and an active metabolite Sweden).14 Likewise, the change in formulation of (beclomethasone-17-monoproprionate) is formed the vehicle propellant from CFC to HFA may in- that has a potency similar to the parent BDP.9 It crease the bioavailability of ICS by improving the would therefore appear that the newer ICS (flutica- airway delivery, thereby increasing the potential for sone and mometasone) have a superior safety profile systemic adverse effects. The HFA formulation of based on hepatic inactivation of noninhaled drug BDP delivers smaller-sized particles (the average and that they should generate less concern about particle size of HFA-BDP is 1.1 ␮m compared with minimizing the swallowed portion of the drug. 3.5 ␮m for CFC-BDP). Furthermore, HFA-BDP’s av- Once present in the systemic circulation, the de- erage spray force is softer (3 times less), and has a gree of lipophilicity of each ICS may also have an longer duration and a warmer temperature, than that important influence. Fluticasone and mometasone of CFC (the temperature is approximately ϩ5°C for are highly lipophilic drugs and therefore are more HFA-BDP vs Ϫ20°C for CFC-BDP). Consequently, easily distributed into the systemic tissue compart- there is more lung deposition and less mouth depo- ments. Consequently, they have a large volume of sition for HFA-BDP than for CFC-BDP.15 In a clinical distribution at steady state. In contrast, triamcino- trial, the dose-response (forced expiratory volume in lone and budesonide have lower lipophilicity and, 1 second [FEV1], % predicted) curve for HFA-BDP consequently, a smaller volume of distribution. Be- was shifted to the left compared with the dose-re- cause the systemic tissue storage of an ICS acts as a sponse curve for CFC-BDP. To achieve the same slow release reservoir, the drugs with higher lipophi- improved FEV1 as HFA-BDP, 2.6 times the dose of licity would take a longer time to be cleared from the CFC-BDP would be required.16 With an increased larger distribution volume. Their lipophilicity could airway delivery, there may be increased absorption thus increase the potential for producing systemic and increased risk of systemic adverse effects. In adverse effects.9 The risk may be offset by the general contrast, HFA formulations of other drugs may de- approach to use relatively lower ␮g doses of the liver lower amounts to the airway compared with the more lipophilic and thus more potent ICS. older CFC formulation.17 The majority of drug in the blood, however, orig- In a separate pharmacokinetic comparison, the inates from that deposited in the lower airways, HFA formulation produced a significantly increased where it is directly absorbed into the vasculature maximum concentration of drug (Cmax) and area Ͻ Ͻ without undergoing metabolism or inactivation. under the curve (AUC(0–12 hrs))(P .001 and P Therefore, minimizing GI bioavailability via the se- .005, respectively) compared with the CFC formula- lection of newer ICS will not necessarily eliminate tion, resulting in up to twofold greater absorption of the possibility of systemic bioavailability, and the BDP. Therefore, clinically important systemic ad- risk of systemic adverse effects, such as growth sup- verse effects may be expected with the HFA if a pression, and a dose-related growth suppression nominal 1:1 dose switch were made between CFC could be expected of both newer and older ICS.10 and HFA formulations of BDP.18 Likewise, factors that increase airway dose and delivery (ie, milder disease, increasing the ␮g dose, use Disease Severity of spacers, formulation changes that result in smaller In children with mild asthma, airways are more particle sizes, improved inhalation technique) may patent than in those with more severe asthma; con- provide better benefit but may also increase the sys- sequently, drug deposition and absorption may be temic bioavailability of the drug and thus increase higher. The resulting increase in steroid absorption the risk of systemic adverse effects. For example, could enhance all the clinical effects of ICS—includ- spacers improve airway delivery and are routinely ing adverse effects—and possibly lead to growth recommended, but they do demonstrate variability suppression. in delivery across devices11 and simultaneously en- Limited evidence for this explanation has been hance systemic bioavailability,12,13 thus raising con- gleaned from studies using ␤-agonists and ICS. Ra- cerns about systemic adverse effects as well. Fortu- dioactively labeled inhaled salbutamol has been nately, most patients can be managed by delivering shown to accumulate much more readily in the pe- relatively low ICS doses to the airways. ripheral lungs of normal persons than in persons with asthma.19 Furthermore, this difference was con- Formulation sistent, regardless of the delivery device used. In Current pressurized metered-dose inhaler (pMDI) addition, a twofold increase in FEV1 was associated formulations of ICS, which use chlorofluorocarbon with a 1.5-fold increase in drug deposition, suggest- (CFC) as the propellant, are being reformulated to ing that the degree of airway patency is directly dry powder inhalers (DPIs) or pMDIs with alterna- correlated with peripheral drug deposition. Addi- tive propellants (eg, hydrofluoroalkane [HFA]). The tionally, when fenoterol was administered by an change is mandatory because of the possible contri- MDI at a fixed dose (4 mg) to either normal or bution of CFC to depletion of the earth’s ozone layer. asthmatic individuals, fenoterol absorption, as mea- Each new formulation of an older drug has unique sured by the maximum concentration of drug (Cmax), airway and GI delivery characteristics and thus was substantially higher in normal persons (3.1 ng/

382 SUPPLEMENT Downloaded from www.aappublications.org/news by guest on September 30, 2021 mL) than in asthmatic individuals (1.6 ng/mL).20,21 growth suppression with ICS nevertheless remains a Concomitantly, the heart rate increased by 45 beats real one for some children. Many factors likely influ- per minute in the normal individuals but only 30 ence this risk including total dose, drug delivery beats per minute in asthmatic individuals. device and technique, genetic predisposition, age, The pharmacokinetics of inhaled fluticasone (1000 adherence, and asthma severity. ␮ ϭ g) have been measured in normal healthy (FEV1 ϭ 108% predicted) and asthmatic individuals (FEV1 54% predicted).22 As shown in the mean plasma Influence of Asthma Severity on ICS-Induced Growth concentration versus time curve (Fig 1), the AUC in Suppression healthy controls was greater (2815 pg/mL/h) than in Three separate but related long-term trials—des- asthma patients (1082 pg/mL/h). Similarly, the ignated A, B, and C—compared the growth-sup- mean peak plasma concentration, Cmax, was greater pressing effects of budesonide nebulizing suspen- (383 pg/mL) in healthy controls than in asthmatic sion with conventional asthma therapy in young patients (117 pg/mL). Of note, systemic availability children 6 months to 8 years of age (Fig 2).4 These ϭ ϭ mildly correlated with baseline FEV1 (r 0.47; P trials included a 12-week, randomized, double-blind .02). phase followed by a 52-week, open-label extension By extension, these data may suggest that, for per- during which growth was monitored. In study A, sons with mild asthma, or for those with the greatest persistent asthma severity was classified as mild per- airway patency, drug deposition and absorption sistent, and patients in this group received no ICS would be substantially greater than in those patients before randomization. Moderate-to-severe persistent who have more severe asthma or the least airway asthmatic patients were included in study B, and patency. Such elevated availability of an ICS in the they had received ICS before randomization with more patent airways of a person with mild asthma additional ICS postrandomization only as needed. could account for the ICS budesonide-associated Mild-to-moderate persistent asthmatic patients in- growth suppression seen in children with mild cluded in study C varied in whether they had re- asthma (see below). Although support for this expla- ceived ICS before randomization, and additional ICS nation can be gleaned from studies using both ␤ - 2 therapy was administered only as needed after ran- agonists and ICS, potential flaws include a lack of domization. Conventional asthma therapy included direct extrapolation of results from a nonasthma to asthma comparison to a comparison across severity any available therapy including ICS in studies B and levels within an asthmatic population. C. No significant differences in growth velocity were detected between the budesonide and conventional GROWTH SUPPRESSION treatment groups in studies B and C. In study A, Although ICS have been proven highly efficacious however, which included ICS-naı¨ve children with for the treatment of childhood asthma, concerns over the mildest degree of asthma, budesonide treatment adverse effects on children’s growth have caused the significantly suppressed growth by 0.8 cm per year. Food and Drug Administration to issue new guide- These studies show that, in children with more se- lines for the labeling of CS, both inhaled and intra- vere asthma and previous exposure to ICS, there is nasal.10 A recent survey indicated that although 71% no difference in growth velocity between those of the respiratory specialists such as allergists and treated with budesonide and those treated with con- pulmonologists believe that clinically important ventional asthma therapies. This contrasts with the growth suppression can be induced by ICS, almost result in milder asthma and may result, in the more 84% of these specialists reported, however, that they severe patients, from a lower degree of airway pa- have rarely or never seen growth suppression in tency and deposition, and thus less systemic bio- their pediatric patients treated with ICS. The risk for availability.

Fig 1. Plasma fluticasone concentration for 12 hours after inhalation. In healthy volunteer controls (open triangles), a 1000-␮g inhalation of fluticasone produced a mean plasma concentration versus time curve that was significantly greater than inhalation of the same quantity of fluticasone in asthmatic patients (filled circles). Such elevated availability of an ICS in more patent airways could account for ICS-associated growth suppression in children with mild asthma. Adapted from Brutsche et al.22

Downloaded from www.aappublications.org/news by guest on September 30, 2021 SUPPLEMENT 383 Fig 2. Three pivotal studies from the United States: mean growth velocity. In children with more severe asthma and previous exposure to ICS, there is no significant difference in growth velocity between those treated with budesonide (filled column) and conventional asthma therapies (unfilled column) by the end of the 1-year open-label phase. ϪICS indicates no prerandomization use of ICS; ϩICS, prerandomization use of ICS; ϮICS, prerandomization use of ICS or bronchodilator therapy. *P ϭ .002 budesonide therapy versus conventional asthma therapy. Adapted from Skoner et al.4

Long-Term Studies the control group decreased from 62 to 18 partici- The effect of ICS on linear growth was examined in pants, mainly owing to patients requiring inhaled or mild-to-moderate asthmatic children 5 to 12 years of oral CS treatment. In addition, this study was not age in the Childhood Asthma Management Program powered to be able to distinguish a 1.1 cm loss of (CAMP).23 Children were randomly assigned to re- height as measured in the CAMP because the equa- ceive budesonide, nedocromil, or placebo twice daily tion used to compute the target adult height had a for 4 to 6 years. The budesonide group demonstrated large variance (a 95% confidence interval of approx- a clear decrease in growth velocity during the first imately Ϯ 10 cm).25 If the 1.1-cm difference occurred, year that resulted in a mean height increase that was it more than likely would not be detectable. 1.1 cm less than the mean increase in the placebo group (22.7 vs 23.8 cm; P ϭ .005). The decreased growth velocity did not continue beyond the first STRATEGIES FOR BALANCING SAFETY AND year and by the end of the study, the growth velocity EFFICACY WITH ICS was similar for all groups. The l.l cm between-group Balancing the unquestionably beneficial actions of difference was still present at the end of the study, ICS against their risk for systemic adverse effects, however, indicating a lack of catch-up growth dur- including growth suppression can be challenging, ing this period (Fig 3). especially in young children. A summary list of these Nevertheless, a separate study suggested that chil- strategies is presented in Table 1. dren treated with ICS still reach their target adult One strategy for achieving a satisfactory benefit/ height.24 Children treated with budesonide for an risk balance in moderate-to-severe asthma may be a average of 9.2 years appeared to reach their calcu- step-down approach to ICS therapy: Start at a high lated target adult height, based on parental height, dose to gain control of asthma-related inflammation compared with 18 control patients with asthma who and then gradually reduce to the minimum effective had never been treated with ICS and also with 51 dose, which would be continued to maintain long- healthy siblings not on asthma therapy. The results term control. Optimally, obtaining a minimum effec- of this study are difficult to interpret, however. First, tive dose could depend on:

Fig 3. Reduction of growth velocity occurs within the first year of budesonide use. Results from CAMP. Left panel: at the end of the treatment period, the mean increase in height in the budesonide group was 1.1 cm less than the mean increase in the placebo group (22.7 vs 23.8 cm; P ϭ .005). The mean height increase was similar in the nedocromil and placebo groups (P ϭ .65). Right panel: the difference between the budesonide and placebo groups in the rate of growth was evident primarily within the first year of treatment and did not increase later. All groups had similar growth velocity by the end of the treatment period. Adapted from CAMP.23

384 SUPPLEMENT Downloaded from www.aappublications.org/news by guest on September 30, 2021 TABLE 1. Techniques for Balancing Efficacy and Safety of ICS Frequently, when an asthmatic child is insuffi- in Children ciently controlled on an appropriate ICS dose, a de- 1. Selection and use of ICS cision must be made about whether to double the • Select safest ICS drug ICS dose or simply add on a second nonsteroidal • Use minimum effective dose controller medication. Support for the latter is • Dose in morning when once-daily dosing • If control is poor, add another controller rather than double gleaned from a study showing that, in children dose of ICS treated with ICS, halving the ICS dose and adding a • To maximize ICS delivery to lung, consider: second nonsteroidal drug was associated with faster a. CFC versus HFA propellant formulation short-term growth with no loss of asthma control, b. pMDI versus DPI formulation versus maintaining the original higher ICS dose c. Use of a spacer device 29 d. Patient technique alone. The results of these safety studies support • Rinse mouth of ICS and discard the widely-held recommendations to use the lowest 2. Use ICS-sparing strategies effective dose, to dose once-daily in the morning if • Reduce allergens and smoke possible, and, in poorly controlled adherent patients, • Inoculate with influenza vaccine • Diagnose and treat rhinosinusitis or gastroesophageal reflux to add on non-ICS therapy rather than to double the disease ICS dose. In other words, when concerned about an • Use add-on therapies ICS dose, consider nonsteroidal add-on therapy to 3. Monitor growth at all ICS doses assist in ICS dose reduction. 4. Monitor eyes* and bone mineral density when using Ն1600 ␮g/day ICS† Safety management includes monitoring the pa- 5. Consider first line alternatives to ICS for mild persistent tient’s growth every 3 to 6 months and interpreting asthma the resultant measurement and changes. Rinsing the * Cataracts/glaucoma; † BDP equivalent. mouth after administration to minimize the swallowed portion) even with spacer use (with pMDI to reduce oropharyngeal deposition) is recommended. 1. Rigorous smoke and allergen environmental con- Furthermore, attention should be given to potency trols (reduce airway inflammation); when considering ␮ 2. Vaccination for influenza (prevent a flu-induced g dosing of a newer, more potent exacerbation); ICS that replaces a less potent, older ICS. For exam- 3. Diagnosis and treatment of concomitant condi- ple, a clinically equivalent dose of fluticasone and tions that could worsen asthma (ie, rhinitis, sinus- BDP may be different by twofold (eg, about half the ␮g dose of BDP for fluticasone). itis, gastroesophageal reflux disease); and When the use of ICS raises concerns about safety, 4. Appropriate use of add-on therapy. alternative therapies can be used. As previously dis- As long as a minimum effective dose is ensured cussed, this may be especially important in children during thoughtful, purposeful, and regularly sched- with the mildest asthma, in whom growth impair- uled assessments, clinicians and parents alike may be ment can result from ICS, but probably not from the willing to accept the risk of growth suppression if the disease itself. This contrasts with moderate-to-severe clinical benefits are sufficiently explained and ade- asthma, where growth impairment may result from quate, and then subsequently realized. In actual clin- the disease, but probably not from ICS. ical practice, the appropriateness of a step-down The following sections review alternative thera- dose usually is based on maintaining improvements pies as well as add-on therapies that can reduce the in symptomatology and pulmonary function, but un- amount of ICS needed to maintain control. Physi- fortunately, inflammation control cannot be used as cians must evaluate the balance of safety and efficacy an additional guide at this time. for each agent to determine the appropriate therapy The time of day when the ICS are administered— for individual patients. morning or evening—appears to influence the risk for growth suppression. A 4-week study that in- CHROMONES cluded children 5 to 12 years of age with moderate Cromolyn has been available for use for over 30 intermittent asthma examined the growth suppress- years as an inhaled antiinflammatory therapy for ing effects of budesonide (800 ␮g) given as a single persistent asthma. Although its exact mechanism of dose in the morning or as 2 divided doses—400 ␮gin action is not known, it is thought to stop the antigen- the morning and 400 ␮g in the evening. Growth rates induced release of mediators of inflammation from were significantly lower in children receiving an mast cells.30 Cromolyn’s efficacy has been demon- evening dose [0.27 Ϯ 0.04 mm/wk] than in children strated in adults,31–34 and used in patients as young receiving only a morning dose [0.38 Ϯ 0.05 mm/ as 2 years of age using a nebulizer. Although patients wk].26 Indeed, evening exposure is one possible ex- taking cromolyn have experienced minor adverse planation for the differential effects on growth of effects such as cough after inhalation and eczema in intranasal beclomethasone (bid, growth suppression) the mouth area, no serious adverse effects have been and intranasal mometasone (qd, no growth suppres- noted.35 sion) in children with allergic rhinitis.27,28 Together, Clinical trials in young children have shown that these findings indicate that morning dosing, in con- cromolyn is safe and efficacious as either mono- 36–40,41 ␤ 3 junction with downward dose titration, are methods therapy or in combination with 2-agonists. that can be used to mitigate the growth suppressing In an earlier 10-week clinical trial, the diary scores actions of ICS while maintaining efficacy in pediatric of asthmatic children aged 8 years and older showed asthma. significant improvement of overall asthma severity

Downloaded from www.aappublications.org/news by guest on September 30, 2021 SUPPLEMENT 385 and breathlessness (P Ͻ .05) and pulmonary function although its effect on pulmonary function has been (peak expiratory flow rate [PEFR] and percent pre- questioned.23,52 In the CAMP study, nedocromil sig- ϭ dicted FEV1 at final visit [P .04] compared with nificantly reduced the number of urgent care visits placebo).36 Cromolyn, therefore, was often recom- (P ϭ .02) and courses of prednisone (P ϭ .01), but mended as first-line therapy in school-aged and pre- was similar to placebo in all other endpoints, includ- school-aged children having mild-to-moderate per- ing airway hyperresponsiveness, prebronchodilator 42 sistent asthma. and postbronchodilator FEV1, rate of hospitalization, This recommendation has been challenged, how- daily symptom score, and rescue bronchodilator ever, especially for the preschool population. A ran- use.23 domized trial in over 200 children 1 to 4 years of age Added to ICS therapy, nedocromil appears to be with moderate asthma showed that cromolyn was no moderately beneficial in asthmatic adults,53,54 but more effective than placebo in this age group.35 Pa- this efficacy has not been demonstrated in children. tients received either cromolyn (10 mg tid) or pla- Pediatric asthma guidelines indicate nedocromil cebo for 5 months using inhalers with spacer devices should not be used as add-on therapy,42 at least until and face masks. The results showed there were no additional studies can prove it is beneficial. significant differences in the percent of symptom- Nedocromil’s safety profile is similar to that of free days, number of symptoms per day, or use of placebo.23,55 Serious adverse effects have not been rescue medication. Such data support the recommen- reported, but patients have complained about dation that cromolyn should not be used as first-line nedocromil’s unpleasant taste.42,55 Similar to cro- preventive therapy in this young patient popula- molyn, nedocromil’s questionable effect on pulmo- tion.35 nary function and bid–tid dosing requirement sug- Cromolyn added to ICS therapy has shown little or gest that other antiinflammatory therapies may be no benefit,43,44,45 suggesting it is not an effective ste- preferable in treating mild-to-moderate asthma. Like roid-sparing therapy, and current pediatric guide- cromolyn, the strength of nedocromil is its safety; its lines do not recommend its use as add-on therapy.42 weakness is its efficacy. Although cromolyn has been shown to be safe for pediatric use, its placebo-like efficacy as prophylactic METHYLXANTHINES therapy in children with mild-to-moderate persistent Although theophylline has been used to treat asthma and its 3 to 4 times daily dosing requirement, asthma for over 60 years, its complete mechanism of together with using a spacer or nebulizer, have con- action is still unclear. As a phosphodiesterase inhib- tributed to its decreased use. The strength of cro- itor, it relaxes airway smooth muscle (bronchodila- molyn therapy is its safety; its weakness is in its tion) and consequently improves airway func- efficacy. tion.56–58 Nedocromil sodium, an inhaled therapy also be- In children, theophylline is effective in treating longing to the chromone class, blocks the release of mild-to-moderate asthma.38 In a year-long study in mediators from mast cells. It also appears to inhibit 195 children aged 6 to 16 years of age with mild-to- the action of eosinophils and their release of media- moderate asthma, theophylline (target blood level tors.46 It has proven to be efficacious in adults with between 8 and 15 ␮g/mL) or BDP (84 ␮g qid) effec- 47–49 mild-to-moderate asthma and is indicated for tively improved pulmonary function (FEV1 [Fig 4] children with mild-to-moderate asthma as young as and PEFR), methacholine hypersensitivity, hospital 6 years of age. visits/physician visits, days out of school, and over- In children, nedocromil has been shown to im- all physicians’ global evaluation. The patients on ␤ prove symptoms and pulmonary function and to beclomethasone, however, required less 2-agonist reduce the need for rescue bronchodilator use,50,51 use and fewer systemic CS rescues (18.6% vs 36.6%

Fig 4. Effect of beclomethasone and theophylline on FEV1. FEV1,expressed as a percent of predicted, is presented over the 36-week study of mild-to-moderate asthmatic children. At no time was there evidence of a difference between the beclomethasone (circle) and theophylline (trian- gle) groups by rank-sum test. Adapted from Tinkelman et al.61

386 SUPPLEMENT Downloaded from www.aappublications.org/news by guest on September 30, 2021 for beclomethasone and theophylline, respectively; as young as 7 years of age. Because it is an inhibitor P ϭ .007). of the CYP450 isoenzyme CYP3A4, however, it can Steroid-dependent asthmatic children demon- increase concentrations of certain concomitant med- strated the added benefit of combining theophylline ications, including theophylline.67 Its use, therefore, with ICS therapy. Patients taking theophylline requires close monitoring of plasma drug levels showed significant improvement in daily PEFR (P Ͻ when concomitantly prescribed. In addition to po- Ͻ ␤ .01), percent symptom-free days (P .01), 2-agonist tential drug interactions, food reduces zafirlukast’s Ͻ ϭ use (P .01), and additional CS therapy (P .02) bioavailability, and it should be taken 1 hour before 59 compared with placebo. These data support the or 2 hours after a meal.68 recommendation that theophylline can be used as add-on therapy to antiinflammatory medications such as ICS, and although it can be considered an Montelukast alternative first-line therapy, it is not preferred for Clinical studies have shown that montelukast, the persistent asthma.42 most recently approved LTRA, is also effective in the In children, theophylline has been linked to management of pediatric asthma. As once-daily oral 38,60 changes in behavior and school performance. therapy, montelukast is indicated for the treatment These adverse effects are more common when blood of mild-to-moderate asthma in adults and children as levels surpass the therapeutic range (10 mg/L–20 young as 2 years of age. In an 8-week study, monte- mg/L in adults, 5 mg/L–15 mg/L in children), but lukast administered once daily was compared with are also seen at therapeutic concentrations. Adverse placebo in asthmatic children as young as 6 years of effects such as headache and other effects on the age.69 Almost 40% of the children were receiving central nervous system, tremor, nausea, vomiting, concomitant ICS therapy during the trial. At base- and gastric irritation have been reported more fre- 61 line, the mean FEV1 was 72% of normal and, on quently in patients taking theophylline. ␤ In addition to its safety profile, the need for opti- average, the children required 3.3 -agonist puffs mal dose determination and plasma concentration daily—reflecting at least mild-to-moderate persistent monitoring have contributed to theophylline’s de- asthma. Significant improvements in FEV1 were cline in popularity, despite its low cost. Theophylline noted for the montelukast group over the course of is metabolized by the cytochrome P450 isoenzymes the study (Fig 5), accompanied by an immediate ␤ in the liver, which raises the possibility of interac- decline in -agonist use beginning on the first day of tions with other drugs metabolized by these com- use (Fig 6). Furthermore, montelukast provided the plexes. For this reason, it is important to monitor same positive effects on pulmonary function blood levels and clearance in patients receiving the- whether the patients were receiving ICS or not.70 ophylline once the physician has determined the best In children 2 to 5 years of age, montelukast’s 4-mg dose. Consequently, although theophylline has chewable tablet efficacy was evaluated during a 12- proven to be efficacious in the treatment of adults week multinational study. Compared with placebo, and children with mild-to-moderate asthma, these montelukast significantly improved ␤-agonist use considerations may make other treatment options (P ϭ .001), daytime asthma symptom score (P ϭ more desirable. .003), days with symptoms (P ϭ .02), days without asthma (P ϭ .002), CS rescues (P ϭ .008), physician’s LEUKOTRIENE RECEPTOR ANTAGONISTS (LTRAs) global evaluation (P ϭ .007), and peripheral blood Because they can reduce the airway inflammation, eosinophils (P ϭ .034). Therefore, montelukast im- bronchial hyperactivity, and smooth muscle contrac- proved asthma control significantly in patients aged 62,63,64 tion associated with asthma, LTRAs may be a 2 to 5 years with asthma.71,72 suitable alternative to ICS in some patients or reduce The safety profile of montelukast is similar to that the need for ICS in others. Pediatric asthma guide- of placebo33,69,72 and there are no known drug inter- lines state that LTRAs may be an alternative to low- actions, which precludes the need for plasma moni- dose ICS therapy in mild persistent asthma and may toring. Furthermore, because montelukast is avail- be an effective add-on to ICS therapy in moderate able for children as young as 2 years of age, a safety persistent asthma.42 Indeed, a recent controlled study was undertaken in 2- to 5-year-old patients study concluded that, in ICS-treated children with persistent asthma, the addition of montelukast 5 mg with asthma who received montelukast (4-mg chew- provided significant improvement in pulmonary able tablet) for 12 weeks. The adverse experience function and in symptoms, despite significant reduc- profile of montelukast was comparable to placebo tion in ␤ -agonist use.65 for all parameters examined (asthma, fever, upper 2 respiratory infection, frequency of discontinuation Zafirlukast attributable to clinical adverse experiences, and the Zafirlukast, the first LTRA approved in the United frequency of individual laboratory adverse experi- States, has demonstrated effectiveness in the man- ences).72 Its bioavailability is not affected by food, so agement of mild-to-moderate asthma in clinical trials it can be taken at any time, regardless of mealtime. by improving pulmonary function and by reducing Because montelukast is available as a chewable tablet the clinical symptoms of asthma as well as the need (5 mg for children 6–14 years of age and 4 mg for for ICS.66 Zafirlukast is indicated as twice-daily oral children 2–5 years of age), its administration is sim- treatment for the management of asthma in children ple and convenient for children.73

Downloaded from www.aappublications.org/news by guest on September 30, 2021 SUPPLEMENT 387 Fig 5. Pediatric chronic asthma study. In an 8-week study, montelukast and placebo were administered once daily to asthmatic children as young as 6 years of age. Significant improvements in FEV1 were noted for the montelukast group (P Ͻ .001). Adapted from Knorr et al.69

Fig 6. Onset of action of montelukast. The effect of montelukast (closed circles) and placebo (open squares) on as-needed ␤-agonist use. The mean percent change of total daily ␤-agonist use declined rapidly, beginning on the first day of use (P Ͻ .02), compared with baseline use. Adapted from Knorr et al.69

␤ LONG-ACTING 2-AGONISTS Longer trials examining the effect of salmeterol in ␤ Salmeterol, a long-acting 2-agonist, is indicated children with mild-to-moderate asthma have pro- for long-term use and is available as both an aerosol duced mixed results. In a 1-year randomized, dou- and an inhaled dry powder, the latter of which is ble-blind trial, in children 6 to 14 years of age, sal- approved for children as young as 4 years of age. meterol did not significantly improve airway Both formulations of salmeterol are more efficacious hyperresponsiveness compared with placebo, but it ␤ than short-acting 2-agonists and placebo in treating did significantly increase pulmonary function (FEV1, mild-to-moderate asthmatic children,74–76 with sig- morning and evening PEFR).78 In another year-long, nificant bronchodilation lasting up to 12 hours.77 randomized, double-blind parallel study in mild-to- In a 12-week, randomized, double-blind study in moderate asthmatic children 6 to 16 years of age, children 4 to 11 years of age with moderate persistent however, children taking salmeterol (50 ␮g bid) did asthma, patients receiving salmeterol (50 ␮g bid) had not experience a significant improvement of FEV1 a significantly higher FEV1 at all time points up to 12 during the study or an improved airway hyperre- hours postdose for 12 weeks compared with patients sponsiveness. At the end of the study, the PD20 de- on placebo (week 12: P Յ .005). Significant improve- clined by a Ϫ0.73 doubling dose (P ϭ .05).79 ments over placebo in mean percent of predicted The reason for the decreased FEV1 and the in- PEFR (P ϭ .008) and patient-measured PEFR (morn- creased airway hyperresponsiveness in salmeterol- ing: P Ͻ .001; evening: P ϭ .010) were also observed treated patients was not determined, but there are 2 for the duration of the study in patients taking sal- possible explanations. First, tolerance may have de- ␤ meterol. Rescue use of the short-acting 2-agonist veloped to salmeterol’s bronchoprotection as it has decreased significantly in the salmeterol group been shown to lead to decreased bronchoprotection (Ϫ0.8 Ϯ 0.2 puffs/day vs Ϫ0.3 Ϯ 0.1 puffs/day for against methacholine challenge80,81 and exercise-in- ϭ 82 salmeterol and placebo, respectively; P .004), but duced bronchoconstriction. The reduction in FEV1 there was no significant change in nights without did not appear to be prevented in mild-to-moderate awakenings.76 asthma patients on ICS therapy.83,84 Although salme-

388 SUPPLEMENT Downloaded from www.aappublications.org/news by guest on September 30, 2021 terol has a protective effect against exercise-induced half the patients held unfounded fears and miscon- asthma, the duration of this effect may wane even ceptions about the adverse effects and efficacy of during regular once-daily salmeterol treatment de- ICS, and they expressed misgivings about taking spite the reduced frequency of dosing and despite these agents regularly. In addition, 75% of these pa- concomitant use of ICS in children.85 Similarly, reg- tients admitted that they had not discussed their ␤ 89 ular treatment with long-acting 2-agonists may de- concerns with their physicians. Such steroid-pho- ␤ crease the effectiveness of short-acting 2-agonists in bia could understandably lead to decreased adher- protecting against bronchoconstriction.86 Another ence to prescribed therapy and, subsequently, dimin- possible reason for the decrease in FEV1 could be ished therapeutic effectiveness. unchecked airway inflammation. Because long-act- Adherence rates have also been shown to be sig- ␤ ing 2-agonists have not been shown to have in vivo nificantly lower with inhaled asthma medication antiinflammatory actions, their bronchodilating and than with oral formulations.90 This raises the possi- symptom-relieving benefits could potentially mask bility that one reason we may not see much ICS- continuing airway inflammation and, consequently, induced growth suppression in children in a clinical worsening asthma over time. Unhindered inflamma- practice setting is that they are self-titrating down- tion could also explain the greater number of asthma ward through poor adherence. Obviously, poor ad- exacerbations that required oral CS courses in the herence is not a solution to the possibility of growth salmeterol-treated patients as compared with ICS- suppression but, rather, part of the challenge in bal- treated patients (17 vs 2, respectively).79 ancing risks and benefits because it also leads to poor Current pediatric guidelines state that long-acting disease control, overutilization of health care re- ␤ 2-agonists should not replace antiinflammatory sources, and unabated airway remodeling. therapy but should be considered as add-on thera- High adherence rates, in contrast, may enhance the py.42 In children with moderate-to-severe asthma, effectiveness of an asthma therapy. In a drug prefer- combining salmeterol with budesonide improved ence study that included asthmatic children 6 to 14 morning PEFR (P Ͻ .001), evening PEFR (significant years of age, the acceptability of once-daily monte- during first 4 weeks of treatment; P ϭ .014), symp- lukast was compared with inhaled cromolyn 4 times tom-free days (P Ͻ .05.), and reduced the use of daily over a 4-week period.91 Over 80% of the chil- rescue medications (during the last 8 weeks; P Ͻ dren, as well as their caregivers, preferred once-daily .05).87 treatment with oral montelukast (P Ͻ .001). Addi- Salmeterol has a safety profile comparable with tionally, significant differences were observed be- placebo.76,78,79,87 As an inhaled therapy, adherence to tween groups in the rates of adherence, with 78% of salmeterol may be adversely affected by its method the montelukast-treated children adhering on more of administration. than 95% of the treatment days compared with 42% of the cromolyn-treated children (P Ͻ .001). The ADHERENCE ISSUES IN PEDIATRIC ASTHMA number of study discontinuations caused by asthma The efficacy of an asthma intervention, as evalu- exacerbations was markedly fewer in the monte- ated in controlled clinical trials, is actually a measure lukast group2 than in the cromolyn group10 as well of whether a particular drug can work, not necessar- (P Ͻ .07). These results suggest that oral therapies ily whether it will work in clinical practice. Actual such as montelukast may encourage adherence in the drug effectiveness, which reflects whether it will pro- management of pediatric asthma, at least when com- duce its intended effect in the clinical setting, is in- pared with an inhaled asthma medication. fluenced by real world variables, the most important Patient satisfaction with medication may also play of which may be patient adherence. Adherence may an important role in the effectiveness of asthma ther- be especially difficult to gain in the mildest patients, apy. In a survey of over 5000 asthma patients, those who clinically have the least disease burden. who did not feel confident about the efficacy of the In controlled clinical trials, doses are often fixed, medication or their ability to take their medications patient adherence is carefully monitored, and the as directed were 8 times more likely to be dissatisfied patients typically receive more extensive asthma ed- with their treatment.92 These patients may require ucation. In other words, the environment is much counseling on the proper use of inhalers or nebuliz- more controlled relative to the everyday clinical ers to increase confidence and thereby improve ad- practice setting where dosing varies widely, patient herence and treatment outcomes. education about asthma is often poor, and, most importantly, patient adherence can vary consider- CONCLUSION ably. Balancing safety and efficacy issues is an ongoing In the clinical setting, patient adherence to the challenge in the treatment of pediatric asthma. ICS prescribed asthma regimen is influenced by numer- continue to be a mainstay in the control of persistent ous factors including mode of administration, dosing asthma because of their clear efficacy. Of all the frequency, onset of action, perceived efficacy, and therapies available for treatment, however, ICS re- anticipated adverse effects. The importance of adher- quire the most attention to maintain the balance be- ence to and proper use of ICS has been demonstrated tween safety and efficacy. Children with mild in a study that showed a significant inverse relation- asthma may be most susceptible to the growth-sup- ship between asthma hospitalization rates and the pressing action of ICS, ostensibly because more of ␤ 88 ratio of ICS to 2-agonist use. A Canadian survey of their distal airways are exposed to the ICS, and more 603 asthmatic adults revealed that approximately drug is absorbed there. This raises the question: Will

Downloaded from www.aappublications.org/news by guest on September 30, 2021 SUPPLEMENT 389 the risk for growth suppression among children with 9. Lipworth BJ, Jackson CM. Safety of inhaled and intranasal moderate or severe asthma increase as airway pa- corticosteroids: lessons for the new millennium. Drug Safety. 2000;23: 11–33 tency and, thus, drug deposition/absorption in- 10. US Food and Drug Administration. Center for Drug Evaluation and crease in response to ongoing ICS therapy? The an- Research Web site. Division of Pulmonary Drug Products. Class label- swer is elusive and complicated by the fact that ing for intranasal and orally inhaled corticosteroid containing drug adherence may decrease over time with ICS therapy, products regarding the potential for growth suppression in children. reducing not only the beneficial actions of these FDA Talk Paper. November 9, 1998. Available at: http://www.fd- a.gov/cder/news/cs-label.htm. Accessed May 1, 1999 agents but masking their potential for adverse effects 11. Ahrens R, Lux C, Bahl T, Han SH. Choosing the metered-dose inhaler as well. Obviously, studies are needed. In addition, spacer or holding chamber that matches the patient’s need: evidence certain techniques, such as using a step-down ap- that the specific drug being delivered is an important consideration. J proach to treatment in children with moderate or Allergy Clin Immunol. 1995;96:288–294 severe asthma, and dosing in the morning, may ame- 12. Mollmann H, Wagner M, Meibohm B, et al. Pharmacokinetic and phar- macodynamic evolution of fluticasone propionate after inhaled admin- liorate the growth-suppressive actions of ICS over istration. Eur J Clin Pharmacol. 1999;53:459–467 the long-term. 13. Wilson AM, Dempsey OJ, Contie WJ, Sios EJ, Lipworth BJ. Importance Nonetheless, alternative asthma therapies may be of drug-device interaction in determining systemic effects of inhaled appropriate in certain children for the treatment of corticosteroids. Lancet. 1999;353:2128 persistent mild-to-moderate asthma, and these 14. Svenonius E, Arborelious M, Wiberg R, Svensson M. A comparison of terbutalizne inhaled by Turbuhaler and by a chlorofluorocarbon (CFC) agents may be less challenging in terms of achieving inhaler in children with exercise-induced asthma. Allergy. 1994;49: a desirable balance between efficacy and safety. The 408–412 chromones, cromolyn and nedocromil, are safe and 15. Leach C. Effect of formulation parameters on hydrofluoralkane- well-established therapies that can be used as mono- beclomethasone dipropionate drug deposition in humans. J Allergy Clin therapy in mild-to-moderate pediatric asthma. The Immunol. 1999;104(suppl):S250–S252 16. Busse WW, Brazinsky S, Jacobson K, et al. Efficacy response of inhaled effectiveness of these agents, however, has been ␤ beclomethasone dipropionate in asthma is proportional to dose and is questioned in a number of studies. Long-acting 2- improved by formulation with a new propellant. J Allergy Clin Immunol. agonists such as salmeterol have proven to be effec- 1999;104:1215–1222 tive add-on therapies to ICS, but questions about the 17. Wilson AM, Sims EJ, Orr LC, Lipworth BJ. Differences in lung bioavail- development of tolerance and unchecked airway in- ability between different propellants for fluticasone propionate. Lancet. 1999;354:1357–1358 flammation may influence physicians in selecting 18. Lipworth BJ, Jackson CM. Pharmacokinetics of chlorofluorocarbon and these therapies for the pediatric population. Theoph- hydrofluoroalkane metered-dose inhaler formulations of beclometha- ylline has proven to be efficacious over many de- sone dipropionate. Br J Clin Pharmacol. 1999;48:866–868 cades, but its safety profile and need for plasma 19. Melchor R, Biddiscombe MF, Mak VH, Short MD, Spiro SG. Lung monitoring and dose optimization may burden busy deposition patterns of directly labelled salbutamol in normal subjects and in patients with reversible airflow obstruction. Thorax. 1993;48: physicians. Several compelling factors support the 506–511 use of LTRAs as primary, controller therapy, and 20. Newnham DM, Wheeldon NM, Lipworth BJ, McDevitt DG. Single add-on therapy for mild-to-moderate persistent dosing comparison of the relative cardiac beta 1/beta 2 activity of asthma, including established efficacy, good safety inhaled fenoterol and salbutamol in normal subjects. Thorax. 1993;48: profiles, and simple, oral, dosing requirements. 656–658 21. Lipworth BJ, Newnham DM, Clark RA, Dhillon DP, Winter JH, McDe- These factors should increase adherence and support vitt DG. 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