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`Clinical lmmunotherapeutics, Biopharmaceuticals and Gene Therapy
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`2001, Vol. 15, No. 7 (pp. 419-489)
`ISSN: 1173-8804
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`Adis Drug Evaluation
`Silymarin: A Review
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`Leading Article
`Pegylated Interferons for Chronic Hepatitis C
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`Review Articles
`Molecular Biology of Pancreatic Cancer
`Anti-Allergy Drugs for Young Children
`Therapeutic Advances in Cutaneous T-Cell Lymphoma
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`Vol. 15, No. 7, 2001
`
`BioDrugS
`
`Contents
`
`Leading Article
`
`Review Articles
`
`Development of Pegylated Interferons for the
`Treatment of Chronic Hepatitis C
`A Kozlowski, _SA Charles, JM Harris
`
`Therapeutic Advances in Biological Response
`'Modifiers in the Treatment of Cutaneous
`T-Cell Lymphoma
`CC Vittorio, AH Rook, LE French, M Slwpiro,
`MS Lehrer, JM Ju11ki11s-Hopki11s
`Molecular Biology of Pancreatic Cancer:
`Potential Clinical Implications
`GH Sakorafas, GG Tsiotos
`Clirtical Prescribing of Allergic Rhinitis
`Medication in the Preschool and Young
`School-Age Child: What are the Options?
`SP Galant, R Wilkinso11
`
`Adis Drug Evaluation
`
`Silymarin: A Review of its Clinical Properties in
`the Management of Hepatic Disorders
`K Wclli11gto11, B Jarvis
`
`419-429
`
`431-437
`
`439-452
`
`453-463
`
`465-489
`
`PHARMACiFL~~6~~S\N
`UNIVERSITY
`12\UG ?, 8 2001
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`Madison , WI 53705
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`BivDrugs is indexed in ll((fex Medicus, Mcdli11e, Clzemical Abstracts, EMBASE/Excerptn Mcdicn, Current Co11/e11ts/Clinical Medici11e, Scie11ce
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`INTERNATIONAL
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`International Editorial Board
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`

`

`REVIEW ARTICLE
`
`BioDrugs 2001 ; 15 (7): 453•463
`1173-8804/01 /0007-0453/$22.00/0
`
`<tl Adis International Limited, All rights ,ese,ved
`
`Clinical Prescribing of Allergic
`Rhinitis Medication in the Preschool
`and-Young School-Age Child
`What are the Options?
`Stanley P. Galant1 and Robert Wilkinson2
`1 Department of Paediatric Allergy /Immunology, University of California, Irvine, California, USA
`2 Department of Pharmacy, St Joseph Hospital, Orange, California, USA
`
`Contents
`. . . . . . .
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`Abstract
`1 . Aetiology, Epidemiology and Impact of Allergic Rhinitis (AR) in Children
`2. Evaluation and Diagnosis
`3. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . .
`4. Treating AR in the Child . . . . . . . . . . . . . . . . . . . .
`4.1 Histamine Hi Receptor Antagonists (Antihistamines) .
`4.2 Decongestants . . . . . .
`Intranasal Corticosteroids
`4.3
`4.4 Mast Cell Stabilisers ....
`4.5 Anticholinergic Agents . .
`5. Conclusions and Recommendations
`
`. 453
`, 454
`454
`455
`455
`456
`458
`... .. 458
`461
`461
`461
`
`Abstract
`
`AUergic rhinitis {AR is the mosL common chronic condition ii, children ~ind
`L'- esLima.tcd to :iffect up lo 40% of all children. lt is usually diagnosed by the age
`of 6 years. The major impact in children is due to co-morbidity of s inusitis, otiti.<;
`media with effusio n, and bronchial asthm,1. AR also has profound effects on
`school absenteeism, perfon11ancc and quality of li fe.
`Pha□n acotherapy for AR should be ba ed on the severity and duration of s igns
`and symptoms. For mild, intermittent symptoms lasting u few hom s tn a few days
`an oral second-generation antihistamine should be used o n an as-needed basis.
`This is preferable· to a less exp e n ivc fi r t-generalio n nntibistamine because of
`the effect of Lhe latte r o n edalion and co_gnitio n. Four second- gene ration anlihj s(cid:173)
`tamines are currently available for children under 12 years of age: cetirizine,
`loratadine, fexofenadine and azelastine nasal spray; each has been found to be
`well tolerated and effective. There are no clearcut advantages to distinguish these
`antihistamines, although for children under 5 years of age, only cctiri2-ine and
`loratadine are approved . Other agents inc lude pscudoephedrine, an oral vasocon(cid:173)
`stric tor, for nasal c'ongestion, arn.J the anticholinergic nasal spray ipratropium
`bromide for rbi non-hoea. Sodium cromoglycatc. a mast cell stabiliser nasal spray.
`may also be useful in this population.
`For patients with more persistent, severe symptoms, intranasal corticosteroids
`
`

`

`454
`
`Gnlmzt & Wilkinson
`
`are indicated, although one might consider azelastine nasal spray, which has anti(cid:173)
`inflammatory activity in addition to its antihistamine effect. With the exception
`of fluticasone propionate for children aged 4 years and older, and mometasone
`furoate for those aged 3 years and older, the other intranasal corticosteroids in(cid:173)
`cluding beclomethasone di propionate, triamcinolone, flunisolide and budesonide
`are approved for children aged 6 years and older. All are effective, so a major
`consideration would be cost and safety. For short term therapy of 1 to 2 months,
`the first-generation intranasal corticosteroids (beclomethasone dipropionate, tri(cid:173)
`amcinolone, budesonide and flunisolide) could be used, and mometasone furoate
`and fluticasone propionate could be considered for longer-term treatment. Al(cid:173)
`though somewhat more costly, these second-generation drugs have lower bio(cid:173)
`availability and thus would have a better safety profile.
`In patients not responding to the above programme or who require continuous
`medication, identification of specific triggers by an allergist can allow for specific
`avoidance measures and/or immunotherapy to decrease the allergic component
`and increase the effectiveness of the pharmacological regimen.
`
`1. Aetiology, Epidemiology and Impact
`of Allergic Rhinitis (AR) in Children
`
`Allergic rhinitis (AR) is currently the most com(cid:173)
`mon of all chronic conditions in children. The dis(cid:173)
`ease can be classified as seasonal or perennial, de(cid:173)
`pending on when the child appears to have
`symptoms most predominantly. Those children
`with seasonal allergic rhinitis (SAR) have symp(cid:173)
`toms predominantly in the spring and fall generally
`due to tree, grass and weed pollen, and occasionally
`mold spores, whereas those with perennial allergic
`rhinitis (PAR) have symptoms all year long sec(cid:173)
`ondary to year-round indoor allergens, such as the
`housedust mite, animal danders, mould spores and
`cockroach allergens (the latter particularly in the
`inner city). PAR generally occurs in younger chil(cid:173)
`dren and is frequently associated with otitis media
`with effusion and sinusitis, while the SAR pattern
`is usually seen in older children and adults. The 2
`conditions can occur together and are not different
`diseases; therefore treatment is the same.
`A 1988 US survey found AR to be present in
`59.7 cases per 1000 children up to the age of 18
`years_[IJ This probably is an underestimate, since it
`included only those with SAR or hayfever. A pro(cid:173)
`spective study of 747 children in Tucson, Arizona,
`found that 42% of families interviewed had a phy(cid:173)
`sician diagnosis of AR by the age of 6 years, and
`half of these children developed this condition in
`
`the first year oflifeP•l The prevalence of AR world(cid:173)
`wide appears to be similar to that of the United
`States)31 The estimated direct expenditure for AR
`and allergic conjunctivitis in children 12 years of
`age or less was estimated to be $2.3 billion in the
`US in 1996.(41 Risk factors for developing AR in(cid:173)
`clude a family history of atopy, serum immuno(cid:173)
`globulin (lg) E levels ~100 IU/ml before the age of
`6 years, higher socioeconomic class, exposure to
`indoor allergens, and a positive skin test indicating
`specific IgE antibodiesJ5l
`AR can have a profound effect on a child's qual(cid:173)
`ity oflife. Children with AR more likely to demon(cid:173)
`strate shyness, depression, anxiety, fearfulness and
`fatigue compared with nonallergic peers.[6l Fur(cid:173)
`thermore, these children miss 2 million days of
`school each year in the US, and even when they
`attend school their ability to learn and process cog(cid:173)
`nitive input is significantly impaired_[?! If left un(cid:173)
`treated, AR can exacerbate and contribute to symp(cid:173)
`toms of asthma, sinusitis and otitis media with
`effusion.[81
`
`2. Evaluation and Diagnosis
`The diagnosis of AR is highly dependent on ob(cid:173)
`taini_ng a comprehensive history from an older
`child or from the parent of a younger child. Signs
`and symptoms in older children with SAR include
`a history of paroxysmal sneezing, nasal itching,
`clear rhinorrhoea and red, itchy, watery eyes, par-
`
`D Adls International Limited. All rights reserved .
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`BioDrugs 200 l ; l S (7)
`
`

`

`Anti-Allergy Drugs for Young Children
`
`455
`
`Liculnrly duTing the pollen season. WiLh PAR, these
`cfra.1-r:iaLic and are often
`symptoms are much le
`characterised by chronic nasal obstruclion wilh
`snoring and moulh breathing, cnronic postna al
`drip f requently associated with chronic cough and
`throat clearing, and inus headaches. r n addition to
`these more locali ed manifestations, many chil(cid:173)
`dren with AR experience systemic symptoms in(cid:173)
`cluding weakne s, malaise, fa6gue. irritability.
`poor appelile and , leep dis mrbances.f8l
`On physical examination, Lhe c lassic signs 1n(cid:173)
`clude allergic shiners, a llergic· nasal crease often
`accompanied by high arched palate, and open
`mouth characteristic of chronic nasal obstruction
`due to enlarged, pale nasal turbinates.
`To establish a diagnosis of AR, however, one
`must identify the presence of specific IgE antibod(cid:173)
`ies by skin or blood tests (i.e. radioallergosorbent
`test) and correlate this with the history. As in
`adults, inhalant allergens are the most frequent
`Lriggers in childhood AR. However, allergy resting
`for pollens is typically done after the age of 2 to 3
`years.l61 Food allergy may be relevant, particularly
`in younger c hildren aged less than 2 years.191
`
`3. Pathogenesis
`Atopic individuals inherit the tendency to de(cid:173)
`velop AR. Prolonged exposure to indoor aJlergens
`result in -produclion of IgE antibodi,e · that bind to
`mucosaJ mast cells and circulating basophil s. Thus
`sensiti ed, the patient develop · acute nasal and oc(cid:173)
`ular symptoms followin g further expo ure.l lOJ Thi ·
`response, which can occur wjth.in minu tes of expo-
`
`sure and is termed the early-phase allergic re(cid:173)
`sponse, is caused primarily by the release of mast
`cell mediators. These include hi. tamine, tryptase,
`pro, taglandin 02 and the cysteinyl le ukotrienes
`tLT) C4, D4 and E4.1 IOJ A late-phase response that
`occurs-+ to 8 how- after allergen exposure in 50%
`of patient i thought lo be due to cyLokine release
`by mast cell· and thy_rnic-decived helper T cells
`called T H2 ceUs. T he late-phase respon se is char(cid:173)
`acterised by profound infiltration and activation of
`migrating and res ident eel ls .1 101 This inflammatory
`re po nse is thoug ht to be responsible for the per-
`i tent, c hmllic signi,; and symptoms of AR, partic(cid:173)
`ularly nasal obstruction and increased sensitivity
`of the nasal mucosa to allergens and irritants.
`
`4. Treating AR in the Child
`The principles of managing chronic AR in chil(cid:173)
`dren are similar to those in adults, and include en(cid:173)
`vironmental avoidance measures, pharmacother(cid:173)
`apy and, in those not responding to the latter 2,
`immunotherapy. In all cases, the goal of therapy
`includes controlled symptoms without altering the
`child's ability to function and, in addition, preven(cid:173)
`tion of the potential sequelae of AR mentioned
`above. Since the main purpose of this paper is to
`describe current concepts in pharmacotherapy,
`readers are referred to an excellent recent review
`by Dykewicz et aU5l for a discussion of the other
`therapeutic modalities.
`The various classes of medication that are use(cid:173)
`ful in AR and their effects on specific symptoms
`are presented in table I and are discussed in detail
`
`Table I. Efficacy of various drug classes for symptoms of allergic rhinitisa,b
`Rhinorrhoea
`Pruritus
`++
`+++
`++
`++t
`±
`++
`±
`+++
`+
`+++
`+++
`
`Oral antihistamines
`Topical antihistamines (e.g. azelastine)
`Oral decongestants
`Antihistamine/decongestant combinations
`Topical decongestantsc
`,,
`:
`Intranasal corticosteroids
`Intranasal sodium cromoglycate
`Intranasal ipratropium bromide
`-H+.
`Oral corticosteroidsd
`a Reproduced from Galan! & Wilkinson,1111 with permission.
`b Range from no efficacy(--) to profound efficacy(+++).
`c Restrict use to never more than 3 consecutive days.
`d Limit use to tempora,ry therapy in urgent or severe cases.
`
`+++
`
`,. ±++
`+
`
`Nasal blockage
`±
`++
`+++
`+++
`+++
`++(+)
`±
`
`+++
`
`Eye symptoms
`+++
`±
`
`+++
`
`+
`
`++
`
`:,, Adis Internatio nal limited . All rights rese rved.
`
`BioDrugs2001; 15 (7)
`
`

`

`456
`
`Gala11t & Wilkinson
`
`Table II. Comparison of selected antihistamines8
`Drug name
`
`Onset of action {h)
`
`Sedation
`
`Dosage schedule
`
`Age (y)
`
`First-generation antihistamines
`Brompheniramine
`Chlorphenamine
`Clemastine
`Cyproheptadine
`Diphenhydramine
`Hydroxyzine
`Triprolidine
`
`Yes
`Yes
`Yes
`Yes
`Yes
`Yes
`Yes
`
`Second-generation antihistamines
`Azelasline0
`Slight
`Cetirizine
`<1
`Slight
`Fexofenadine
`1-2
`No
`Loratadine
`1-3
`No
`a Reproduced from Lasley and Shapiro,1161 with permission, and Galan! and Wilkinson.£1 11
`b Consult a physician.
`c
`Intranasal application.
`bid = twice daily; od = once daily; qid = 4 times daily; tid = 3 times daily.
`
`tid-'qid
`tid-qid
`bid
`bid-lid
`tid-qid
`tid-qid
`tid-qid
`
`bid
`od
`bid
`ad
`
`<6b
`>2
`>6
`>2
`>2
`<6b
`<6b
`
`>5
`>2
`>6
`>2
`
`below. These discussions will be followed by gen(cid:173)
`eral therapeutic recommendations for patients with
`mild, moderate and severe AR based on the relative
`merits of the drug classes and pharmacoeconomic
`consideration where appropriate.
`
`4. l Histamine H1 Receptor
`Antagonists (Antihistamines)
`
`First- and second-generation antihistamines are
`very effective in the treatment of AR because they
`alleviate both nasal and ocular symptoms. Antihis(cid:173)
`tamines antagonise histamine directly, but revers(cid:173)
`ibly, at the H 1 receptor, thereby blocking the phys(cid:173)
`iological effects of histamine on blood vessels,
`mucous-secreting glands, and sensory nerve end(cid:173)
`ings in the nose.l 11 l In addition, several antihista(cid:173)
`mines, including the second-generation agents
`fexofenadine hydrochloride and loratadine, also
`appear to block release of histamine and other in(cid:173)
`flammatory mediators from mast cells and baso(cid:173)
`phils in vivoJ 12l The second-generation antihista(cid:173)
`mine cetirizine inhibits LTC4 and D4 production
`in nasal secretions and inhibits recruitment of eo(cid:173)
`sinophils in the cutaneous late-phase modeJ.( 13,141
`Another second-generation agent, azelastine hy(cid:173)
`drochloride, in addition to high affinity for the H 1
`
`receptor administered as a nasal spray, is inhibitory
`to several cells and chemical mediators of the in(cid:173)
`flammatory response.r151
`In children, as in adults, oral antihistamines con(cid:173)
`tinue to be the mainstay of treatment for AR. Two
`generations of antihistamines are currently avail(cid:173)
`able, the first-generation sedating antihistamines,
`some of which are available without prescription
`(e.g. diphenhydramine and chlorphenamine), and
`the second-generation nonsedating antihistamines,
`which require a prescription (table II). The first(cid:173)
`and second-generation antihistamines are equally
`effective. However, the problems of nonspecificity,
`sedation and frequent drug administration limit the
`usefulness of the first-generation antihistamines.
`In addition, these agents have been associated with
`paradoxical stimulation (particularly in the young
`child), blurred vision, urinary retention, dry mouth,
`tachycardia, constipation and weight gain, particu(cid:173)
`larly with cyproheptadine) 17•18l Thus, second-gen(cid:173)
`eration antibistan\incs h~ve. advantages over the
`first-generation antihistamines, including greater
`specificity, with binding predominantly at the H 1
`receptor and minimal binding to serotonin, cholin(cid:173)
`ergic or a -adrenergic receptors. This specificity of
`binding results in a decreased drying effect at the
`mucosal surface, and .less gastrointestinal upset.
`
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`BloDrugs2001 ; 15 (,7)
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`

`

`Anti-Allergy Drugs for Young Children
`
`457
`
`The second-generation ant'ihistamines are also
`more lipophobic, with minimal penetration into the
`central nervous system (CNS), and thus have min(cid:173)
`imal sedation.f 17•19l Th~ absence of sedation and
`cognitive effect is a critical advantage in children
`as in adults. Vuurman et aI.l7l found that children
`with AR scored substantially better in learning
`measures when treated with second-generation an(cid:173)
`tihistamines compared with-those treated with
`first-generation antihistamines, suggesting that the
`fo1mer should be used in children whenever possible.
`Four second-generation antihistamines are cur(cid:173)
`rently available for children tinder 12 years of age.
`Cetirizine is approved for children aged 2 years
`and above for both SAR and PAR, loratadine for
`those 2 years and above with SAR, azelastine for
`those aged 5 years and above for SAR, and
`fexofenadine is approved for children 6 years of
`age and older with SAR. Pharmacological charac(cid:173)
`teristics in adults of these 4 drugs are shown in
`table III. Pharmacokinetic studies have shown that
`the te1minal elimination half-life for antihistamines
`undergoing extensive first-pass metabolism in the
`liver cytochrome P450 system is often shorter in
`infants and young children.l20l These differences
`are not found for histamine H1 receptor antagonists
`that are eliminated largeiy unchanged.[20l Pharma(cid:173)
`cokinetic data for cetirizine show that children
`aged less than 12 years have a greater clearance and
`elimination half-life compared with adults,(211
`while the clearance for loratadine and fexofenad(cid:173)
`ine is not significantly different in children and
`adults.[22,231 Pharmacokinetic data for intranasal
`azelastine is not available in children under 12 years.
`
`Dosages and costs in the US of the second(cid:173)
`generation antihistamines are shown and compared
`with an example of the first-generation product
`dephenhydramine HCL in table IV. Cetirizine (5mg,
`10mg), loratadine (10mg), and fexofenadine (30mg)
`are available as tablets; cetirizine (5mg/5ml) and
`loratadine (5mg/5ml) are available as a syrup; and
`loratadine has a rapidly dissolving tablet (10mg)
`[table III]. Cetirizine has been evaluated in doses
`ranging from 2.5mg to 10mg in double-blind,
`controlled studies in children as young as 2 years
`of age with SAR and PAR, and found to be effec(cid:173)
`tive and well tolerated.[25,261 In children aged 6 to
`11 years, the major adverse effects were abdominal
`pain in 4.4% receiving 5mg and 5.6% in those re(cid:173)
`ceiving 10mg compared with 1.9% in the placebo
`group. Somnolence was found in 1.9% and 4.2%
`receiving 5mg and 10mg, respectively, compared
`with 1.3% in those receiving placebo.f25,261 In ad(cid:173)
`dition, the efficacy and tolerability of loratadine
`has been reported in children as young as 2 years
`taking 5mg or 10mg.[27l No significant adverse ef(cid:173)
`fects, particularly somnolence, were found.[271 The
`effectiveness of fexofenadine 30mg tablets was
`demonstrated in 1 study in children aged 6 to 11
`years with SAR compared with placebo controls,
`along with extrapolation of efficacy in patients
`over 12 years of age and pharmacokinetic compar(cid:173)
`isons in adults and childrenJ281 The tolerability of
`this product was demonstrated in 2 placebo-control(cid:173)
`led 2-week studiesP91 Again no significant adverse
`events, particularly somnolence, were reported.
`Azelastine nasal spray (0.14 mg/metered dose
`per nostril twice daily) was reported to be effective
`
`Table Ill. Pharmacokinetics of second-generation antihistamines•,b
`Cetirizine
`
`Time to peak concentration {h)
`<1
`Onset of action (h)
`4-8
`Time to peak effect {h)
`7-10
`Half-life {h)
`24
`Duration - single dose (h)
`Renal
`Elimination pathway
`No
`Active metabolites
`13.7%/6.3%
`Drowsiness/somnolence (drug/placebo)
`a Reproduced from Galant & Wilkinson,1111 with permission.
`In adults.
`b
`c 0.5 to 2h for intranasal azelastine.
`
`Loratadine
`1.3
`1-3
`8-12
`8.4-15
`24-48
`Hepatic
`Yes
`8%/6%
`
`Fexofenadine
`2.6
`
`2-3
`14.4
`12-24
`Renal/faeces
`No
`1.3%/0,9%
`
`Azelastine
`4-6
`0.5-2°
`4
`22-36
`10-12
`Hepatic
`Yes
`11 .5/5%
`
`~J Adis Inte rnatio nal Limited. All rights reserved.
`
`Bio Drugs 2001 ; 15 (7)
`
`

`

`458
`
`Gnlant & Wilkinson
`
`Table IV. Dosages and costs of second-generation antihistamine produ~tsa . .
`Drug name
`Loratadine
`
`Formulation
`10mg tablets
`10mg rapid-dissolve tabs
`Syrup (5 mg/tsp)
`
`Cetirizine
`
`1 0mg tablets
`5mg tablets
`Syrup (5 mg/tsp)
`
`Azelastine nasal spray
`
`1.37 µg/spray
`
`Fexofenadine
`30mg tablets
`Diphenhydramine0
`Syrup (12.5 mg/tsp)
`a Reproduced from Galan! & Wilkinson,1111 with permission.
`b Based on US average wholesale price according to 2000 Drug Topics Red Book.1241
`c 2 teaspoon (tsp) dose.
`d 1 tsp dose.
`e First-generation antihistamine for comparative cost.
`bid = twice daily; od = once daily; tid = 3 times daily.
`
`Children aged 6-11y
`Not approved
`1 tablet od
`1-2 tsp od
`1 tsp od for children 2-5y
`NA
`1-2 tablets od
`1-2 tsp od
`0.5-1 tsp od for children 2-5y
`1 spray/nostril bid
`(100 actuations/bottle)
`30mg bid
`0.5-1 tsp lid
`
`Cost/monthb
`$67.20
`$76.81
`$39.78-$79.56
`
`$57.30
`$57.30
`$70.ooc
`$35.00d
`$47.00
`
`$31.08
`$8.00 generic
`
`and well tolerated in children aged 5 to 12 years
`with PAR by Herman et al.[30l using a placebo-con(cid:173)
`trolled, double-blind protocol. In addition to relief
`of the usual symptoms of AR, nasal obstruction
`was also reduced. Safety and tolerability have also
`been established in this age group with SAR, and
`this is the indication for this product in the US.
`Efficacy was based on extrapolation of efficacy in
`adults and supportive data from European trials in
`children aged 5 to 12 years. Tolerability data were
`established in 3 well controlled European studies
`in children 5 to 12 years of age.l311 The major ad(cid:173)
`verse events noted in adults included a bitter taste,
`19.7% compared with 0.6% with placebo, and som(cid:173)
`nolence, 11.5% compared with 5.4%, respectively;
`these effects were also seen in children.
`
`4.2 Decongestants
`
`Decongestants such as pseudoephedrine and
`phenylpropanolamine produce vasoconstriction
`within the nasal mucosa through stimulation of the
`a-adrenergic receptor. They may be useful as ad(cid:173)
`junctive therapy for AR since antihistamines alone
`generally do not reduce nasal obstruction. How(cid:173)
`ever, these agents have no effect on rhinorrhoea,
`
`pruritus or sneezing. Therefore, they may be most
`effective when used in combination with antihista(cid:173)
`minesP21 However, currently there are no combi(cid:173)
`nations that employ a decongestant with a non(cid:173)
`sedating antihistamine for children under 12 years
`of age, although several are in clinical trials. De(cid:173)
`congestants can also be applied topically, in which
`case agents such as phenylephrine or oxymetazol(cid:173)
`ine should not be taken for more than 4 consecutive
`days to avoid rebound congestion, termed rhinitis
`rnedicamentosa. [ 1_71
`The most commonly used oral decongestant in
`children is pseudoephedrine, which is given every
`6 hours as needed either as a 30mg per teaspoon
`syrup or a 30mg tablet. The dose is 15mg for -chil(cid:173)
`dren aged 2 to 5 years, and 30mg for children 6 to
`11 years. Although most children tolerate these
`agents well, they can produce adverse effects such
`as CNS stimulation, increased blood pressure, dys(cid:173)
`uria, palpitations and tachycardia. [ 171
`
`4.3 Intranasal Corticosteroids
`
`Intranasal corticosteroids are highly effective
`and have be~n approved for use in children with
`both SAR and PAR They relieve a range of signs
`
`© Adis International Limited. All rights reserved.
`
`Bio Drugs 200 l; 15 (7)
`
`

`

`Anti-Allergy Drugs for Young Children
`
`459
`
`and symptoms that include nasal congestjon, .rhi(cid:173)
`norrhoea, itching and sneezing, but ate less effec(cid:173)
`tive for ocular symptoms.l33,34l Since AR can be
`viewed as a chronic inflammatory all~rgic disease,
`intranasal corticosteroids would appear well suited
`to reverse this process. Although the exact mecha(cid:173)
`nism of action is not known, the major pathway
`involves binding of the steroid molecule to a
`cytoplasmic receptor that is then transported to the
`nucleus where it binds to the DNA at the
`glucocorticoid response element.r33l T~is results in
`inhibition of a variety of pro-inflammatory cyto(cid:173)
`kines that decrease the inflammatory response.
`With the current exception of fluticasone propi(cid:173)
`onate (for children 4 years of age and up) and
`mometasone furoate (for children 3 years of age
`and up), intranasal corticosteroids sprays are gen(cid:173)
`erally approved for use in children as young as 6
`years (table V). Phamiacokinetic and pharmacody(cid:173)
`namic data shown in table VI have been derived in
`adults since data are lacking in children.(35,371 Both
`local and systemic . adverse effects have been re(cid:173)
`ported. Local effects due to irritation include pain,
`epistaxis and, rarely, perforation of the septum re(cid:173)
`ported in adults. However, no atrophic changes
`have been reported after up to 10 years of usage in
`adults.(381 These effects can usually be overcome
`by aiming the nozzle away from the septum and/or
`
`using an aqueous preparation instead of a pre(cid:173)
`ssurised propellant, if available. In addition, benz(cid:173)
`alkonium chloride, an antimicrobial preservative,
`has been proposed to cause burning, irritation and
`dryness by inhibition of mucociliary transportJ 39l
`In some patients, selection of a benzalkonium
`chloride-free preservative may be helpful.
`Although asthmatic children appear to eliminate
`inhaled corticosteroids (e.g. budesonide) twice as
`quickly as adults,[40l systemic adverse effects, par(cid:173)
`ticularly hypothalamic-pituitary-adrenal (HPA)
`axis and growth suppression, continue to be areas
`of concern in this population. The amount of cor(cid:173)
`ticosteroid that reaches the systemic circulation is
`a product of both nasal and oral bioavailability.
`Most of the intranasal corticosteroid is swallowed,
`and thus the majority of systemic bioavailability is
`determined by the absorption from the gastrointes(cid:173)
`tinal tract and degree of first-pass hepatic degrada(cid:173)
`tion.(351 This explains the rather high bioavailabil(cid:173)
`ity of 20 to 50% for beclomethasone di propionate,
`flunisolide and budesonide, compared with less
`than 1 % for fluticasone propionate and mometasone
`furoate.l35l Furthermore, it is important to differen(cid:173)
`tiate between systemic effects, which are usually
`short term, and systemic adverse effects, seen with
`chronic intranasal corticosteroid usage. [35A1l Thus,
`short term effects of these agents on the HPA axis,
`
`Beclomethasone dipropionate (MDI)
`Beclomethasone dipropionate
`
`Table V. Dosages and costs of intranasal corticosteroidsa
`Dose