REVIEW ARTICLE
`
`BioDrugs 2001; 15 (7): 453-463
`1173-8804/01/0007-0453/$22.00/0
`
`© Adis International Limited. All rights reserved.
`
`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
` . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453
`Abstract
`1. Aetiology, Epidemiology and Impact of Allergic Rhinitis (AR) in Children . . . . . . . . . . . . . . 454
`2. Evaluation and Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454
`3. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455
`4. Treating AR in the Child . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455
`4.1 Histamine H1 Receptor Antagonists (Antihistamines) . . . . . . . . . . . . . . . . . . . . . . . . 456
`4.2 Decongestants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 458
`4.3 Intranasal Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 458
`4.4 Mast Cell Stabilisers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461
`4.5 Anticholinergic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461
`5. Conclusions and Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461
`
`Abstract
`
`Allergic rhinitis (AR) is the most common chronic condition in children and
`is estimated to affect up to 40% of all children. It is usually diagnosed by the age
`of 6 years. The major impact in children is due to co-morbidity of sinusitis, otitis
`media with effusion, and bronchial asthma. AR also has profound effects on
`school absenteeism, performance and quality of life.
`Pharmacotherapy for AR should be based on the severity and duration of signs
`and symptoms. For mild, intermittent symptoms lasting a few hours to a few days,
`an oral second-generation antihistamine should be used on an as-needed basis.
`This is preferable to a less expensive first-generation antihistamine because of
`the effect of the latter on sedation and cognition. Four second-generation antihis-
`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 cetirizine and
`loratadine are approved. Other agents include pseudoephedrine, an oral vasocon-
`strictor, for nasal congestion, and the anticholinergic nasal spray ipratropium
`bromide for rhinorrhoea. Sodium cromoglycate, a mast cell stabiliser nasal spray,
`may also be useful in this population.
`For patients with more persistent, severe symptoms, intranasal corticosteroids
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`454
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`Galant & Wilkinson
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`are indicated, although one might consider azelastine nasal spray, which has anti-
`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-
`cluding beclomethasone dipropionate, 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-
`amcinolone, budesonide and flunisolide) could be used, and mometasone furoate
`and fluticasone propionate could be considered for longer-term treatment. Al-
`though somewhat more costly, these second-generation drugs have lower bio-
`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-
`mon of all chronic conditions in children. The dis-
`ease can be classified as seasonal or perennial, de-
`pending on when the child appears to have
`symptoms most predominantly. Those children
`with seasonal allergic rhinitis (SAR) have symp-
`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-
`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-
`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.[1] This probably is an underestimate, since it
`included only those with SAR or hayfever. A pro-
`spective study of 747 children in Tucson, Arizona,
`found that 42% of families interviewed had a phy-
`sician diagnosis of AR by the age of 6 years, and
`half of these children developed this condition in
`
`the first year of life.[2] The prevalence of AR world-
`wide appears to be similar to that of the United
`States.[3] 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.[4] Risk factors for developing AR in-
`clude a family history of atopy, serum immuno-
`globulin (Ig) 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 antibodies.[5]
`AR can have a profound effect on a child’s qual-
`ity of life. Children with AR more likely to demon-
`strate shyness, depression, anxiety, fearfulness and
`fatigue compared with nonallergic peers.[6] Fur-
`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-
`nitive input is significantly impaired.[7] If left un-
`treated, AR can exacerbate and contribute to symp-
`toms of asthma, sinusitis and otitis media with
`effusion.[8]
`
`2. Evaluation and Diagnosis
`The diagnosis of AR is highly dependent on ob-
`taining 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-
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`ticularly during the pollen season. With PAR, these
`symptoms are much less dramatic and are often
`characterised by chronic nasal obstruction with
`snoring and mouth breathing, chronic postnasal
`drip frequently associated with chronic cough and
`throat clearing, and sinus headaches. In addition to
`these more localised manifestations, many chil-
`dren with AR experience systemic symptoms in-
`cluding weakness, malaise, fatigue, irritability,
`poor appetite and sleep disturbances.[8]
`On physical examination, the classic signs in-
`clude allergic shiners, allergic 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-
`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
`triggers in childhood AR. However, allergy testing
`for pollens is typically done after the age of 2 to 3
`years.[6] Food allergy may be relevant, particularly
`in younger children aged less than 2 years.[9]
`
`3. Pathogenesis
`Atopic individuals inherit the tendency to de-
`velop AR. Prolonged exposure to indoor allergens
`results in production of IgE antibodies that bind to
`mucosal mast cells and circulating basophils. Thus
`sensitised, the patient develops acute nasal and oc-
`ular symptoms following further exposure.[10] This
`response, which can occur within minutes of expo-
`
`sure and is termed the early-phase allergic re-
`sponse, is caused primarily by the release of mast
`cell mediators. These include histamine, tryptase,
`prostaglandin D2 and the cysteinyl leukotrienes
`(LT) C4, D4 and E4.[10] A late-phase response that
`occurs 4 to 8 hours after allergen exposure in 50%
`of patients is thought to be due to cytokine release
`by mast cells and thymic-derived helper T cells
`called TH2 cells. The late-phase response is char-
`acterised by profound infiltration and activation of
`migrating and resident cells.[10] This inflammatory
`response is thought to be responsible for the per-
`sistent, chronic signs and symptoms of AR, partic-
`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-
`dren are similar to those in adults, and include en-
`vironmental avoidance measures, pharmacother-
`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-
`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 al.[5] for a discussion of the other
`therapeutic modalities.
`The various classes of medication that are use-
`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
`Pruritus
`Rhinorrhoea
`+++
`++
`Oral antihistamines
`+++
`++
`Topical antihistamines (e.g. azelastine)
`±
`--
`Oral decongestants
`+++
`++
`Antihistamine/decongestant combinations
`±
`Topical decongestantsc
`--
`+++
`+++
`Intranasal corticosteroids
`+
`+
`Intranasal sodium cromoglycate
`+++
`--
`Intranasal ipratropium bromide
`+++
`+++
`Oral corticosteroidsd
`a Reproduced from Galant & Wilkinson,[11] with permission.
`b Range from no efficacy (--) to profound efficacy (+++).
`c Restrict use to never more than 3 consecutive days.
`d Limit use to temporary therapy in urgent or severe cases.
`
`Nasal blockage
`±
`++
`+++
`+++
`+++
`++(+)
`±
`--
`+++
`
`Eye symptoms
`+++
`±
`--
`+++
`--
`+
`--
`--
`++
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`Table II. Comparison of selected antihistaminesa
`Drug name
`
`Onset of action (h)
`
`Sedation
`
`Dosage schedule
`
`Age (y)
`
`First-generation antihistamines
`Brompheniramine
`Chlorphenamine
`Clemastine
`Cyproheptadine
`Diphenhydramine
`Hydroxyzine
`Triprolidine
`
`1
`1
`1
`1
`1
`1
`1
`
`Yes
`Yes
`Yes
`Yes
`Yes
`Yes
`Yes
`
`Second-generation antihistamines
`Azelastinec
`Slight
`1
`Slight
`<1
`Cetirizine
`No
`1-2
`Fexofenadine
`No
`1-3
`Loratadine
`a Reproduced from Lasley and Shapiro,[16] with permission, and Galant and Wilkinson.[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-tid
`tid-qid
`tid-qid
`tid-qid
`
`bid
`od
`bid
`od
`
`<6b
`>2
`>6
`>2
`>2
`<6b
`<6b
`
`>5
`>2
`>6
`>2
`
`below. These discussions will be followed by gen-
`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.
`
`4.1 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-
`tamines antagonise histamine directly, but revers-
`ibly, at the H1 receptor, thereby blocking the phys-
`iological effects of histamine on blood vessels,
`mucous-secreting glands, and sensory nerve end-
`ings in the nose.[11] In addition, several antihista-
`mines, including the second-generation agents
`fexofenadine hydrochloride and loratadine, also
`appear to block release of histamine and other in-
`flammatory mediators from mast cells and baso-
`phils in vivo.[12] The second-generation antihista-
`mine cetirizine inhibits LTC4 and D4 production
`in nasal secretions and inhibits recruitment of eo-
`sinophils in the cutaneous late-phase model.[13,14]
`Another second-generation agent, azelastine hy-
`drochloride, in addition to high affinity for the H1
`
`receptor administered as a nasal spray, is inhibitory
`to several cells and chemical mediators of the in-
`flammatory response.[15]
`In children, as in adults, oral antihistamines con-
`tinue to be the mainstay of treatment for AR. Two
`generations of antihistamines are currently avail-
`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-
`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-
`larly with cyproheptadine.[17,18] Thus, second-gen-
`eration antihistamines have advantages over the
`first-generation antihistamines, including greater
`specificity, with binding predominantly at the H1
`receptor and minimal binding to serotonin, cholin-
`ergic or α-adrenergic receptors. This specificity of
`binding results in a decreased drying effect at the
`mucosal surface, and less gastrointestinal upset.
`
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`The second-generation antihistamines are also
`more lipophobic, with minimal penetration into the
`central nervous system (CNS), and thus have min-
`imal sedation.[17,19] The absence of sedation and
`cognitive effect is a critical advantage in children
`as in adults. Vuurman et al.[7] found that children
`with AR scored substantially better in learning
`measures when treated with second-generation an-
`tihistamines compared with those treated with
`first-generation antihistamines, suggesting that the
`former should be used in children whenever possible.
`Four second-generation antihistamines are cur-
`rently available for children under 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-
`teristics in adults of these 4 drugs are shown in
`table III. Pharmacokinetic studies have shown that
`the terminal elimination half-life for antihistamines
`undergoing extensive first-pass metabolism in the
`liver cytochrome P450 system is often shorter in
`infants and young children.[20] These differences
`are not found for histamine H1 receptor antagonists
`that are eliminated largely unchanged.[20] Pharma-
`cokinetic data for cetirizine show that children
`aged less than 12 years have a greater clearance and
`elimination half-life compared with adults,[21]
`while the clearance for loratadine and fexofenad-
`ine is not significantly different in children and
`adults.[22,23] Pharmacokinetic data for intranasal
`azelastine is not available in children under 12 years.
`
`Dosages and costs in the US of the second-
`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-
`tive and well tolerated.[25,26] 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-
`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.[25,26] In ad-
`dition, the efficacy and tolerability of loratadine
`has been reported in children as young as 2 years
`taking 5mg or 10mg.[27] No significant adverse ef-
`fects, particularly somnolence, were found.[27] 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-
`isons in adults and children.[28] The tolerability of
`this product was demonstrated in 2 placebo-control-
`led 2-week studies.[29] 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 III. Pharmacokinetics of second-generation antihistaminesa,b
`Cetirizine
`1
`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,[11] with permission.
`b In adults.
`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
`1
`2-3
`14.4
`12-24
`Renal/faeces
`No
`1.3%/0.9%
`
`Azelastine
`4-6
`0.5-2c
`4
`22-36
`10-12
`Hepatic
`Yes
`11.5/5%
`
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`Table IV. Dosages and costs of second-generation antihistamine productsa
`
`Drug name
`Loratadine
`
`Cetirizine
`
`Formulation
`10mg tablets
`10mg rapid-dissolve tabs
`Syrup (5 mg/tsp)
`
`10mg tablets
`5mg tablets
`Syrup (5 mg/tsp)
`
`Azelastine nasal spray
`
`1.37 μg/spray
`
`30mg tablets
`Fexofenadine
`Diphenhydraminee
`Syrup (12.5 mg/tsp)
`a Reproduced from Galant & Wilkinson,[11] with permission.
`b Based on US average wholesale price according to 2000 Drug Topics Red Book.[24]
`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 tid
`
`Cost/monthb
`$67.20
`$76.81
`$39.78-$79.56
`
`$57.30
`$57.30
`$70.00c
`$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.[30] using a placebo-con-
`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.[31] The major ad-
`verse events noted in adults included a bitter taste,
`19.7% compared with 0.6% with placebo, and som-
`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
`α-adrenergic receptor. They may be useful as ad-
`junctive therapy for AR since antihistamines alone
`generally do not reduce nasal obstruction. How-
`ever, these agents have no effect on rhinorrhoea,
`
`pruritus or sneezing. Therefore, they may be most
`effective when used in combination with antihista-
`mines.[32] However, currently there are no combi-
`nations that employ a decongestant with a non-
`sedating antihistamine for children under 12 years
`of age, although several are in clinical trials. De-
`congestants can also be applied topically, in which
`case agents such as phenylephrine or oxymetazol-
`ine should not be taken for more than 4 consecutive
`days to avoid rebound congestion, termed rhinitis
`medicamentosa.[17]
`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-
`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-
`uria, palpitations and tachycardia.[17]
`
`4.3 Intranasal Corticosteroids
`
`Intranasal corticosteroids are highly effective
`and have been approved for use in children with
`both SAR and PAR. They relieve a range of signs
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`and symptoms that include nasal congestion, rhi-
`norrhoea, itching and sneezing, but are less effec-
`tive for ocular symptoms.[33,34] Since AR can be
`viewed as a chronic inflammatory allergic disease,
`intranasal corticosteroids would appear well suited
`to reverse this process. Although the exact mecha-
`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.[33] This results in
`inhibition of a variety of pro-inflammatory cyto-
`kines that decrease the inflammatory response.
`With the current exception of fluticasone propi-
`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-
`erally approved for use in children as young as 6
`years (table V). Pharmacokinetic and pharmacody-
`namic data shown in table VI have been derived in
`adults since data are lacking in children.[35,37] Both
`local and systemic adverse effects have been re-
`ported. Local effects due to irritation include pain,
`epistaxis and, rarely, perforation of the septum re-
`ported in adults. However, no atrophic changes
`have been reported after up to 10 years of usage in
`adults.[38] These effects can usually be overcome
`by aiming the nozzle away from the septum and/or
`
`using an aqueous preparation instead of a pre-
`ssurised propellant, if available. In addition, benz-
`alkonium chloride, an antimicrobial preservative,
`has been proposed to cause burning, irritation and
`dryness by inhibition of mucociliary transport.[39]
`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,[40] systemic adverse effects, par-
`ticularly hypothalamic-pituitary-adrenal (HPA)
`axis and growth suppression, continue to be areas
`of concern in this population. The amount of cor-
`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-
`tinal tract and degree of first-pass hepatic degrada-
`tion.[35] This explains the rather high bioavailabil-
`ity of 20 to 50% for beclomethasone dipropionate,
`flunisolide and budesonide, compared with less
`than 1% for fluticasone propionate and mometasone
`furoate.[35] Furthermore, it is important to differen-
`tiate between systemic effects, which are usually
`short term, and systemic adverse effects, seen with
`chronic intranasal corticosteroid usage.[35,41] Thus,
`short term effects of these agents on the HPA axis,
`
`Beclomethasone dipropionate (MDI)
`Beclomethasone dipropionate
`
`No. doses per
`container
`200
`200
`200
`200
`60
`200
`120
`120
`100
`120
`
`Table V. Dosages and costs of intranasal corticosteroidsa
`Drug
`Dose per spray
`(μg)
`42
`84
`42
`32
`Budesonide (MDI)
`32
`Budesonide (aqueous)
`25
`Flunisolide (aqueous)
`50
`Fluticasone propionate (MDI)
`55
`Mometasone furoate (MDI)
`55
`Triamcinolone acetonide (MDI)
`55
`Triamcinolone acetonide (aqueous)
`a Reproduced from Galant & Wilkinson,[11] with permission.
`b In each nostril.
`c For adult dosage; based on average wholesale price according to 2000 Drug Topics Red Book.[24]
`d Children aged 4 years or older.
`e Children aged 3 years and older.
`bid = twice daily; MDI = metered-dose inhaler; od = once daily; tid = 3 times daily.
`
`Sprays per dayb
`(children aged 6-11y)
`1 tid
`1-2 od
`1-2 bid
`2 bid or 4 od
`1 od
`1 tid or 2 bid
`1-2 odd
`1 ode
`2 od
`Not approved
`
`Cost/monthc
`($)
`43.94-44.74
`53.12
`45.05
`37.98
`48.00
`40.67
`53.36
`51.17
`41.89
`38.71
`
`© Adis International Limited. All rights reserved.
`
`BioDrugs 2001; 15 (7)
`
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`
`

`

`460
`
`Galant & Wilkinson
`
`Table VI. Selected pharmacokinetic and pharmacodynamic characteristics of intranasal corticosteroidsa
`Systemic bioavailability (%)
`Systemic clearance (L/h)
`44
`230
`Beclomethasone dipropionate
`Budesonideb
`34
`84
`40-50
`48
`Flunisolide
`<1
`69
`Fluticasone propionate
`<1
`NA
`Mometasone furoate
`NA
`37
`Triamcinolone acetonide
`a Reproduced from Galant & Wilkinson,[11] with permission, and product package inserts and Allen.[35]
`b Bioavailability shown for budesonide is for the aqueous pump spray; estimated values for pressurised MDI is 21% and Turbuhaler
`(not available in the US) is 41%.[36]
`NA = data not available.
`
`Onset of action
`3d
`24h
`4-7d
`12h
`12h
`24h
`
`as measured by basal area under the curve, plasma
`cortisol levels or 24-hour urinary free cortisol, re-
`flect the effects of intranasal corticosteroids on hy-
`pothalamic-pituitary feedback inhibition, whereas
`assessment of adrenal function by adrenocortico-
`tropic hormone stimulation measures the effect of
`intranasal corticosteroids on HPA axis function. In
`this respect, there are no studies that show intra-
`nasal corticosteroids induced HPA axis suppres-
`sion regardless of the basal cortisol effect.[35,41]
`Growth inhibition has been found to be a more
`sensitive indication of intranasal corticosteroids-
`induced systemic adverse effects than HPA axis
`suppression.[42] Short term (<6 months) evaluation
`of growth inhibition by knemometry assesses the
`systemic effect of intranasal corticosteroids, com-
`pared with intermediate (≥12 months) and long
`term (>3 years) evaluation, which measures sys-
`temic adverse effects.[35] For the short term effect,
`budesonide 200μg bid showed significant growth
`inhibition,[43] while budesonide 200 and 400μg in
`the morning[44] and mometasone furoate 100 and
`200μg in the morning did not.[45] A single dose of
`methylprednisolone acetate, 60mg intramuscu-
`larly, caused suppression for 4 weeks, while
`budesonide 200μg twice daily caused suppression
`throughout the 6-week trial.[43]
`Since the reliability of knemometry to reflect
`risk of long term growth suppression is tenuous at
`best,[46] long term studies utilising stadiometry
`have been evaluated. Growth suppression (average
`0.9cm) has been reported with beclomethasone
`dipropionate (168μg twice daily),[42] but not
`mometasone furoate 100μg once daily after contin-
`
`uous daily use for 1 year.[47] In the former study,
`HPA axis was not affected.[42] Although there are
`no data with fluticasone propionate, long term
`studies in asthma using 100μg bid showed no sig-
`nificant growth suppression.[48] One would there-
`fore predict that intranasal fluticasone propionate,
`with a much lower bioavailability (26.4% vs less
`than 1%), would have a negligible effect on
`growth.[35,37] Two recent long term studies (<3
`that budesonide 200μg[49] and
`years) suggest
`400μg[50] daily for asthma had little long term ef-
`fect after transient slowing of growth at 1 year, and
`patients even obtained normal predicted height.[51]
`Children participating in growth studies were
`mostly between 5 and 11 years of age, although
`prepubescent children up to 16 years were included
`in some studies.
`These studies suggest that intranasal corticoste-
`roids with high bioavailability can cause short term
`growth inhibition when used for less than 6 months
`(e.g. budesonide 200μg twice daily),[47] or when
`used on a long term basis (e.g. beclomethasone di-
`propionate twice daily for ≥12 months).[42] There-
`fore, systemic adverse effects may be minimised
`by using the lowest effective dose, and administra-
`tion in the morning, particularly with intranasal
`corticosteroids having the lowest bioavailability.
`Finally, it should be emphasised that combining
`intranasal corticosteroids for AR with inhaled cor-
`ticosteroids for bronchial asthma can increase the
`bioavailability of the corticosteroid and, therefore,
`the risk of systemic adverse effects.
`
`© Adis International Limited. All rights reserved.
`
`BioDrugs 2001; 15 (7)
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`

`Anti-Allergy Drugs for Young Children
`
`461
`
`4.4 Mast Cell Stabilisers
`
`Mast cell stabilisers such sodium cromoglycate
`are less potent than intranasal corticosteroids, but
`can be useful in relieving nasal itching, rhinor-
`rhoea and sneezing in patients with primarily
`SAR.[51] They are approved for children 6 years of
`age and older, but are well tolerated in even youn-
`ger children.[52] Because of the short duration of
`action of these agents, however, they need to be
`administered 4 times a day to be effective, thus
`reducing compliance in most families. The effect
`of mast cell stabilisers can generally be seen within
`4 to 7 days, but may take 2 weeks for more refrac-
`tory cases. These agents are currently available
`over the counter. No clinically significant adverse
`effects are associated with these agents, which
`could make them more attractive in children.
`
`4.5 Anticholinergic Agents
`
`Cholinergic stimulation of the nose can lead to
`diffuse rhinorrhoea. This can be prevented or re-
`duced with the use of the topical anticholinergic
`agent ipratropium bromide, which has been shown
`to be effective in children with rhinorrhoea second-
`ary to SAR.[53] The recommended dosage of 0.03%
`solution is 2 sprays in each nostril twice to 3 times
`daily for children 6 years of age and older. Ipra-
`tropium bromide works quickly and can be used as
`needed. Adverse effects include dryness of the
`mouth, which can occur in up to 25% of patients,
`and a bitter taste.
`
`5. Conclusions and Recommendations
`Pharmacotherapy for AR in children should be
`based on the severity and persistence of symptoms.
`In a fashion similar to that in bronchial asthma, one
`can use a step-up programme in cases ranging from
`mild to severe AR.
`For patients with mild, intermittent symptoms
`that last from hours to a few days, an oral second-
`generation antihistamine on an as-needed basis
`might be tried. If nasal congestion is a major factor,
`pseudoephedrine can be added to the nonsedating
`antihistamine since there are no nonsedating anti-
`histamine decongestant combinations currently
`available for use in children. Although first-gener-
`
`ation antihistamines are relatively inexpensive and
`effective, sedation and reduced cognitive effects
`preclude their use in most children because these
`effects in