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`Best Practice
`
`Nancy P. Lee
`Edgar R. Arriola
`Drug Information
`Center
`Deparunem of
`Pharmaceutical
`Services
`UClA Medical
`Center
`University of
`Califumia,
`Los Angeles
`Los Angeles, CA
`
`Correspondence ro:
`nlee@medner. ucla.edu
`
`MEDICINE CABINET
`How to treat allergic rhinitis
`
`INTRODUCTION
`Allergic rhinitis is an IgE-mediated inflammatory disease
`of the nasal mucosal membranes characterized mainly by
`sneezing, rhinorrhea, nasal pruritis, and congestion. It is
`the most common form of rhinitis, affecting 20 to 40
`million Americans annually, and it is considered one of
`the most prevalent chronic diseases in the United States.1
`It is also well documented that allergic rhinitis can nega(cid:173)
`tively impact the quality of life and contribute signifi(cid:173)
`cantly to loss of work productivity. 2
`Allergic rhinitis may be categorized as seasonal "hay
`fever" or perennial (when symptoms persist year-round).
`Often, patients may react to multiple allergens and have
`seasonal exacerbation of symptoms in addition to peren(cid:173)
`nial rhinitis. Tree, grass, and weed pollens are common sea(cid:173)
`sonal allergens because they become airborne in large
`concentrations during a particular season of the year.
`Important perennial allergens include house dust mites,
`indoor molds, animal dander, and occupational allergens.
`
`MANAGEMENT OVERVIEW
`Treatment options for allergic rhinitis include allergen
`avoidance, use of pharmacological agents for prevention
`and control of symptoms, and allergen immunotherapy
`for desensitization of patients in whom avoidance strate(cid:173)
`gies and pharmacotherapy have failed to produce a satis(cid:173)
`factory response.
`
`ALLERGEN AVOIDANCE
`Whenever possible, environmental control measures
`should be emphasized as a fundamental part of the treat(cid:173)
`ment plan. For instance, patients with pollen or outdoor
`mold allergies should remain in closed environments
`whenever possible. Patients sensitive to dust mites should
`enclose all mattresses and pillows with allergen-proof cas(cid:173)
`ings and eliminate carpeting, if possible, to reduce expo(cid:173)
`sure; bedclothes should be frequently laundered in hot
`water to remove allergens. Although not always feasible,
`patients with animal allergies should consider removal of
`pets from home.
`
`Antihistamines, however, are generally not effective in
`alleviating nasal congestion.
`
`First-generation antihistamines
`Various 1st-generation antihistamines are widely available
`with and without prescription. Although effective and eco(cid:173)
`nomical, the usefulness of these agents is limited by their
`sedative and anticholinergic properties due to penetration of
`the central nervous system and poor receptor specificity.
`All 1st-generation antihistamines are sedating to
`some degree and may cause performance impairment
`in 1 Oo/o to 40% of users. 3.4 In general, the ethanolamines
`(e.g., diphenhydramine) and phenothiazines (e.g.,
`promethazine) are the most sedating. The ethylenedi(cid:173)
`amines (e.g., pyrilamine) cause moderate sedation, and
`the alkylamines (e.g., chlorpheniramine, brompheni(cid:173)
`ramine) are considered the least sedating. The use of
`1st-generation antihistamines at bedtime, which are less
`expensive, and newer nonsedating agents during the
`day has been advocated as a cost-saving strategy. This
`therapeutic approach may not be cost-effective, how(cid:173)
`ever, as residual effects of the bedtime dose may result
`in daytime sedation and performance impairment.1o3
`The anticholinergic effects of 1st-generation antihis(cid:173)
`tamines (dry mucous membranes, urinary retention,
`blurred vision) may preclude their use in cenain patients.
`Elderly patients are especially sensitive to these adverse
`effects. These older agents should be used cautiously in
`patients with narrow angle glaucoma or prostatic hyper(cid:173)
`trophy or in those taking other medications that may
`potentiate these side effects.
`Although 2nd-generation antihistamines are general(cid:173)
`ly prescribed due to ease of dosing and favorable side-effects
`profile, clinicians should be cognizant of available non(cid:173)
`prescription antihistamines, as many patients may be self(cid:173)
`managing with over-the-counter products (see Table 1).
`
`Second-generation antihistamines
`The newer antihistamines are devoid of anticholinergic
`and sedative effects with the exception of cetirizine, which
`
`Antihistamines
`
`Antihistamines (H !-antagonists) are typically prescribed
`as first-line agents for allergic rhinitis. They exert their
`actions by competitively antagonizing histamine at the
`H 1- receptor sites and thereby suppress symptoms attrib(cid:173)
`utable to histamine release, such as sneezing, rhinorrhea,
`nasal itching, conjunctival itching, and lacrimation.
`
`Table 1 Selected 1 st-genn-ation antihistamines
`
`Generic
`Brompheniramine
`
`Brand
`Dimetane, others
`
`Chlorpheniramine
`
`Chlor-Trimeton, others
`
`Clemastine
`Diphenhydramine
`
`Tavist, others
`Benadryl, others
`
`Usual doses
`4 mg q 6-8 hours
`Extended Release: 12mg q 12 hours
`4mg q 6-8 hours
`Extended Release: 12mg q 12 hours
`1.34-2.68mg q 12 hours
`25-somg q 6-8 hours
`
`Note: available OTC, often in combination with various decongestants, analgesics, and antitussives
`
`Volume 17 1 July 1999 WJm 3 1
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`

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`Case 1:14-cv-01453-LPS Document 49-1 Filed 11/30/15 Page 3 of 11 PageID #: 1755
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`Table 2 Second-generation antihistamines
`
`Generic
`
`Brand
`
`Onset
`
`Astemizole
`
`Hismanal
`
`2-5 days
`
`(discontinued June 1999)
`
`T 0
`20-24 h
`(metabolite
`10-20 days)
`
`Usual doses
`1omg po qd
`on empty stomach
`
`Cost per month
`$68.56
`
`Cetirizine
`
`Zyrtec
`
`Within 1 h
`
`7·9 h
`
`5mg-wmg po qd
`
`$55.80
`
`Fexofenadine
`Fexofenadine/
`Pseudoephedrine
`
`Loratadine
`
`Loratadine/
`Pseudoephedrine
`
`Allegra
`
`1h
`
`14·18 h
`
`6omg po bid
`
`Allegra-D
`
`Claritin
`
`Claritin-D 12
`Claritin-D 24
`
`1 to 3 h
`
`12-15 h
`
`1omg po qd
`
`6omg/12omg po bid
`
`5mg/12omg po bid
`wmg/24omg po qd
`
`Azelastine
`
`Astelin
`
`Within 1 h
`
`22-25 h
`
`2 sprays per nostril bid
`
`Cost: based on average wholesale prices (AWP), May 1999
`
`$59-30
`
`$66.71
`
`$65-40
`
`$]3.80
`$72.00
`
`$53-71
`
`Comments
`Avoid concomitant use with
`P450 3A inhibitors &
`proarrhythmogenic agents
`
`Also available in syrup (smg/5ml);
`may cause drowsiness
`
`Active metabolite of
`terfenadine-devoid of
`cardiotoxic risk
`
`Also available in syrup (smg/5ml)
`& rapidly disintegrating tablets
`
`May cause drowsiness
`
`may be mildly sedating in some patients. The low inci(cid:173)
`dence of side effects is attributed to their high selectivity
`for peripheral H 1-receptors and low propensity to cross
`the blood-brain barrier. Three 2nd-generation antihista(cid:173)
`mines for oral administration are currently available in the
`United States: cetirizine, fexofenadine, and loratadine. All
`appear effective in mitigating the symptoms of allergic
`rhinitis. Table 2 lists available agents and dosages.
`Cardiotoxicity associated with astemizole and terfe(cid:173)
`nadine is the most serious side effect associated with the
`2nd-generation antihistamines. Serum accumulation of
`these agents may deleteriously prolong the QT interval.
`Serious ventricular arrhythmias (including Torsades de
`pointes), cardiac arrest, and death have ensued as a result
`of overdoses and concomitant use of medications that
`impair the metabolism of terfenadine and astemizole
`(potent inhibitors of cytochrome P450 3A4 isoenzymes,
`such as erythromycin, clarithromycin, ketoconazole, itra(cid:173)
`conazole, ritonavir, indinavir, fluoxamine). These reac(cid:173)
`tions and interactions have not been associated with the
`currently available agents. (Both terfenadine and astem(cid:173)
`izole have since been voluntarily withdrawn from the US
`market; terfenadine has been replaced with its nonar(cid:173)
`rhythmogenic metabolite, fexofenadine.)
`Azelastine is a new topically administered 2nd-gen(cid:173)
`eration antihistamine that has demonstrated efficacy in
`improving both early- and late-phase symptoms of aller(cid:173)
`gic rhinitis. 5 Symptomatic response may be seen as early
`as 30 minutes after dose. 6 In comparative trials, intranasal
`azelastine appears equally as efficacious as oral antihista(cid:173)
`mines but generally less effective than corticosteroids in
`relieving nasal symptoms.6 The most commonly report(cid:173)
`ed adverse effects are bitter taste, application site irritation,
`and somnolence. Azelastine is administered 2 sprays per
`nostril twice daily.
`
`Decongestants
`
`Nasal congestion is a common complication of allergic
`rhinitis. Congestion resulting from initial allergen expo(cid:173)
`sure is usually limited; generation of other inflammatory
`mediators (e.g., leukotrienes) contributes, however, to
`the prominence of congestion in the late-phase inflam(cid:173)
`matory response period.7•8 Consequently, many patients
`will require a decongestant in addition to antihistamine
`therapy. Decongestants are also useful in clearing nasal
`passages at the onset of intranasal corticosteroid therapy
`to improve drug delivery.
`Decongestants exert their effects by activation of
`alpha-adrenergic receptors in the vascular smooth mus(cid:173)
`cle of the respiratory mucosa, thereby causing vaso(cid:173)
`constriction in the turbinates. Oral formulations such
`as pseudoephedrine and phenylpropanolamine are
`available alone or in combination with various antihis(cid:173)
`tamines. Decongestants may produce unwanted side
`effects, such as excitation of the central nervous sys(cid:173)
`tem (e.g., insomnia, restlessness, agitation), tachycar(cid:173)
`dia, urinary retention, and elevations in blood pressure.
`These agents should be administered cautiously in
`patients with hypertension, hyperthyroidism, diabetes
`mellitus, cardiovascular disease, or urinary obstructive
`diseases.
`Topical decongestants (e.g., oxymetazoline, xylometa(cid:173)
`zoline) can rapidly improve symptoms with minimal sys(cid:173)
`temic effects. However, overuse may lead to the
`development of rhinitis medicamentosa (rebound con(cid:173)
`gestion associated with nasal hyperreactivity, mucosal
`swelling, and tolerance). 9 For this reason, topical decon(cid:173)
`gestants are contraindicated for chronic nasal conges(cid:173)
`tion, and their use should be limited to 3 to 5 days
`of therapy.
`
`32 Wjm Volume 171 July 1999
`
`

`
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`
`Corticosteroids
`
`The use of intranasal corticosteroids is increasingly becom(cid:173)
`ing first-line therapy for many patients with allergic rhini(cid:173)
`tis, especially those with moderate to severe symptoms or
`those with perennial allergic rhinitis in which nasal symp(cid:173)
`toms predominate. 10 Intranasal corticosteroids specifically
`inhibit the allergic inflammatory processes that contribute
`to the late-phase response of nasal congestion. When used
`prophylactically, they can also inhibit the early-phase
`response to allergens.11 Overall, they are effective in reliev(cid:173)
`ing sneezing, nasal itching, rhinorrhea, and congestion.
`Table 3lists available intranasal corticosteroids, along with
`dosing information and comparative costs. In general, these
`agents are considered more cost-effective for use as monother(cid:173)
`apy than 2nd-generation antihistamines. A recent meta(cid:173)
`analysis found intranasal corticosteroids to be more effective
`than oral antihistamines in reducing nasal blockage, nasal dis(cid:173)
`charge, sneezing, nasal itch, posmasal drip, and total nasal
`symptoms.12 No significant difference was detected for nasal
`discomfort, nasal resistance, and eye symptoms. No partic(cid:173)
`ular product has demonstrated clinical superiority; selection
`of drug should be based on factors such as response, ease of
`administration, cost, and formulation.
`Application site irritation {e.g., nasal irritation, burn(cid:173)
`ing, or sneezing after administration) is the most com(cid:173)
`monly encountered side effect. Patients complaining of
`local irritation may be switched to various aqueous for(cid:173)
`mulations. Although rare, mucosal erosion and septal per(cid:173)
`forations have been reported with long-term use. 13 To
`minimize septal irritation, patients should be instructed
`to direct the spray upwards and toward the lateral por(cid:173)
`tion of the nose. Periodic examination of the nasal sep(cid:173)
`tum should be performed.1
`Although systemic effects from intranasal corticos(cid:173)
`teroids at recommended doses are considered minimal,
`there are some concerns regarding long-term exposure.
`
`Reports of posterior subcapsular cataract formation have
`been linked with the use of intranasal or inhaled corti(cid:173)
`costeroids;14 however, more recent prospective trials did
`not reveal evidence of posterior subcapsular cataract for(cid:173)
`mation or elevation in intraocular pressure.15'16
`In 1998, the FDA's advisory committees on pul(cid:173)
`monary and allergy drugs and on metabolic endocrine
`drugs convened to assess data suggesting that intranasal
`corticosteroids may have an effect on growth velocity in
`children. Consequently, a new class labeling for pediatric
`use of inhaled and intranasal corticosteroids was man(cid:173)
`dated. At this time, the long-term significance of growth
`velocity reduction on final adult height is unknown. The
`FDA recommends routine monitoring of growth in pedi(cid:173)
`atric patients using intranasal corticosteroids and titration
`to the lowest effective dose to minimize systemic risks.
`Patient education is essential in ensuring proper use
`and compliance to intranasal corticosteroid therapy.
`Patients should be instructed on instillation techniques
`and informed about the possible delay in symptomatic
`response. Assessment of maximal response may require
`a therapeutic trial of several weeks. The drug should be
`administered regularly on a daily basis, rather than as
`needed for rescue relie£
`For patients with severe disease, the combined use of
`intranasal corticosteroids and antihistamines may be nec(cid:173)
`essary to control symptoms. The use of oral corticosteroids
`should be reserved for patients with severe exacerbations or
`intractable disease due to high risk of systemic adverse effects.
`
`Cromolyn sodium
`
`Cromolyn sodium stabilizes mast cells and thereby pre(cid:173)
`vents the degranulation of chemical mediators upon
`antigen presentation. Intranasal cromolyn ameliorates
`symptoms such as sneezing, rhinorrhea, and nasal pru(cid:173)
`ritis but lacks efficacy for nasal congestion. Cromolyn
`
`Table 3 Intranasal corticostnoids
`
`Generic
`
`Beclomethasone dipropionate
`
`Budesonide
`Flunisolide
`Fluticasone
`Mometasone
`Triamcinolone acetonide
`
`Brand
`Beconase
`Beconase AQ
`Vancenase
`Vancenase AQ
`Vancenase DS
`
`Rhinocort
`Nasarel
`Flonase
`Nason ex
`Nasacort
`Nasacort AQ
`
`Usual dose per nostril
`1·2 sprays bid
`1·2 sprays bid
`1·2 sprays bid
`1·2 sprays bid
`1·2 sprays qd
`
`2 sprays bid or 2·4 sprays qd
`1·2 sprays bid
`1-2 sprays qd
`1-2 sprays qd
`1-2 sprays qd
`1-2 sprays qd
`
`Formulation
`Aerosol
`Aqueous
`Aerosol
`Aqueous
`Aqueous
`
`Aerosol
`Aqueous
`Aqueous
`Aqueous
`Aerosol
`Aqueous
`
`Cost: based on average wholesale prices (AWP), May 1999
`
`Inhalations per bottle Cost per month
`200
`$25.8s·$s1.69
`200
`$26.so·$s3.oo
`200
`$2s.s6·$s1.12
`200
`$34-73"$69-47
`120
`$25.30·$so.s9
`
`200
`200
`120
`120
`100
`120
`
`$21.70·$43-40
`$23.02·$46.03
`$24-94·$49-87
`$24-96·$49-92
`$25.42·$so.83
`$19-39·$38-78
`
`Volume 171 july 1999 W)m 33
`
`

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`Case 1:14-cv-01453-LPS Document 49-1 Filed 11/30/15 Page 5 of 11 PageID #: 1757
`
`is generally less efficacious than intranasal corticos(cid:173)
`teroids.17 Therapy adherence may be problematic, as it
`necessitates frequent dosing (3 to 4 times daily).
`However, cromolyn may be safely administered, even
`to very young children, with negligible side effects.
`Intranasal cromolyn is now available without prescrip(cid:173)
`tion. Patients should be advised to initiate therapy with
`cromolyn before the start of the allergy season or in
`anticipation of allergen exposure.
`
`lpratropium bromide
`
`Ipratropium bromide is a well-tolerated topical anti(cid:173)
`cholinergic agent that is available in a 0.03% nasal for(cid:173)
`mulation. It is indicated for rhinorrhea associated with
`allergic and nonallergic perennial rhinitis. (A 0.06% for(cid:173)
`mulation is approved for rhinorrhea associated with the
`common cold.) This agent quickly and effectively reduces
`nasal hypersecretion but has no effect on other symp(cid:173)
`toms of rhinitis such as sneezing and congestion. The most
`commonly reported adverse effects are nasal dryness and
`epistaxis.18 The recommended dose of intranasal iprat(cid:173)
`ropium bromide is 2 sprays per nostril2 to 3 times daily.
`
`CONCLUSION
`Pharmacotherapy remains the mainstay of management
`in patients with allergic rhinitis. Given the wide selec(cid:173)
`tion of available agents, the ideal regimen should be
`individualized to reflect disease severity and specific symp(cid:173)
`toms. Factors such as the potential for side effects, risk
`for drug interactions, ease of administration, and cost
`should also be considered. Most importantly, patients
`should be routinely followed to assess therapeutic response
`and to monitor for side effects or complications.
`
`References
`I Dykewicz M, Fineman S, Skoner D, et a!. Diagnosis and management
`of rhinitis: complete guidelines of the Joint Task Force on Practice
`Parameters in Allergy, Asthma, and Immunology. American Academy
`of Allergy, Asthma, and Immunology. Ann Allergy Asthma lmmunol
`1998;81(5 pt 2):478-518.
`2 Fineman P. Treatment of allergic rhinitis: effect on occupation produc(cid:173)
`tivity and work force costs. Allergy Asthma Proc 1997;18(2):63-67.
`3 Ferguson B. Cost-effective pharmacotherapy for allergic rhinitis. Oto(cid:173)
`laryngol Clin North Am 1998;31(1):91-110.
`4 Nolen T. Sedative effects of antihistanlines: safety, performance, learn(cid:173)
`ing and quality oflife. Clin Ther 1997;19(1):39-55.
`5 Lieberman P. Management of allergic rhinitis with a combination anti(cid:173)
`histarnine/antiinflarnmatoty agent. J Allergy Clin Immunol
`1999;1 03(Suppl):400-404.
`6 McNeely W, WISeman L. Intranasal azelastine. Drugs 1998 July;
`56(1}:91-114.
`7 Naclerio R. Clinical manifestation of the release of histamine and other
`inflarnmatoty mediators. J Allergy Clin Immunol 1999; I 03(Suppl):
`382-385.
`8 Hadley, J. Evaluation and management of allergic rhinitis. Med Clin of
`North Am 1999;83(1):13-25.
`9 GrafP. Rhinitis medicarnentosa: aspects of pathophysiology and treat(cid:173)
`ment. Allergy 1997;52(Suppl):28-34.
`10 Slater J, Zechnich A, Haxby D. Second-generation antihistanlines: a
`comparative review. Drugs 1999;57(1):331-347.
`II LaForce C. Usc of nasal steroids in managing allergic rhinitis. J Allergy
`Clin lmmunoi1999;103(Suppl}:388-394.
`12 Weiner J, Abramson M, Puy R. Intranasal conicosteroids versus oral
`HI receptor ancagonists in allergic rhinitis: systematic review of ran(cid:173)
`domiscd controlled trials. BMJ 1998;317(7173):1624-1629.
`13 LaForce C, Davis V. Nasal septal perforation with intranasal
`beclomcthasone. J Allergy Clin lmmunol1985;75:186.
`14 Fraunfelder, F, Meyer S. Posterior subcapsular cataracts associated
`with nasal or inhalation conicosteroids. Am J Ophthalmol
`1990; I 09:489-490.
`IS Ozturk F, Yuceturk A, Kun E, et al. Evaluation of intraocular pressure
`and cataract formation following the long-term usc of nasal corticos(cid:173)
`teroids. Ear Nose Throat J 1998;77(1 0}:846-848,850-851.
`16 Howland, W. Fluticasone propionate: topical or systemic effects? Clin
`Exp Allergy 1996; 26(Suppl3}:18-22.
`17 Wdsh P, Stricker W, Chu C, et al. Efficacy of beclomethasone nasal
`solution, flunisolide, and cromolyn in relieving symptoms of ragweed
`allergy. Mayo Clin Proc 1987 ;62: 125-134.
`18 Kaiser HB, Findlay SR. Gcorgitis ]w, et al. The anticholinergic agent,
`ipratropium bromide, is useful in the treatment of rhinorrhea associated
`with perennial allergic rhinitis. Allergy Asthma Proc 1998;19(1}:23-29.
`
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`
`34 Wfm Volume l 71 July l 999
`
`

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`EXHIBIT 2
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`EXHIBIT 2
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`Fourth Edition
`
`Michael
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`es
`
`EDITOR IN
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`MACMILLAN ° USA
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`Webster’s New World” College Dictionary, Fourth Edition
`Copyright © 1999 by Macmillan USA
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`This edition is a major revision of Websterk New World” College Dictionary,
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`
`A Webster’s New World“ Book
`MACMILLAN is a registered trademark of Macmillan USA.
`W'EBSTER’S NEW WORLD DICTIONARY
`is a trademark of Macmillan USA.
`
`Dictionary Editorial Offices:
`New World Dictionaries
`850 Euclid Avenue
`Cleveland, Ohio 44114
`
`Library of Congress Cata.logi.ng—in—Publication Data
`Webster’s New World college dictionaryl Michael Agnes, editor in
`chief. — 4th ed.
`p.
`cm.
`“A Webster’s New World book”—T.p. verso.
`ISBN O-02-863118-8 (thumb-indexed). —— ISBN O-02-86311!)-6 (plain-edged).
`-—— ISBN 0~02-863120—X (leatherkraft). — ISBN 0-02-863471—3 (deluxe).
`1. English language——Dictionaries.
`I. Agnes, Michael.
`II. Title: College dictionary.
`PE1628.W5629 1999
`
`423—dc21
`
`99-21175
`CIP
`
`Manufactured in the United States of America
`12345678910
`9900010203
`
`
`
`

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`administers 2 an executive or official of a business, institution,
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