Advances
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`In Therapy”
`
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`Nnvenil)erz’l)ecenilii-‘r I ‘)9 5
`
`Adding Loratadine to Topical
`Nasal Steroid Therapy
`Improves Moderately
`Severe Seasonal Allergic
`Rhinoconjunctivitis
`
`Michel A. Drouin, M.[).
`William H. Yang, M.D.
`Section of Allergy and Clinical
`Imrnunology
`Ottawa Civic Hospital
`University of Ottawa
`Ottawa, Caiiatla
`Friedrich Horak, M.D.
`HNO University fflinit;
`University of Vienna
`Vienna, Austria
`
`Paul H. van de Heyning, M.D.
`Department of ENT and I lead
`and Neck Surgery
`University Clinic of Antwerp
`Antwerp, Belgium
`Gert H. I-(unlcel, M.D.
`Department of Clinical lriimiinolngy
`and Asthma O.l’.|).
`
`University Clinic Charlotlcnliurp, of
`the Free University of Berlin
`Berlin, Germany
`Charles I. Backhouse, M.D.
`The Medical Centre
`
`East l--lorsiey, Surrey, England
`
`Melvyn R. Danzig, Ph.D.
`Schering-Plough Research Institute
`Kenilworth, New Jersey
`
`ABSTRACT
`
`This Sllitly assessed the efficacy of arltllng the iionserlaiing selective H, anti-
`histamine loratadtne to topical intranasal hecloniethastme tlipmpimiale il-lI,)l‘i
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`ARGENTUM
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`In a double-blind, ran-
`'-u treat patients with seasonal allergic rhinoconjunctivitis ISAR).
`-'.'0iTIlZ('_‘(l, parallel-group trial, I54 patients, ages I8 to ()5, with moderately symptomatic
`'-,At< were treated with inlranasal BDP ll 00 pg in each nostril twice daily] combined with
`ill mg of loratadine or [)l.‘I(.t.?I)() for 7 (lays. Four nasal and four non—nasal symptoms were
`exasluatecl following 3 and 7 days of treatment, and patients recorded daily symptoms and
`oossilile adverse effects in a diary. BDP alone improved the symptoms of SAR; however,
`BDP plus loratadine provided further improvement. Patients treated with BDP plus
`!*:ratar.'line achieved significantly greater t.~"<.()5l relief of hoth nasal and non-nasal symp-
`-oms than those treated with BDP plus placebo. No differences were noted in the
`rtrzitlence or type of adverse effects in the two treatment groups. Loratadine plus topical
`'r~.tranasa| BDP controls S/\R more effectively than does BDP alone, without any increase
`‘rt adverse effects.
`
`Keywords:
`
`antihistamine; topical corticosteroid; loratadine; beclomethasone
`dipropionate; allergic rhinitis
`
`INTRODUCTION
`
`Current pharmacologic management of rhinitis provides less than complete
`relief of symptoms and may be associated with variable degrees of adverse effects.‘
`Because many of the drugs currently available affect different components of the
`allergic response, combinations of drugs with complementary effects can Inaxlmlze
`therapeutic efficacy.
`Loratadine is an orally effective and long-acting antihistamine? It has a high
`1‘filectlVlty for peripheral histamine H, receptors and a low affinity for central
`nervous system H,, cholinergic, or alpha-aclrenergic receptors in vitro or In v1vo.3-‘
`Loratadine does not readily cross the l:Ilood—brain barrier and has an incidence of
`-.r..-dation equal to that of placebo?‘ Loratadine is rapidly absorbed, with P931‘
`"srmcentra tions in serum reached within 2 hours, an effect consistent with its rapid
`onset of action." Loratadine relieves most of the symptoms related to SAR3 and 15 as
`-effective as terfenadine,” astemizole,"“' and cetirizine.”
`The nasal response to allergen challenge can be divided into an early reaction
`‘occurring within minutes of allergen exposure) and a late-phase reaction
`“occurring 4 to 10 hours after allergen challenge in about half of patl€1"lt5)- A
`rec-hailenge reaction may occur with a second exposure to allergen 10 hours after
`the first challenge, resulting in increasecl symptoms and associated physiologic
`effects." Systemic corticosteroids reduce symptoms and mediator release 11"t the late
`and rechallenge phases of the process but have little effect on the early phase.
`lntranasally applied steroids are effective in all three phases of the respOnSe;
`however.‘-"‘ Studies on their mode of action have shown that they reduce the
`number of eosinophils, the presence of eosinophil cationic protein, and the number
`of mast-cell progenitors in the nasal mucosa.‘
`Topical steroids, including BDI‘, flunisolide, budesonide, triamcinolone acetonide.»
`flu ticasone propionate, and mornetasone furoate, are efficacious agents for all the
`nasal symptoms of SAR.‘ HI‘reCept()r antagonists relieve the ocular symptoms that
`
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`accompany SAR‘5“'“ and help prevent and relieve sneezing, nasal itching, and
`rhinorrhea; however, they do not relieve nasal blockage.” In a recent report,
`Frolund‘-‘l’ compared the effects of loratadine with those of intranasal BDP and
`concluded that although both medications were effective in patients with SAR, the
`two drugs controlled different symptoms. Patients treated with BDP had signifi-
`cantly less nasal blockage; those treated with loratadine had more relief of ocular
`symptoms. This study attempts to determine whether combination treatment with
`BDP and loratadine maximizes clinical efficacy.
`
`PATIENTS
`
`Five medical centers participated in this double—blind, randomized, parallel-
`group study designed to determine the efficacy of adding 1 week of loratadine
`treatment to therapy with topical nasal steroids to alleviate the signs and svmp-
`toms of SAR. The centers were located in Austria, Belgium, Canada, Germany, and
`England. An institutional review committee at each center approved the studv
`protocol and statement of informed consent, and each study participant gave
`written informed consent.
`
`Study Design
`
`Outpatients between 18 and 65 years of age with a history of moderately severe
`SAR were admitted to the study. IgE-mediated hypersensitivity was confirmed by a
`positive skin prick or an intradermal test with relevant seasonal allergens.
`'
`Patients were excluded from the study if they were pregnant, lactating, or not
`using medically accepted birth control; had severe asthma or chronic obstructive
`pulmonary disease; had nasal polyps or significant nasal structural abnormalities;
`or had any significant current disease that might interfere with treatment evalua-
`tion. Anyone undergoing immunotherapy with pollen extracts must have been
`receiving a stable dose for at least 1 month before beginning the study.
`Before dosage, patients were required to stop taking oral antihistamines {for
`48 hours, except astemizole for 1 month), oral decongestants (for 24 hours},
`systemic and orally inhaled steroids (for 1 month), nasally inhaled steroids (for
`72 hours), cromolyn sodium (for 1 week), and topical decongestants (for 24 hours}.
`Before beginning the study, patients had to have at least moderately severe SAR
`symptoms. They were evaluated for nasal, ocular, and ear/palate symptoms
`according to the following rating scale: 0 = none (not visible to physician or patient);
`1 = mild (noticed by physician or patient or both but not disturbing); 2 = moderate
`(definitely present and disturbing to the patient some of the time); and 3 : severe
`(very disturbing most of the time). Nasal symptoms evaluated included rhinorrhea,
`stuffiness, itching, and sneezing. Ocular symptoms evaluated were itching, tearing,
`and redness. Ear/palate itching was also assessed. To be included in the study,
`patients had to demonstrate a nasal score of at least 6 (including nasal discharge and
`one other nasal symptom of moderate severity) and an ocular score of at least 5.
`Individual symptoms were summed, creating nasal, ocular, and total scores.
`Patients were randomly assigned to treatment with either intranasal BDP plus
`loratadine or intranasal BDP plus placebo. Patients were instructed to take one
`
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`-_;.}_»,]ef of loratadine I ll} mg) or matched placebo daily in the morning and two sprays
`=4, 1.1;;/spray) of BDI’ in each nostril every morning and evening for 7 days. All
`fltjents kept a daily diary of symptom severity and adverse effects between visits.
`after 3 and 7 days of treatrnent, patients were evaluated by the investigator. In
`_.._1,_1jtion to scoring individual symptoms at each visit, the patient and physician
`:-:.adL‘ an overall global assessment of response to treatment on day 7 (or on the last
`_; -“'.r of treatment if a patient discontinued earlier than day 7), using a rating scale 0f1
`-., 5 fl , excellent; 5, treatment failure). Adverse events were also elicited.
`
`I-rittstical /limlysis
`
`C,'0ntinLIous demographic variables (age, weight, duration of condition, and
`:._[ration of episode) were evaluated by means of a two-way analysis of variance
`-:r|r_;dL‘l_ I-’isher’_=; Exact Test was used to assess the comparability of sex and race. A
`-_-_.,u_rway analysis of variance was used to analyze total symptom scores, which
`H-i_.-re confirmed with the Wilcoxon rank-sum test. The incidence of adverse events
`i,-_» ,tal and specific) was analyzed with Fisher’s Exact Test.
`
`RESULTS
`
`The study enrolled "I56 patients. One patient from each group was dropped from
`‘Ine Study For Failure to return for follow-up evaluation after the initial visit. Table 1
`.i~.‘es the clemographic information for the two study groups. Race, age. W_€1S1}t_: and
`:..a=,L*line total symptom scores were comparable (172.27). Sex had slgnlflfaflf
`f."-'fJ:‘Iih“lC'I"lt-by-C€ntL’I'
`interaction (P = .[}3) but was determined to have no malor
`_-mpdct on overall efficacy comparisons.
`
`Table 1. Demographic Information
`
`|
`
`
`
`Loratadine + BDP Placebo + BDP_
`
`.o. of palients
`iwr
`
`.".-"ill! age, y
`
`,-'.r»;iii wt-iglit, kg
`
`.1r»,:n rlurution of SAR, y
`
`76
`43x33
`
`31
`
`70
`
`9
`
`78
`33549
`
`32
`
`63
`
`12
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`4
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`Efficacy
`
`In general, patients treated with loratadine plus BDP showed greater clinical
`improvement in most symptoms of SAR than those treated with placebo plus BDI‘
`(Table 2).
`
`Table 2.
`
`Improvement in Symptom Scores at Days 3 and 7
`
`Evaluation
`
`Day
`
`Loratadine +
`Placebo +
`
`BDP, %
`BDP, “/1
`P Value
`
`Total symptom score
`
`Total nasal score
`
`Nasal discharge
`
`Nasal stuffiness
`
`Nasal itching
`
`Sneezing
`
`Total ocular score
`
`|{L-hing
`
`Tearing
`
`Redness
`
`Earfpalate itching
`
`NS = not significant.
`
`3
`7
`
`3
`7
`
`3
`7
`3
`7
`
`3
`7
`
`3
`7
`
`3
`7
`
`3
`7
`
`3
`7
`-3
`7
`
`3
`7
`
`S4
`68
`
`55
`6f:
`
`58
`()7
`43
`62
`
`61
`72
`
`57
`67
`
`53
`70
`
`48
`65
`
`56
`72
`53
`73
`
`60
`80
`
`46
`58
`
`48
`'39
`
`52
`(:5
`40
`55
`
`48
`02
`
`46
`5‘)
`
`45
`57
`
`39
`S2
`
`52
`6|
`46
`54
`
`38
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`NS
`NS
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`
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`
`Patients receiving loratadine plus BDP showed significantly greater improve-
`ment in total symptom score at day 7 (Fig 1), total nasal score at day 3, and total
`ocular more at day 7 (P<.05). Greater improvement with loratacline plus BDP was
`also noted in several individual symptoms. These included less nasal itching on
`days 3 and 7, less sneezing on day 3, less eye itching and tearing on day 7 (P<.t)5),
`and decreased eye redness on day 7 (P = .07). The two groups did not differ" in
`effects on nasal discharge or nasal stuffiness.
`
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`Fig 1. Total symptom score.
`
`I
`
`|
`
`30
`
`D Placebo + BDP
`E] Loratadina + BDP
`
`
`
`‘ii;Improvement
`
`50
`
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`
`20
`
`Evaluation Day
`
`'Pv'.iI-'i.
`
`The last non-nasal score, ear/palate itching, was considerably different between
`zine two groups at both evaluation clays {P-<.{J5). At day 7, this symptom had
`i."-ciproved 80% in the loratadine plus BDP group, compared with 50% in the
`placebo plus BDP group.
`Figs 2 and 3 illustrate the physicians’ and patients’ global evaluation at the
`-_-mlpoint of the study. Physician evaluation showed that 84% of patients in the
`mratadine plus BDI’ group had a good to excellent response, compared with 71% of
`_;-ieitients in the placebo plus BDP group (l’<.[}5). In ‘the loratadine plus BDP group
`‘:4"’£. of patients had an excellent response, compared with only 17% in the placebo
`plus BDP group. Similarly, patient evaluation showed that 90% of pilfiflnfs in the
`I-uratadine plus BDP group had a good to excellent response, compared with 73% of
`‘hose receiving placebo plus BDP (P<.{}5). Again, the percentage of patients who
`'a ted the treatment effect as excellent was substantially greater in the loratadine
`plus BDI’ group than in the placebo plus BDP group (39% vs 19%, respectively)-
`
`3 rzfiei_1;
`
`Both groups reported similar incidence and types of adverse effects (Table 3).
`i'x.renty~three (3[)"/.,) patients in the loratadine plus BDP group and 20 (26%) patients
`.n the placebo plus BDI’ group reported treatment-related adverse events. Somn0l~
`-':nr_'e was reported by 4 (5%) patients receiving loratadine and 5 (6%) patients
`rr-ceiving placebo. No patient dropped out of the study because of adverse effects.
`
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`Fig 2. Physicians’ global evaluation at endpoint.‘
`
`Loraladine + BDP
`
`Placebo + BDP
`
`Excellent
`34%
`
`Poor + Failure
`5%
`
`Good
`54%
`
`Excellent
`
`W9”
`Poor -+- Fa1iJu:--
`59;,
`
`Fair
`24%
`
`Good
`50%
`
`Fair
`11%
`
`'Pr..i]5 iur (_'(ir'np.irisi)n.
`
`i Fig 3. Patients’ global evaluation at endpoint.‘
`
`Loratadine + BDP
`
`Placebo + BDP
`
`Good
`51%
`
`Excellent
`39%
`
`Good
`54%
`
`I
`Poor+ Failure
`
`7%
`
`Fair
`3%
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`N,,_ (0/0) of Patients
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`
`DISCUSSION
`
`Although some authors have found no difference in effectivenesS,'7'2' smdlet 1“
`--'l'i‘-‘ll an intranasal corticosteroid has been directly compared with a nonsedating
`-""“l‘l-Slilmine have generally shown that steroid nasal sP1‘3Y5 Control nalsal Symptoms
`"'i'rr<.' effectively.1‘-‘"3’-3*" Clinically, patients respond differently following tr9a”‘.“"“‘
`"'l all‘-‘U%lC rhinitis with antihistamines or intranasal steroids. AI"ll:il'liSta1'mI‘lE5 1‘El1~‘3-V9
`:"“"m”5* 5““*‘7-int-l» rhinorrhea, and ocular symptoms but do not control nasal 9t‘,1ff_
`or.-s_s. lntranasal steroids can attenuate all nasal symptoms but are most Pffectlve
`'-"-»’,*lm'~'|'f stuffiness and rhinorrhea. Thus, treatment that combines an antihistarnme
`---‘I’-l
`ti steroid nasal spray may maximize clinical efficacy.
`l5c"iCkhouse and colleagues?" found that terfenadine reduced SAR syITlPl°m§ but
`'l'“l lerfenadine plus flunisolide nasal spray relieved sympl0m5 U101’? effeCtf"'?l_Y
`'53!“ did terfenadine alone. Wihl et al3“ showed that astemizole iII1Pr°Ved fimllms
`L-'mI£>toms but that astemizole plus BDP nasal spray was more effective. _I_Ul'l1P91'
`5'1"" Showed that sneezing. nasal obstruction, and rhinorrhea were significantly
`--'“Pl0VeLl in patients taking only BDI’ over those taking only astemizolei BDP Plus
`'=--l-'0rni2:ole did not control rhinitis better than did BDP alone. Individuals taking
`'
`'-»l'.‘mizole alone or with BDP had fewer ocular symptoms and used fewer eye
`._{r”_P‘*' than those taking BDI’ alone; eye symptoms were best controlled when
`E”-ll|'.*nts took both medications.
`This study demonstrates that the addition of an antihistamine to topical Ultra"
`.'-asgil steroid therapy improved the control of most SAR symptoms. l-Ofaladme Plus
`: tranasal BDP improved the symptoms of moderately severe SAR t0 3 great?‘
`'l"3§ree than did BDI’ plus placebo. Patients had significantly improved responses In
`wtal symptom score as well as in overall nasal and ear/palate itching scores when
`we two agents were combined. The addition of loratadine also improved ocular
`jrmptoms. This is not surprising, as nasally administered steroids, because Of their
`
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`localized site of action, cannot be expected to provide control of conjunctivitis, even
`if some studies of intranasal steroids have revealed partial relief of eye symptoms.--"~
`Patients using BDP plus loratadine had increased symptomatic control of SAR but
`had no more adverse effects than did patients using only BDP.
`
`CONCLUSION
`
`Oral loratadine added to intranasal BDP improves the treatment of patients with
`SAR. Each drug apparently compensates for the other’s shortcomings and enhances
`therapeutic outcome without producing any limiting adverse effects.
`
`REFERENCES
`
`1. Naclerio RM. Allergic rhinitis. N‘ Engl J Med. 1991;325:860-869.
`
`2. Clissold SP, Sorkin EM, Goa Kl... Loratadine: a preliminary review of its pliarmacodynamic
`properties and therapeutic efficacy. Drugs. 1989,'37:42-57.
`
`3. Aim HS, Barnett A. Selective displacement of 3! I-mepyrarnine from peripheral versus central
`nervous system receptors by loratadine, a nonsedating antihistamine. Eur ,I' Plmm.-mrnl. 1980;
`127:153-155.
`
`4. Bamett A, lorio LC, Kreutner W, et al. Evaluation of the CNS properties of SCH 2985'], a
`potential non-sedating antihistamine. /tgcrits Actions. 1984;14:590-597.
`
`5. Van Cauwenberge PB. New data on the safety of loratadine. Drug lm:es.‘. l992;4:283-29].
`
`6. Hilbert J, Radwanski E, Weglein R, et a1. Pharmacokinetics and dose proportionality of
`loratadine. I Clin Plmrnmcol. 1987;27:694-698.
`
`Gutkowski A, Bedard R De] Carpio], et al. Comparison of the efficacy and safety of loratatline.
`terfenadine and placebo in the treatment of seasonal allergic rhinitis. I Allergy Clin lrimnmol.
`1988;81:9D2—907.
`
`Banov CH. Comparative efficacy of once daily lorataclinc versus terfenadine in the treatment of
`allergic rhinitis. J Int Med Res. 1989;17:15t)—l 56.
`
`D€lCa1'1350L Kabbafih L. TUFEUHB Y, 95 al. Efficacy and safety of loratadine (10 mg once dai|_v),
`terfenadine (60 mg twice dailY), and placebo in the treatment of seasonal allergic rhinitis.
`J Allergy Clin lnmmiml. 1989;84:741-746.
`
`10.
`
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