Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. legcriii,weesams afo h colaepplto ssniie ooeo oecommon more decades or last the one in to trend upward sensitized steady is a following population rise school-age to H the expected are of numbers half these and almost families allergens, burdens whereas their socioeconomic considerable rhinitis, and have children and allergic worldwide the children of both number for large a affect conditions Allergic RCTs, head-to-head of paucity Introduction the duration. firm to follow-up draw short due not and AHs could AEs, newer-generation we Our of However, the reporting Conclusion: of profile. and mild tolerability AHs. definitions profile of in newer-generation and safety variation were safety other comparative favorable reported the the in a AEs than regarding have AEs Most sedating AHs conclusions serious RCTs. more newer-generation between reported is that varied RCTs cetirizine confirm Four AEs that occurrence findings to The month. indicates due AE. evidence a discontinuations serious Indirect to treatment drug-related possibly and up intensity. a AEs of experienced drug-related included patients period RCTs two AEs, of follow-up only of majority but a The AH, had newer-generation criteria. a and risk eligibility receiving Cochrane’s met rhinitis patients 2017 the allergic and using 1989 RCTs with between included children published the RCTs school-aged Fourty-five of quality Results: a methodological events tool. the adverse bias performed interventions, assessed aged[?]12 of population, We children and study orally discontinuations, in on an treatment data placebo Methods: extracted and between or independently montelukast (AEs) parameters CENTRAL, scrutiny. generation), safety and second- MEDLINE need of or searched We (first- to comparisons still AH years. included compared population another which effects with (RCTs) pediatric adverse AH trials commonly newer-generation the fewer controlled administered most with in randomized the associated harms of of are review one relative AHs systematic being their Newer-generation diseases, However, allergic Pediatrics. of in treatment first-generation. medications the of for classes used widely prescribed are (AHs) H1-antihistamines Background: Abstract 2020 1, December 4 3 2 1 Mavroeidi Miligkos Michael in review events systematic adverse a of children: risk the and antihistamines Newer-generation rsrbdcasso eiain ntepdarcpopulation pediatric the in medications of classes prescribed des ffcscmae ofis-eeainathsaie u oterhge eetvt o h H1-receptor the for fewer selectivity with higher associated their generally to are due antihistamines antihistamines Newer-generation first-generation paucity to children. relative compared in the effects despite use adverse worldwide their practice regarding clinical data in used of widely still lacrimal secretion are and antihistamines salivary induced First-generation the histamine in and the constriction decreasing available their by preventing by tissues tissues gland muscle smooth vascular and testinal ainl&Kpdsra nvriyo Athens of University Kapodistrian & National University Monmouth Doctors Junior of Society Hospital Children’s Sofia Agia 1 athsaie r ieyue o h ramn falri iess en n ftems commonly most the of one being diseases, allergic of treatment the for used widely are -antihistamines 5 n hyaegnrlysbiie notogop:fis-adnwrgnrto antihistamines. newer-generation and first- groups: two into subdivided generally are they and 2 an Pankozidou oanna , 1 ai Dakoutrou Maria , 2 rn Papaconstadopoulos Irene , 1 ti siae htapoiaey4%o hlrnsffrfrom suffer children of 40% approximately that estimated is It . 1 ln Statha Eleni , 1 3 2 4 hymil c ntersiaoy gastroin- respiratory, the in act mainly They . ioet Theochari Nikoletta , oeta 5athsaie r currently are antihistamines 45 than More . 3 n ioasPapadopoulos Nikolaos and , 2 lkr Antonia Ilektra , 1,2 . 4 Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. 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Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. etwr o lal eotdi otRT.AlbttoRT eotddul-lnig h te RCTs other The double-blinding. reported RCTs two conceal- but allocation All and RCTs. sequence most randomized open-label in a were of reported Generation among clearly varied not assessment. bias were treatment of ment of years risk our duration 6-11 summarizes The children month. 2 Table in a old. > bias OD than children years of less mg for 2-12 risk lasted 2.5 OD at children of studies 5mg and administered for Assessment of and old was OD kg majority years mg Desloratadine 10-25 The 1-5 children 10 weeks). children for age. was (1-72 OD in The dose on studies mg OD Bilastine based old. 2.5 mg months OD, i.e., kg. 6-11 1.25 weight-based, mg 25 children was infants, children 60 for dosing in for OD to Rupatadine (BD) OD mg mg daily old. 1mg children 1.25 twice 15 in of and mg OD from old dose 1.25 5 dosing mg years old, ranged a to Loratadine 10 1-2 years fexofenadine and 2.5 children 6-12 old. 30kg of children old, for years for OD years [?] 6-12 dose OD 0.125mg/kg children children 2 mg in old, for than 5 years OD OD less was mg 1-5 mg children dose (5 10 Levocetirizine for studies and daily 30kg). included old > twice the years in mg/kg 2-6 weight-based 0.2 children generally was for was (OD) cetirizine daily of once dose mg the studies most In orRT eotdsrosavreeet nptet eevn newer-generation (AST increase 10-fold a a RCTs observed discontinuation. head-to-head treatment investigators in study receiving after antihistamines the month to Newer-generation a cetirizine, normal according of patients to returned infections, initiation levels the subclinical transaminases UI/ml) in after >1000 with ALT weeks associated and 5 events asymptomatic be and mild experienced levels also he and could adverse days 14 which authors for BD) neutropenia, (30mg serious fexofenadine transient received patient first The reported event. events adverse serious not RCTs antihistamine of did occurrence RCTs the Four regarding Four data 3. provided Table RCTs in Thirteen shown are events RCT adverse each Serious in events adverse events regarding adverse data with numerical patients provide of proportions The tolerability and days events 7 Adverse of period washout a had RCT con- with patients studies of inclusion 10 studies reported in studies ten loratadine and medications asthma concomitant comitant regarding evidence any publications seven and urticaria rhinitis children iopathic allergic school-aged was antihistamines included years of 15 studies use to months-old months Most 6 [?]24 2017. predominance. children children included - male RCTs included 1989 The overall USA. between an and published Europe with were in old conducted that were studies studies of included majority the The of characteristics the summarizes 1 Table each trials 109 publications controlled and separate irrelevant, randomized characteristics two as 45 in Study 2249 included reported excluded we data we Finally, with citations, review. RCTs 2358 two full-text were screened for We retrieved yield. were search articles our summarizes 1 Figure search Literature Results 23,24,33,41 33 h eodptet 4mnhodtdlr a lgtyeeae aeietransaminases baseline elevated slightly had toddler, 14-month-old a patient, second The . 15,25,33,43&44 18 elrtdn n4studies 4 in desloratadine , 16,17,28,33,34,40,47,52-54 15,20,30,35,38,42 n investigator-blinded and 43&44 14,18,31,37,39,42,46-47,59 u nytoptet xeine osbydu-eae eiu adverse serious drug-related possibly a experienced patients two only but , h ode eandaypoai hogottesuypro n the and period study the throughout asymptomatic remained toddler The . n tpcdermatitis atopic and 20,25,27,31,35,43&44 34 eiiiewsamnsee n2 studies 22 in administered was Cetirizine . . 31,5 17-21„23,24,26,28-30,32-36,39-42,45-52,55-58 13,14,15, 13,16,27,30 59 n C a ieeta ost follow-up to loss differential had RCT One . eoeiiiei studies 6 in levocetirizine , 13,22,48&49,53 h otfeun yeo odto htrqie the required that condition of type frequent most The . uaaiei studies 2 in rupatadine , 25,35,37,43,44,54 3 . h aoiyo tde i o provide not did studies of majority The . 43&44,48&49 19-21,25,28,29 16,17 . 14,15,19,21,25-29,32,33,36,43&44 n iatn n1study 1 in bilastine and 14,21,26,32,34-36,38,40,45,47-58 olwdb hoi id- chronic by followed , eoeaiei 4 in fexofenadine , 24 n crossover One . 13-59 There . 15 . , . Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. niitmns ncnrs,teohrnwrgnrto niitmnsddntapa oesdtn than first-generation sedating more and appear cetirizine not with did treated antihistamines newer-generation patients placebo note, other between the Of the in observed patients contrast, with infections. was In compared tract difference cetirizine antihistamines. reported respiratory the no frequently somnolence, in upper whereas patients most specifically by and groups, The reported and diarrhea frequently symptoms more vomiting, 4. was Table respiratory pain, somnolence in and abdominal summarized gastrointestinal insomnia, are neurological, headache, RCTs minor included included the AEs in group reported age events month- Adverse 9-11 the than events month- adverse 6-8 years the reported 1-5 However, in aged Commonly children frequent 3). to more (Table compared groups generally AE were placebo an AEs experience and to cetirizine-related treatment likely active and more the were between levocetirizine AEs received who with infants patients of proportion the in old RCTs. years both RCTs 2 in Seven treatment [?] discontinued children patient in No RCTs antihistamines reported. small Newer-generation were two AEs of in occurrence montelukast the with regarding compared first was the groups. Cetirizine to both compared in treatment chlor- group discontinued antihistamines ketotifen, antihistamines patients newer-generation Newer-generation few oxatomide, the a i.e., Only in lower antihistamine, group. slightly antihistamines generation generation were first AEs a with cyproheptadine patients with and newer dexchlorphenamine a phenamine, compared AEs studies drug-related Seven AEs, of frequency the antihistamines in Newer-generation placebo and bilastine between difference discontinuations no frequentlyor study was less one occurred there AEs in RCT, studies drug-related one group however two similar, in rupatadine were placebo the AEs with with in patients compared of was proportions Rupatadine the studies, treatment. discontinued patients of 1% use RCT the largest compared between studies the studies In similar four Three placebo were discontinuations. in with treatment discontinuations desloratadine or placebo of treatment AEs with regarding or difference compared significant AEs was clinically or (drug-related) Fexofenadine AEs RCTs with six (drug-related) in patients with groups. in compared patients of were AEs size of placebo proportions and to proportion sample Levocetirizine The due the RCTs AEs. large treatment in seven to discontinued groups due a in discontinuations patient between placebo treatment with differences no with RCTs significant RCTs compared clinically eight in was no in Loratadine patients and groups. included treatment placebo the both to comparable of adverse drug-related was 5% regarding cetirizine information than provided RCTs less compared the in was of Half Cetirizine groups. varied. both events AEs in with similar RCTs patients generally was 16 of in proportions placebo the with trials, placebo-controlled all regarding Across reported were small data a no antihistamines in desloratadine; Newer-generation compared on patients also received to were who compared discontinuations loratadine patients treatment AEs and more (drug-related) However, Cetirizine fewer rienced groups. AEs. loratadine to and due RCT cetirizine treatment in discontinued similar were loratadine rates AEs antihistamines newer-generation related) compared directly RCTs five Only 47 14,26,35,40,43&44,54,56,57 opteteprecdadu-eae Eo icniudtetet ainso uaaieexpe- rupatadine on Patients treatment. discontinued or AE drug-related a experienced patient no ; 20,23,25,27,31,35,43&44 15 27 . oeptet ntedsoaaiegopeprecddu-eae E,btls than less but AEs, drug-related experienced group desloratadine the in patients more , 14,21,26,32,34-36,40,43&44,48&49,50,53,54,56-58 16 rgrltdAsocre nsmlrfeunisi ramn rusand groups treatment in frequencies similar in occurred AEs Drug-related . . 16,27,30 nlddifns(?6mnh l)o on odes hr a odifference no was There toddlers. young or old) months ([?]6 infants included n eotdsihl oe ae favreeet ntepaeogroup. placebo the in events adverse of rates lower slightly reported and 16 vs. vs. vs. odt eeaalbergrigtetetdsotnain.In discontinuations. treatment regarding available were data No . te drugs other antihistamines generation first placebo 18,22,36,38,51,52,59 4 vrl,teocrec favreevents adverse of occurrence the Overall, . 26,32 14,17,22,45,47 23,24,33,41 cosalRT,tepootosof proportions the RCTs, all Across . ociial ennfldifferences meaningful clinically No . oeo hmrpre any reported them of None . nalreRCT large a In . 14,43&44 14,22,31,37,39,42,46 h oeaiiyof tolerability The . 19,21,23,25,28,29 16,17 14 hr were There . h (drug- the , nboth In . 35 20 . . Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. n eoeiiiesol eamnsee wc al o piu ocnrto npam,wihmyaffect preference, may taste which fexofenadine plasma, as cetirizine, in example, such concentration For optimum antihistamine, overdosing. for of desired daily cases twice the in administered adults safety of be affect and should selection not dose levocetirizine may of the and volume that in doses, factors the of other consideration to number pediatrics, due into daily draw in antihistamines taken not importance findings newer-generation be could clinical the Our we Of should of However, RCTs. profile children. profile.. head-to-head safety tolerability of in comparative and paucity the antihistamines safety regarding favorable newer-generation a conclusions of have firm medications use data. different these the the with that of investigates patients suggest synthesis review in quantitative the antihistamines systematic (e.g., to precluded of heterogeneity This tools) ability administration methodological validated our AEs, and of restricted of use clinical have limited observed monitoring may diseases, the and Finally, performance definitions psychomotor in interest. measure or and variation clinical objectively schemes alertness which of up-dosing limit RCTs, on use, differences single-dose period, off-label antihistamines of detect follow-up of exclusion of longer the reports may effect hand, (e.g., a other which findings the have the our studies and On of non-interventional circumstances generalizability administration). of the long-term review certain exclusion increase systematic in the to present practice ability evidence, the our clinical available in everyday the only reflect a of RCTs serious of better level of tolerability absence of inclusion highest and the definition safety the the note, relative A Although provides the Of for cards. reported. antihistamines. evidence indirect not newer-generation diary only generally and of provides or RCTs were period visits head-to-head medications follow-up of trial concomitant number short therefore on sufficient at a and data interviews had parameters RCTs and either safety events of assess adverse through majority to At AEs, The designed patient-reported undertaken. results. primarily the were used not interpreting comparisons when were statistical RCTs considered the formal most be no in to level, need reported trial which frequently individual limitations, more the several were has review newer-generation AEs systematic a these Our either AEs, with of treated occurrence years group. 2 the age ad- younger In reported [?] aged placebo placebo. antihistamines; patients and or there newer-generation of antihistamines antihistamine RCTs, whereas newer-generation other proportions head-to-head remaining patients, comparable the the of although placebo-treated than between more dition, paucity observed than sedating were was the frequently difference more levocetirizine more to such is and no somnolence due cetirizine cetirizine study, experienced that patients our both evidence cetirizine-treated In and indirect antihis- placebo desloratadine. only newer-generation to or is that compared loratadine suggested differences sedation adults than relevant more in sedating clinically studies in no included resulted with the children, tamines However, in concluded events. They tolerated adverse well urticaria. regarding or were rhinitis antihistamines allergic with antihistamines newer-generation children and of that adults type in trials latter non-interventional or the controlled with associated colleagues impairment and performance and sedation avoid hntsadisIpc nAtm AI)gopadteGoa leg n shaErpa Network European Asthma and Allergic Allergy the Global (EAACI), the Immunology and Clinical group such and (ARIA) guidelines Allergy Asthma International of on (GA Academy market. Impact European the its the and from most but by Rhinitis withdrawn antihistamines, published antihistamines of intensity. use those and/or mild the of as adults regarding were evidence included RCTs of them the experienced state the in patients of examined two drug- reported have only AEs reviews AEs, Importantly, systematic most of Several and RCTs. occurrence AE of clinically serious the majority no drug-related general, the antihistamines, in possibly in though newer-generation a RCTs, observed between received were varied AEs who differences to old meaningful due discontinuations years treatment and 12 AEs related [?] children In these in proportions Discussion observed RCTs. the included overall the but in groups, groups patients of treatment cetirizine proportions the low the in were levocetirizine, higher or RCTs loratadine slightly with were cetirizine somnolence of RCTs with head-to-head four In placebo. 2 E)rcmedteueo ee-eeainoe rtgnrto niitmnsi natmtto attempt an in antihistamines generation first over newer-generation of use the recommend LEN) 8 14,21,45,47 sesdteecc n am fnwrgnrto niitmnsi edt-ed placebo- head-to-head, in antihistamines newer-generation of harms and efficacy the assessed hr een infiatdffrne eadn E aaeesbtenany between parameters EEG regarding differences significant no were There . 5 60-62 Carson . Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. 1)Pte ,MtaE akiL ee ,Snaai ,IqiroI ta.Rptdn seffec- study. solution placebo-controlled is oral double-blind, Rupatadine Rupatadine randomized, al. et A RA, al. rhinitis: Baillieau I, et allergic Immunol Nemeth years. persistent Allergy I, L, Barkai with 2-11 Izquierdo J, children aged Vermeulen E, in JF, children Maspero Santamaria in P, Potter urticaria G, (17) spontaneous Mezei chronic L, of Barkai treatment munol E, the in Mitha tive P, bilastine Potter of tolerability (16) and diseases. Safety allergic R. with Valiente children M, in weeks Tortajada-Girbes 498. P, 12 Kuna for administered I, mg Kiss 10 A, Yanez rhinitis. Z, Novak allergic (15) seasonal placebo- with a Randomized, children al. in et rhinitis: loratadine KB, Franklin allergic and 2017;38(3):222-230. MK, cetirizine Patel of ER, of Urdaneta symptoms study CF, LaForce controlled acute between WE, Berger with Association AS, Nayak children al. (14) et trial. of JMD, clinical treatment Silva controlled RB, the and Collabo- Amazonas randomized in Cochrane F, double-blind, Sano The prednisolone LF, al. and Ensina et trials. C, desloratadine AD, randomised Miranda Oxman GF, in D, Wandalsen bias (13) Moher of P, risk Juni assessing PC, for Gotzsche tool learning DG, ration’s Altman machine JPT, interactive Higgins an (12) Deploying TA. Trikalinos abstrackr. J, center: Lau (IHI) practice Symposium CE, evidence-based Brodley an in in K, Antihistamines system Small al. et BC, M, Wallace Giudice (11) Del Miraglia update. A, practical Licari A A, 2 adolescents: Corsico G, and differences Update Ciprandi children inter-drug S, of Report Leonardi Review GF, Final Parisi update. (10) an Antihistamines: antihistamines: ratios. and Newer impairment Sedation J. proportional Review: Boyle using L, Class Trick K, Drug McDonald (9) S. Thakurta N, human 2010. Lee the [Internet] of S, Structure Carson al. et (8) V, doxepin. Katritch with of G, complex Risk Winter H, receptor al. Tsujimoto H1 S, et Weyand histamine J, M, Shiroishi Bousquet T, P, Shimamura Cauwenberge (7) paper. van position C, GA(2)LEN Bindslev-Jensen a FE, Simons H(1)-antihistamines: in progress. M, first-generation of Maurer use century MK, Antihistamine Church a HA. (6) celebrating in Brough H1-antihistamines: antihistamines N, and of Shah Histamine Immunol Use G, KJ. Clin Toit Simons FE, du al. Simons W, et (5) Thornhill I, LA, Davila Poel M, der Ferrer van children. I, R, Jauregui Fitzsimons J, man- (4) the Montoro in J, considerations Sastre Safety A, R. pediatrics. Cuvillo Boev AN, Del antihistamines. Pampura (3) on E, focus Paraskakis diseases: K, allergic Chugh of B, MS. agement Rogala Blaiss K, Yanai RF, (2) Lockey GW, Canonica ST, Update Holgate antihistamines. newer-generation R, of counselling Pawankar effects with adverse help and (1) may possible duration patients and sufficient to dosing frequency, important of use, parameters RCTs safety appropriate head-to-head assess on Well-designed parents to instruments (10). validated of dosing use daily with once to compared adherence 2016;27(1):55-61. ol leg raiain(A) 2013. (WAO); Organization Allergy World . rhDsCidEu rc Ed Pract Educ Child Dis Arch netgAlro lnImmunol Clin Allergol Investig J 2011;128(6):1139-1150.e4. 2013;24(2):144-150. 2012:819-824. u Psychopharmacol Hum 2015;100(3):122-131. 071 up 2:28-40. Suppl 2007;17 leglImnpto (Madr) Immunopathol Allergol Nature 6 urMdRsOpin Res Med Curr 2011;475(7354):65-70. rzJOtorhinolaryngol J Braz rco h C nentoa elhInformatics Health International ACM the of Proc BMJ 2008;23(7):555-570. 2011;343:d5928. eit leg Immunol Allergy Pediatr Allergy A ht oko leg 2013 Allergy on Book White WAO 2012;28(4):623-642. 2010;65(4):459-466. 2020;S0301-0546(20)30066-5. . 2017;83(6):633-639. leg shaProc Asthma Allergy eit leg Im- Allergy Pediatr 06 27(5):493- 2016; Allergy J Pediatr Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. 3)SglA,MlzrE,Lce F rne M icelD,TnemnD,e l Once-Daily al. Asthma. et Intermittent without DG, and Tinkelman with DQ, Rhinitis Mitchell Allergic Immunology with BM, & Children Prenner Allergy for RF, Asthma, Effective Pediatric and Lockey Safe EO, Is Treating Meltzer Cetirizine for AT, Montelukast efficacious Segal is and Fexofenadine (34) Cetirizine al. rhinitis. allergic et of seasonal G, with Hedlin Comparison years) P, 6-11 Decosta 769. A (aged ML, children Kowalski Y. in AF,Jr, safe Lin Finn and EO, H, Meltzer U, Sun man- Wahn Study. (33) D, Prophylactic I Lai Preventia Rhinitis. al. K, Allergic the et Perennial Lue Childhood D, infections: J, Adam respiratory Hsieh MP, upper (32) Borres recurrent S, for Bonini risk GW, at children. Allergy Canonica children in ST, of syrup Holgate agement desloratadine A, of Grimfeld Safety (31) J. Herron H, Staudinger 2004;20(12):1959-1965. M, symptoms Bloom on placebo-controlled levocetirizine (30) double-blind, a of rhinitis: safety and allergic and efficacy trial. perennial with Efficacy evidenced clinical children randomized of children: Group. life of in Study quality Levocetirizine Levocetirizine health-related and Paediatric MC. trial. PC, Pujazon rhinitis Potter R, allergic (29) Alt seasonal E, randomized in Billard 6-week Syrup a U, Desloratadine Wahn in of safety J, Placebo-Controlled Safety Blic Double-Blinded, al. de Randomized, et A (28) L, Age: Larsen of K, Years trial Kim 2 R, placebo-controlled Than Younger Study. Cardona Randomized to A, Months Bueso MC. yr. Six R, 2-6 Children Chou Ballona aged KH, B, children Prenner Lue in (27) rhinitis WT, allergic Chang perennial HL, treating Immunol for Sun Allergy cetirizine KH, and montelukast Lu levoceti- comparing of ST, Safety study. Chen 18-month Group. Study An (26) (EPAAC) children: Children atopic Atopic treatment young in the in Asthma for treatment of fexofenadine rizine Prevention old. Early of years FE, tolerability 5 Simons and to (25) Safety 2 FC. children Hampel in R, rhinitis. rhinitis Lanier allergic allergic B, of with Kittner 30 years H, and 2 Milgrom 15 (24) to hydrochloride, fexofenadine months of 6 tolerability aged and children Safety 2007;99(6):549-554. in JH. Bavel daily by van twice children B, young mg, Kittner in FC, wheezing Hampel recurrent (23) of for Prevention placebo ketotifen. T. and with Thongkaew levocetirizine compared T, cetirizine, loratadine Wirawarn of comparison J, The Ngamphaiboon rhinitis. KH. (22) allergic Lue MS, perennial infants Ku childhood KH, in of Lu treatment dihydrochloride HL, the levocetirizine Sun of CF, urticaria. tolerability Lee chronic (21) and or Safety rhinitis JM. allergic Haeusler with P, children and Ratner and F, activity Anti-inflammatory Hampel al. children. (20) et mite-allergic G, in Cara therapy Di cypro- levocetirizine E, 3-month and Ugolini 2011;10(1):32-38. G, a syrup Allocca of P, loratadine efficacy Abate years. of clinical LG, 2-12 study Sensi aged F, comparative children Marcucci Taiwanese A (19) in CJ. rhinitis Chen allergic CL, perennial Pharmacol Hsu treating Immunopathol TY, for Wang solution HCL TH, heptadine Li KG, Wu (18) eiti sha leg Immunology & Allergy Asthma, Pediatric 2004;34(11):1665-1672. 2006;17(1):49-54. n leg shaImmunol Asthma Allergy Ann 2012;25(1):231-237. e so Thai Assoc Med J eiti sha leg Immunology & Allergy Asthma, Pediatric 2003;16(4):265-274. n leg shaImmunol Asthma Allergy Ann 2006;19(2):91-99. 7 eit leg Immunol Allergy Pediatr 2009;92(3):351-355. leg shaProc Asthma Allergy 2005;95(2):175-180. eit leg Immunol Allergy Pediatr eit leg Immunol Allergy Pediatr leg lnImmunol Clin Allergy J 2010;31(4):290-295. n leg shaImmunol Asthma Allergy Ann namAlryDu Targets Drug Allergy Inflamm 2007;99(4):358-363. 2009;20(5):493-499. 2004;17(1):59-69. 2005;16(3):267-275. urMdRsOpin Res Med Curr 2007;18(6):535-542. 2003;111(4):763- lnExp Clin Pediatr n J Int Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. 5)Cpad ,TsaM ic ,PsaaqaG icoA,Bgac ,e l eiiietetetof treatment Cetirizine al. et M, activity. antiallergic Bagnasco its AM, of Riccio evidence in G, allergy: 1166. Cetirizine Passalacqua pollen with V, with children Ricca Prolongation in M, rhinitis QTc Tosca of G, Absence Ciprandi DS. (50) Years. Pearlman placebo-controlled 11 WR, double-blind, to Lumry 6 randomized, treatment MJ, Aged a the Children Noonan years: in JA, 11 effective Winder to cetirizine (49) 6 Once-daily aged MJ. children the Noonan in of JA, study. rhinitis cardiotoxicity Winder allergic WR, potential seasonal Lumry of the DS, of Pearlman children. Evaluation (48) atopic CK. in Naspitz cetirizine D, and with loratadine, Sole Immunol children astemizole, A, in terfenadine, Pferferman Loratadine-pseudoephedrine antihistamines LF, H. Ascierto Delgado FM, (47) trial. and Devoto double-blind LF, cetirizine controlled Rizzo a rhinitis. of O, rhinitis, allergic comparison Alves allergic perennial Double-blind with HA, years Serra B. 6 (46) Rio-Navarro to Child. 2 Del Atopic ages A, the children in of Gazca-Aguilar double- loratadine Treatment a JJ, Early in Sienra-Monge ETAC. cetirizine (45) of of influence results the first and Immunol asthma Allergy trial: of Pediatr placebo-controlled development the randomised, with Child. blind, very associated Atopic factors in the Allergic cetirizine of Treatment (44) antagonist Early H1-receptor Group. the Study ETAC of Immunol evaluation dermatitis. Clin atopic safety with long-term children Prospective, young FE. Simons years. (43) 5 to electrocar- 2 pharmacokinetics, aged The children MB. in Affrime syrup R, loratadine 621. Lorber of D, tolerability Padhi and children C, effects, in Banfield diographic fexofenadine JM, of Herron Safety LM, J. Salmun Long (42) J, rhinitis. Portnoy EO, allergic Meltzer seasonal A, for Goldsobel treated DI, Bernstein allergic DF, reduces Graft (41) treatment cetirizine Long-term allergy. GW. mite with Canonica children 226. G, in prescriptions Passalacqua drug M, and years. symptoms Tosca 12 randomized to G, 3 and Ciprandi aged placebo-controlled, children (40) double-blind, in rhinitis A allergic Immunol BL. of Allergy treatment Chiang J the MJ, for Pac Tsai syrup MY, urticaria (Clarityne) loratadine Lu idiopathic of YT, chronic study Lin in YH, oxatomide multicenter Yang Double-blind with (39) compared al. et cetirizine N, of Oggiano children. tolerability G, preschool Barberio and A, in efficacy Corrias the G, Marchese on S, study Leonardi M, Rosa La cream. cent (38) per 0.1 furoate cetirizine, mometasone loratadine with of of treated safety 2002;85(4):482-487. safety dermatitis and atopic efficacy and Therapeutic childhood efficacy S. in rhinitis. Viravan the syrup S, Wananukul allergic of W, Wisuthsarewong perennial comparison A, childhood Chunharas The (37) of HS. treatment Lee the KL, for Immunol Lin placebo Asthma in JC, a cetirizine Hsieh and of KH, ketotifen, Safety oxatomide, Lue DS, al. et Lai study. AO, (36) placebo-controlled Olufade double-blind, D, randomized, a Chapman J, age: of Catuogno 2003;111(6):1244-1248. months JM, 11 Portnoy to P, 6 infants Silas FE, Simons (35) lnPdar(Phila) Pediatr Clin 1998;80(4):333-337. 99142P 1):433-440. Pt 1999;104(2 2002;89(6):589-598. n leg shaImmunol Asthma Allergy Ann 2001;19(3):171-175. 1998;9(3):116-124. 1997;36(4):209-215. eiti sha leg Immunology & Allergy Asthma, Pediatric n leg shaImmunol Asthma Allergy Ann rJCi Pharmacol Clin J Br 2001;87(1):48-53. 8 n leg shaImmunol Asthma Allergy Ann 2001;87(1):22-26. 1998;45(2):147-150. mJTher J Am 1996;10(4):181-190. lnEpAllergy Exp Clin lnTher Clin 1999;6(3):149-155. leg lnImmunol Clin Allergy J n leg Asthma Allergy Ann e so Thai Assoc Med J 1997;27(10):1160- 2000;22(5):613- 2001;87(3):222- n Allergy Ann Allergy J Asian Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (14) 2017 al., et Nayak (13) 2017 al., et Wandalsen Region (Reference) Year Study, Risk al. et J, Bousquet P, Cauwenberge paper. 1. van Table position C, GA(2)LEN Bindslev-Jensen a Rhinitis FE, Allergic H(1)-antihistamines: Simons first-generation al. M, of et Maurer S, MK, Bosnic-Anticevich revision. Church guidelines-2016 C, (62) (ARIA) Bachert Asthma A, on Agarwal Impact I, its Agache rhinitis: and J, Paediatric Immunology. Bousquet al. Clinical JL, Bro˙zek et and (61) PW, Allergy Hellings of S, Academy Halken European A, Custovic the 1116. LM, of Borrego paper M, position Xatzipsalti G, suspension rhinitis. loratadine Roberts of allergic (60) safety with and children Efficacy A. of Andreoli treatment E, Marchesi the C, in Richelli P, Miglioranzi double-blind AL, placebo. multicentre Boner and A (59) cetirizine Rhinitis. of Allergic rhino- doses Chronic allergic two with seasonal of Children in study in cetirizine Cetirizine of Dupont,P. years. trial Baelde,Y., 12 (58) placebo-controlled to aged A 6 children H. aged Venne in children de rhinitis van in allergic R, conjunctivitis seasonal Candiani for M, Masi Cetirizine placebo. (57) with Y. comparison Baelde double-blind HG, A Wieseman years. J, three 2-6 rhinitis. Paupe of allergic safety L, perennial and efficacy with Allegra the children (56) of in Assessment daily H. once Venne cetirizine given de van of cetirizine A, of study Schubert levels W, Double-blind dose Wijngaart JA. den Bellanti van S, A, Jobst Corrias (55) F, children. Guglielmo in I, eczema Musarra ICAM-I C, atopic reduces Ranno in Cetirizine M, mite-allergic Rosa al. with La et children (54) I, asymptomatic Grimaldi in inflammation MA, Tosca persistent minimal S, nasal asthma. Cozzani Chil- during C, cells in Pronzato epithelial G, Rhinitis on Asthma, Ciprandi Allergic Pediatric L, Seasonal Fasce Study. (53) of Multicenter Treatment A SP. Galant Chlorpheniramine: Efficacy DQ, or ogy Mitchell Cetirizine 10-Day, al. J, with A et Kemp dren MM, Rhinitis: DG, Giudice Allergic Tinkelman Perennial del (52) With PL, Children Giorgi Young AL, in 1997;11(2):119-128. Boner Study. Oxatomide Parallel-Group L, Randomized, and Double-Blinded, Armenio Cetirizine Multicenter, N, of Forenza Safety FM, and Benedictis de (51) 1996;10(1):9-17. n rhAlryImmunol Allergy Arch Int ra characteristics Trial S SAR USA America S. years) (6-11 years) (2-12 PAR range) (age type Disease n Allergy Ann 1996;109(3):272-276. 1994;73(2):117-122. placebo LRD CTZ DCPN DLRD groups Treatment rgInvest Drug eit leg Immunol Allergy Pediatr Allergy eit leg Immunol Allergy Pediatr 9 92 4(6):466-472. 1992; OD po 10mg OD po 10mg TD po 1-2mg OD po 2.5mg 1.25- dose Treatment 1989;44(6):437-441. leg lnImmunol Clin Allergy J eiti sha leg Immunology & Allergy Asthma, Pediatric Allergy 9344Suppl):47-52. 1993;4(4 0 0 D4 46 45 220 228 ND 105 2 105 1 weeks tion, dura- Treatment 2010;65(4):459-466. . 1993;4(3):157-161. Allergy Allergy 2017;140(4):950-958. . leg Immunol- & Allergy 219 n Patients, 1994;49(8):598-604. 2013;68(9):1102- . 8.9 8.9 8.6 years Age, ++ 46.3 42.2 42.5 % Female, Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (21) 2009 al., et Lee (20) 2010 al., et Hampel (19) 2011 al., et Marcucci (18) 2012 al., et Wu (17) 2013 al. et Potter (16) 2016 al., et Potter (15) 2016 al., et Novak Region (Reference) Year Study, America S. Africa Europe Chronic Europe America S. Europe, uoePAR Europe or AR USA PAR Europe (2-12 PAR Asia years) (6-12 years) (1-5 urticaria Chronic or AR months) (6-11 urticaria Chronic years) (6-12 years) years) (6-11 PAR years) (2-11 urticaria neous sponta- years) (2-12 ial urticar- chronic or tis juctivi- rhinocon- Allergic range) (age type Disease placebo LCTZ placebo LCTZ placebo LCTZ CPHD LRD placebo RPD placebo [3]DLRD RPD placebo BLN groups Treatment placebo LCTZ CTZ 10 oOD po 5mg OD po 10mg 9.73 BD po 1.25mg 30 30 OD po 12 1.25mg ND (<30kg,>30kg) TD po 2-4mg (<30kg,>30kg) OD po 5-10mg ([?]25kg) OD po 5mg (<25kg), OD po 2,5mg OD dose standard (>25kg) OD po 5mg (10-25kg), OD po 2.5mg OD po mg 10 dose Treatment 22 62 8.19 27 26 27 3.78 59 12 114 8.87 24 2 45 34.7 61.5 2 6.6 5.8 30 30 41.1 8.8 8.7 2 180 180 [3]6.1 6 5.6 69 [3]71 66 27.3 6 7.4 7.5 249 260 12 weeks tion, dura- Treatment n Patients, 8.12 8.79 3.75 months 9.03 months 6.1 (total) years Age, ++ 38.3 27.8 54.0 62.5 58.0 61.0 57.0 54.2 37.8 42 [3]45.1 56.1 (total) 60.0 % Female, Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (30) 2004 al., et Bloom (29) 2005 al., et Potter (28) 2005 al., et Blic de (27) 2006 al., et Prenner (26) 2006 al., et Chen (25) 2007 al., et Simons (24) 2007 al., et Milgrom (23) 2007 al., et Hampel (22) 2009 al., et Ngamphaiboon Region (Reference) Year Study, S AR USA Recurrent Asia S Ror AR USA PAR Africa SAR Europe Africa S. ica, Amer- (2-6 PAR S. USA, Taiwan AD Canada (2-5 AR USA years) (6-11 CIU or AR years) (2-5 CIU years) (6-12 years) (6-12 months) (6-24 ND years) months) (12-24 years) years) (1-2 AR months) (6-12 years) (<6 ing wheez- range) (age type Disease placebo MLK CTZ placebo LCTZ placebo FXD placebo FXD FXD placebo FXD FXD placebo KTF LRD groups Treatment placebo DLRD placebo DLRD placebo LCTZ placebo LCTZ placebo DLRD 11 oOD po 2.5mg OD po 1.25mg OD po 5mg OD po 5mg yrs) (1-2 OD po 1.25mg yr) (<1 OD po 1.0mg OD po 4mg OD po 5mg OD po 0.125mg/kg OD po 30mg OD po 30mg OD po 15mg OD po 30mg OD po 15mg OD po 0.25ml/kg OD po 0.25ml/kg dose Treatment 55 . . 44.0 3.4 3.5 35.7 56 55 9.9 29.2 9.9 152 154 9.9 9.9 2 88 89 4 12.6 45.0 40.0 6 4.4 4.5 4.5 129 131 20 20 20 19.3 44.6 2 255 255 12 3.6 3.6 231 222 72 103 2 27 8.8 69 5 8 58 2.9 3.2 26 25 27 8 16 weeks tion, dura- Treatment 06 . . 48.0 8.5 7.9 60 60 2 131 n Patients, months 13.3 months 19.4 ND months 10.4 months 2.9 ND months 17.9 months 16.1 years Age, ++ 45.0 42.8 38.6 55.0 44.9 53.0 44.0 35.7 39.2 46.3 40.0 43.1 34.6 52.0 29.6 38.5 39.8 48.1 % Female, 65.0 Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (36) 2002 al., et Lai (35) 2003 al., et Simons (34) 2003 al., et Segal (33) 2003 al., et Wahn (32) 2004 al., et Hsieh (31) 2004 al., et Grimfeld Region (Reference) Year Study, Australia USA, Africa, Europe, PAR Taiwan America S. and C. Asia, Africa, S. Europe, saPAR Asia America N. SAR USA years) (6-12 months) (6-11 antihistamines H with ment treat- required that disorder other or AD ticaria, ur- AR, years) (6-11 years) (6-11 SAR years) (6-12 months) (12-30 tis bronchi- or tis laryngi- media, otitis acute gitis, rhinopharyn- Rhinitis, range) (age type Disease 1 - placebo KTF OXD CTZ placebo CTZ placebo CTZ placebo FXD placebo MLK CTZ placebo LRD groups Treatment 12 OD po 1mg OD po 1mg OD po 10mg BD po 0.25mg/kg ([?]25kg) OD po 10mg (<25kg), OD po 5mg BD po 30mg OD po 5mg OD po 10mg yrs) (>2 OD po 5mg yrs) ([?]2 OD po 2.5mg dose Treatment 22 020 20 20 12 8.5 35.8 43 42 9.1 9.2 40.0 1 86 86 8.8 8.8 471 464 8.2 8.1 2 22 21 21 2 12 23.9 208 204 52 weeks tion, dura- Treatment 20 n Patients, (female) months 7.2 (male), months 8.0 (female) months 7.9 (male), months 8.1 months 24 months . 8.3 7.4 8.3 8.2 years Age, ++ 53.5 50.0 37.3 33.5 45.0 35.0 40.0 42.0 35.8 56.2 56.2 56.6 58.7 % Female, Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (45) 1999 al., et Monge Sienra- (44) 1998 al., et Wahn and (43) 1999 al., et Simons (42) 2000 al., et Salmun (41) 2001 al., et Graft (40) 2001 al., et Ciprandi (39) 2001 al., et Yang (38) 2001 al., et Rosa La (37) 2002 al., et Chunharas Region (Reference) Year Study, + saAR Asia Chronic Europe AD Asia .AeiaA (2-6 AR America C. America N. or AR USA Canada USA, Perennial Europe years) years) (1-2 AD years) (2-5 CIU years) (6-11 SAR years) (3-10 asthma mittent inter- mild tis, junctivi- rhinocon- years) (3-12 years) (2-6 urticaria years) (2-12 range) (age type Disease placebo LRD placebo FXD FXD FXD placebo CTZ placebo LRD CTZ OXD placebo LRD groups Treatment T R 0.2mg/kg LRD CTZ placebo CTZ 13 oOD po 0.2mg/kg OD po BD po 0.25mg/kg OD po 5mg BD po 60mg BD po 30mg BD po 15mg OD po 5mg ([?]30kg) OD po 10mg (<30kg), OD po 5mg OD po 5mg OD po 25mg (>30kg) OD po 10ml ([?]30kg) OD po 5ml dose Treatment 04 . . 0035.0 40.0 4.4 4.3 40 40 4 55.0 16.8 3.5 396 3.7 399 61 60 72 212 208 2 223 30.0 2 6.7 6.2 36.4 10 10 6.6 6.0 ND ND 24 30 30 ND ND 31 31 3 71.0 4 24 24 2 weeks tion, dura- Treatment 229 n Patients, months 17.2 months months 76.3 months 9.2 9.0 9.1 9.1 years Age, ++ 55.7 20.0 50.0 37.6 38.1 50.0 54.0 7039.0 47.0 41.0 37.0 % Female, Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (53) 1996 al., et Fasce (52) 1996 al. et Tinkelman (51) 1997 al., et deBenedictis (50) 1997 al. et Ciprandi (49) 1996 al., et Winder (47) 1998 al., et Delgado (46) 1998 al., et Serra Region (Reference) Year Study, + rzlPAR, Brazil SAR Argentina uoeMite Europe SAR USA PAR Europe Allergic Europe AR USA years) (5-14 asthma allergic years) (6-11 years) (2-6 years) (6-15 tis junctivi- rhinocon- years) (6-11 years) (5-12 Sinusitis years) (3-15 range) (age type Disease CPN CTZ CTZ OXD CTZ placebo CTZ placebo CTZ CTZ CTZ CTZ LRD LRD placebo PSD LRD- groups Treatment placebo CTZ 14 OD po 5mg TD po 2mg ([?]25kg) BD po 5mg (<25kg), BD po 2.5mg ([?]25kg) OD po 10mg (<25kg), OD po 5mg BD po 12mg OD po 5mg OD po 0.15mg/kg OD po 10mg OD po 5mg OD po 10mg ([?]30kg) OD po 10mg (<30kg), OD po 5mg BD po 0.2mg/kg dose Treatment 01 8.3 10 10 2 9.1 8.6 34.0 63 62 63 4.8 4.6 52 53 2 8.5 d 10 10 10 4 8.6 9.1 68 72 69 60.0 4 ND ND 10 10 10 20 20 2 2 weeks tion, dura- Treatment 10 n Patients, (total) 8.7 (total) 8.8 . . 50.0 9.3 7.2 years Age, ++ 40.0 60.0 DND ND 30.2 29.5 35.5 (total) 55.0 36.8 27.1 33.3 50.0 50.0 50.0 % Female, Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (59) 1989 al., et Boner (58) 1992 al., et Baelde (57) 1993 al., et Masi (56) 1993 al., et Allegra (55) 1994 al., et Jobst (54) 1994 al., et LaRosa Region (Reference) Year Study, uoePAR Europe AD Europe uoeSAR Europe PAR Europe Seasonal Europe SAR Europe years) (4-12 years) (2-14 years) (6-12 tis junctivi- rhinocon- allergic years) (2-6 years) (6-12 years) (6-12 range) (age type Disease DCPN LRD placebo CTZ CTZ placebo CTZ placebo CTZ placebo CTZ CTZ CTZ placebo CTZ groups Treatment 15 <6yrs) or (<20kg TD po 0.5mg yrs), [?]6 or ([?]20kg TD po 1mg <6yrs) or (<20kg OD po 2.5mg yrs), [?]6 or ([?]20kg OD po 5mg BD po 2.5mg BD po 5mg BD po 5mg OD po 5mg OD po 10mg OD po 5mg OD po 2.5mg (>30kg) OD po 10mg ([?]30kg), OD po 5mg dose Treatment 11 . . 33.3 7.8 7.6 19 21 8.5 8.8 46 46 46 2 10.1 33.3 2 61 63 4.3 4.6 53 54 2 2 76 85 84 7.0 2 11 12 8 weeks tion, dura- Treatment 83 n Patients, 8.6 10.2 (total) . 8.9 9.3 9.2 8.6 years Age, ++ 36.8 28.3 39.1 30.4 30.4 37.7 39.7 63.6 41.6 45.8 42.1 29.4 45.2 % Female, Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. aRs ta. 94(4 nla nla o o o o o ieeta s fcnoiatdrugs concomitant of interview) use and Differential (diary AEs patient-reported reported, not group per (diary) observed AEs AEs were with patient-reported AEs patients important of no number that safety; for reported evaluated Only not patients 3 recorded were AEs how Unclear AEs AEs Patient-reported Patient-reported tests recorded laboratory were and AEs (interview) how Low AEs Unclear Patient-reported (diary) (diary) AEs interview) AEs patient-reported and patient-reported tolerability; (diary safety; assess AEs assess to patient-reported to designed tests pts, Low designed Primarily laboratory other Primarily (interview) and by AEs interview) Low replaced patient-reported and were (interview) reported; (diary violators AEs not AEs Protocol Low patient-reported withdrawals patient-reported safety; of safety; for Reasons assess Low evaluated to patients tests designed all laboratory Primarily Low Not and interview) and (diary AEs Patient-reported Low recorded interview) were recorded Low tests and were AEs Low laboratory (diary how AEs and AEs AEs how Unclear AEs patient-reported patient-reported Unclear patient-reported safety; safety; tests or for assess laboratory Observed evaluated to and development Low Low not designed interview) psychomotor pts Primarily and of 5 assessment (diary Low and AEs Low interview) (diary) development patient-reported Low Low and psychomotor safety; AEs (diary of assess patient-reported AEs assessment to phase, Patient-reported tests, follow-up designed and laboratory Primarily treatment (interviews), Low AEs both Low High Patient-reported for AEs, calls Unclear Low reported of phone Low AEs definitions through Low safety; and Low assess visits to trial Low designed at Primarily recording Low AE Low safety; assess to Low Low Low designed (interview) Low Unclear Primarily AEs Patient-reported Unclear interview) tests Low and laboratory (diary and AEs Low Low AEs patient-reported patient-reported safety; Unclear Unclear safety; for (interview) Low AEs assess Low evaluated Low AEs Low patient-reported to patients patient-reported safety; designed all Unclear safety; assess Primarily Not Low AEs for to evaluated High patient-reported designed patients Low reported; Primarily Low Low all not Not Low group Low per particular AEs in with somnolence/sedation, AEs Low patients and (diary) Patient-reported Low Unclear Low of assessment AEs Unclear Unclear number AE Low patient-reported safety, Low Detailed Low safety; for for evaluated evaluated patients Low Unclear patients Low all (interview) the Low Not AEs of Patient-reported Unclear 67% Low Unclear Unclear Unclear Low Unclear Low Low AEs Low patient-reported or High Low (diary) Low Observed AEs safety; Low Patient-reported for evaluated Low not Unclear patients Low 5 Low Unclear Unclear Low Unclear Unclear Unclear Low Low Unclear High Low Low Low Low Unclear Unclear Unclear Low Low Unclear Unclear Low Low Unclear Low Unclear Low Low Low Low Low Unclear Low Low Unclear Unclear Unclear Low Low Low Unclear Low Low Low Low Low Unclear Low Unclear Unclear Unclear Unclear Unclear Unclear Low Low Unclear Low Low Unclear Unclear Low Unclear Low Unclear Unclear Unclear Unclear Low High Unclear Low Low Low Low Unclear Unclear Unclear Unclear Low Unclear Unclear Low Unclear Low Unclear Unclear Unclear Unclear Low Unclear Low Low Unclear Low Low Unclear Unclear Low Unclear Unclear Low Unclear Low Unclear Low Unclear High Unclear Unclear Low Low Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear Low (54) Unclear Low 1994 Low al., et Rosa Low (53) La Low Low 1996 Low al., Unclear et Low (52) Fasce Unclear 1996 Low Unclear Unclear al., et (51) Tinkelman 1997 al., Unclear et (50) deBenedictis 1997 Unclear High Unclear Unclear al., Unclear Unclear Unclear et Low (48) Ciprandi 1997 Unclear al., Low et Unclear (47) Unclear Pearlman 1998 al., Low et (46) Delgado 1998 Low al., Unclear et (45) Serra Low 1999 Low al., et (43) Unclear Sienra-Monge Unclear Unclear 1999 al., et Unclear (42) Simons High 2000 Unclear Unclear al., et (41) Unclear Salmun 2001 al., et (40) Graft 2001 al., Low Unclear et Unclear (39) Low Ciprandi 2001 High Unclear al., (38) et Low 2001 Yang al., Unclear et Rosa (37) La 2002 Unclear al., et Unclear (36) Chunharas Unclear 2002 Unclear al., Unclear et (35) Unclear Lai 2003 al., et (34) Simons 2003 Unclear al., et (33) Segal 2003 Unclear al., et (32) Wahn Unclear 2004 Unclear al., Unclear Comments et (31) Unclear Hsieh 2004 al., reporting et (30) Grimfeld outcome Unclear 2004 Selective al., et (29) Bloom Unclear 2005 Attrition al., (28) et 2005 Potter Low al., Assessors et Blinding/ Blic (27) de Unclear 2006 al., Caregivers et Blinding/ (26) Prenner 2006 al., et Patients (25) Chen Blinding/ 2007 al., Unclear et (24) Simons concealment 2007 al., Allocation et (23) Milgrom 2007 al., iko isi nlddtrials included in bias of Risk and and ane l,19 4)LwLwLwLwLwLwLwPiaiydsge oass aey oeatv oioig vrrprigacrigt h uhr;ptetrpre E dayadinterview) and (diary AEs patient-reported authors; the to according over-reporting monitoring, active more safety; assess to designed Primarily Low Low Low Low Low Low Low (44) 1998 al., et Wahn idre l,19 4)UcerUcerLwLwLwLwLwNme fptet ihAsprgopntrpre;ptetrpre E dayadinterview) and (diary AEs patient-reported reported; not group per AEs with patients of Number Low Low Low Low Low Unclear Unclear (49) 1996 al., et Winder 16 Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. alee l,19 5)LwUcerLwLwLwLwLw4psnteautdfrsft;ptetrpre E dayadinterview) and (diary AEs patient-reported safety; for evaluated not pts 4 interview) interview) and and (diary (diary interview) AEs AEs and Patient-reported Patient-reported (diary AEs (diary) Patient-reported AEs Patient-reported Low Low Low Low Low Low Low Low Low Low (17) 2013 al., Low et Unclear Potter (16) Low 2016 Low al., Low et Potter High Low Low Low Low High Low Low (15) 2016 Low al, Low et Novak (14) 2017 al., et Nayak Unclear Unclear Unclear Unclear Unclear Comments Unclear reporting outcome Selective (13) 2017 Low Attrition Unclear al., et Assessors Blinding/ Wandalsen Low Caregivers Low Blinding/ Patients Blinding/ ence) concealment Allocation (Refer- generation Sequence Year Study, 3. Table (59) 1989 al. et (58) Boner 1992 al., et (57) Baelde 1993 al., et (56) Masi 1993 al., et (55) Allegra 1994 al., et Jobst (Reference) Year Study, des vnsadtetetdiscontinuations treatment and events Adverse placebo RPD placebo DLRD RPD placebo BLN placebo LRD CTZ DCPN DLRD (n) groups Treatment 8 8 DN 723. . . DND ND 5.5 6.1 30.0 37.2 ND ND ND 180 ND 180 clinically No 69 71 66 0.8 1.1 8.0 5.8 67.5 68.5 3.6 0.7 Six 249 260 219 1.9 0.9 220 228 ND ND ND ND ND ND 105 105 n Patients, ND 21.8 19.7 0 0 0 % AEs, serious with Patients 17 54.0 65.0 61.0 22.7 % AE, [?]1 with Patients . . . DND ND 7.2 5.6 1.5 3.9 5.6 2.6 2.6 4.5 4.8 %+ drug, study to related AEs with Patients ND % AEs, to due tions tinua- discon- Treatment trials original in Comments examination physical or parameters ECG values, laboratory clinical signs, vital for placebo and bilastine between differences relevant statistically and/or study the of end the at changes ECG presented group DCPN the in 11 and group DLRD the in patients Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. 07(24) 2007 al., et Milgrom (23) 2007 al., et Hampel (22) 2009 l., et Ngamphaiboon (21) 2009 al., et Lee (20) 2010 al., et Hampel (19) 2011 al., et Marucci (18) 2012 al., et Wu placebo FXD 12years] [1-2 placebo FXD FXD months] [6-11 placebo FXD FXD placebo KTF LRD placebo LCTZ CTZ years] [1-5 placebo LCTZ months] [6-11 placebo LCTZ placebo LCTZ CPHD LRD 2 3 DN 005. . . DN No ND ND 8.2 9.5 50.2 50.0 ND ND 231 222 71311N ND ND 131 103 27 72 6N DN DN DN DN DN DAfew A ND ND ND ND ND ND ND ND ND ND 0 0 ND ND 0 ND 3.8 3.7 69 5 58 11.9 ND 7.0 ND ND clinically No 35.6 35.1 0 26 0 25 0 27 ND ND 27 0 26 6.7 27 ND ND 59 4.2 0 114 11.1 0 ND ND 70.8 64.4 13.0 10.5 0 14.3 ND ND 13.0 0 0 0 24 45 ND ND 30 30 30 30 ND ND 18 52.3 35.0 40.7 40.6 40 39.7 studies) both in placebo for total (in 9.5 studies) both in FXD for total (in 8.8 ND . 5.3 3.1 . . oclinical No 4.3 3.2 0 0 0 changes. ECG relevant clinically variable. ECG any or sign vital any for placebo and groups treatment nadine fexofe- the between observed were differences l groups. all in AEs mild had patients noted were parameters ECG or tests, laboratory signs, vital in trends or changes relevant Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (29) 2005 al., et Potter (28) 2005 al., et Blic de (27) 2006 al., et Prenner (26) 2006 al., et Chen (25) 2007 al., et Simons placebo LCTZ placebo LCTZ placebo DLRD placebo MLK CTZ placebo LCTZ 5 5 525. . . . 1.3 1.3 1.0 0 5.9 7.8 5.6 5.6 52.6 55.2 30.7 33.7 statis- No 0 0 0 0 1.6 0.8 152 154 0 0 0 21.8 88 26 89 0 0 10.0 58.9 67.2 0 0 10.0 0.8 0 0 0 129 0 131 There 20 20 20 1.2 2.0 6.3 5.1 95.7 96.9 14.5 12.2 255 255 19 ters parame- ECG in differences relevant clinically or significant tically results. test laboratory to respect with children treated placebo- and levocetirizine- between differences significant no were . Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (32) 2004 al., et Hsieh (31) 2004 al., et Grimfeld (30) 2004 al., et Bloom placebo MLK CTZ placebo LRD placebo DLRD placebo DLRD 12 2000505.0 was 5.0 There 0 0 0 0.5 0 0 0 22 ND 21 ND 21 0 0 85.0 80.9 10.0 1.7 ND ND ND ND 208 204 60 60 No 0 0 0 3.6 10.7 12.7 ND ND 56 55 20 10.0 ND ND ND 0 0 0 parameters. laboratory or ECG regarding groups between difference no groups. placebo and ratadine deslo- the in similar was incidence the but years, years–5 2 aged subjects of study the in observed was rate heart in Increase signs. vital mean or values test laboratory clinical median in noted were changes relevant clinically Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. 02(37) 2002 al., et Chunharas (36) 2002 al. et Lai (35) 2003 al., et Simons (34) 2003 al., et Segal (33) 2003 al., et Wahn placebo LRD placebo KTF OXD CTZ placebo CTZ placebo CTZ placebo FXD 42 DN 2580N D420 4.2 ND ND 8.0 12.5 ND ND 16.7 15.8 24 0 24 0 0 0 20 20 cause 20 All 20 6.9 7.1 0 62.8 0 45.2 88.4 ND 73.8 ND 20.9 ND 32.1 ND ND ND 43 42 86 There 86 0 0.6 3.0 2.3 18.7 18.3 ND 0.2 471 464 21 2512.5 12.5 ND ND ND ND ND ND ND ND g group. age 11-month to 9 the in than group age month 8- to 6- the in frequent more generally were AEs related treatment and groups. treated placebo- and fexofenadine- the between results signs vital and laboratory clinical in changes in differences significant no were Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (41) 2001 al., et Graft (40) 2001 al., et Ciprandi (39) 2001 al., et Yang (38) 2001 al., et Rosa La placebo FXD FXD hema- FXD The placebo CTZ 3.2 0 placebo LRD 3.2 0 3.2 0 ND ND 31 31 OXT CTZ 01 DN 0 0 ND ND 0 0 0 0 0 0 0 ND 229 0 ND 212 208 223 ND ND 10 10 30 30 DND ND ND ND 22 4736.2 34.7 36.8 35.3 DND ND ND ND .02.20 0.50 1.40 0.40 groups. among consistent signs vital able, unremark- changes ECG - Lab treatment. the of end the at and before patients all in limits normal the within were tests urinary and chemical, hemato- tologic, Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (46) 1998 al., et Serra (45) al.,1999 et Monge Sienra- (44) 1998 al., et Wahn (43) 1999 al., et Simons (42) 2000 al., et Salmun and T R 04 DN . DN . ND 5.0 ND ND 0 5.0 ND ND placebo LRD-PSD 40 40 LRD CTZ placebo CTZ placebo LRD 02 DN . D000No 0 0 0 ND 0 5.0 ND ND 20 20 There 3.8 2.8 1.8 0.5 98.7 98.5 13.6 9.3 396 399 There 0 0 ND ND 41.0 32.0 ND ND 61 60 23 tests. lab or signs vital in changes assessments. ioral/developmental behav- or interval QTc in groups between differences significant cally statisti- no were group. either in signs vital or findings, physical values, laboratory in changes relevant clinically no were There variable. ECG any in groups between differences significant no were Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. 96(52) 1996 al., et Tinkelman (51) 1997 al., et Benedictis (50) 1997 al., et Ciprandi (49) 1996 al., et Winder (48) 1997 al., et Pearlman (47) 1998 al., et Delgado and T X 35 DN . . DN No 0 0 ND ND CPN CTZ CTZ 7.7 8.0 ND ND 52 53 OXD CTZ placebo CTZ placebo CTZ CTZ CTZ LRD CTZ LRD 36 3N ND ND 0 0 63 62 63 ND 20.0 10.0 ND 10 10 No ND ND ND ND ND ND ND ND ND ND ND ND 68 72 69 10 10 10 10 ND ND ND ND ND 24 363. DND ND 38.1 33.6 ECG The 0 0 0 0 0 0 0 0 0 0 0 0 ND 0 0 0 evaluation. follow-up the at rhythm sinusal with presented children all and treatment, following limits normal within remained ters parame- patient. oxatomide one for except found were tests laboratory in changes significant clinically placebo. with difference significant statistically no groups, cetirizine between AEs of incidence the in differences pronounced Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (57) 1993 al., et Masi (56) al.,1993 et Allegra (55) 1994 al., et Jobst (54) 1994 al., et Rosa La (53) 1996 al., et Fasce placebo CTZ placebo CTZ placebo CTZ CTZ CTZ placebo CTZ placebo CTZ 36 DN 222. DN . . Minor 1.6 3.2 ND ND 22.9 22.2 Minor ND ND 3.8 1.8 61 63 0 5.6 ND ND 20.7 No 24.1 ND 0 ND ND 0 0 ND 0 53 54 ND ND ND ND 83 76 85 84 ND ND 11 12 ND ND 10 10 DND ND ND ND 25 2418.4 22.4 14.0 25.0 DND ND ND ND 1.2 1.3 2.9 4.8 relevant. clinically be to not considered were tests laboratory clinical in changes relevant. clinically be to not considered and reviewed carefully were tests laboratory clinical in changes reported. reactions adverse important Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. brvain:A des vn;BN=Blsie PD=Cpoetdn;CN=Chlorpheniramine; = CPN Cyproheptadine; = CPHD Bilastine; = BLN event; Adverse = AE Abbreviations: (59) 1989 al., et Boner (58) 1992 al., et Baelde DCPN LRD Placebo CTZ CTZ 11 D1. 15N . Hematological 0 4.7 ND 31.5 19.0 ND 19 21 Leucocytosis 0 0 0 ND ND ND 13.0 17.3 6.5 ND ND ND 46 46 46 26 effects. toxic of devoid were used dosages the at ramine pheni- dexchlor- and loratadine that showed analysis chemical bio- and counts levels. creatinine or urea blood in changes significant clinically no groups, three the in patients some in occurred function liver’s the on effect no with levels AST in increase unimportant clinically and slight a relevant, clinically considered not was groups three the in patients some in occurred that Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (13) 2017 al., et Wandalsen ence) er- (Ref- Year = the OXD Study, by data; assessed was No drug = study ND to 4. Montelukast; Relation Table + = Rupatadine; MLK trial. = = each KTF Loratadine; RPD of Fexofenadine; = authors Pseudoephedrine; = LRD = FXD Desloratadine; PSD Levocetirizine; = Oxotamide; = DLRD Dexchlorpheniramine; LCTZ = Ketotifen; DCPN Cetirizine; = CTZ LDDR LDDR LDDR CNDP CNDP CNDCPN DCPN DCPN DCPN DCPN DCPN DLRD DLRD DLRD DLRD DLRD DLRD group ment treat- per (%) Events verse Ad- with Patients des vnsrpre nicue RCTs included in reported events Adverse group ment treat- per (%) Events verse Ad- with Patients group ment treat- per (%) Events verse Ad- with Patients group ment treat- per (%) Events verse Ad- with Patients group ment treat- per (%) Events verse Ad- with Patients group ment treat- per (%) Events verse Ad- with Patients group ment treat- per (%) Events verse Ad- with Patients 27 group ment treat- per (%) Events verse Ad- with Patients group ment treat- per (%) Events verse Ad- with Patients group ment treat- per (%) Events verse Ad- with Patients group ment treat- per (%) Events verse Ad- with Patients group ment treat- per (%) Events verse Ad- with Patients group ment treat- per (%) Events verse Ad- with Patients group ment treat- per (%) Events verse Ad- with Patients group ment treat- per (%) Events verse Ad- with Patients group ment treat- per (%) Events verse Ad- with Patients group ment treat- per (%) Events verse Ad- with Patients Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. 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(14) 2017 al., et Nayak T T T T T T R R R R R R PlaceboPlaceboPlaceboPlaceboPlacebo LRD LRD LRD LRD LRD LRD CTZ CTZ CTZ CTZ CTZ CTZ Nausea Fever ness less- Breath- Headache ness Dizzi- ity tabil- ri- Ir- ment cite- Ex- pain nal i- dom- Ab- Pain rhea ar- Di- burn Heart petite ap- creased In- Vomit nia som- In- taxis Epis- changes ECG Cough Somnolence 0 0 0 0 0.9 0.9 0.9 1.9 1.9 1.9 1.9 1.9 2.9 2.9 2.9 6.1 6.6 8.6 0 0 0 0 0.9 0.9 0.9 1.9 1.9 1.9 1.9 1.9 2.9 2.9 2.9 6.1 6.6 8.6 0 0 0 0 0.9 0.9 0.9 1.9 1.9 1.9 1.9 1.9 2.9 2.9 2.9 6.1 6.6 8.6 0 0 0 0 0.9 0.9 0.9 1.9 1.9 1.9 1.9 1.9 2.9 2.9 2.9 6.1 6.6 8.6 Pain taxis Epis- burn Heart Vomit ness Dizzi- sea Nau- ity tabil- ri- Ir- nia som- In- ness less- Breath- ment cite- Ex- pain nal i- dom- Ab- rhea ar- Di- Headache Fever Cough petite ap- creased In- changes ECG Somnolence Pain taxis Epis- burn Heart Vomit ness Dizzi- sea Nau- ity tabil- ri- Ir- nia som- In- ness less- Breath- ment cite- Ex- pain nal i- dom- Ab- rhea ar- Di- Headache Fever Cough petite ap- creased In- changes ECG Somnolence 28 0 0 0.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 2.9 2.9 2.9 3.8 4.8 4.8 11.3 17.1 0 0 0.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 2.9 2.9 2.9 3.8 4.8 4.8 11.3 17.1 0 0 0.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 2.9 2.9 2.9 3.8 4.8 4.8 11.3 17.1 0 0 0.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 2.9 2.9 2.9 3.8 4.8 4.8 11.3 17.1 Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. 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(15) 2016 al., et Novak L L L PlaceboPlaceboPlaceboPlacebo BLN BLN BLN Asthma thy phadenopa- Lym- lence no- Som- tis nusi- Si- ing it- Vom- Fever tis gi- Pharyn- Headache related: Treatment- Asthma thy phadenopa- Lym- lence no- Som- tis nusi- Si- ing it- Vom- Fever tis gi- Pharyn- Headache related: Treatment- Asthma thy phadenopa- Lym- lence no- Som- tis nusi- Si- ing it- Vom- Fever tis gi- Pharyn- Headache related: Treatment- 0.4 0.4 1.3 1.3 1.3 1.8 3.5 3.5 0.4 0.4 1.3 1.3 1.3 1.8 3.5 3.5 0.4 0.4 1.3 1.3 1.3 1.8 3.5 3.5 Asthma Fever taxis Epis- sea Nau- thy phadenopa- Lym- tis nusi- Si- ing it- Vom- tis gi- Pharyn- Headache related: Treatment- 29 Asthma Fever taxis Epis- sea Nau- thy phadenopa- Lym- tis nusi- Si- ing it- Vom- tis gi- Pharyn- Headache related: Treatment- Asthma Fever taxis Epis- sea Nau- thy phadenopa- Lym- tis nusi- Si- ing it- Vom- tis gi- Pharyn- Headache related: Treatment- Asthma Fever taxis Epis- sea Nau- thy phadenopa- Lym- tis nusi- Si- ing it- Vom- tis gi- Pharyn- Headache related: Treatment- 0.5 0.9 1.4 1.8 1.8 1.8 2.7 2.7 3.6 0.5 0.9 1.4 1.8 1.8 1.8 2.7 2.7 3.6 Epistaxis sea Nau- ing it- Vom- Fever tis chi- Bron- Asthma tis nusi- Si- tis gi- Pharyn- Headache related: Treatment- Epistaxis sea Nau- ing it- Vom- Fever tis chi- Bron- Asthma tis nusi- Si- tis gi- Pharyn- Headache related: Treatment- Epistaxis sea Nau- ing it- Vom- Fever tis chi- Bron- Asthma tis nusi- Si- tis gi- Pharyn- Headache related: Treatment- 0.9 0.9 0.9 0.9 1.3 1.3 1.7 3.5 3.1 0.9 0.9 0.9 0.9 1.3 1.3 1.7 3.5 3.1 Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (16) 2016 al., et Potter Headache related: Treatment- DSLRDDSLRDDSLRDDSLRDDSLRDDSLRDPlaceboPlaceboPlaceboPlaceboPlacebo RPD RPD RPD RPD RPD RPD infection ral Vi- tis chi- Bron- tis rhini- gic ler- Al- Pyrexia tis gi- sopharyn- Na- tis tivi- junc- con- gic ler- Al- tis gi- Pharyn- Cough Headache Headache related: Treatment- infection ral Vi- tis chi- Bron- tis rhini- gic ler- Al- Pyrexia tis gi- sopharyn- Na- tis tivi- junc- con- gic ler- Al- tis gi- Pharyn- Cough Headache . . . . Treatment- 1.5 1.5 1.5 1.5 infection ral Vi- tis chi- Bron- tis rhini- gic ler- Al- Pyrexia tis gi- sopharyn- Na- tis tivi- junc- con- gic ler- Al- tis gi- Pharyn- Cough Headache 3.8 3.8 5.0 6.2 9.2 9.2 9.6 8.8 11.5 3.8 3.8 5.0 6.2 9.2 9.2 9.6 8.8 11.5 3.8 3.8 5.0 6.2 9.2 9.2 9.6 8.8 11.5 Nausea tion pa- sti- Con- Headache ness Dizzi- petite ap- creased De- related: infection ral Vi- tis chi- Bron- tis rhini- gic ler- Al- Pyrexia tis gi- sopharyn- Na- tis tivi- junc- con- gic ler- Al- tis gi- Pharyn- Cough Headache 30 Nausea tion pa- sti- Con- Headache ness Dizzi- petite ap- creased De- related: Treatment- infection ral Vi- tis chi- Bron- tis rhini- gic ler- Al- Pyrexia tis gi- sopharyn- Na- tis tivi- junc- con- gic ler- Al- tis gi- Pharyn- Cough Headache Nausea tion pa- sti- Con- Headache ness Dizzi- petite ap- creased De- related: Treatment- infection ral Vi- tis chi- Bron- tis rhini- gic ler- Al- Pyrexia tis gi- sopharyn- Na- tis tivi- junc- con- gic ler- Al- tis gi- Pharyn- Cough Headache Nausea tion pa- sti- Con- Headache ness Dizzi- petite ap- creased De- related: Treatment- infection ral Vi- tis chi- Bron- tis rhini- gic ler- Al- Pyrexia tis gi- sopharyn- Na- tis tivi- junc- con- gic ler- Al- tis gi- Pharyn- Cough Headache 1.4 1.4 1.4 1.4 1.4 6.4 5.6 8.4 9.2 6.8 7.6 6.4 8.8 10.4 1.4 1.4 1.4 1.4 1.4 6.4 5.6 8.4 9.2 6.8 7.6 6.4 8.8 10.4 Constipation pain nal i- dom- Ab- per up- pain nal i- dom- Ab- ALP creased In- related: Treatment- Constipation pain nal i- dom- Ab- per up- pain nal i- dom- Ab- ALP creased In- related: Treatment- Constipation pain nal i- dom- Ab- per up- pain nal i- dom- Ab- ALP creased In- related: Treatment- 1.4 1.4 1.4 1.4 1.4 1.4 1.4 1.4 1.4 1.4 1.4 1.4 Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. 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(18) 2012 al., et Wu (17) 2013 al., et Potter (19) 2011 al., et Marucci (20) 2010 al., et Hampel AEs CPHD CPHD CPHD CPHD No CPHD CPHD LRD LRD LRD LRD LRD LRD Somnolence fluenza In- Eczema, taxis, Epis- pain, nal i- dom- Ab- Cough, Headache PlaceboPlaceboPlaceboPlaceboPlaceboPlacebo RPD RPD RPD RPD RPD RPD HeadacheHeadacheHeadacheHeadache14.3 Headache 14.3 PlaceboPlaceboPlaceboPlaceboPlaceboPlacebo LCTZ LCTZ LCTZ LCTZ LCTZ LCTZ OD) mg (1.25 LCTZ AEs No Somnolence fluenza In- Eczema, taxis, Epis- pain, nal i- dom- Ab- Cough, Headache OD) mg (1.25 LCTZ AEs No Somnolence fluenza In- Eczema, taxis, Epis- pain, nal i- dom- Ab- Cough, Headache OD) mg (1.25 LCTZ 1.1 <4.0 12.8 AEs No OD) mg (1.25 LCTZ 1.1 <4.0 12.8 AEs No OD) mg (1.25 LCTZ 1.1 <4.0 12.8 AEs No OD) mg (1.25 LCTZ Influenza Eczema, taxis, Epis- pain, nal i- dom- Ab- Cough, Headache drowsiness creased In- petite ap- Increased pain nal i- dom- Ab- PlaceboPlaceboPlaceboPlaceboPlaceboPlacebo 31 Influenza Eczema, taxis, Epis- pain, nal i- dom- Ab- Cough, Headache drowsiness creased In- petite ap- Increased pain nal i- dom- Ab- Headache <4.0 5.6 4.3 8.7 5.3 10.5 <4.0 5.6 4.3 8.7 5.3 10.5 <4.0 5.6 4.3 8.7 5.3 10.5 <4.0 5.6 4.3 8.7 5.3 10.5 Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (20) 2010 al., et Hampel BD) mg (1.25 LCTZ disorders sue tis- neous ta- cu- sub- and Skin Cough lence no- Som- URTI ral Vi- dia me- tis Oti- tis nusi- Si- URTI ity tabil- ri- Ir- Pyrexia tion pa- sti- Con- Teething Diarrhea BD) mg (1.25 LCTZ disorders sue tis- neous ta- cu- sub- and Skin Cough lence no- Som- URTI ral Vi- dia me- tis Oti- tis nusi- Si- URTI ity tabil- ri- Ir- Pyrexia tion pa- sti- Con- Teething Diarrhea BD) mg (1.25 LCTZ disorders sue tis- neous ta- cu- sub- and Skin Cough lence no- Som- URTI ral Vi- dia me- tis Oti- tis nusi- Si- URTI ity tabil- ri- Ir- Pyrexia tion pa- sti- Con- Teething Diarrhea BD) mg (1.25 LCTZ disorders sue tis- neous ta- cu- sub- and Skin Cough lence no- Som- URTI ral Vi- dia me- tis Oti- tis nusi- Si- URTI ity tabil- ri- Ir- Pyrexia tion pa- sti- Con- Teething Diarrhea BD) mg (1.25 LCTZ 13.3 2.2 4.4 2.2 4.4 2.2 4.4 2.2 15.6 6.7 6.7 13.3 BD) mg (1.25 LCTZ 13.3 2.2 4.4 2.2 4.4 2.2 4.4 2.2 15.6 6.7 6.7 13.3 disorders sue tis- neous ta- cu- sub- and Skin Cough lence no- Som- dia me- tis Oti- ity tabil- ri- Ir- Pyrexia tion pa- sti- Con- Diarrhea PlaceboPlaceboPlaceboPlaceboPlaceboPlacebo 32 disorders sue tis- neous ta- cu- sub- and Skin Cough lence no- Som- dia me- tis Oti- ity tabil- ri- Ir- Pyrexia tion pa- sti- Con- Diarrhea disorders sue tis- neous ta- cu- sub- and Skin Cough lence no- Som- dia me- tis Oti- ity tabil- ri- Ir- Pyrexia tion pa- sti- Con- Diarrhea 29.2 8.3 4.2 8.3 12.5 16.7 4.2 4.2 29.2 8.3 4.2 8.3 12.5 16.7 4.2 4.2 29.2 8.3 4.2 8.3 12.5 16.7 4.2 4.2 29.2 8.3 4.2 8.3 12.5 16.7 4.2 4.2 Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (21) 2009 al., et Lee (22) 2009 al., et Ngamphaiboon (23) 2007 al., et Hampel T T T T T T CZLT CZLT CZLT PlaceboPlaceboPlaceboPlaceboPlacebo LCTZ LCTZ LCTZ sedation LCTZ LCTZ LCTZ Mild CTZ CTZ CTZ CTZ CTZ CTZ R R R R R R T T T T T T PlaceboPlaceboPlaceboPlaceboPlacebo KTF KTF KTF KTF Somnolence KTF Irritability KTF LRD LRD LRD LRD LRD LRD disorders sue tis- neous ta- cu- sub- and Skin Cough lence no- Som- URTI ral Vi- dia me- tis Oti- tis nusi- Si- URTI Pyrexia tion pa- sti- Con- Teething Diarrhea BD) mg (15 HCL FXD sedation Mild Somnolence Irritability disorders sue tis- neous ta- cu- sub- and Skin Cough lence no- Som- URTI ral Vi- dia me- tis Oti- tis nusi- Si- URTI Pyrexia tion pa- sti- Con- Teething Diarrhea BD) mg (15 HCL FXD sedation Mild Somnolence Irritability disorders sue tis- neous ta- cu- sub- and Skin Cough lence no- Som- URTI ral Vi- dia me- tis Oti- tis nusi- Si- URTI Pyrexia tion pa- sti- Con- Teething Diarrhea BD) mg (15 HCL FXD sedation Mild Somnolence Irritability disorders sue tis- neous ta- cu- sub- and Skin Cough lence no- Som- URTI ral Vi- dia me- tis Oti- tis nusi- Si- URTI Pyrexia tion pa- sti- Con- Teething Diarrhea BD) mg (15 HCL FXD . . Mild 3.7 3.7 4.4 3.5 0.9 0.9 2.6 0.9 2.6 4.4 0.9 1.8 3.5 DN Irritability ND ND BD) mg (15 HCL FXD 4.4 3.5 0.9 0.9 2.6 0.9 2.6 4.4 0.9 1.8 3.5 BD) mg (15 HCL FXD fatigue disorders sue tis- neous ta- cu- sub- and Skin Cough ity tiv- ac- per- hy- tor chomo- Psy- lence no- Som- URTI ral Vi- tis nusi- Si- URTI Pyrexia Diarrhea Somnolence BD) mg (30 HCL FXD 33 disorders sue tis- neous ta- cu- sub- and Skin Cough ity tiv- ac- per- hy- tor chomo- Psy- lence no- Som- URTI ral Vi- tis nusi- Si- URTI Pyrexia Diarrhea fatigue Mild Somnolence Irritability BD) mg (30 HCL FXD disorders sue tis- neous ta- cu- sub- and Skin Cough ity tiv- ac- per- hy- tor chomo- Psy- lence no- Som- URTI ral Vi- tis nusi- Si- URTI Pyrexia Diarrhea fatigue Mild Somnolence Irritability BD) mg (30 HCL FXD 1.7 8.5 5.1 3.4 3.4 3.4 3.4 1.7 3.4 . . . . No 3.8 3.8 3.8 3.8 DN DN Irritability ND ND ND ND BD) mg (30 HCL FXD 1.7 8.5 5.1 3.4 3.4 3.4 3.4 1.7 3.4 BD) mg (30 HCL FXD 1.7 8.5 5.1 3.4 3.4 3.4 3.4 1.7 3.4 BD) mg (30 HCL FXD 1.7 8.5 5.1 3.4 3.4 3.4 3.4 1.7 3.4 PlaceboPlaceboPlaceboPlaceboPlacebo AEs Somnolence DN ND ND ND Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (23) al.,2007 et Hampel BD) mg (15 HCL FXD pendages ap- and Skin dia me- tis Oti- tion fec- In- Fever tis Rhini- URTI creased in- Cough tem sys- tory ra- pi- Res- tis teri- troen- Gas- rhea ar- Di- ing it- Vom- tem sys- Digestive BD) mg (15 HCL FXD pendages ap- and Skin dia me- tis Oti- tion fec- In- Fever tis Rhini- URTI creased in- Cough tem sys- tory ra- pi- Res- tis teri- troen- Gas- rhea ar- Di- ing it- Vom- tem sys- Digestive BD) mg (15 HCL FXD pendages ap- and Skin dia me- tis Oti- tion fec- In- Fever tis Rhini- URTI creased in- Cough tem sys- tory ra- pi- Res- tis teri- troen- Gas- rhea ar- Di- ing it- Vom- tem sys- Digestive BD) mg (15 HCL FXD pendages ap- and Skin dia me- tis Oti- tion fec- In- Fever tis Rhini- URTI creased in- Cough tem sys- tory ra- pi- Res- tis teri- troen- Gas- rhea ar- Di- ing it- Vom- tem sys- Digestive BD) mg (15 HCL FXD 6.9 1.7 3.4 1.7 3.4 1.7 1.7 12.2 3.4 5.2 15.5 25.9 BD) mg (15 HCL FXD 6.9 1.7 3.4 1.7 3.4 1.7 1.7 12.2 3.4 5.2 15.5 25.9 URTI tem sys- tory ra- pi- Res- ing it- Vom- tem sys- Digestive BD) mg (30 HCL FXD 34 URTI tem sys- tory ra- pi- Res- ing it- Vom- tem sys- Digestive BD) mg (30 HCL FXD URTI tem sys- tory ra- pi- Res- ing it- Vom- tem sys- Digestive BD) mg (30 HCL FXD 20 20 20 20 BD) mg (30 HCL FXD 20 20 20 20 BD) mg (30 HCL FXD 20 20 20 20 BD) mg (30 HCL FXD 20 20 20 20 PlaceboPlaceboPlaceboPlaceboPlacebo pendages ap- and Skin dia me- tis Oti- tion fec- In- jury in- tional ten- in- Un- Fever URTI tem sys- tory ra- pi- Res- rhea ar- Di- ing it- Vom- tem sys- Digestive 1.4 7.2 2.9 1.4 5.8 5.8 10.1 1.4 14.5 15.9 1.4 7.2 2.9 1.4 5.8 5.8 10.1 1.4 14.5 15.9 1.4 7.2 2.9 1.4 5.8 5.8 10.1 1.4 14.5 15.9 Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (24) 2007 al., et Milgrom HCL FXD appendages and Skin der or- dis- Ear tis thalmi- Oph- dia me- tis Oti- jury in- tional ten- in- Un- Fever URTI creased in- Cough tem sys- tory ra- pi- Res- tis teri- troen- Gas- rhea ar- Di- ing it- Vom- tem sys- Digestive HCL FXD appendages and Skin der or- dis- Ear tis thalmi- Oph- dia me- tis Oti- jury in- tional ten- in- Un- Fever URTI creased in- Cough tem sys- tory ra- pi- Res- tis teri- troen- Gas- rhea ar- Di- ing it- Vom- tem sys- Digestive HCL FXD appendages and Skin der or- dis- Ear tis thalmi- Oph- dia me- tis Oti- jury in- tional ten- in- Un- Fever URTI creased in- Cough tem sys- tory ra- pi- Res- tis teri- troen- Gas- rhea ar- Di- ing it- Vom- tem sys- Digestive HCL FXD appendages and Skin der or- dis- Ear tis thalmi- Oph- dia me- tis Oti- jury in- tional ten- in- Un- Fever URTI creased in- Cough tem sys- tory ra- pi- Res- tis teri- troen- Gas- rhea ar- Di- ing it- Vom- tem sys- Digestive HCL FXD 3.7 3.7 3.7 7.4 3.7 3.7 3.7 3.7 7.4 3.7 3.7 11.1 18.5 HCL FXD 3.7 3.7 3.7 7.4 3.7 3.7 3.7 3.7 7.4 3.7 3.7 11.1 18.5 appendages and Skin dia me- tis Oti- tion fec- In- jury in- tional ten- in- Un- Fever tis Rhini- URTI creased in- Cough tem sys- tory ra- pi- Res- lence u- Flat- tis teri- troen- Gas- rhea ar- Di- ing it- Vom- tem sys- Digestive PlaceboPlaceboPlaceboPlaceboPlaceboPlacebo 35 appendages and Skin dia me- tis Oti- tion fec- In- jury in- tional ten- in- Un- Fever tis Rhini- URTI creased in- Cough tem sys- tory ra- pi- Res- lence u- Flat- tis teri- troen- Gas- rhea ar- Di- ing it- Vom- tem sys- Digestive appendages and Skin dia me- tis Oti- tion fec- In- jury in- tional ten- in- Un- Fever tis Rhini- URTI creased in- Cough tem sys- tory ra- pi- Res- lence u- Flat- tis teri- troen- Gas- rhea ar- Di- ing it- Vom- tem sys- Digestive 3.9 6.8 1.9 1.0 4.9 2.9 3.9 3.9 11.7 1.0 1.0 5.8 4.9 15.5 3.9 6.8 1.9 1.0 4.9 2.9 3.9 3.9 11.7 1.0 1.0 5.8 4.9 15.5 3.9 6.8 1.9 1.0 4.9 2.9 3.9 3.9 11.7 1.0 1.0 5.8 4.9 15.5 3.9 6.8 1.9 1.0 4.9 2.9 3.9 3.9 11.7 1.0 1.0 5.8 4.9 15.5 appendages and Skin der or- dis- Ear dia me- tis Oti- tion fec- In- Fever tis Rhini- URTI creased in- Cough tem sys- tory ra- pi- Res- lence u- Flat- tis teri- troen- Gas- rhea ar- Di- ing it- Vom- tem sys- Digestive 5.4 2.3 4.6 6.2 10.8 6 6.2 6.2 18.5 3.1 1.5 2.3 13.1 20.8 5.4 2.3 4.6 6.2 10.8 6 6.2 6.2 18.5 3.1 1.5 2.3 13.1 20.8 5.4 2.3 4.6 6.2 10.8 6 6.2 6.2 18.5 3.1 1.5 2.3 13.1 20.8 Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (25) al.,2007 et Simons CZLT CZLT CZLT PlaceboPlaceboPlaceboPlaceboPlaceboPlacebo LCTZ LCTZ LCTZ LCTZ LCTZ LCTZ senses cial Spe- pain Ear dia me- tis Oti- Headache rhea ar- Di- pain GI ing it- Vom- tion fec- In- jury in- tal den- ci- Ac- Fever tis gi- Pharyn- tis Rhini- URTI creased in- Cough tem sys- Respiratory senses cial Spe- pain Ear dia me- tis Oti- Headache rhea ar- Di- pain GI ing it- Vom- tion fec- In- jury in- tal den- ci- Ac- Fever tis gi- Pharyn- tis Rhini- URTI creased in- Cough tem sys- Respiratory senses cial Spe- pain Ear dia me- tis Oti- Headache rhea ar- Di- pain GI ing it- Vom- tion fec- In- jury in- tal den- ci- Ac- Fever tis gi- Pharyn- tis Rhini- URTI creased in- Cough tem sys- Respiratory senses cial Spe- pain Ear dia me- tis Oti- Headache rhea ar- Di- pain GI ing it- Vom- tion fec- In- jury in- tal den- ci- Ac- Fever tis gi- Pharyn- tis Rhini- URTI creased in- Cough tem sys- Respiratory 5.9 1.4 3.6 3.2 2.3 2.7 5.0 3.6 4.5 5.9 2.7 4.1 4.1 4.5 20.3 5.9 1.4 3.6 3.2 2.3 2.7 5.0 3.6 4.5 5.9 2.7 4.1 4.1 4.5 20.3 senses cial Spe- pain Ear dia me- tis Oti- Headache rhea ar- Di- pain GI ing it- Vom- tion fec- In- jury in- tal den- ci- Ac- Fever tis gi- Pharyn- tis Rhini- URTI creased in- Cough tem sys- Respiratory 36 senses cial Spe- pain Ear dia me- tis Oti- Headache rhea ar- Di- pain GI ing it- Vom- tion fec- In- jury in- tal den- ci- Ac- Fever tis gi- Pharyn- tis Rhini- URTI creased in- Cough tem sys- Respiratory senses cial Spe- pain Ear dia me- tis Oti- Headache rhea ar- Di- pain GI ing it- Vom- tion fec- In- jury in- tal den- ci- Ac- Fever tis gi- Pharyn- tis Rhini- URTI creased in- Cough tem sys- Respiratory 5.6 2.6 1.3 3.9 3.0 2.6 4.8 6.1 3.0 5.6 0.9 2.6 6.9 3.0 17.3 5.6 2.6 1.3 3.9 3.0 2.6 4.8 6.1 3.0 5.6 0.9 2.6 6.9 3.0 17.3 5.6 2.6 1.3 3.9 3.0 2.6 4.8 6.1 3.0 5.6 0.9 2.6 6.9 3.0 17.3 5.6 2.6 1.3 3.9 3.0 2.6 4.8 6.1 3.0 5.6 0.9 2.6 6.9 3.0 17.3 Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. disorder Sleep ness vous- Ner- nia som- In- Headache sions vul- con- Febrile Epilepsy sions vul- Con- nia mo- neu- chop- Bron- tion ta- i- Ag- ior hav- be- mal nor- Ab- events: logic/behavioral ro- Neu- ticaria Ur- sion vul- con- Febrile nia mo- neu- chop- Bron- Cough tis teri- troen- Gas- atopic tis mati- Der- ing Wheez- AEs: Serious disorder Sleep ness vous- Ner- nia som- In- Headache sions vul- con- Febrile Epilepsy sions vul- Con- nia mo- neu- chop- Bron- tion ta- i- Ag- ior hav- be- mal nor- Ab- events: logic/behavioral ro- Neu- ticaria Ur- sion vul- con- Febrile nia mo- neu- chop- Bron- Cough tis teri- troen- Gas- atopic tis mati- Der- ing Wheez- AEs: Serious disorder Sleep ness vous- Ner- nia som- In- Headache sions vul- con- Febrile Epilepsy sions vul- Con- nia mo- neu- chop- Bron- tion ta- i- Ag- ior hav- be- mal nor- Ab- events: logic/behavioral ro- Neu- ticaria Ur- sion vul- con- Febrile nia mo- neu- chop- Bron- Cough tis teri- troen- Gas- atopic tis mati- Der- ing Wheez- AEs: Serious disorder Sleep ness vous- Ner- nia som- In- Headache sions vul- con- Febrile Epilepsy sions vul- Con- nia mo- neu- chop- Bron- tion ta- i- Ag- ior hav- be- mal nor- Ab- events: logic/behavioral ro- Neu- ticaria Ur- sion vul- con- Febrile nia mo- neu- chop- Bron- Cough tis teri- troen- Gas- atopic tis mati- Der- ing Wheez- AEs: Serious 0.4 0.4 1.2 0.4 2.0 0.4 0.4 1.6 0.4 0.8 0.4 1.6 1.6 1.6 0.8 1.2 4.7 0.4 0.4 1.2 0.4 2.0 0.4 0.4 1.6 0.4 0.8 0.4 1.6 1.6 1.6 0.8 1.2 4.7 Syncope lence no- Som- der or- dis- Sleep mare Night- ity tabil- ri- Ir- nia som- In- Headache sions vul- con- Febrile tion sa- sen- ing Burn- ety i- Anx- sion gres- Ag- ior hav- be- mal nor- Ab- events: logic/behavioral ro- Neu- chronic tis chi- Bron- ticaria Ur- nia mo- neu- chop- Bron- Cough tis teri- troen- Gas- atopic tis mati- Der- ing Wheez- AEs: Serious 37 Syncope lence no- Som- der or- dis- Sleep mare Night- ity tabil- ri- Ir- nia som- In- Headache sions vul- con- Febrile tion sa- sen- ing Burn- ety i- Anx- sion gres- Ag- ior hav- be- mal nor- Ab- events: logic/behavioral ro- Neu- chronic tis chi- Bron- ticaria Ur- nia mo- neu- chop- Bron- Cough tis teri- troen- Gas- atopic tis mati- Der- ing Wheez- AEs: Serious Syncope lence no- Som- der or- dis- Sleep mare Night- ity tabil- ri- Ir- nia som- In- Headache sions vul- con- Febrile tion sa- sen- ing Burn- ety i- Anx- sion gres- Ag- ior hav- be- mal nor- Ab- events: logic/behavioral ro- Neu- chronic tis chi- Bron- ticaria Ur- nia mo- neu- chop- Bron- Cough tis teri- troen- Gas- atopic tis mati- Der- ing Wheez- AEs: Serious 0.4 0.4 0.4 0.4 1.6 0.8 1.6 0.4 0.4 0.4 0.4 1.2 1.2 1.2 0.4 0.8 2.0 2.4 7.5 0.4 0.4 0.4 0.4 1.6 0.8 1.6 0.4 0.4 0.4 0.4 1.2 1.2 1.2 0.4 0.8 2.0 2.4 7.5 0.4 0.4 0.4 0.4 1.6 0.8 1.6 0.4 0.4 0.4 0.4 1.2 1.2 1.2 0.4 0.8 2.0 2.4 7.5 0.4 0.4 0.4 0.4 1.6 0.8 1.6 0.4 0.4 0.4 0.4 1.2 1.2 1.2 0.4 0.8 2.0 2.4 7.5 Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (26) 2006 al., et Chen (27) 2006 al., et Prenner sedation duced in- tion PlaceboPlaceboPlaceboPlaceboPlacebo MLK ca- MLK MLK i- MLK med- MLK MLK Mild CTZ CTZ CTZ CTZ CTZ CTZ LDDR LDDR LDDR PlaceboPlaceboPlaceboPlaceboPlaceboPlacebo DLRD DLRD DLRD DLRD DLRD DLRD sedation duced in- tion ca- i- med- Mild sedation duced in- tion ca- i- med- Mild sedation duced in- tion ca- i- med- Mild 001. No 10.0 10.0 AEs 38 AEs No AEs No AEs No Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (28) 2005 al., et Blic de Somnolence taxis Epis- Headache PlaceboPlaceboPlaceboPlaceboPlaceboPlacebo LCTZ LCTZ LCTZ LCTZ LCTZ LCTZ (unrelated) tion fec- in- moderate to- Mild- taxis Epis- ing Cough- tis chi- Bron- ity tabil- ri- Ir- nia som- In- rhea ar- Di- lence no- Som- Fever petite ap- creased In- Anorexia related: Treatment- Somnolence taxis Epis- Headache (unrelated) tion fec- in- moderate to- Mild- taxis Epis- ing Cough- tis chi- Bron- ity tabil- ri- Ir- nia som- In- rhea ar- Di- lence no- Som- Fever petite ap- creased In- Anorexia related: Treatment- Somnolence taxis Epis- Headache (unrelated) tion fec- in- moderate to- Mild- taxis Epis- ing Cough- tis chi- Bron- ity tabil- ri- Ir- nia som- In- rhea ar- Di- lence no- Som- Fever petite ap- creased In- Anorexia related: Treatment- Somnolence taxis Epis- Headache (unrelated) tion fec- in- moderate to- Mild- taxis Epis- ing Cough- tis chi- Bron- ity tabil- ri- Ir- nia som- In- rhea ar- Di- lence no- Som- Fever petite ap- creased In- Anorexia related: Treatment- 1.1 5.6 4.5 0.8 0.8 1.5 0.8 6.9 2.3 6.1 5.3 3.1 2.3 3.1 1.1 5.6 4.5 0.8 0.8 1.5 0.8 6.9 2.3 6.1 5.3 3.1 2.3 3.1 (unrelated) tis oli- chi- bron- ral vi- Mild lated) re- (un- tion fec- in- moderate to- Mild- ing Cough- ity tabil- ri- Ir- rhea ar- Di- lence no- Som- Fever petite ap- creased In- Anorexia related: Treatment- Epistaxis Headache 39 (unrelated) tis oli- chi- bron- ral vi- Mild lated) re- (un- tion fec- in- moderate to- Mild- ing Cough- ity tabil- ri- Ir- rhea ar- Di- lence no- Som- Fever petite ap- creased In- Anorexia related: Treatment- Epistaxis Headache (unrelated) tis oli- chi- bron- ral vi- Mild lated) re- (un- tion fec- in- moderate to- Mild- ing Cough- ity tabil- ri- Ir- rhea ar- Di- lence no- Som- Fever petite ap- creased In- Anorexia related: Treatment- Epistaxis Headache 0.8 1.6 1.6 5.6 2.4 7.3 0.8 2.4 1.6 1.1 9.1 0.8 1.6 1.6 5.6 2.4 7.3 0.8 2.4 1.6 1.1 9.1 0.8 1.6 1.6 5.6 2.4 7.3 0.8 2.4 1.6 1.1 9.1 0.8 1.6 1.6 5.6 2.4 7.3 0.8 2.4 1.6 1.1 9.1 Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (29) 2005 al., et Potter (30) 2004 al., et Bloom (31) 2004 al., et Grimfeld (30) 2004 al., et Bloom Influenza URTI Headache PlaceboPlaceboPlaceboPlaceboPlaceboPlacebo LCTZ LCTZ LCTZ LCTZ LCTZ LCTZ HeadacheHeadacheHeadacheHeadache1.7 Headache 1.7 PlaceboPlaceboPlaceboPlaceboPlaceboPlacebo DLRD DLRD DLRD DLRD DLRD DLRD R R R R R R PlaceboPlaceboPlaceboPlaceboPlaceboPlacebo LRD LRD LRD LRD LRD LRD infection tract nary Uri- Rash cella Vari- tion fec- in- ral Vi- Headache Fever PlaceboPlaceboPlaceboPlaceboPlaceboPlacebo DLRD DLRD DLRD DLRD DLRD DLRD Influenza URTI Headache infection tract nary Uri- Rash cella Vari- tion fec- in- ral Vi- Headache Fever Influenza URTI Headache infection tract nary Uri- Rash cella Vari- tion fec- in- ral Vi- Headache Fever Influenza URTI Headache infection tract nary Uri- Rash cella Vari- tion fec- in- ral Vi- Headache Fever 3.6 3.6 3.6 1.8 1.8 5.5 5.2 8.4 12.3 3.6 3.6 3.6 1.8 1.8 5.5 5.2 8.4 12.3 Vomiting tis teri- troen- Gas- media tis Oti- tion fec- in- ral Vi- Headache Fever Influenza URTI Headache 40 media tis Oti- tion fec- in- ral Vi- Headache Fever Vomiting tis teri- troen- Gas- Headache Influenza URTI Headache media tis Oti- tion fec- in- ral Vi- Headache Fever Vomiting tis teri- troen- Gas- Headache Influenza URTI Headache 1.8 1.8 5.4 5.4 3.3 3.3 6.7 9.2 11.8 11.2 1.8 1.8 5.4 5.4 3.3 3.3 6.7 9.2 11.8 11.2 1.8 1.8 5.4 5.4 3.3 3.3 6.7 9.2 11.8 11.2 1.8 1.8 5.4 5.4 3.3 3.3 6.7 9.2 11.8 11.2 Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (33) al.,2003 et Wahn (32) al.,2004 et Hsieh T T T T T T L L L L L L PlaceboPlaceboPlaceboPlaceboPlacebo MLK Headache MLK MLK HCL 5.0 MLK FXD MLK MLK 5.0 HeadacheHeadacheHeadache5.0 CTZ SedationSedationSedationSedation5.0 CTZ 5.0 5.0 CTZ CTZ CTZ CTZ Vomiting tion fec- in- ral Vi- tis li- sil- Ton- ing Cough- cella Vari- Fever tis Rhini- tis teri- troen- Gas- dia me- tis Oti- tis chi- Bron- Pharyngitis HCL FXD Vomiting tion fec- in- ral Vi- tis li- sil- Ton- ing Cough- cella Vari- Fever tis Rhini- tis teri- troen- Gas- dia me- tis Oti- tis chi- Bron- Pharyngitis HCL FXD Vomiting tion fec- in- ral Vi- tis li- sil- Ton- ing Cough- cella Vari- Fever tis Rhini- tis teri- troen- Gas- dia me- tis Oti- tis chi- Bron- Pharyngitis HCL FXD Vomiting tion fec- in- ral Vi- tis li- sil- Ton- ing Cough- cella Vari- Fever tis Rhini- tis teri- troen- Gas- dia me- tis Oti- tis chi- Bron- Pharyngitis HCL FXD 5.5 5.5 5.5 7.3 8.5 6.7 7.9 7.9 9.1 15.8 18.8 HCL FXD 5.5 5.5 5.5 7.3 8.5 6.7 7.9 7.9 9.1 15.8 18.8 Vomiting tion fec- in- ral Vi- tis li- sil- Ton- ing Cough- cella Vari- Fever tis Rhini- tis teri- troen- Gas- dia me- tis Oti- tis chi- Bron- Pharyngitis PlaceboPlaceboPlaceboPlaceboPlaceboPlacebo 41 Vomiting tion fec- in- ral Vi- tis li- sil- Ton- ing Cough- cella Vari- Fever tis Rhini- tis teri- troen- Gas- dia me- tis Oti- tis chi- Bron- Pharyngitis Vomiting tion fec- in- ral Vi- tis li- sil- Ton- ing Cough- cella Vari- Fever tis Rhini- tis teri- troen- Gas- dia me- tis Oti- tis chi- Bron- Pharyngitis 3.4 4.5 5.1 5.1 4.5 7.3 7.3 7.9 13.0 13.0 18.1 3.4 4.5 5.1 5.1 4.5 7.3 7.3 7.9 13.0 13.0 18.1 3.4 4.5 5.1 5.1 4.5 7.3 7.3 7.9 13.0 13.0 18.1 3.4 4.5 5.1 5.1 4.5 7.3 7.3 7.9 13.0 13.0 18.1 Fatigue 5.0 5.0 5.0 5.0 5.0 5.0 Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (34) 2003 al., et Segal T T T T T T PlaceboPlaceboPlaceboPlaceboPlaceboPlacebo CTZ CTZ CTZ CTZ CTZ CTZ (severe) nia trope- Neu- pain nal testi- troin- Gas- tion fec- In- Asthma jury in- tal den- ci- Ac- Rash sea Nau- tis nusi- Si- tis gi- Pharyn- URTI taxis Epis- Headache (severe) nia trope- Neu- pain nal testi- troin- Gas- tion fec- In- Asthma jury in- tal den- ci- Ac- Rash sea Nau- tis nusi- Si- tis gi- Pharyn- URTI taxis Epis- Headache (severe) nia trope- Neu- pain nal testi- troin- Gas- tion fec- In- Asthma jury in- tal den- ci- Ac- Rash sea Nau- tis nusi- Si- tis gi- Pharyn- URTI taxis Epis- Headache (severe) nia trope- Neu- pain nal testi- troin- Gas- tion fec- In- Asthma jury in- tal den- ci- Ac- Rash sea Nau- tis nusi- Si- tis gi- Pharyn- URTI taxis Epis- Headache 0.2 0.2 0.2 0.6 0.9 1.1 1.1 1.3 1.3 1.5 1.5 5.0 0.2 0.2 0.2 0.6 0.9 1.1 1.1 1.3 1.3 1.5 1.5 5.0 pain nal testi- troin- Gas- tion fec- In- Asthma jury in- tal den- ci- Ac- Rash sea Nau- tis gi- Pharyn- URTI taxis Epis- Headache 42 pain nal testi- troin- Gas- tion fec- In- Asthma jury in- tal den- ci- Ac- Rash sea Nau- tis gi- Pharyn- URTI taxis Epis- Headache pain nal testi- troin- Gas- tion fec- In- Asthma jury in- tal den- ci- Ac- Rash sea Nau- tis gi- Pharyn- URTI taxis Epis- Headache 1.1 1.1 1.9 1.3 0.6 0.2 0.2 1.1 1.1 2.8 1.1 1.1 1.9 1.3 0.6 0.2 0.2 1.1 1.1 2.8 1.1 1.1 1.9 1.3 0.6 0.2 0.2 1.1 1.1 2.8 1.1 1.1 1.9 1.3 0.6 0.2 0.2 1.1 1.1 2.8 Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (35) 2003 al., et Simons Rash tis Rhini- tis gi- Pharyn- Fever Tremor tion ta- i- Ag- URTI dia me- tis Oti- rhea ar- Di- Toothache+ lence no- Som- nia som- In- PlaceboPlaceboPlaceboPlaceboPlaceboPlaceboNervousness CTZ CTZ CTZ CTZ CTZ CTZ pain nal i- dom- Ab- ness vous- Ner- sea Nau- Rash lence no- Som- Headache Rash tis Rhini- tis gi- Pharyn- Fever Tremor tion ta- i- Ag- URTI dia me- tis Oti- rhea ar- Di- Toothache+ lence no- Som- nia som- In- Nervousness pain nal i- dom- Ab- ness vous- Ner- sea Nau- Rash lence no- Som- Headache Rash tis Rhini- tis gi- Pharyn- Fever Tremor tion ta- i- Ag- URTI dia me- tis Oti- rhea ar- Di- Toothache+ lence no- Som- nia som- In- Nervousness pain nal i- dom- Ab- ness vous- Ner- sea Nau- Rash lence no- Som- Headache Rash tis Rhini- tis gi- Pharyn- Fever Tremor tion ta- i- Ag- URTI dia me- tis Oti- rhea ar- Di- Toothache+ lence no- Som- nia som- In- Nervousness pain nal i- dom- Ab- ness vous- Ner- sea Nau- Rash lence no- Som- Headache 2.4 4.8 4.8 4.8 4.8 4.8 7.1 7.1 7.1 9.5 21.4 23.8 28.6 2.4 2.4 3.6 3.6 9.1 8.3 2.4 4.8 4.8 4.8 4.8 4.8 7.1 7.1 7.1 9.5 21.4 23.8 28.6 2.4 2.4 3.6 3.6 9.1 8.3 Rash tis Rhini- Cough Fever Tremor tion ta- i- Ag- URTI dia me- tis Oti- rhea ar- Di- Toothache+ lence no- Som- nia som- In- Nervousness Nervousness sea Nau- lence no- Som- Headache 43 Rash tis Rhini- Cough Fever Tremor tion ta- i- Ag- URTI dia me- tis Oti- rhea ar- Di- Toothache+ lence no- Som- nia som- In- Nervousness Nervousness sea Nau- lence no- Som- Headache Rash tis Rhini- Cough Fever Tremor tion ta- i- Ag- URTI dia me- tis Oti- rhea ar- Di- Toothache+ lence no- Som- nia som- In- Nervousness Nervousness sea Nau- lence no- Som- Headache 4.7 4.7 4.7 4.7 4.7 16.3 2.3 4.7 9.3 9.3 30.2 44.2 44.2 2.3 1.2 1.2 9.3 4.7 4.7 4.7 4.7 4.7 16.3 2.3 4.7 9.3 9.3 30.2 44.2 44.2 2.3 1.2 1.2 9.3 4.7 4.7 4.7 4.7 4.7 16.3 2.3 4.7 9.3 9.3 30.2 44.2 44.2 2.3 1.2 1.2 9.3 4.7 4.7 4.7 4.7 4.7 16.3 2.3 4.7 9.3 9.3 30.2 44.2 44.2 2.3 1.2 1.2 9.3 Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (36) 2002 al., et Lai (37) 2002 al., et Chuncharas (39) 2001 al., et Yang (40) 2001 al., et Ciprandi (38) 2001 al., et Rosa La (41) 2001 al., et Graft T T T T T T X X X X X X T T T T T PlaceboPlaceboPlaceboPlacebo KTF KTF KTF KTF KTF OXD OXD OXD OXD Fatigue OXD OXD Sedation CTZ CTZ CTZ CTZ CTZ CTZ Impetigo sea Nau- Dizziness PlaceboPlaceboPlaceboPlaceboPlaceboPlacebo LRD LRD LRD LRD LRD LRD AEs No PlaceboPlaceboPlaceboPlaceboPlaceboPlacebo LRD LRD LRD LRD LRD LRD AEs PlaceboPlaceboPlaceboPlaceboPlaceboPlaceboNo CTZ CTZ CTZ CTZ CTZ CTZ reaction gic ler- al- ral o- CTZ ri- CTZ pe- CTZ Moderate CTZ CTZ CTZ OXD OXD OXD OXD OXD OXD BD) mg (15 FXD Fatigue Sedation Impetigo sea Nau- Dizziness AEs No reaction gic ler- al- ral o- ri- pe- Moderate AEs No BD) mg (15 FXD Fatigue Sedation Impetigo sea Nau- Dizziness AEs No reaction gic ler- al- ral o- ri- pe- Moderate AEs No BD) mg (15 FXD Fatigue Sedation Impetigo sea Nau- Dizziness reaction gic ler- al- ral o- ri- pe- Moderate AEs No AEs No BD) mg (15 FXD 5.3 10.5 . . DN ND ND ND 3.2 3.2 4.2 4.2 4.2 BD) mg (15 FXD 5.3 10.5 4.2 4.2 4.2 BD) mg (15 FXD Fatigue Sedation Anorexia Dizziness AEs No AEs No BD) mg (30 FXD 44 Fatigue Sedation Anorexia Dizziness AEs No AEs No BD) mg (30 FXD Fatigue Sedation Anorexia Dizziness AEs No AEs No BD) mg (30 FXD 5.6 11.1 4.2 4.2 BD) mg (30 FXD 5.6 11.1 4.2 4.2 BD) mg (30 FXD 5.6 11.1 4.2 4.2 BD) mg (30 FXD 5.6 11.1 4.2 4.2 BD) mg (60 FXD Nausea Sedation BD) mg (60 FXD 6.3 6.3 BD) mg (60 FXD 6.3 6.3 BD) mg (60 FXD 6.3 6.3 BD) mg (60 FXD Sedation Headache PlaceboPlaceboPlaceboPlacebo Sedation Headache 6.3 6.3 6.3 6.3 Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (42) 2000 al., et Salmun (43) 1999 al., et Simons Vomiting Fever sia pep- Dys- ness Drowsi- Coughing PlaceboPlaceboPlaceboPlaceboPlaceboPlacebo LRD LRD LRD LRD LRD LRD T T T T T T PlaceboPlaceboPlaceboPlaceboPlaceboPlacebo CTZ CTZ CTZ CTZ CTZ CTZ Headache Fever pain nal i- dom- Ab- dent ci- ac- jury In- ing Cough- tis gi- Pharyn- URTI Vomiting Fever sia pep- Dys- ness Drowsi- Coughing Headache Fever pain nal i- dom- Ab- dent ci- ac- jury In- ing Cough- tis gi- Pharyn- URTI Vomiting Fever sia pep- Dys- ness Drowsi- Coughing Headache Fever pain nal i- dom- Ab- dent ci- ac- jury In- ing Cough- tis gi- Pharyn- URTI Vomiting Fever sia pep- Dys- ness Drowsi- Coughing Headache Fever pain nal i- dom- Ab- dent ci- ac- jury In- ing Cough- tis gi- Pharyn- URTI 5.0 7.0 2.0 7.0 3.0 8.0 1.8 2.7 1.8 1.3 4.0 4.9 5.0 7.0 2.0 7.0 3.0 8.0 1.8 2.7 1.8 1.3 4.0 4.9 Vomiting Headache Fever sia pep- Dys- ness Drowsi- Coughing treatment) to lated re- (un- lence no- Som- Headache Fever pain nal i- dom- Ab- dent ci- ac- jury In- ing Cough- tis gi- Pharyn- URTI 45 Vomiting Headache Fever sia pep- Dys- ness Drowsi- Coughing treatment) to lated re- (un- lence no- Som- Headache Fever pain nal i- dom- Ab- dent ci- ac- jury In- ing Cough- tis gi- Pharyn- URTI Vomiting Headache Fever sia pep- Dys- ness Drowsi- Coughing treatment) to lated re- (un- lence no- Som- Headache Fever pain nal i- dom- Ab- dent ci- ac- jury In- ing Cough- tis gi- Pharyn- URTI 0.5 7.2 2.4 1.9 2.9 3.8 2.9 4.3 5.0 7.0 8.0 7.0 7.0 5.0 0.5 7.2 2.4 1.9 2.9 3.8 2.9 4.3 5.0 7.0 8.0 7.0 7.0 5.0 0.5 7.2 2.4 1.9 2.9 3.8 2.9 4.3 5.0 7.0 8.0 7.0 7.0 5.0 0.5 7.2 2.4 1.9 2.9 3.8 2.9 4.3 5.0 7.0 8.0 7.0 7.0 5.0 Headache Fever pain nal i- dom- Ab- dent ci- ac- jury In- ing Cough- tis gi- Pharyn- URTI 9.4 1.9 2.3 4.2 2.3 2.8 1.4 9.4 1.9 2.3 4.2 2.3 2.8 1.4 9.4 1.9 2.3 4.2 2.3 2.8 1.4 Somnolence Headache Fever pain nal i- dom- Ab- dent ci- ac- jury In- ing Cough- tis gi- Pharyn- URTI Somnolence Headache Fever pain nal i- dom- Ab- dent ci- ac- jury In- ing Cough- tis gi- Pharyn- URTI 0.9 6.6 0.9 3.5 1.3 1.3 1.9 1.7 0.9 6.6 0.9 3.5 1.3 1.3 1.9 1.7 Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. 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Somnolence ness vous- Ner- nia som- In- sia ne- ki- per- Hy- ity bil- la- tional Emo- tigue Fa- sions vul- con- Febrile Ataxia jury in- ter af- cope Syn- mur mur- Heart tion ca- pli- com- tion niza- mu- Im- tion fec- in- ral vi- Other toms symp- like fluenza In- Toothache tion ac- re- gic ler- Al- ticaria Ur- cella Vari- tis gi- Pharyn- ing it- Vom- tis teri- troen- Gas- rhea ar- Di- Fever URTI Rhinitis Somnolence ness vous- Ner- nia som- In- sia ne- ki- per- Hy- ity bil- la- tional Emo- tigue Fa- sions vul- con- Febrile Ataxia jury in- ter af- cope Syn- mur mur- Heart tion ca- pli- com- tion niza- mu- Im- tion fec- in- ral vi- Other toms symp- like fluenza In- Toothache tion ac- re- gic ler- Al- ticaria Ur- cella Vari- tis gi- Pharyn- ing it- Vom- tis teri- troen- Gas- rhea ar- Di- Fever URTI Rhinitis Somnolence ness vous- Ner- nia som- In- sia ne- ki- per- Hy- ity bil- la- tional Emo- tigue Fa- sions vul- con- Febrile Ataxia jury in- ter af- cope Syn- mur mur- Heart tion ca- pli- com- tion niza- mu- Im- tion fec- in- ral vi- Other toms symp- like fluenza In- Toothache tion ac- re- gic ler- Al- ticaria Ur- cella Vari- tis gi- Pharyn- ing it- Vom- tis teri- troen- Gas- rhea ar- Di- Fever URTI Rhinitis Somnolence ness vous- Ner- nia som- In- sia ne- ki- per- Hy- ity bil- la- tional Emo- tigue Fa- sions vul- con- Febrile Ataxia jury in- ter af- cope Syn- mur mur- Heart tion ca- pli- com- tion niza- mu- Im- tion fec- in- ral vi- Other toms symp- like fluenza In- Toothache tion ac- re- gic ler- Al- ticaria Ur- cella Vari- tis gi- Pharyn- ing it- Vom- tis teri- troen- Gas- rhea ar- Di- Fever URTI Rhinitis 2.2 1.2 8.8 1.2 1.2 3.2 0.5 0.5 0.2 0.7 7.0 6.0 8.0 9.0 6.0 23.0 24.0 21.0 28.0 29.0 38.0 58.0 79.0 2.2 1.2 8.8 1.2 1.2 3.2 0.5 0.5 0.2 0.7 7.0 6.0 8.0 9.0 6.0 23.0 24.0 21.0 28.0 29.0 38.0 58.0 79.0 Somnolence ness vous- Ner- nia som- In- sia ne- ki- per- Hy- ity bil- la- tional Emo- tigue Fa- sions vul- con- Febrile Ataxia tole trasys- Ex- mia rhyth- ar- Other dia car- Tachy- mur Mur- tion ca- pli- com- tion niza- mu- Im- tion fec- in- ral vi- Other toms symp- like fluenza In- Toothache tion ac- re- gic ler- Al- ticaria Ur- cella Vari- tis gi- Pharyn- ing it- Vom- tis teri- troen- Gas- rhea ar- Di- Fever URTI Rhinitis 46 Somnolence ness vous- Ner- nia som- In- sia ne- ki- per- Hy- ity bil- la- tional Emo- tigue Fa- sions vul- con- Febrile Ataxia tole trasys- Ex- mia rhyth- ar- Other dia car- Tachy- mur Mur- tion ca- pli- com- tion niza- mu- Im- tion fec- in- ral vi- Other toms symp- like fluenza In- Toothache tion ac- re- gic ler- Al- ticaria Ur- cella Vari- tis gi- Pharyn- ing it- Vom- tis teri- troen- Gas- rhea ar- Di- Fever URTI Rhinitis Somnolence ness vous- Ner- nia som- In- sia ne- ki- per- Hy- ity bil- la- tional Emo- tigue Fa- sions vul- con- Febrile Ataxia tole trasys- Ex- mia rhyth- ar- Other dia car- Tachy- mur Mur- tion ca- pli- com- tion niza- mu- Im- tion fec- in- ral vi- Other toms symp- like fluenza In- Toothache tion ac- re- gic ler- Al- ticaria Ur- cella Vari- tis gi- Pharyn- ing it- Vom- tis teri- troen- Gas- rhea ar- Di- Fever URTI Rhinitis 2.0 1.8 5.3 2.3 1.5 1.3 1.0 0.5 0.2 0.2 0.2 0.7 6.0 7.0 9.0 14.0 16.0 22.0 28.0 22.0 27.0 28.0 42.0 62.0 77.0 2.0 1.8 5.3 2.3 1.5 1.3 1.0 0.5 0.2 0.2 0.2 0.7 6.0 7.0 9.0 14.0 16.0 22.0 28.0 22.0 27.0 28.0 42.0 62.0 77.0 2.0 1.8 5.3 2.3 1.5 1.3 1.0 0.5 0.2 0.2 0.2 0.7 6.0 7.0 9.0 14.0 16.0 22.0 28.0 22.0 27.0 28.0 42.0 62.0 77.0 2.0 1.8 5.3 2.3 1.5 1.3 1.0 0.5 0.2 0.2 0.2 0.7 6.0 7.0 9.0 14.0 16.0 22.0 28.0 22.0 27.0 28.0 42.0 62.0 77.0 Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (44) 1998 al., et Wahn T T T T T T PlaceboPlaceboPlaceboPlaceboPlaceboPlacebo CTZ CTZ CTZ CTZ CTZ CTZ 47 Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. complication tion na- ci- Vac- ticaria Ur- lence no- Som- tis gi- Laryn- nia som- In- sia ne- ki- per- Hy- creased in- zymes en- atic Hep- tigue Fa- creased in- petite Ap- Anorexia tion ac- re- gic ler- Al- tion ta- i- Ag- pain Abdominal complication tion na- ci- Vac- ticaria Ur- lence no- Som- tis gi- Laryn- nia som- In- sia ne- ki- per- Hy- creased in- zymes en- atic Hep- tigue Fa- creased in- petite Ap- Anorexia tion ac- re- gic ler- Al- tion ta- i- Ag- pain Abdominal complication tion na- ci- Vac- ticaria Ur- lence no- Som- tis gi- Laryn- nia som- In- sia ne- ki- per- Hy- creased in- zymes en- atic Hep- tigue Fa- creased in- petite Ap- Anorexia tion ac- re- gic ler- Al- tion ta- i- Ag- pain Abdominal complication tion na- ci- Vac- ticaria Ur- lence no- Som- tis gi- Laryn- nia som- In- sia ne- ki- per- Hy- creased in- zymes en- atic Hep- tigue Fa- creased in- petite Ap- Anorexia tion ac- re- gic ler- Al- tion ta- i- Ag- pain Abdominal 3.3 5.8 2.3 7.3 8.8 1.3 1.3 3.3 0.5 3.3 9.1 0.3 4.3 3.3 5.8 2.3 7.3 8.8 1.3 1.3 3.3 0.5 3.3 9.1 0.3 4.3 complication tion na- ci- Vac- ticaria Ur- lence no- Som- tis gi- Laryn- nia som- In- sia ne- ki- per- Hy- creased in- zymes en- atic Hep- tigue Fa- ties i- mal- nor- ab- ECG creased in- petite Ap- Anorexia tion ac- re- gic ler- Al- tion ta- i- Ag- pain Abdominal 48 complication tion na- ci- Vac- ticaria Ur- lence no- Som- tis gi- Laryn- nia som- In- sia ne- ki- per- Hy- creased in- zymes en- atic Hep- tigue Fa- ties i- mal- nor- ab- ECG creased in- petite Ap- Anorexia tion ac- re- gic ler- Al- tion ta- i- Ag- pain Abdominal complication tion na- ci- Vac- ticaria Ur- lence no- Som- tis gi- Laryn- nia som- In- sia ne- ki- per- Hy- creased in- zymes en- atic Hep- tigue Fa- ties i- mal- nor- ab- ECG creased in- petite Ap- Anorexia tion ac- re- gic ler- Al- tion ta- i- Ag- pain Abdominal 5.5 16.1 2.0 9.3 5.3 2.5 1.8 1.3 0.3 0.3 4.0 13.4 0.5 4.3 5.5 16.1 2.0 9.3 5.3 2.5 1.8 1.3 0.3 0.3 4.0 13.4 0.5 4.3 5.5 16.1 2.0 9.3 5.3 2.5 1.8 1.3 0.3 0.3 4.0 13.4 0.5 4.3 5.5 16.1 2.0 9.3 5.3 2.5 1.8 1.3 0.3 0.3 4.0 13.4 0.5 4.3 Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (46) 1998 al., et Serra (45) 1999 al., et Monge Sienra- (47) 1998 al., et Delgado (49) al.,1996 et Winder and (48) al.,1997 et Pearlman PSD. LRD- rash ized al- er- Gen- ity tabil- ri- LRD ir- LRD mild LRD and LRD Somnolence LRD LRD CTZ CTZ CTZ CTZ CTZ CTZ insomnia sient tran- Slight OD) mg 10 or mg (5 LRD AEs No OD) mg (10 CTZ rash ized al- er- Gen- ity tabil- ri- ir- mild and Somnolence PSD. LRD- insomnia sient tran- Slight OD) mg 10 or mg (5 LRD OD) mg (10 CTZ AEs No rash ized al- er- Gen- ity tabil- ri- ir- mild and Somnolence PSD. LRD- insomnia sient tran- Slight OD) mg 10 or mg (5 LRD OD) mg (10 CTZ AEs No rash ized al- er- Gen- ity tabil- ri- ir- mild and Somnolence PSD. LRD- insomnia sient tran- Slight OD) mg 10 or mg (5 LRD OD) mg (10 CTZ AEs No 2.5 2.5 PSD. LRD- . . No 5.0 5.0 OD) mg 10 or mg (5 LRD OD) mg (10 CTZ 2.5 2.5 PSD. LRD- OD) mg 10 or mg (5 LRD OD) mg (10 CTZ AEs No PlaceboPlaceboPlaceboPlaceboPlaceboPlacebo AEs OD) mg (10 CTZ AEs No OD) mg (5 CTZ 49 AEs No AEs No OD) mg (10 CTZ AEs No OD) mg (5 CTZ AEs No AEs No OD) mg (10 CTZ AEs No OD) mg (5 CTZ OD) mg (10 CTZ OD) mg (5 CTZ OD) mg (10 CTZ OD) mg (5 CTZ OD) mg (10 CTZ OD) mg (5 CTZ OD) mg 10 or mg (5 LRD PlaceboPlaceboPlaceboPlaceboPlacebo OD) mg 10 or mg (5 LRD AEs No OD) mg 10 or mg (5 LRD OD) mg 10 or mg (5 LRD OD) mg 10 or mg (5 LRD OD) mg (10 CTZ AEs No OD) mg (10 CTZ AEs No OD) mg (10 CTZ OD) mg (10 CTZ Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (53) al.,1996 et Fasce (51) 1997 al., et Benedictis (50) 1997 al., et Ciprandi (52) 1996 al., et Tinkelman DN DN DN ND ND ND ND ND ND PlaceboPlaceboPlaceboPlaceboPlaceboPlacebo CTZ ND CTZ CTZ CTZ CTZ CTZ OXD OXD OXD OXD OXD OXD SleepinessSleepinessSleepinessSleepiness8.0 CTZ Sleepiness CTZ CTZ 8.0 CTZ CTZ CTZ PlaceboPlaceboPlaceboPlaceboPlaceboPlaceboHeadacheHeadacheHeadacheHeadache10.0 CTZ 20.0 HeadacheHeadacheHeadache20.0 CTZ 20.0 CTZ 10.0 20.0 CTZ CTZ CTZ OD) mg 10 (5- CTZ Epistaxis pain nal i- dom- Ab- tis gi- Pharyn- Headache headache and sea Nau- tigue Fa- lence no- Som- pain Abdominal OD) mg 10 (5- CTZ Epistaxis pain nal i- dom- Ab- tis gi- Pharyn- Headache headache and sea Nau- tigue Fa- lence no- Som- pain Abdominal Epistaxis pain nal i- dom- Ab- tis gi- Pharyn- Headache OD) mg 10 (5- CTZ headache and sea Nau- tigue Fa- lence no- Som- pain Abdominal Epistaxis pain nal i- dom- Ab- tis gi- Pharyn- Headache headache and sea Nau- tigue Fa- lence no- Som- pain Abdominal OD) mg 10 (5- CTZ Epistaxis pain nal i- dom- Ab- tis gi- Pharyn- Headache headache and sea Nau- tigue Fa- lence no- Som- pain Abdominal OD) mg 10 (5- CTZ Epistaxis pain nal i- dom- Ab- tis gi- Pharyn- Headache headache and sea Nau- tigue Fa- lence no- Som- pain Abdominal OD) mg 10 (5- CTZ Epistaxis pain nal i- dom- Ab- tis gi- Pharyn- Headache SGPT creased in- Slightly headache and sea Nau- tigue Fa- lence no- Som- pain Abdominal OD) mg 5 (2.5- CTZ 50 Epistaxis pain nal i- dom- Ab- tis gi- Pharyn- Headache headache and sea Nau- tigue Fa- lence no- Som- pain Abdominal SGPT creased in- Slightly Sleepiness OD) mg 5 (2.5- CTZ Epistaxis pain nal i- dom- Ab- tis gi- Pharyn- Headache headache and sea Nau- tigue Fa- lence no- Som- pain Abdominal SGPT creased in- Slightly Sleepiness OD) mg 5 (2.5- CTZ 7.1 9.4 10.1 15.1 3.2 4.0 8.0 9.6 1.9 7.7 OD) mg 5 (2.5- CTZ 7.1 9.4 10.1 15.1 3.2 4.0 8.0 9.6 1.9 7.7 OD) mg 5 (2.5- CTZ 7.1 9.4 10.1 15.1 3.2 4.0 8.0 9.6 1.9 7.7 OD) mg 5 (2.5- CTZ 7.1 9.4 10.1 15.1 3.2 4.0 8.0 9.6 1.9 7.7 P P P P CPN CPN CPN CPN CPN Epistaxis pain nal i- dom- Ab- tis gi- Pharyn- Headache Headache sea Nau- tigue Fa- lence no- Som- pain Abdominal 4.3 4.5 13.6 19.7 6.3 1.6 6.3 7.9 4.8 4.3 4.5 13.6 19.7 6.3 1.6 6.3 7.9 4.8 4.3 4.5 13.6 19.7 6.3 1.6 6.3 7.9 4.8 Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (54) al.,1994 et Rosa La (55) al.,1994 et Jobst (57) al.,1993 et Masi (56) al.,1993 et Allegra AEs PlaceboPlaceboPlaceboPlaceboPlaceboPlaceboNo CTZ CTZ CTZ CTZ CTZ CTZ OD) mg (2.5 CTZ T T T T T T PlaceboPlaceboPlaceboPlaceboPlaceboPlacebo CTZ CTZ CTZ CTZ CTZ CTZ tract ND tory ND ra- pi- Res- nia som- In- ness vous- Ner- ND lence no- Som- rhea ar- Di- petite ap- creased In- pain nal ND i- ND dom- ND Ab- Fever Headache events: PlaceboPlaceboPlaceboPlaceboPlaceboPlaceboof CTZ Number CTZ ND CTZ CTZ ND CTZ ND CTZ ND AEs No OD) mg (2.5 CTZ tract tory ra- pi- Res- nia som- In- ness vous- Ner- lence no- Som- rhea ar- Di- petite ap- creased In- pain nal i- dom- Ab- Fever Headache events: of Number AEs No OD) mg (2.5 CTZ tract tory ra- pi- Res- nia som- In- ness vous- Ner- lence no- Som- rhea ar- Di- petite ap- creased In- pain nal i- dom- Ab- Fever Headache events: of Number AEs No OD) mg (2.5 CTZ tract tory ra- pi- Res- nia som- In- ness vous- Ner- lence no- Som- rhea ar- Di- petite ap- creased In- pain nal i- dom- Ab- Fever Headache events: of Number 3 1 2 3 1 1 1 2 1 OD) mg (2.5 CTZ 3 1 2 3 1 1 1 2 1 OD) mg (2.5 CTZ DN ND ND ND tract tory ra- pi- Res- sion pres- De- nia som- In- ness vous- Ner- ing it- Vom- rhea ar- Di- pain Α Η events: of Number OD) mg (5 CTZ bdominal eadache 51 Η events: of Number tract tory ra- pi- Res- sion pres- De- nia som- In- ness vous- Ner- ing it- Vom- rhea ar- Di- pain Α OD) mg (5 CTZ eadache bdominal Η events: of Number tract tory ra- pi- Res- sion pres- De- nia som- In- ness vous- Ner- ing it- Vom- rhea ar- Di- pain Α OD) mg (5 CTZ eadache bdominal 7 1 1 1 1 1 2 1 OD) mg (5 CTZ 7 1 1 1 1 1 2 1 OD) mg (5 CTZ 7 1 1 1 1 1 2 1 OD) mg (5 CTZ 7 1 1 1 1 1 2 1 OD) mg (10 CTZ OD) mg (10 CTZ OD) mg (10 CTZ OD) mg (10 CTZ OD) mg (10 CTZ PlaceboPlaceboPlaceboPlacebo Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. (59) al.,1989 et Boner (58) 1992 al., et Baelde R R R R R R CNDP CNDP CNDCPN DCPN DCPN DCPN DCPN DCPN LRD LRD LRD LRD LRD LRD OD) (10mg CTZ pain/diarrhea nal i- dom- Ab- crease in- petite Ap- change Mood Tiredness Pharyngitis cough creased In- pain nal i- dom- Ab- mouth Dry petite ap- creased In- Rash tigo Ver- Headache Somnolence OD) (10mg CTZ pain/diarrhea nal i- dom- Ab- crease in- petite Ap- change Mood Tiredness Pharyngitis cough creased In- pain nal i- dom- Ab- mouth Dry petite ap- creased In- Rash tigo Ver- Headache Somnolence OD) (10mg CTZ pain/diarrhea nal i- dom- Ab- crease in- petite Ap- change Mood Tiredness Pharyngitis cough creased In- pain nal i- dom- Ab- mouth Dry petite ap- creased In- Rash tigo Ver- Headache Somnolence pain/diarrhea nal i- dom- Ab- crease in- petite Ap- change Mood Tiredness OD) (10mg CTZ Pharyngitis cough creased In- pain nal i- dom- Ab- mouth Dry petite ap- creased In- Rash tigo Ver- Headache Somnolence 2.2 2.2 2.2 2.2 1.6 1.6 1.6 1.6 1.6 3.2 1.6 3.2 9.5 OD) (10mg CTZ 2.2 2.2 2.2 2.2 1.6 1.6 1.6 1.6 1.6 3.2 1.6 3.2 9.5 OD) (10mg CTZ Pharyngitis cough creased In- pain nal i- dom- Ab- Anorexia ing it- vom- - sea Nau- Headache Somnolence other pain/diarrhea nal i- dom- Ab- crease in- petite Ap- change Mood ing wak- ness/difficulty Sleepi- Tiredness OD) (5mg CTZ 52 Pharyngitis cough creased In- pain nal i- dom- Ab- Anorexia ing it- vom- - sea Nau- Headache Somnolence other pain/diarrhea nal i- dom- Ab- crease in- petite Ap- change Mood ing wak- ness/difficulty Sleepi- Tiredness OD) (5mg CTZ Pharyngitis cough creased In- pain nal i- dom- Ab- Anorexia ing it- vom- - sea Nau- Headache Somnolence other pain/diarrhea nal i- dom- Ab- crease in- petite Ap- change Mood ing wak- ness/difficulty Sleepi- Tiredness OD) (5mg CTZ 4.9 4.9 1.6 1.6 4.9 1.6 3.3 2.2 [2]2.2 2.2 2.2 [2]6.5 2.2 OD) (5mg CTZ 4.9 4.9 1.6 1.6 4.9 1.6 3.3 2.2 [2]2.2 2.2 2.2 [2]6.5 2.2 OD) (5mg CTZ 4.9 4.9 1.6 1.6 4.9 1.6 3.3 2.2 [2]2.2 2.2 2.2 [2]6.5 2.2 OD) (5mg CTZ 4.9 4.9 1.6 1.6 4.9 1.6 3.3 2.2 [2]2.2 2.2 2.2 [2]6.5 2.2 PlaceboPlaceboPlaceboPlaceboPlacebo other pain/diarrhea nal i- dom- Ab- Headache ing wak- ness/difficulty Sleepi- Tiredness 2.2 [2]4.3 4.3 [2]4.3 2.2 2.2 [2]4.3 4.3 [2]4.3 2.2 2.2 [2]4.3 4.3 [2]4.3 2.2 Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. Rtdlr.wO ebr*t Rnoae.wO eiti*t Rpaediatric*.tw) OR pediatric*.tw OR neonate*.tw infant*.tw OR OR (child*.tw Fexofenadine.af newborn*.tw AND OR OR Bilastine.af) Loratadine.af toddler*.tw OR Rupatadine.af OR OR OR Cetirizine.af Desloratadine.af OR OR Levocetirizine.af antihistamin*.af OR OR Antagonists.sh H1 strategy (Histamine search CENTRAL and publications MEDLINE separate Ovid two in reported data with RCTs Appendix two were there included; were citations each. 47 total, In * 1. Pseudoephedrine; Figure = PSD Oxotamide; infection. = OXD tract = Legends daily); respiratory MLK Figure (once Dexchlorpheni- Cetirizine; Upper Levocetirizine; die = = = = in URTI CTZ LCTZ omne DCPN Rupatadine; Loratadine; Bilastine; = = = Desloratadine; OD = RPD LRD data; = BLN HCL; No daily); Ketotifen = DLRD = (twice ND Montelukast; Cyproheptadine; KTF die Fexofenadine; = in = FXD bis CPHD ramine; = Clorpheniramine; BD = events; Adverse CPN = AE Abbreviations: Lipothymia and ing it- vom- sea, Nau- taxis epis- Moderate umr feiec erhadselection and search evidence of Summary Lipothymia and ing it- vom- sea, Nau- taxis epis- Moderate Lipothymia and ing it- vom- sea, Nau- taxis epis- Moderate Lipothymia and ing it- vom- sea, Nau- taxis epis- Moderate 4.7 14.2 4.7 14.2 epistaxis Mild Somnolence 53 epistaxis Mild Somnolence epistaxis Mild Somnolence 10.5 21.0 10.5 21.0 10.5 21.0 10.5 21.0 Posted on Authorea 1 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160680607.70423821/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. Citations identified in MEDL RCTs until Septemberuntil 2020 Articles retrie

included

ved for full in in the systematic review 45 (n= (n= 2358(n=

afte r r removal duplicates of - text reviewtext (n= 109 ) INE andCENTRAL

     Excluded with reasons (n= 62 n not not anRCTnot s age >12years 24)(n= tudy duration < 4 weeks ot comparisonot of interest (n= 8 Excluded after tit relevant outcome measures (n= (n= 54 ) )

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